Textbook of Medicine (MRCP Study Guides)

Edited by R

L

Souhami

MD FRCP FMedSci

Emeritus Professor of Medicine, University College London, UK J Moxham MD FRCP Professor of Respiratory Medicine and Vice-Dean, Guy's King's and St Thomas' School of Medicine, King's College Hospital, London, UK

CHURCHILL LIVINGSTONE

EDINBURGH LONDON NEW YORK OXFORD PHILADELPHIA ST LOUIS SYDNEY TORONTO 2002

CHURCHILL LIVINGSTONE An imprint of Elsevier Limited © Pearson Professional Limited 1996 Assigned to Harcourt Brace and Company 1998 © 2002, Elsevier Science Limited. All rights reserved. © 2004, Elsevier Limited. All rights reserved.

Commissioning Editor: Laurence Hunter Project Development Manager: Barbara Simmons Project Manager: Nancy Arnott Designer: Erik Bigland

The right of Robert Souhami and John Moxham to be identified as editors of this work has been asserted by them in accordance with the Copyright, Designs and Patents Act 1988. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without either the prior permission of the publishers or a licence permitting restricted copying in the United Kingdom issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London WIT 4LP. Permissions may be sought directly from Elsevier's Health Sciences Rights Department in Philadelphia, USA: phone: (+1) 215 238 7869, fax: (+1) 215 238 2239, e-mail: [email protected]. You may also complete your request on-line via the Elsevier Science homepage (http://www.elsevier.com), by selecting 'Customer Support' and then 'Obtaining Permission First edition 1990 Second edition 1994 Third edition 1997 Fourth edition 2002 Reprinted 2004 ISBN 0-443-06464-4

British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library

Library of Congress Cataloging in Publication Data A catalog record for this book is available from the Library of Congress

Note Medical knowledge is constantly changing. As new information becomes available, changes in treatment, procedures, equipment and the use of drugs become necessary. The authors and the publishers have taken care to ensure that the information given in this text is accurate and up to date. However, readers are strongly advised to confirm that the information, especially with regard to drug usage, complies with the latest legislation and standards of practice. your source for books, journals and multimedia in the health sciences www.elsevier hea lth.com

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Preface The Fourth Edition of this textbook continues the approach, first begun fifteen years ago, to provide a comprehensive account of internal medicine that incorporates the ideas of modern medical science. The intervening years have strengthened our belief that an understanding of cellular and physiological processes makes medicine more exciting and less arbitrary. The emphasis of the book is clinical, giving a full description of the presentation, investigation and treatment of disease. We have attempted to interpret these clinical aspects by reference to the underlying mechanisms whenever possible. Modern integrated curricula demand this approach. The textbook is primarily intended for students of medicine, but we hope and anticipate that it will continue to be of value to trainee doctors and health care professionals in many fields. The Fourth Edition has been completely revised to incorporate all major developments and advances, leading to an expansion of many sections especially in the areas of infectious disease including AIDS, and cardiovascular disease. Many of the illustrations have been replaced or extended to include the most up-to-date epidemiological data. We hope that these will give the reader a sense of the way medicine is developing and where future advances in practice may lead. The most important innovation, however, affects the entire book. By linking the book to an easily-accessed internet site we

have been able to incorporate case problems, multiple choice questions and clinical images throughout the text. The illustrative case problems, some of which are in the textbook itself, are designed to allow the reader to test his or her knowledge by practical application in clinical problem solving. Knowledge and understanding can also be assessed by multiple choice questions, formerly in a companion volume but which are now located on the associated internet site. In addition the website contains 500 supplementary clinical images. This extra information, all of which is clearly cross-referenced in the text, represents for the reader an important additional compendium of knowledge, which expands the versatility of the book as a learning aid. The range and depth of specialised medical knowledge necessary for a major textbook has led us to select our authors from a wide range of medical schools. They have been chosen for their acknowledged reputation in clinical and scientific medicine. In this Fourth Edition we have again expanded the team of authors. All of us would be pleased to receive suggestions which will help the book change and develop for future editions. London 2002

RLS JM

V

Acknowledgements As in previous editions we are greatly indebted to Laurence Hunter for his help in the planning and realisation of the new edition. He has a very effective production team that have made our task much easier. Our editor Barbara Simmons has, as usual, been helpful, efficient and outstandingly courteous even in the face of occasionally rather provoking circumstances. We owe her a lot and are very grateful.

vi

The multiple choice questions and answers for the website have been developed by Dr Andrew Freedman, Dr Richard Watts and Dr Richard Evans. We are very grateful to them for their painstaking work, which has added greatly to the educational value of the book. We are also grateful to Dr Donncha O'Gradaigh for writing the rheumatology case studies.

Contributors Geoffrey J Bellingan PhD MRCP Senior Lecturer, Department of Medicine, University College London Medical School; Consultant, Department of Intensive Care Medicine, University College London Hospitals, London, UK Brian T Cooper BSC MD FRCP Consultant Gastroenterologist, City Hospital, Birmingham; Senior Clinical Lecturer in Medicine, University of Birmingham, UK John Costello MD FRCP FRCPI Consultant Physician and Clinical Director of Medicine, King's College Hospital, London, UK

Jeremy Holmes MD MRCP FRCPsych Consultant Psychotherapist, Devon Partnership Trust; Senior Lecturer, University of Exeter, Exeter, UK Cameron T C Kennedy MA MB BChir FRCP Consultant Dermatologist and Clinical Senior Lecturer, Bristol Dermatology Centre, Bristol, UK Michael E J Lean MA MD FRCP Professor of Human Nutrition, University of Glasgow; Consultant Physician, Glasgow Royal Infirmary; Non-executive Director, Health Education Board for Scotland, Glasgow, UK David C Linch BA MB BChir FRCP FRCPath FMedSci

John Cunningham MD FRCP Professor of Renal and Metabolic Medicine, Barts and the London, Queen Mary's School of Medicine and Dentistry, University of London, UK J David M Edgar BSc(Hons) FRCP MRCPath Consultant Immunologist, Regional Immunology Service, The Royal Hospitals Belfast, N Ireland

Professor of Haematology, Royal Free and University College London Medical School, London, UK Richard G Long MD(Lond) FRCP (Lond) Consultant Gastroenterologist, City Hospital and Queen's Medical Centre, Nottingham; Clinical Teacher, Nottingham University Medical School, Nottingham, UK

Jeremy M Gibbs MD FRCP Consultant Neurologist and Honorary Senior Lecturer, Royal Free Hospital, London, UK

John P Monson MD FRCP Professor of Endocrinology, Department of Endocrinology, Barts and the London, Queen Mary's School of Medicine and Dentistry, London, UK

John Goldstone MD FRCA Consultant in Intensive Care Medicine and Consultant Anaesthetist, University College London Hospitals, London, UK

John Moxham MD FRCP Professor of Respiratory Medicine and Vice-Dean, Guy's King's and St Thomas' School of Medicine, King's College Hospital, London, UK

Robin A C Graham-Brown BSc MB FRCP Consultant and Honorary Senior Lecturer in Dermatology, University Hospital of Leicester NHS Trust and Leicester Royal Infirmary, Leicester, UK

John O'Grady MD FRCPI Consultant Hepatologist, King's College Hospital, London, UK

Brian Hazleman MA FRCP Consultant Rheumatologist, Addenbrooke's Hospital, Cambridge; Director Rheumatology Research Unit; Fellow, Corpus Christi College, Cambridge, UK

Peter W Overstall FRCP Consultant in Geriatric Medicine, Hereford Hospital, Hereford, UK

VII

Philip A Routledge MD FRCP FRCPE Professor of Clinical Pharmacology, University of Wales College of Medicine, Cardiff; Honorary Consultant Physician, Cardiff and Vale NHS Trust, Cardiff, UK

John Wilding DM FRCP Reader in Medicine and Honorary Consultant Physician, University of Liverpool and University Hospital Aintree, Liverpool, UK

John W Scadding MD FRCP Consultant Neurologist, The National Hospital for Neurology and Neurosurgery and Whittington Hospital, London, UK

Gareth Williams MA MD FRCP Professor of Medicine and Honorary Consultant Physician, Clinical Sciences Centre, University Hospital Aintree, Liverpool, UK

Herb F Sewell MB ChB MSC PHD FRCP FRCPath FMedSci Professor and Consultant Immunologist, University of Nottingham, Queen's Medical Centre, Nottingham, UK Martin Smith MBBS FRCA Consultant Neuroanaesthetist, Department of Neuroanaesthesia and Intensive Care, The National Hospital for Neurology and Neurosurgery, London, UK Robert L Souhami MD FRCP FMedSci Emeritus Professor of Medicine, University College London, UK L B Tan DPM FRCP FESC Consultant Cardiologist, Leeds General Infirmary, Leeds, UK J Malcolm Walker MD FRCP Consultant Cardiologist and Clinical Director of the Hatter Institute of Cardiovascular Studies, University College Hospitals, London, UK Mark H Wansbrough-Jones MSC FRCP Consultant Physician and Senior Lecturer in Infectious Diseases, St George's Hospital and Medical School, London, UK Antony P Weetman MD DSC FRCP Professor of Medicine, University of Sheffield; Honorary Consultant Physician, Sheffield Teaching Hospitals Trust, Sheffield, UK

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Ian G Williams BSC MRCP Senior Lecturer, Department of Sexually Transmitted Diseases, University College London Medical School, London, UK Robin M Winter FRCP FMedSci Professor of Dysmorphology and Clinical Genetics, Institute of Child Health, London, UK Stephen G Wright MB FRCP Consultant Physician, Hospital for Tropical Diseases, London; Honorary Senior Lecturer, London School of Hygiene and Tropical Medicine, London, UK

MULTIPLE CHOICE QUESTIONS Richard H Evans MRCP Specialist Registrar in Infectious Diseases and General (Internal) Medicine, University Hospital of Wales, Cardiff, UK Andrew Freedman MA MD FRCP Senior Lecturer in Infectious Diseases, University of Wales College of Medicine; Consultant Physician, University Hospital of Wales, Cardiff, UK Richard A Watts MA DM FRCP Consultant Rheumatologist Ipswich Hospital NHS Trust, Ipswich, UK

Contents 1. Therapeutics and toxicology

14. Critical care medicine

1

725

J Goldstone, G J Bellingan, M Smith

P A Routledge

2. Acute physical and environmental disorders 45

15. Gastrointestinal disease 751 R G Long, B T Cooper

J Moxham, R L Souhami

16. Liver and biliary tract disease 835 3. The genetic basis of disease

57

J O'Grady

R M Winter

17. Endocrine disease 4. Immunological disorders

79

883

A P Weetman

J D M Edgar, H F Sewell

5. Nutrition in clinical medicine

105

18. Metabolic bone disease and mineral metabolism 953 J Cunningham, J P Monson

M E J Lean

6. Cancer medicine

19. Diabetes mellitus and lipid metabolism

145

979 J Wilding, G Williams

R L Souhami

7. Ageing and disease 171 20. Renal and urinary disease 1031 J Cunningham

P W Overstall

8. Psychological medicine

205 21. Salt and water homeostasis and acidbase balance 1099

J Holmes

9. Infectious, tropical and parasitic disease 259 M H Wansbrough-Jones, S G Wright

10. Skin disease

J P Monson

22. Musculoskeletal and connective tissue disease 1119

379

B Hazleman

C T C Kennedy, RAG Graham-Brown

23. Haematological disorders 1201 11. AIDS and genitourinary disease

439

D C Linch

I G Williams

24. Neurological disease 12. Cardiovascular disease

463

1283

J W Scadding, J Gibbs

J M Walker, L B Tan

Index 13. Respiratory disease J Moxham, J Costello

1443

605 ix

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n Therapeutics andToxicology Philip A Routledge

Pharmacodynamic variability refers to differences in response to the same drug concentration at its effector site. This is sometimes related to differences in the number and/or activity of specific receptors or other effector sites (e.g. ion channels). The very young and the elderly appear to have an increased sensitivity to several drugs, particularly those affecting the central nervous system. An increased sensitivity to drugs acting on the central nervous system is also seen in patients with chronic renal and liver disease. The elderly appear also to have less adaptable homeostatic mechanisms and are therefore more prone to drug-induced postural hypotension or hypothermia. Hyperthyroid patients are more sensitive to the effects of oral anticoagulants and less sensitive to digoxin.

Causes of variability in drug response 1

Poisoning with gases and volatile solvents 33

PHARMACOKINETIC VARIABILITY

Adverse drug reactions 5

Overdose with alcohols 35

Drug interactions 7

Poisoning with corrosive agents 36

This occurs when the handling of a drug is altered in disease or in different physiological states. The causes of variability are shown in Summary 1 (p. 4).

Therapeutic drug monitoring 11 Specific drugs 12 Drug regulation and development 13

Drug overdose 15

Poisoning with insecticides, herbicides, fungicides and rodenticides 37 Poisonous plants and fungi 39 Poisonous animals 41

Diagnosis of poisoning 16 Principles of management of poisoning 18

Poisoning by metals 43

Management of specific drug overdose 23

Therapeutics is the branch of medicine that deals with the treatment and cure of disease and ill health. Medicines are the most important tool in therapeutics, and an understanding of their pharmacology in normal dose and excess dose (toxicology) is essential in ensuring their safe and effective use. Therapeutics developed as a specialty because of the need to understand the causes of biological variability in drug response in humans, particularly in disease states.

CAUSES OF VARIABILITY IN DRUG RESPONSE PHARMACODYNAMIC VARIABILITY There are three major ways in which a drug can produce pharmacological effects: • By combination with specific receptors; • By alteration of physiological enzyme processes; • By direct physical or chemical action.

Absorption Drugs are usually given by mouth and must therefore pass through the bowel wall in order to enter the bloodstream. This occurs via four different mechanisms: • Passive diffusion, which involves diffusion down a concentration gradient from the gut into the bloodstream. For this to occur the drug must dissolve in the gastrointestinal fluids, traverse the cell membrane and enter the bloodstream. The rate at which it does so depends on both the concentration gradient and the lipid solubility of the drug. This is the most important mechanism of absorption for most drugs. • Active transport, a less important mechanism by which some drugs, because of their resemblance to naturally occurring substances, use existing transport systems. Thus, levodopa is absorbed by the active process responsible for absorption of the amino acid tyrosine. • Filtration through pores, a route generally limited to molecules of molecular weight less than 100 (e.g. urea). Most drugs are too large to traverse the pores between cells. • Endocytosis, by which drugs or particles are engulfed by cells in the bowel wall. This is of relatively little importance to drug absorption. Factors affecting absorption Absorption is affected by the chemical nature and formulation of the drug, as well as the physiological characteristics of the absorption site. Thus, some drugs cannot be administered orally because they are broken down by gastrointestinal enzymes (e.g. the polypeptide insulin) or are unstable at extremes of pH (e.g. benzyl penicillin at gastric pH). Most drugs are either weak acids or weak bases and thus exist in two forms in solution - as ions or as undis-

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sociated molecules. At the low pH encountered in the stomach, a weakly acidic drug exists mainly in its undissociated form; it is thus more lipid soluble and will tend to be more easily absorbed. Basic drugs, on the other hand, are largely ionized at low pH and exist predominantly in the undissociated form only in the alkaline medicine of the small bowel. Despite these considerations, both acidic and basic drugs tend to be absorbed predominantly in the small intestine, because they are there for longer and because the inner surface of the intestine provides a much greater absorptive area than the stomach. Formulation factors are important in determining the rate and extent of drug absorption. Most drugs consist not only of an active agent but also of diluents, granulating and binding agents, lubricants and disintegrating agents, any of which may have a marked effect on absorption. Particle size of the active constituent may also be important, and sustained- or delayed-release preparations will also delay absorption rate. Gastrointestinal motility affects the rate of absorption. Delays in gastric emptying will result in delayed drug absorption, although the extent of absorption is normally unchanged. Food has a variable effect. Some drugs (e.g. propranolol) have greater bioavailability in the presence of food because of reduced presystemic elimination, whereas others (e.g. rifampicin) are more poorly absorbed. Such factors may be important in determining the times of administration of drugs. The route of administration is also important. Alternatives to the oral route are:

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• Intramuscular injection, either to speed the onset of effects or to enhance bioavailability when the oral route is suboptimal. Use of the intramuscular route can, however, cause local pain, and some drugs (e.g. phenytoin and diazepam) are poorly and variably absorbed when administered in this way, because of poor solubility at tissue pH. Absorption rate varies with the muscle group used and may be slow in situations of poor tissue perfusion. • Rectal administration can sometimes be used, but because the haemorrhoidal veins drain partly into the portal tract, presystemic elimination is not completely avoided. The suppository may also be variably retained or have poor and erratic absorption. • Buccal administration can completely avoid presystemic elimination and is used for drugs (e.g. glyceryl trinitrate) that are rapidly metabolized after the oral route. Unfortunately, not all such drugs can rapidly penetrate the buccal mucosa and enter the systemic circulation. • Transdermal administration is an alternative to the buccal route for drugs such as glyceryl trinitrate or the antihistamine hyoscine. The rate of absorption varies with the skin site used and the extent of absorption is limited, so that only very potent drugs (effective dose <10mg) can be usefully administered by this route. Absorption is normally rapid, but membranes are being developed to control the rate.

• Intrapulmonary route. Some drugs, and all anaesthetic gases, are administered by the intrapulmonary route. Non-gaseous compounds are difficult to introduce into the lungs. Only 10% of a drug administered by pressurized aerosol actually enters the lungs: the remainder is deposited in the buccal cavity and subsequently swallowed. Absorption of drugs is normally so efficient that it is unusual to see differences in the extent of absorption of most modern drugs, even in the presence of extensive bowel resection. However, reduced absorption may occur in severe malabsorption syndromes or in severe diarrhoea, or in severe congestive cardiac failure because of oedema of the small intestine. Differences in bowel motility may affect the rate (often more than the extent) of absorption. Gastric emptying is slow and erratic in the very young and in adults who are shocked or in pain. In such circumstances (e.g. myocardial infarction) threshold concentrations for drug effect may not be achieved rapidly, or at all, and the drug (e.g. analgesic treatment) may be more effective when given by an alternative, non-alimentary route.

Distribution If drug distribution did not occur, only those drugs with an action within the vascular compartment would provoke biological effects. Like absorption, distribution is dependent on the physicochemical characteristics of the drug as well as upon biological factors. The major physicochemical properties determining drug distribution are lipid solubility and (if the drug is a weak electrolyte) the degree of dissociation (ionization) in tissues. Highly lipid-soluble drugs are generally distributed throughout all fluid compartments and, because they can cross lipid membranes readily, can reach most organs, including the brain. Poorly lipid-soluble drugs are normally able to enter the interstitial fluid, but if they are weak electrolytes only the undissociated form can penetrate the cells, and then only to a limited extent, depending on the lipid-water partition coefficient. Biological factors determining the distribution of drugs in the body include the degree of both plasma protein binding and of uptake by tissue, either by binding or by active transport mechanisms. The blood contains approximately 180 g of protein, half of which is albumin. Albumin is thus the most abundant single protein in the plasma and, because of its structure, is able to reversibly bind many drugs by Van der Waals forces, hydrogen bonds or hydrophobic bonds. However, its binding capacity is relatively limited and it has been estimated that only 200 mg of drug of average molecular weight (300) would be bound to albumin in plasma if there were only one binding site available on each albumin molecule. For some drugs there may be more than one binding site and the binding capacity will be relatively greater. Major sites of binding are the so-called site 1 (warfarin site), which also binds the endogenous compound bilirubin, and site 2 (diazepam

1

FIG. 1.1 Relationship between the percentage of diazepam and theophylline free in plasma and plasma albumin concentration in different disorders See text for details.

FIG. 1.2 Relationship between the percentage of lidocaine (lignocaine) free in plasma and plasma AAG concentration in several disease states and in neonates

site), the site at which the endogenous amino acid tryptophan also binds. Drugs may bind to either or both of these sites and can competitively displace each other. The relationship between the serum albumin concentration and the proportion of two drugs in the free (unbound) form is shown in Figure 1.1. It can be seen that the differences in protein binding are likely to be relatively, small over the range of serum albumin concentrations seen in health. In situations of hypoalbuminaemia, however, even small further decreases in serum albumin concentration may cause marked increases in the proportion of drug free in the plasma. Another plasma protein, a,-acid glycoprotein (AAG) also binds drugs, particularly those of a basic nature. Although its plasma concentration is much lower (c. 2%) than that of albumin, its affinity for drugs is high and some drugs (e.g. lidocaine (lignocaine), erythromycin and disopyramide) may bind appreciably more to this protein than to albumin. Because of its low concentration, however, its binding capacity is relatively limited and, for several drugs, protein binding falls with increasing drug concentration. The tissues also contain proteins which combine with drugs (60% of the total exchangeable body albumin is outside the vascular compartment), whereas body fat can serve as an important reservoir for lipid-soluble agents such as thiopentone. Finally, active transport mechanisms - such as the uptake of adrenergic neuron-blocking drugs by the adrenergic neuron - may also contribute to high tissue concentrations of a drug. Extensive tissue binding tends to result in the drug having a large apparent volume of distribution (Vci), as most of the drug is outside the intravascular space. Distribution of drugs may be altered by changes in regional blood flow in disease. The volume of distribution of lidocaine (lignocaine), for example, appears to be lower in patients with cardiac failure. Protein binding also determines drug distribution. Albumin concentrations are low in the neonate, begin to decline over the age of 40, and are reduced during pregnancy. Severe hypoalbuminaemia also

occurs in nephrotic syndrome and chronic liver disease. In patients with chronic renal failure the proportion of drug in the free form is greater than would be expected from the reduction in serum albumin alone, indicating either structural changes in albumin or the presence of endogenous inhibitors of binding. AAG is reduced in neonates and in pregnancy but tends to be normal in healthy elderly individuals. It is markedly increased in patients with rheumatoid arthritis and other inflammatory diseases, including chronic renal disease, after myocardial infarction, and in cancer. As with albumin, it may be reduced in patients with nephrotic syndrome or chronic liver disease. Concomitant changes in plasma protein binding of drugs also occur, the effects depending on the relative strength of binding of the drug to these two proteins and on the disease state in question (Fig. 1.2), which may alter the amount bound to free drug. Thus the total plasma concentration of drug (free + bound), which is generally measured in clinical practice, may not always reflect the free (active) concentration. Therapeutic ranges for total drug may therefore need to be altered in diseases where plasma protein binding is affected (see Therapeutic drug monitoring).

Metabolism The liver is the main organ of drug metabolism, although some may also occur in the gastrointestinal tract, lung, blood or kidney. Metabolism is particularly important for lipid-soluble drugs, which more readily enter cells and are also prevented by their lipid solubility from being excreted unchanged by the kidney. The routes of metabolism are relatively non-specific and are shared by a variety of drugs. In most instances, more water-soluble metabolites (which are more easily excreted by the kidney) are produced. There are two groups of metabolic reaction: phase I and phase II. Phase I reactions involve the enzyme mono-oxygenase, situated in the smooth endoplasmic reticulum of cells with metabolic function, especially the liver. These are called

3

cytochrome P450 enzymes and are responsible for oxidation, reduction, hydrolysis and dealkylation of drugs with the relevant molecular structure. A given drug may be metabolized by one or more of these routes to produce more water-soluble (and thus biologically active) metabolites. Phase II reactions are conjugation reactions of more water-soluble molecules to the drug or metabolite. Conjugation with glucuronide (glucuronidation) is the commonest pathway, but conjugation can also occur with sulphate, amino acids such as glutathione, or acetylCoA (acetylation). Most of these conjugated metabolites (except for some acetylated compounds) are biologically inactive. Although most metabolic processes are controlled by environmental factors, acetylation is under genetic control: 45% of the UK population are slow acetylators and the remainder either intermediate or fast acetylators. Approximately 7% of the British population have a reduced ability to hydroxylate several drugs (e.g. debrisoquine, nortriptyline and phenformin), which may lead to an increased risk of adverse reactions to drugs metabolized by this route. Metabolism of drugs may be diminished at the extremes of age. Neonates have a reduced capacity for phase I, and most phase II reactions. Thus the effect of caffeine (a phase I pathway) is markedly reduced. Reaction of phase II pathways such as the glucuronidation of chloramphenicol, for example, may lead to grey baby syndrome in the neonate. Immaturity of these processes is greatest in the premature neonate, who is therefore at greatest risk of adverse drug reactions. In the healthy elderly, impairment of drug metabolism is only slight and tends to be overshadowed by changes in pharmacodynamic response. However, marked reductions in drug metabolism may be seen in the frail elderly. Dietary and environmental factors, such as smoking, may affect the rate of metabolism of some drugs; and chronic liver disease is often associated with an impairment of metabolism, particularly of phase I pathways. In liver disease the serum albumin concentration correlates roughly with the degree of impairment of drug metabolism (i.e. the lower the albumin the more severe the impairment). The effect of impairment of metabolism in liver disease will be greater for those drugs with extensive presystemic metabolism. The bioavailability of propranolol is much greater in patients with chronic liver disease, not because of better absorption (absorption is virtually complete in health) but because it cannot be efficiently metabolized on its first passage through the liver. This is due not only to the reduced hepatocyte metabolic activity, but also to intra- and extrahepatic shunting of blood past the liver cells and a consequent reduction in effective liver blood flow.

A MCQ1.1-1.5

4

SUMMARY 1 Pharmacokinetic causes of variability in drug response Absorption Extent of drug absorption reduced only in rare circumstances Distribution Altered in disease by changes in regional blood flow, altered plasma protein binding (e.g. hypoalbuminaemia in hepatic cirrhosis), or changes in activity of energy dependent transporter systems (e.g. P-glycoprotein) Metabolism Diminished in neonates (particular if premature) and the elderly (especially if frail). Affected by genetic factors (e.g. genetic polymorphisms), environmental factors (e.g. smoking) and liver disease Excretion Immature in neonates (particularly if premature) Impaired in renal disease and declines with advancing age over 40 years

In cardiac failure and shock, cardiac output is reduced and a disproportionately greater reduction in hepatic blood flow (normally around 1.5L/min) may result in a marked reduction in the systemic clearance of normally efficiently cleared compounds (e.g. lidocaine (lignocaine)), for which hepatic blood flow is the major determinant of delivery of drug to and clearance by the liver. In addition, the liver can be affected by the increased venous backpressure caused by failure of the right side of the heart in biventricular (congestive) cardiac failure. This results in increased size and congestion of the liver and derangement of liver function, with reduced hepatocyte clearance of several drugs. Genetic factors play a major role in determining drug response and handling, and susceptibility to adverse drug reactions. Allelic variations affecting pharmacokinetics with a frequency of at least 1% in the population are often termed genetic polymorphisms (e.g. acetylation) and are associated with a bimodal or trimodal (rather than the normal unimodal) distribution of clearance values. Some clinically important pathways of drug metabolism showing such polymorphisms are ./V-acetylation, oxidation (hydroxylation) via the cytochrome (CYP) P450 isoform, CYP2D6, succinylcholine hydrolysis (de-esterification) and thiopurine s-methylation. More are being recognized as detection techniques improve.

Excretion The vast majority of drugs must first be metabolized to more water-soluble compounds before they can be excreted in the urine. Those drugs (e.g. cimetidine, digoxin, aminoglycosides, lithium, cephalosporins, penicillins, atenolol and chlorpropamide) that are largely excreted unchanged tend to be relatively water-soluble and are not appreciably bound to plasma proteins and so can enter the glomerular filtrate. Lipid-soluble drugs may also enter the glomerular filtrate, provided they are not extensively plasma protein bound, but they then readily pass back

through the proximal tubular cells into the bloodstream by passive diffusion down a concentration gradient. Only when they have been metabolized to more water-soluble compounds will they have difficulty in passing back through the renal tubular cells and therefore be excreted in the urine. Weak electrolytes can also be actively secreted in the proximal renal tubules - weak bases sharing one mechanism and weak acids another - and there is some evidence for an active transport system promoting the excretion of digoxin in the distal renal tubule. Drugs may also be excreted in the bile, normally as conjugates and particularly if they have a high molecular weight. The drug may, however, be reabsorbed from the intestine, either directly or after deconjugation by intestinal microflora, to create an enterohepatic cycle. This may reduce the clearance of the drug and thus prolong its effect. Excretion of drugs is reduced in neonates (particularly if premature) because of a reduced glomerular filtration rate (GFR) relative to their body surface area, and also because their active renal tubular secretory mechanisms are not fully developed. These processes mature relatively rapidly and are fully functional after 6-12 months, but GFR begins to fall again over the age of 40 (the renal tubular secretory mechanisms appear to be less affected by age). Thus, the dose of digoxin or gentamicin (drugs excreted predominantly by glomerular filtration) may need to be reduced in the elderly or the very young. Renal disease is associated predominantly with a fall in GFR, with active renal tubular secretion mechanisms being less affected. Measurement of serum creatinine or creatinine clearance is therefore useful in calculating the optimum dose of drugs excreted predominantly by glomerular filtration, but it is of less value for drugs such as penicillins, which are actively secreted at the proximal renal tubule. 1

ADVERSE DRUG REACTIONS It has been estimated that approximately 5 % of all hospital admissions are because of adverse reactions to a drug; 1 in 10 patients admitted for other reasons will develop an adverse reaction to a drug while in hospital; and perhaps 1 in 1000 deaths in hospital are due to an adverse reaction to a drug, making adverse reactions between the fourth and sixth most common cause of death in the USA, for example. Adverse reactions are also common in general practice. The drug groups most commonly associated with adverse reactions are antihypertensives, anticoagulants, antirheumatics (particularly the non-steroidal antiinflammatories), cytotoxic agents, corticosteroids and digoxin. Although adverse reactions can affect all systems of the body, they are most often described in the skin and central nervous system, perhaps because detection tends to be easier. The very young (i.e. under 1 year of age) and the elderly are particularly at risk, and women appear to be at greater risk than men, although the reason for this is

unknown. Patients with a history of atopy, or who have had a drug reaction in the past, are more likely to develop further reactions, even to a drug in some other therapeutic group. The presence of disease, particularly heart failure or liver or renal disease, predisposes to a risk of adverse reactions, as may genetic factors, such as enzyme deficiencies.

1

TYPES OF ADVERSE DRUG REACTION Adverse reactions have been classified into two major types.

Type A The most common type is the dose-dependent adverse reaction (type A), which is an 'augmentation' or 'accentuation' of a known pharmacological effect of the drug not necessarily always the wanted effect. Thus, fisympathomimetic agents can cause increased tremor, a recognized pharmacological effect of the drug but one that may limit their use in bronchodilator therapy. Type A reactions account for about 75% of all adverse reactions and, because they are often insidious in onset, may go unrecognized for some time. They may therefore produce considerable morbidity, but the mortality from type A reactions is generally low. They may occur because of altered pharmacokinetic or pharmacodynamic factors and are therefore commonest in diseases (e.g. renal and liver disease) where these are most affected.

Type B The occurrence of type B reactions is not dependent on the dose given. They are unpredictable or 'bizarre' reactions to a drug that may be present only in tiny concentrations, although the severity of the reaction may be greater if a larger dose is administered rapidly (e.g. after intravenous administration). Because of their lack of predictability and their often acute onset they have a proportionally higher mortality than type A reactions, but associated morbidity is relatively low if the patient survives the initial event. Like type A reactions, type B reactions can be related to pharmacokinetic or pharmacodynamic factors. There are many ingredients in medications other than the active

SUMMARY 2 Types of adverse drug reaction (ADR) Type A Dose-dependent 'accentuation' of known pharmacological effect. Account for 75% of ADRs. Cause considerable morbidity but mortality is low. Can sometimes be treated by dose reduction rather than cessation of treatment Type B Non-dose dependent, 'bizarre' and unpredictable. Higher mortality. Type B reactions can be related to hereditary enzyme deficiencies or allergic mechanisms. Usually treated by discontinuing treatment immediately

5

compound: reactions may occur to the preservative, filler, dye, binder or solubilizing agent in the tablet or injection. Type B reactions may occur because individual subjects metabolize the drug through a novel pathway that produces a toxic metabolite. In other cases the presence of hereditary enzyme deficiencies may predispose the patient to the toxic effects of drugs or their metabolites. Thus, haemolysis caused by dapsone and other oxidizing agents is commoner in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. Similarly, many agents can precipitate an attack of acute intermittent porphyria (p. 1027) in those carrying a gene for this disorder. Type B reactions are also often related to allergic mechanisms, and may involve any or all forms of antibody- or cellmediated tissue damage. Thus, anaphylaxis may occur as a result of immediate (type I) hypersensitivity associated with cell-bound IgE, after the administration of drugs such as penicillin. Cell surface (type II hypersensitivity) damage may occur as a result of the combination of methyldopa with red cell (or quinine with platelet) membranes and subsequent haemolysis or thrombocytopenia, 1 respectively. Toxic immune complexes may be formed in patients receiving gold or penicillamine, resulting in skin toxicity by a type III hypersensitivity mechanism. Cell-mediated (type IV) tissue damage is thought to be the mechanism of the relatively common (but usually mild) rash associated with ampicillin therapy 2 or the more serious erythroderma sometimes associated with drugs such as gold. 34

DIAGNOSIS AND MANAGEMENT OF ADVERSE DRUG REACTIONS Diagnosis It is rarely possible to make a diagnosis of drug-induced adverse reaction with complete certainty. Either an infective agent or the antibiotic with which the patient was being treated, for example, may cause erythema multiforme. It is therefore necessary to weigh up all circumstantial evidence carefully before making the diagnosis. This includes taking a full drug history, remembering that patients may not consider over-the-counter and herbal remedies, or even the oral contraceptive pill, as medicines or drugs. The brand names of the agents may also be important, as different pharmaceutical formulations may contain different dyes, binders, fillers, preservatives or lubricants, and reactions may occur only with certain formulations. Physical examination provides only limited information. Some physical signs may be directly attributable to drug therapy, e.g. the blue discoloration of the skin

1

Fig. 1.1

4

Case 1.1 Case 1.2

2 Fig. 1.2

3

© Fig. 1.3 6

MCQ1.6

Fig. 1.4

associated with amiodarone therapy 0 is rarely caused by disease. Similarly, an eruption occurring at a fixed site on the skin may suggest a drug-induced fixed drug eruption. 6 However, in most cases the organs affected have a limited number of responses to noxious stimuli. Biochemical tests are also of limited value, but measurement of plasma drug concentration may help to confirm the suspicion of a dose-dependent (type A) adverse reaction. In some cases measurement of metabolic phenotype may also be helpful. It is extremely rare, for example, for patients who are fast acetylators to develop drug-induced lupus erythematosus after hydralazine therapy. Probably the most helpful indication of the drug responsible for the adverse reaction is the time course relative to drug treatment, particularly the rate of resolution of symptoms on stopping a specific drug (dechallenge). Subsequent re-exposure (rechallenge) associated with a recurrence of the symptoms or signs gives the strongest evidence of causation, but it is rarely ethically justifiable unless the patient's need for the drug outweighs the potential risk of the adverse reaction.

Management The only choice with most type B reactions is to stop the suspected drug completely. With type A reactions it is sometimes possible to reduce the dose to prevent the unwanted effects while still obtaining therapeutic benefit. If an adverse reaction does occur, the patient's medical notes and prescription chart should be clearly marked with an eye-catching label to indicate the nature and date of the reaction. Any serious adverse reaction should also be reported to the Committee on Safety of Medicines using a yellow card. In addition, even minor adverse reactions to drugs that have been recently introduced (marked with an inverted black triangle in the British National Formulary) should be reported.

PREVENTION OF ADVERSE REACTIONS It must be remembered that although drugs provide enormous benefit to patients, all are potentially toxic and should be used selectively, particularly in those at greatest risk of adverse reactions, i.e. the very young, the very old and those with severe disease. The risk of developing an adverse reaction appears to increase disproportionately with increasing number of drugs prescribed concomitantly. Prescriptions should therefore be reviewed and, whenever possible, drug therapy rationalized at frequent intervals. When a drug is prescribed, the prescription should be written legibly, in block letters, and preferably using the approved name. Failure to do so may lead to errors in prescribing. In some cases the risk of adverse reactions to certain drugs is such that they should be avoided if at all possible. There are particular dangers during pregnancy or breastfeeding, when certain drugs may cause an adverse reaction in the fetus or breastfed child (Table 1.1).

TABLE 1.1 Some drugs to avoid during pregnancy or breastfeeding Pregnancy

Breastfeeding

Antibiotics

Tetracyclines Sulphonamides Aminoglycosides Chloramphenicol Trimethoprim Nitrofurantoin Quinolones

Tetracyclines Sulphonamides Isoniazid Chloramphenicol Metronidazole Nitrofurantoin Vancomycin

Antithyroids

All, including radioiodine

All, including radioiodine

Analgesics

Opiates NSAIDs

Aspirin NSAIDs (several)

Anticoagulants

Warfarin Acenocoumarol (nicoumalone)

Phenindione

Antidepressants Antihypertensives

SSRIs (several) Lithium ACE inhibitors Angiotensin receptor antagonists Thiazide, loop and potassium-sparing diuretics Hydralazine Minoxidil

Angiotensin receptor antagonists Calcium channel blocker (some)

Antineoplastics

Most

Most

Antidiabetics

Biguanides Sulphonylureas

Use with caution

Antirheumatics

Gold Penicillamine

Antiulcer drugs

Misoprostol Most proton pump inhibitors

DRUG INTERACTIONS

1

Drug interactions have been recognized for over 100 years and were described under the classic headings of antagonism, synergism or potentiation. Many of these interactions are beneficial and have been used to therapeutic advantage, but unwanted or adverse interactions also account for 10-20% of all adverse reactions to drugs. There are around 2000 potentially interacting drug pairs, but the number of clinically significant adverse interactions is much lower, largely involving drugs with a relatively low margin between safety and toxicity (i.e. a narrow 'therapeutic ratio'). Thus, they are most often described with oral anticoagulants, some antidiabetic drugs, anticonvulsants, antiarrhythmics (especially digoxin), tricyclic antidepressants, antihypertensive drugs, NSAIDs, neuroleptic drugs, lithium, anticancer/immunosuppressive agents and theophylline (Tables 1.2-1.4). The elderly, particularly if frail and suffering from multiple medical conditions, are more likely to experience an interaction and more likely to have serious adverse consequences. As with adverse reactions in general, the risk of developing an adverse interaction increases disproportionately with the number of drugs being prescribed concomitantly; the mechanisms of interaction are also similar, in that both pharmacodynamic and pharmacokinetic interactions may occur. Interactions may also take place, however, before the drugs even enter the body, and these have been termed 'pharmaceutical' interactions. 7

PHARMACEUTICAL INTERACTIONS Misoprostol Proton pump inhibitors

Antivirals

Most

Anxiolytics

Benzodiazepines Chloral derivatives

Sex hormones

Androgens, oestrogens and high-dose progestogens

Androgens, oestrogens and high-dose progestogens

Hypolipidaemics

Fibrates Statins

Fibrates

Miscellaneous

Vitamin D and its analogues Live vaccines Podophyllum resin and podophyllotoxin Tamoxifen Thrombolytics

Anthraquinone laxatives and phenolphthalein Amiodarone

NB Absence of a drug from this list does not imply safety. Further information can be obtained by consulting the manufacturer's datasheet, the British National Formulary, or by contacting the National Teratology Centre (0191-232-1525).

Interactions may occur prior to the drug entering the body when drugs are mixed together for infusion, or when a drug interacts with the infusion material itself. Guides to intravenous mixtures are available and should be consulted before compounds are given by intravenous infusion or mixed together. In general terms, it is advisable to avoid adding drugs to infusion fluids unless absolutely necessary, and certainly to avoid adding more than one drug if at all possible. Infusion fluids particularly likely to be associated with pharmaceutical incompatibilities include blood and blood products, amino acids and lipid solutions, mannitol and sodium bicarbonate.

PHARMACODYNAMIC INTERACTIONS Pharmacodynamic interaction occurs where one drug alters the response to another by interacting either at the receptor site or at a different site to enhance or diminish the primary drug effect. Partial agonists initiate a minor response but, by occupying a significant fraction of the receptors, they antagonize the action of more potent agonists. Nalorphine, for example, is a partial antagonist

7

TABLE 1.2 Some drug interactions of clinical importance resulting in increased drug effect Drug (A)

May interact with B

Effect of interaction

Mechanism of interaction

ACE inhibitors Antidepressants (tricyclic) Antihypertensive agents

NSAIDs Enzyme inhibitors Vasodilators (e.g. nitrates for angina) neuroleptics and some antidepressants NSAIDs

Hyperkalaemia, reduced renal function Increased effect of A Postural hypotension

Additive nephrotoxic effects Reduced clearance of A Combined hypotensive effects

Peptic ulceration

Enzyme inhibitors Verapamil NSAIDs (including aspirin) Enzyme inhibitors Amiodarone Diltiazem Verapamil Diuretics (loop and thiazide) ACE inhibitors Potassium supplements NSAIDs Thiazide diuretics Anticholinergic drugs (e.g. some antihistamines/tricyclic antidepressants) Enzyme inhibitors NSAIDs

Increased effect of A

Increased risk of peptic ulceration Reduced clearance of A

Increased risk of peptic ulceration Increased effect of A Increased effect of A

Corticosteroid prevents healing? Reduced clearance of A Reduced clearance of A

Increased effect of A (e.g. arrhythmias) Hyperkalaemia, impaired renal function

Diuretic-induced hypokalaemia Combined potassium-elevating effects

Increased effect of A

Reduced clearance of A

Excessive anticholinergic effects

Combined anticholinergic effects

Increased effect of A Seizures

Reduced clearance of A Pharmacodynamic interaction at CNS effector site Pharmacodynamic interaction Reduced clearance of A Reduced clearance of A

Aspirin (low-dose) Carbamazepine Corticosteroids (oral) Ciclosporin Digoxin Digoxin Diuretics (potassium-sparing) Lithium Phenothiazines and butyrophenones Phenytoin Quinolones Sildenafil (Viagra) Theophylline Warfarin

Nitrates Saquinavir Enzyme inhibitors (e.g. macrolides and 4-quinolones) See Table 1.4

Increased hypotensive effect of A Increased hypotensive effect of A Increased effect of A

TABLE 1.3 Some drug Interactions resulting in reduced drug effect Drug (A)

May interact with B

Effect of interaction

Mechanism of interaction

Antidepressants Antihypertensives (e.g. ACE inhibitors, thiazides and p-blockers) Calcium channel blockers Corticosteroids (oral) Ciclosporin Digoxin

Enzyme inducers NSAIDs

Reduced effect of A Reduced effect of A

Enzyme inducers Enzyme inducers Enzyme inducers Colestyramine (cholestyramine) Colestipol Enzyme inducers Broad spectrum antibiotics Enzyme inducers Colestyramine (cholestyramine) Colestipol Antacids Enzyme inducers Enzyme inducers Colestyramine (cholestyramine) and colestipol See Table 1.4

Reduced effect of A Reduced effect of A Reduced effect of A Reduced effect of A

Increased clearance of A Pharmacodynamic antagonism of anti hypertensive effect of A Increased clearance of A Increased clearance of A Increased clearance of A Reduced absorption of A

Reduced effect of A Reduced effect of A Reduced effect of A Reduced effect of A

ncreased clearance of A nterruption of enterohepatic recycling of A? ncreased clearance of A Reduced absorption of A

Reduced effect of A Reduced effect of A Reduced effect of A

ncreased clearance of A ncreased clearance of A Reduced absorption of A

Oral contraceptives Phenytoin Quinolone antibiotics

Theophylline Thyroxine

8

Warfarin

TABLE 1.4 Important drug interactions involving warfarin

Interacting drug

Effect of interaction on anticoagulant effect

Colestyramine (cholestyramine) Colestipol

Reduced anticoagulant effect

Impaired absorption and increased elimination of warfarin. Long-term treatment may cause impaired vitamin K absorption and enhance anticoagulant effect

Barbiturates Carbamazepine Griseofulvin Phenytoin (see also below) Primidone Rifampicin Ritabutin St John's wort

Reduced anticoagulant effect

Induction of warfarin metabolism

Amiodarone Azapropazone Chloramphenicol Cimetidine Ciprofloxacin Clarithromycin Dextropopoxyphene Erythromycin Fluconazole Itraconazole Ketoconazole Mefenamic acid Metronidazole Miconazole Nalidixic acid Norfloxacin Ofloxacin Phenylbutazone Sulfinpyrazone Sulphonamides (e.g. in co-trimoxazole)

Increased anticoagulant effect

Inhibition of warfarin metabolism

Anabolic steroids Bezafibrate Clofibrate Danazol D-thyroxine Gemfibrozil L-thyroxine Phenytoin (see also above) Salicylates/aspirin (high-dose) Stanozolol Tamoxifen

Increased anticoagulant effect

Pharmacodynamic potentiation of anticoagulant effect

NSAIDs (including aspirin at all doses) clopidogrel and ticlopidine

Increased risk of bleeding

Additive effects on coagulation and haemostasis

Oral contraceptives, oestrogens and progestogens Vitamin K (e.g. in some enteral feeds)

Reduced anticoagulant effect

Pharmacodynamic antagonism of anticoagulant effect

Probable mechanism(s)

but may add to the respiratory depression produced by opioids, whereas naloxone, despite having no opioidlike effects itself, antagonizes the pharmacological effects of most opioids. Many pharmacodynamic interactions occur when the physician forgets that a drug known to be acting at one receptor may also act at another. Thus, antihistamines, phenothiazines and tricyclic antidepressants may have muscarinic anticholinergic activity in addition to their desired pharmacological effects: administration of two or more of these agents (particularly in the elderly) may lead to pronounced anticholinergic symptoms and signs. Pharmacodynamic interaction may also occur when two drugs act at different sites, e.g. the interaction of digoxin and diuretics. Here, hypokalaemia caused by diureticinduced reduction of potassium reabsorption in the kidney may potentiate the effects of digoxin on the heart.

1

PHARMACOKINETIC INTERACTIONS Absorption Drugs may interact with each other to prevent either the rate or the extent of absorption of another compound. Drugs that increase gastric emptying (e.g. metoclopramide) will increase the rate of absorption of many other drugs, so that the peak concentration of that drug will tend to be higher. The opposite effect is achieved by agents - such as the anticholinergic compounds atropine, trihexyphenidyl (benzhexol) and propantheline - that diminish gastric emptying. These changes are likely to be more important after single-dose administration in a situation where a threshold concentration for drug effect exists, e.g. for analgesics. Under these circumstances (particularly if the rate of elimination of the drug is high), a delay in absorption may result in an inability to reach therapeutic drug concentrations. The extent of absorption of the drug may be impaired by the presence of another through the formation of chelates, ion pairs or complexes. Ion exchange resins such as colestyramine (cholestyramine) and colestipol combine with warfarin, levothyroxine (thyroxine) and digitalis glycosides to im-pair absorption. Similarly, the calcium, magnesium or aluminium ions in antacids or milk may interact with 4-quinolones such as ciprofloxacin. In most cases these interactions can be prevented by ensuring a time interval of at least 2 hours between administrations of the two compounds. In the case of warfarin and digitoxin, however, colestyramine (cholestyramine) or colestipol may also affect enterohepatic recirculation and reduce concentrations of these drugs, even if they are administered after absorption has been completed.

Distribution Drugs may compete for both plasma protein-binding sites and active transport processes in the body. The importance of plasma protein-binding displacement interactions has

9

TABLE 1.5 Some drugs causing induction of drug metabolism Barbiturates and primidone Carbamazepine Cigarette smoking* Phenytoin Rifampicin and rifabutin St John's wort * Selective induction (e.g. of theophylline metabolism).

FIG. 1.3 Factors determining the distribution of drugs in the body

been much exaggerated (Fig. 1.3). For most drugs, only the free form in plasma is available for metabolism. Thus, an increase in the percentage of free drug will result in a concomitant increase in total clearance and the rapid return of the free (biologically active) drug concentration to its original value. (The net result is a lower total drug concentration, but a larger percentage of this is in the free form.) The temporary increase in free drug concentration is only likely to be important if the drug is normally highly protein bound (e.g. >90%) and has a low apparent volume of distribution. If the displacing agent is given by a rapid intravenous injection, the temporary increase in free drug concentration of the displaced agent may also be important, but clinically significant examples of this interaction are difficult to find. At present, whenever significant clinical interactions have been shown to be associated with protein-binding displacement, other mechanisms (e.g. competition for metabolism) have been shown to be the major causes of the interaction. It is therefore possible that plasma protein-binding displacement merely reflects the physicochemical similarities of the two compounds, which leads to their competing for transport or metabolic processes. Inhibition of active transport of one drug by another can result in significant interactions. P-glycoprotein is a surface phosphoglycoprotein that functions as an energydependent efflux. It is coded by the human MDR1 (multidrug resistance) gene and is present in a wide variety of tissues, including the gut, kidney, liver, brain, testes, placenta and adrenals. Human P-glycoprotein has been shown to transport a wide range of structurally unrelated drugs such as digoxin, quinidine, ciclosporin and HIV-1 protease inhibitors. Competition for this pump between quinidine and digoxin, for example, can result in increased concen-

O MCQ 1.7-1.11

10

trations of digoxin entering the CNS and corresponding toxicity. If potent and safe inhibitors of P-glycoprotein and other similar transporters (multidrug resistance-associated proteins or MRPs) can be found, the interaction could possibly be used to therapeutic effect in overcoming the intrinsic or acquired multidrug resistance of human cancers.

Metabolism Compounds in cigarette smoke and a variety of other drugs (Table 1.5) can stimulate drug metabolism by the hepatic mono-oxygenase system. Enzyme induction is related to an increase in the amount of cytochromes present, and may therefore take 7-14 days to develop fully and a similar lag period to wear off after the inducing agent is discontinued. This time lag tends to disguise any causal relationship between the drug interaction and administration of the inducing agent. Furthermore, if the dose of the active drug has been increased to maintain adequate effects, marked increases in drug concentration and toxic effects may be seen when induction wears off. Other agents can impair the metabolism of concomitantly administered drugs, either by competing for metabolism or in a non-competitive manner (Table 1.6). Cimetidine is an interesting example in that, although not itself metabolized (it is excreted largely unchanged in the urine), it inhibits the metabolism of drugs by the liver. As the effect of enzyme inhibitors is generally direct, the lag time for this effect to occur is shorter than with enzyme inducers and the effects disappear more quickly after discontinuation. The effects also tend to be more selective than with enzyme induction. Thus, allopurinol has little effect on drugs metabolized by the mono-oxygenase pathway but, by inhibiting the enzyme xanthine oxidase, can impair the metabolism of azathioprine and 6mercaptopurine and potentiate their toxicity. If a drug has a carbon atom with four different substituents, it exists as two optical isomers or enantiomers, which are mirror images of each other. Most chemical syntheses will result in equal amounts of the two steroisomers, and this is termed a racemic mixture. One isomer may be much more potent than the other (e.g. S-warfarin is at least five times more potent than R-warfarin), or the toxicity

1

TABLE 1.6 Some drugs causing inhibition of metabolism Allopurinol Amiodarone Cimetidine Metronidazole Monoamine oxidase inhibitors Sulphonamides Macrolides (e.g. erythromycin, clarithromycin, azithromycin) Some antifungals (e.g. ketaconazole, fluconazole, itraconazole, miconazole) Some quinolones (e.g. ciprofloxacin, norfloxacin, ofloxacin, nalidixic acid) Some HIV-protease inhibitors (e.g. saquinavir, indinavir, nelfinavir, ritonavir) Some SSRIs (e.g. fluoxetine, fluvoxamine, nefazodone, paroxetine, sertraline)

of the two isomers may differ. The enantiomers may also differ in metabolic route or interact differently with other compounds. Cimetidine inhibits the metabolism of Rwarfarin, metronidazole inhibits the S enantiomer, and amiodarone inhibits the metabolism of both enantiomers.

Excretion It is unlikely that drug-induced changes in GFR will markedly alter the excretion of other drugs by the kidney. However, drugs that alter urinary pH may have a marked effect on the renal clearance of weak bases or acids, because of the effects on passive reabsorption in the proximal tubule. The administration of bicarbonate, for example, may enhance the removal of weak acids (such as phenobarbital and aspirin) by increasing the proportion of drug in the ionized form in the urine, thus preventing passive reabsorption. Similarly, acidification of the urine (using ammonium chloride) reduces tubular reabsorption of weak bases such as amphetamine, an effect that was once used in overdose to enhance renal excretion. Acidic drugs may compete with each other for the active renal tubular secretory pathway. Salicylates and thiazides may potentiate the toxicity of methotrexate in this way. No clinically important interactions involving basic drugs at this site have been reported. Quinidine and verapamil may compete with digoxin for an active tubular secretory mechanism in the distal convoluted tubule. This mechanism is now thought to be P-glycoprotein (see earlier), so that the digoxin-quinidine interaction results in reduced renal clearance of digoxin (as well as the increased CNS penetration of digoxin described earlier), thus causing increased plasma and CNS digoxin concentrations and increased risk of toxicity. P-glycoprotein may also be a factor in the excretion of some drugs into the gut via the intestinal wall and the bile, and may thus determine the apparent bioavailability of certain drugs such as ciclosporin. Like CYP450 enzymes, P-glycoprotein activity can be enhanced by enzyme induction, and this may well be an important determinant of rifampicin-induced reduction in ciclosporin bioavailability, for example (Fig. 1.4). 1

FIG. 1.4 Schematic representation of the effect of P-glycoprotein activity on the disposition and bioavailability of drugs

AVOIDANCE OF DRUG INTERACTIONS There are a number of strategies that can be adopted to decrease the risk of potential clinical problems. The number of drugs prescribed for an individual should be limited to as few as is necessary. The drug list (including over-the-counter and herbal preparations) should be reviewed on a regular basis, potentially unnecessary medicines withdrawn and the patient's progress monitored subsequently. Patients should be encouraged into a 'prescribing partnership', alerting doctors, pharmacists and other healthcare professionals to symptoms that occur when new drugs are introduced. The prescriber should be alert for the presence of medicines (e.g. particularly likely to be associated with interaction (e.g. enzyme inducers and inhibitors)) and avoid such combinations. He or she should also be prepared to check (there are excellent tables in the British National Formulary} before prescribing any new or unfamiliar drug, particularly in those already receiving drugs with a low therapeutic ratio. Clinicians should also report via the appropriate postmarketing surveillance scheme any drug-drug interactions they feel they have encountered.

THERAPEUTIC DRUG MONITORING Therapeutic drug monitoring refers to the measurement of drug concentrations in plasma to aid in optimizing drug efficacy and reducing the risk of toxicity.

11

TABLE 1.7 Drug concentration associated with optimal efficacy in most patients Usual half-life (hours) Carbamazepine Ciclosporin Digoxin Gentamicin

2-10 30-40 2-3

Lithium Phenytoin

7-20 20-60

Theophylline

4-15

Usual therapeutic plasma concentrations

Toxic concentrations

Principal route of elimination

4-1 2 mg/L 1 00-200 ^g/L 0.8-2 ng/L Trough <2mg/L Peak 4-8 mg/L 0.4-1 .0 mmol/L Plasma 10-20 mg/L Saliva 1-2 mg/L Plasma 10-20 mg/L Saliva 6-1 2 mg/L

>12mg/L >200^g/L >2 g/L Trough >2 mg/L Peak >12 mg/L >1.5mmol/L >20mg/L >2mg/L >20mg/L >12mg/L

Hepatic metabolism Hepatic metabolism Renal excretion Renal excretion

The ideal way to monitor drug therapy is, of course, to measure wanted and unwanted effects directly: where good measures of these exist (e.g. in anticoagulant therapy), measurement of plasma drug concentrations has a very limited role. There are, however, situations in which drug efficacy or toxicity is more difficult to measure and, both here and where the drug is being given prophylactically to prevent serious events (e.g. antiepileptic and antiarrhythmic drugs), therapeutic drug monitoring may have a role to play (Table 1.7). Measurement of plasma (or urine) drug concentration is also of value in detecting overdose (either deliberate or accidental) and in monitoring compliance with therapy in patients who may not be responding normally to the drug. For therapeutic drug monitoring to be of value in optimizing therapeutic benefit, the drug should work by a reversible mechanism without the development of tolerance. The possibility of accumulation of active metabolites that are not detected by the drug assay must also be considered. Procainamide, for example, is metabolized to Nacetylprocainamide, which also has antiarrhythmic activity and, ideally, should also be measured.

Renal excretion Hepatic metabolism Hepatic metabolism

tration taken just before the next dose will correlate most closely with the steady-state concentration. As it takes approximately five half-lives before steady state is achieved, sampling before this time will tend to underestimate the subsequent steady-state concentration and is only indicated if toxicity due to drug accumulation is possible. Details of sampling time, time and extent of last change in dose, and time of administration of the most recent dose should always be given on the assay request form to enable the plasma concentration to be interpreted correctly. Total drug concentrations are normally measured and these generally mirror the free plasma concentration. This may not be true in diseases where changes in plasma protein binding of drugs is likely, such as hepatic and renal disease. For some drugs (e.g. phenytoin and theophylline) the concentration in saliva may be a closer reflection of the free plasma concentration: in young children, saliva collection (stimulated by a drop of citric acid solution on the tongue) may avoid venepuncture.

SPECIFIC DRUGS

Sample collection

12

Unlike many endogenous compounds, such as creatinine, which are produced at a continuous rate, drugs are normally administered at fixed intervals and the plasma concentration will therefore vary markedly with time after administration. Early after administration the plasma concentration may be affected by the rate of gastric emptying. However, if there is extensive distribution of the drug early samples may be higher than the average, or steady-state, concentration during the dosing interval, and may not accurately reflect the concentration at the site of action of the drug. It is therefore preferable to wait at least 8 hours after administration of an oral dose of digoxin, or 12 hours after lithium, before sampling. If peak levels are important, samples should be taken 2-3 hours after a conventional tablet, or later if a sustained-release formulation has been administered, or 30-60 minutes after intramuscular injection. In most cases, however, a trough concen-

Anticonvulsants Phenytoin metabolism shows saturation rather than firstorder kinetics, so that clearance falls with increasing dose and the risk of toxicity increases. Half-life also increases with increasing dose, and so it will take longer for steady state to be achieved. Most patients tend to be given too small a dose of phenytoin, but therapeutic monitoring has reduced the tendency to prescribe a second antiepileptic drug in many patients who initially received subtherapeutic doses. Therapeutic monitoring of other anticonvulsants except carbamazepine is of limited value except in the identification of poor compliance.

Antiarrhythmics Because of their serious toxicity and the narrow margin between therapeutic and toxic doses, monitoring of several

antiarrhythmic drugs may help to reduce adverse effects and improve response. The half-life of most antiarrhythmics is short, but that of amiodarone is around 30-45 days. A loading dose is therefore necessary to achieve early therapeutic concentrations of this drug, and prolonged monitoring will help to detect the accumulation of amiodarone and its major (and possibly toxic) metabolite desethylamiodarone.

and regular monitoring of plasma concentration and renal function may be helpful in reducing the risks of nephrotoxicity.

Digoxin

The importance of drug regulation has grown with the rapid increase in the number of therapeutic agents developed over the last 50 years. Increased efficacy of new compounds is often associated with a risk of serious adverse effects.

The plasma digoxin concentration is one of the determinants of toxicity of the drug, particularly noncardiovascular toxicity, causing lassitude, depression and anorexia. Monitoring is particularly important in patients with reduced renal function (e.g. in the elderly), whose digoxin clearance is reduced, and will also help to identify poor compliance.

Theophylline Patients vary greatly in metabolic clearance of this potentially toxic bronchodilator, and dose adjustment is facilitated by the measurement of plasma theophylline concentrations.

Antibiotics The aminoglycosides (gentamicin in particular, but also amikacin, kanamycin, netilmicin and tobramycin) are the most frequently monitored antibiotics. The risk of ototoxicity can be reduced by preventing excessive plasma drug concentrations, but the nephrotoxic effects of the drugs are less closely related to the plasma concentration, so that renal function must also be carefully monitored during therapy. The antibiotic vancomycin is used systemically in the prophylaxis and treatment of endocarditis and other serious infections caused by Gram-positive cocci, including multiresistant staphylococci. Vancomycin (added to dialysis fluid) is also used in the treatment of peritoneal dialysis-associated peritonitis. After parenteral administration, vancomycin may be associated with renal damage and ototoxicity, and plasma concentrations are of help in minimizing toxicity.

Lithium Lithium is used in the treatment of hypomania, and because toxicity may develop insidiously (p. 27) therapeutic monitoring is essential.

Ciclosporin Ciclosporin is an immunosuppressant used in organ transplantation to prevent graft rejection and for the prophylaxis of graft-versus-host disease. It is also used in the treatment of severe atopic dermatitis, psoriasis and rheumatoid arthritis. It may cause renal damage,

1

DRUG REGULATION AND DEVELOPMENT

THE UNITED KINGDOM MEDICINES ACT (1968) AND THE MEDICINES FOR HUMAN USE REGULATIONS (1994) In the late 1950s thalidomide was introduced as a new hypnotic drug and was widely used in Europe, including in pregnant women. In 1961 an epidemic of appalling proportions occurred in which hundreds of the babies were born with limb abnormalities (phocomelia). The connection with thalidomide administration was soon realized and the drug was soon withdrawn. The nature of this adverse reaction and the public pressure it provoked resulted in the formation, in the UK, of the Committee on Safety of Drugs (the Dunlop Committee) in 1965, and the subsequent development of strict legislation concerning all aspects of drug manufacture, testing and selling. This legislation is contained in the United Kingdom Medicines Act (1968). In 1994, the European Union regulations were implemented in the UK by statutory instrument (the Medicines for Human Use Regulations) and the European Medicines Evaluation Agency (EMEA) was set up in London in 1995 to develop a centralized European procedure for drug evaluation. Each EU member state is required to have a national system for drug safety surveillance (pharmacovigilance) in place. In the UK this system is administered by the Medicines Control Agency (MCA), an executive agency of the

SUMMARY 3 Drug development Synthesis/isolation of new chemical entity Animal studies Pharmacological/toxicological studies Clinical trials Phase 1 Dose-finding tests in healthy volunteers (c 50) Phase 2 Tested in carefully selected patients (c 200) Phase 3 Formal, larger-scale trials (normally up to 2000) Efficacy, safety and comparison with other established therapies Phase 4 Post-marketing studies on a much larger population of patients

13

Department of Health, which is tasked to safeguard public health by ensuring that all medicines on the UK market meet appropriate standards of safety, quality and efficacy. It is advised by an independent Committee, the Committee on Safety of Medicines (CSM), which gives advice to the Licensing Authority (in this case the UK government) on whether new products (new active substances) submitted to the MCA should be granted a marketing authorization. It also helps to monitor the safety of marketed medicines.

DEVELOPING NEW DRUGS

14

Virtually all new drugs are developed within the pharmaceutical industry, because of the enormous financial investment (about £560 million for a new product in 2001) and the huge amount of work involved. Because a patent taken out on a new compound lasts for only 17 years, the 10-12 years (or longer) required for most drugs to reach the stage of a product licence erodes the patent life alarmingly. The industry therefore has to look very carefully at the likely returns on its investment over the short period that it alone can market the drug under patent. Developing drugs for less common diseases becomes commercially unattractive under these circumstances. Apart from the basic chemistry and pharmacology required to develop a new drug, a large amount of toxicological data from animal testing is also required from the pharmaceutical company to satisfy the licensing authority that the drug is unlikely to cause serious adverse reactions in humans. If it is so satisfied, the authority will grant a Clinical Trials Exemption (CTX) or Clinical Trials Certificate (CTC), both of which allow the drug to be tested in patients before an application for marketing authorization is made. In Europe, authorization for a marketing (product) licence can be sought by either a centralized or a decentralized procedure. The former process gives approval throughout Europe and is compulsory for medicinal products derived from biotechnology. The decentralized procedure (or mutual recognition procedure) applies to the majority of conventional medicines and is based upon the principle of mutual recognition by member states. The EMEA provides any arbitration between the member states before the final decision is made, normally by the European Commission. Member states can still, if they wish, give authorization for medicines to be marketed only in their own country. Clinical trials are usually divided into four phases. In phase 1 a small number of healthy volunteers (usually around 50) are given the drug for the first time. The initial doses are very low, and are titrated up to doses likely to show activity, with very careful monitoring for possible toxicity. In the UK, a CTX or CTC is not required for studies in healthy volunteers. If the results are satisfactory, around 200 or so carefully selected but clinically stable patients are given the drug to discover whether pharmacological and therapeutic effects occur in humans (phase

2). In the third phase, formal and larger-scale clinical trials are performed in order to confirm the drug's therapeutic benefit in a broader range of patients (around 2000 on average) with other concomitant conditions, to evaluate its adverse effects and compare it with alternative established therapies. At this point, assuming that the results are satisfactory, an application will be made for a product licence so that marketing and promotion of the drug can begin. It is thus unusual for more than 2500 individuals to have received the drug up to this point in time. Therefore, postmarketing surveillance is crucial to detect any rare (incidence <1 in 1000) ADRs that are unlikely to have been detected during the drug development process. Companies may institute formal (phase 4) prospective cohort studies at this stage, particularly if they wish to examine any potential drug safety issues on a much larger population of patients.

NATIONAL INSTITUTE FOR CLINICAL EXCELLENCE (NICE) This body was set up in 1999 to assess the cost-effectiveness and clinical effectiveness of new and existing technologies, including certain drugs, and to provide patients, health professionals and the public in England and Wales with authoritative, robust and reliable guidance on current 'best practice'. When a cost-effective treatment already exists, this is used as a benchmark against which any existing or newly marketed treatment is appraised, as to whether it is a clinically effective and cost-effective use of NHS resources. Details of the appraisals can be found at http://www.nice.org.uk.

MONITORING ADVERSE DRUG REACTIONS One of the MCA/CSM's most important tools in monitoring safety of marketed medicines is the yellow card system. Set up in 1964 in the wake of the thalidomide tragedy, it now has more than 480000 reports of suspected ADRs that have been submitted on a voluntary basis by doctors, dentists, pharmacists and coroners, and (under statutory obligation) by pharmaceutical companies. If a serious reaction is suspected, or any possible reaction to a newly marketed drug (marked with an inverted triangle in the British National Formulary), a card should be sent to the Medicines Control Agency (MCA), in certain areas via the appropriate Regional Monitoring Centre. A substantial data bank is thereby accumulated and analysed regularly for associations between suspected adverse reactions and individual drugs. Data from the UK scheme and from more than 40 other countries is shared with the WHO Collaborating Centre for International Drug Monitoring in Uppsala, Sweden. Each year more than 150000 such reports are received and the cumulative database now contains over 1.4 million records, so that potential ADR

1

FIG. 1.5 Drugs involved in self-poisoning Number and percentage of admission to the Cardiff Poisons Treatment Unit in 1999 involving the seven most frequently taken drugs/drug groups. (Some patients take more than one drug).

FIG. 1.6 The relationship between age and the incidence of poisoning in children Figures are based on enquiries concerning accidental poisoning made to the National Poisons Information Service (Cardiff Centre) in 1999.

signals can be detected more sensitively. Such spontaneous reporting schemes are relatively inexpensive and extremely cost-effective. Unfortunately, less than 10% of even serious suspected ADRs are reported via these schemes, and they could be even more effective if more health professionals regularly reported their drug-safety concerns.

Whereas death from carbon monoxide poisoning predominates in adults, there are approximately 20 accidental deaths per year from all other agents, particularly tricyclic antidepressants, iron, aspirin and barbiturates in young children. The incidence of accidental poisoning in childhood is partly determined by availability.

DELIBERATE SELF-POISONING DRUG OVERDOSE Approximately 4000 people die each year of poisoning in England and Wales, a quarter of them of carbon monoxide poisoning. Approximately two-thirds of the remaining deaths occur outside hospital. Nevertheless, more than 100000 patients are admitted to hospital in England and Wales each year with poisoning, accounting for 10% of all acute admissions. The unadjusted admission rates in the USA range from 80 per 100000 in patients aged 65-74 years to 400 per 100000 in patients aged between 15 and 24 years. Toxic compounds may be ingested or inhaled either accidentally or deliberately, or may be administered accidentally or deliberately. This forms the basis for a classification of poisoning incidents, separating them into broad epidemiological categories. The major causes of admission due to poisoning are shown in Figure 1.5.

ACCIDENTAL POISONING Accidental poisoning can occur at any age but is much more likely to occur in children under 5 years of age (Fig. 1.6). Peak incidence is around 2 years, when children have become independently mobile, and boys appear to be more at risk. This contrasts with other categories of poisoning, in which women are involved more than men. Fortunately, the mortality from accidental poisoning is relatively small.

Deliberate self-poisoning is commoner in adults who, unlike children, ingest medicinal agents more readily than they do household chemicals and other non-medicinal compounds. Women are more often involved than men, and the vast majority of instances are not intended to be ultimately fatal. Generally they represent a response to an apparently insoluble personal predicament (Ch. 8), but some have a definite suicidal intent. Patients who successfully commit suicide tend to be older and may have been recently divorced or bereaved, may be living alone, suffering from a physical illness, unemployed or abusers of alcohol.

NON-ACCIDENTAL POISONING Non-accidental poisoning usually involves children and is a form of abuse. The parents of such children may have suffered child abuse or deprivation themselves, and often have marital or financial problems or difficulties in managing the child at the time of the poisoning episode.

HOMICIDAL POISONING Although often featured in novels and plays, homicidal poisoning is uncommon. When it does happen, it is often

15

caused by a close relative or friend and generally involves the use of poisons producing chronic, rather than acute, symptoms.

DIAGNOSIS OF POISONING Laboratory tests cannot identify every agent to which an individual might be exposed. A full history and clinical examination is therefore an integral part of the diagnosis. As the patient may be unwilling or unable to give a history on presentation, it is important to talk to relatives or friends, the GP or the ambulance personnel who brought the patient into hospital. Particular difficulties are encountered with the patient who is found alone and unconscious and in whom poisoning is just one of the differential diagnoses. The first priority in the unconscious patient is maintenance of the airway, ventilation and cardiovascular function. When this has been assured, the question arises as to whether the patient is poisoned. Other causes of unconsciousness are discussed in Chapter 24. In deep coma due to drug overdose the pupillary reflexes are often preserved, but the oculovestibular responses (e.g. 'doll's eye response') are absent. Focal neurological signs are rare in overdose and, unless they can be accounted for by previous pathology, these should alert the clinician to the possibility of another cause. Papilloedema due to drug overdose is rare, unless the overdose has been associated with cerebral hypoxia and oedema. If the patient shows no improvement in level of consciousness by 12 hours after admission, another pathology should be suspected.

TABLE 1,8 Physical signs suggestive of overdose or poisoning: head and neck Sign

Possible cause

Dilated pupils

Anticholinergics Tricyclic antidepressants Amphetamines Ecstasy Carbamazepine Sympathomimetics Cocaine LSD Glutethimide Methanol

Constricted pupils

Opiates Organophosphates and carbamates

Strabismus

Carbamazepine

Nystagmus

Barbiturates Carbamazepine Phenytoin Phencyclidine

Perforated nasal septum

Cocaine abuse

Acneiform rash

Solvent abuse

Erythema/burns

Corrosives Paraquat

Mouth dryness

Anticholinergics

Hypersalivation

Parasympathomimetics Organophosphates and carbamates Arsenic Strychnine Clormethiazole Clozapine

CLINICAL EXAMINATION It is sometimes possible to identify the poison by the clinical signs on examination, although it may be more difficult if the patient has taken several agents. The most helpful clinical signs are shown in Tables 1.8 and 1.9.

Mouth

Eyes Pupillary dilatation occurs in poisoning with anticholinergic drugs, such as the tricyclic antidepressants, antiparkinsonian agents, antihistamines and phenothiazines. It also occurs with agents that stimulate the sympathetic nervous system, such as amphetamines, LSD and theophyllines. Unequal pupils are occasionally seen in poisoning. Strabismus is not uncommon, particularly in carbamazepine poisoning. Papilloedema, however, is rare, except as a

1

16

result of methanol, carbon monoxide or glutethimide poisoning. Agents affecting the central nervous system (CNS), particularly phenytoin, may cause nystagmus.

Fig. 1.5

2

Fig. 1.6

Acneiform lesions around the buccal cavity may suggest solvent abuse, O and the characteristic odour of solvent or alcohol may be present on the breath. Examination of the oral cavity may reveal ulceration due to corrosion by acids or alkalis. The mouth may be abnormally dry because of anticholinergic compounds, and increased salivation may be seen in subjects who have taken agents that stimulate the parasympathetic nervous system, e.g. carbamate insecticides and anticholinesterases.

Cardiorespiratory Chest wheeze may be caused by inhalation of irritant compounds: pulmonary oedema can also be caused by these

TABLE 1.9 Physical signs suggestive of overdose or poisoning: trunk and limbs Sign

Possible cause

Bronchospasm

Irritant gases NSAIDs (rare) Arthropod envenomation Scombroid fish

Pulmonary oedema

Irritant gases Paraquat Opioid analgesics Aspirin

Tachycardia

Anticholinergics Sympathomimetics Cocaine Phencyclidine Theophylline Amphetamines Aspirin

Bradycardia

Cardiac glycosides p-Blockers Verapamil Organophosphates and carbamates

Hypertension

Sympathomimetics Amphetamines Phencyclidine MAOIs Clonidine Cocaine SSRIs (rare)

Needle tracks

Drugs of addiction

Absent bowel sounds

Anticholinergics Tricyclic antidepressants Opioids

Bladder distension

Anticholinergics Tricyclic antidepressants

Hypothermia

Phenothiazines Tricyclic antidepressants MAOIs (rare)

Hyperthermia

MAOIs Sympathomimetics Anticholinergics MAOIs SSRIs (rare) Amphetamines Ecstasy Aspirin

Hyperreflexia

Anticholinergics Sympathomimetics Opioids

Blisters

Barbiturates Carbon monoxide Opioids Tricyclic antidepressants

Extensor plantar responses

Anticholinergics Tricyclic antidepressants

agents, or by ingestion of drugs such as opioids or aspirin. There may be tachycardia with poisoning due to anticholinergics, salicylates or drugs that stimulate the sympathetic nervous system. Verapamil, (3-blockers or drugs that stimulate the parasympathetic nervous system, on the other hand, may cause bradycardia. Cardiac arrhythmias may be associated with hypoxia, but are particularly troublesome in patients who have taken tricyclic antidepressants, drugs stimulating the sympathetic nervous system, phenothiazines or quinine. Many agents can cause hypotension, but hypertension is rarer and usually associated with monoamine oxidase inhibitors or clonidine, which in overdose may act like a-adrenoceptor agonists.

1

Abdomen Absent bowel sounds or bladder enlargement suggest the possibility of anticholinergic poisoning. Rectal examination should be performed and may reveal melaena due to poisoning by iron, non-steroidal anti-inflammatories or other agents that damage the gut mucosa. The rectal temperature should be recorded using a low-reading thermometer. This may reveal hypothermia (e.g. with phenothiazine poisoning) or hyperthermia (in poisoning by salicylates, anticholinergic compounds or drugs that stimulate the sympathetic nervous system).

Skin and nails The hands, arms and legs may show needle tracks indicating drug abuse. Blisters over the bony prominences, commoner on the lower limbs, are seen in patients who have taken a barbiturate, opioid or tricyclic antidepressant overdose, 2 or are suffering from carbon monoxide poisoning (Fig. 1.7). Their presence reflects the combination of severe hypoxia and pressure, and they often occur where the patient has been lying against a hard surface. They should alert the physician to the possibility of hypoxic damage of other organs such as muscle, since there is sometimes associated rhabdomyolysis. The nails may show transverse white (Mee's) lines in poisoning with the heavy metals, arsenic and thallium (Fig. 1.8).

Neuromuscular Examination of the limbs normally reveals hypotonia and hyporeflexia in poisoning, but anticholinergic drugs, some opioids and drugs that stimulate the sympathetic nervous system may cause hypertonia, hyperreflexia and, occasionally, myoclonus. Anticholinergic compounds may also produce an extensor plantar response that is usually bilateral. Convulsions may be caused directly by a variety of compounds, including the anticholinergic agents and drugs stimulating the sympathetic nervous system, opioids, mefenamic acid and isoniazid, or may be secondary to hypoxia or hypoglycaemia associated with overdose. Dystonic reactions are much less commonly seen, and are generally

17

FIG. 1.7 Poison blister Blister on the knee of a 25-year-old male who took an overdose of the opiate drug, dextropropoxyphene. He subsequently developed signs of rhabdomyolysis.

FIG. 1.8 Mee's lines in the nails of a patient with thallium poisoning These dystrophic changes causing a white line distal to the cuticle are also seen in poisoning with arsenic.

related to poisoning with drugs with antidopaminergic activity, such as metoclopromide, the phenothiazines and butyrophenones.

The urea and electrolytes are rarely of diagnostic value. Hypokalaemia can be caused by theophylline and drugs stimulating the sympathetic nervous system, or may indicate potassium loss owing to diuretic or purgative overdose. Hyperkalaemia is sometimes seen in severe digoxin overdose. Reduction in the serum bicarbonate may indicate metabolic acidosis and should be investigated by arterial blood gas analysis. The alcohols and glycols, as well as aspirin, may cause a metabolic acidosis, often with a high anion gap (see p. 1114). The presence of both a high anion and an osmolal gap in the absence of detectable ethanol is suggestive of methanol or ethylene glycol poisoning. Profound hypoglycaemia may indicate overdose with oral hypoglycaemic agents or be secondary to overdose with alcohols, salicylates or paracetamol. Clinical judgment must be used in deciding which test will give useful diagnostic or prognostic information. It is useful to store blood for future reference.

LABORATORY INVESTIGATIONS Routine laboratory investigations are sometimes helpful in identifying the drug ingested.

Urine The urine should be examined both macroscopically and microscopically. A specimen should also be stored for possible future analysis even if this is not indicated initially. Red discoloration may be caused by rifampicin or phenindione, 1and haematuria by drugs affecting haemostasis or clotting, or by drugs causing haemolysis, such as chlorates. Drugs that contain methylene blue (e.g. some commercial analgesics) may colour the urine blue or green; a greyish discoloration may indicate poisoning with phenols or cresols. Microscopic haematuria or albuminuria may be the first sign of renal damage. Crystalluria can occur with primidone and some of the sulphonamides, and calcium oxalate crystals may be present in ethylene glycol poisoning.

Blood Brown discoloration of venous blood may indicate methaemoglobinaemia, which can be caused by oxidizing agents such as dapsone. Pink discoloration of the plasma indicates haemolysis, which may be drug induced.

O Fig. 1.7

18

Specific tests An increasing number of compounds can now be detected specifically in either urine (which tends to be more useful as it concentrates the drugs or its metabolites) or blood. Toxicological analyses are not a substitute for clinical judgment and the physician should consider whether the result would alter his or her management.

PRINCIPLES OF MANAGEMENT OF POISONING General supportive measures to prevent complications are usually more important than specific therapies to treat the particular poison, since the latter are not always available.

SUMMARY 4 Principles of management of poisoning • General supportive management, particularly of airway, breathing and circulation (ABC), is of prime importance • Identification of the cause of poisoning can be made by history and clinical and toxicological examination • Decontamination procedures should then be considered to prevent further adsorption of drug remaining in the gastrointestinal tract • Elimination of some drugs can be enhanced. Procedures can produce complications and should only be considered when clearly indicated • General supportive care. Prevention and treatment of complications remains the mainstay of management

SUPPORTIVE MANAGEMENT

• Increased capillary permeability, resulting in a reduced circulating blood volume. In hypotensive patients a central venous pressure line should be inserted. If the venous pressure is low the blood volume should be increased using a plasma expander, such as Haemaccell. If the hypotension does not respond, intravenous (i.v.) dopamine or dobutamine may restore the blood pressure: low-dose dopamine may prevent subsequent acute renal failure (see Ch. 14). Cardiac arrhythmias, which may be a direct effect of the drug or a result of hypoxia and acidosis, may also contribute to hypotension by reducing cardiac output. It is important to correct the predisposing causes if possible before considering specific antiarrhythmic therapy, as many antiarrhythmics may further reduce cardiac output. The choice of an antiarrhythmic agent is usually based on the arrhythmia rather than the specific toxin.

Maintenance of respiratory function

Prevention of complications

Maintenance of an adequate airway and respiration is the first priority in an unconscious patient, as many early deaths from poisoning are due to airway obstruction. Dentures should be removed, the tongue pulled forward and the mouth and pharynx cleared of saliva and vomitus. If the patient has no cough reflex, a cuffed endotracheal tube is necessary to protect the lungs; in other cases a short oropharyngeal tube should be inserted. The patients is then moved into a semiprone position and, if there is any suspicion of inadequate ventilation, oxygen should be administered. Assisted ventilation may be necessary. In less urgent circumstances arterial blood gas analysis is the best guide to assessing the adequacy of ventilation. Drugs that stimulate respiration (e.g. doxapram) should be used cautiously in poisoned patients as they may provoke convulsions or cardiac arrhythmias. The shock lung syndrome (acute respiratory distress syndrome, ARDS; see p. 697) may appear at about 24 hours. The patient begins to hyperventilate but remains hypoxic, and develops a respiratory and metabolic acidosis. A chest radiography may show changes similar to pulmonary oedema and, in severe cases, the lung fields may be completely obscured. Assisted ventilation using positive endexpiratory pressure (PEEP) may help to support the patient through this severe complication. The treatment of aspiration pneumonia is discussed on page 635.

Good nursing care of the unconscious patient is essential. Skin and muscle compression injuries associated with prolonged immobility and hypoxia are a particular problem. The bladder can sometimes be emptied by firm suprapubic pressure, but if it is markedly distended catheterization may be necessary, particularly when measurement of urine production is required. The level of consciousness should be measured using a scale such as the Glasgow Coma Scale (GCS) (Table 1.10). If the conscious level does not improve after 12 hours, this may indicate neurological complications of the overdose or that there is an alternative cause of the

TABLE 1.10 Assessment of consciousness (Glasgow Coma Scale) Score Eyes open

Best motor response To verbal command To painful stimulus

Maintenance of circulatory function Maintenance of circulatory function is essential. Hypotension and reduced peripheral perfusion may be caused by several mechanisms, including: • Depression of the vasomotor centre; • A direct cardiodepressant action; • Increased venous capacitance, leading to reduced venous return to the heart and a consequent fall in cardiac output;

1

Spontaneously To verbal command To pain No response

4 3 2 1

Obeys Localizes pain Flexion-withdrawal Flexion-abnormal (decorticate rigidity) Extension (decerebrate rigidity) No response

6

Orientated and converses Disorientated and converses Inappropriate words Incomprehensible sounds No response

5 4 3 2 1

5 4 3 2 1

Best verbal response

Total

3-15

19

coma. Cerebral oedema is the most life-threatening complication of overdose, and may be caused by hypoxia, hypoglycaemia, hypercapnia or hypotension. It is particularly likely to occur after cardiorespiratory arrest and may respond to dexamethasone or mannitol. Convulsions may also be secondary to hypoxia or cerebral oedema, but otherwise are generally short-lived and do not always require specific therapy. If necessary, intravenous diazepam may be used, but if the patient is vomiting, temporary intubation and mechanical ventilation may be necessary to prevent aspiration pneumonia. Gastrointestinal bleeding or paralytic ileus may be seen in patients with drug overdose. Insertion of a nasogastric tube and regular emptying of the stomach help to reveal bleeding early and prevent the aspiration pneumonia or acute gastric dilatation sometimes seen with paralytic ileus.

MEASURES TO PREVENT FURTHER DRUG ABSORPTION Emptying the stomach can sometimes reduce further absorption of the drug from the gut. Such measures are only indicated if the amount of poison taken is likely to cause serious symptoms, and are of little value if the material ingested has already left the stomach. They should therefore generally only be considered when less than 1 hour has elapsed since ingestion of the toxin, although they may sometimes still be worthwhile if the time of ingestion is unknown.

Gastric lavage Gastric lavage has been the most widely used method of emptying the stomach in adults. It is contraindicated in patients who have taken corrosive agents, unless the danger of systemic toxicity associated with a corrosive agent is greater than the risk of local damage. It is also usually contraindicated after oral ingestion of petroleum distillates, because of the risk of aspiration pneumonia. In the unconscious patient, a cuffed endotracheal tube must always be inserted first. Lavage should be carried out in the left lateral position in a bed or trolley raised at the foot. A large-bore Jaques stomach tube (external diameter

SUMMARY 5 Prevention of further drug absorption

20

• Activated charcoal prevents further absorption of many drugs, if administered sufficiently early, and is the safest and most effective method if the substance is adsorbed by charcoal • Gastric lavage may prevent absorption of the drug if performed within 1 hour of drug ingestion • Emptying the stomach by lavage should not be attempted if the airway cannot be protected • Emesis induced by syrup of ipecacuanha is no longer recommended in children or adults

TABLE 1.11 Substances not effectively adsorbed to charcoal Boric acid Cyanide Ethanol Ethylene glycol Iron salts Lithium salts Malathion Methanol Petroleum distillates Strong acids and alkalis

c 14mm) is introduced into the stomach and the contents removed. Aliquots of water warmed to body temperature are then introduced and removed until the returned fluid is clear of particles. However, gastric emptying by lavage is often relatively inefficient and may be difficult or even dangerous in some individuals (e.g. small children and patients with tricyclic antidepressant poisoning, who may become hypoxic).

Emesis There is little benefit from inducing vomiting. Although syrup of ipecacuanha produces emesis, its effect is delayed for 20-30 minutes and there is no good evidence that it reduces drug absorption significantly in poisoned patients. In addition it has side-effects (e.g. persistent vomiting) which may increase morbidity and make diagnosis more difficult. Salt and water should never be used to produce emesis, as death may occur from hypernatraemia, particularly in small children.

Oral adsorbents Activated charcoal is increasingly being used as it may reduce the absorption of many drugs. Drugs not adsorbed effectively to charcoal are listed in Table 1.11. Charcoal is most effective for agents with high-toxicity taken at low total dose, as 10 times as much charcoal as drug is required to provide optimum adsorption. The charcoal must be given soon after the overdose (normally within 1 hour) to achieve maximum efficacy. A dose of 50-100 g (lg/kg in children) can be administered orally or, in an adult, by nasogastric tube. It is of particular value in accidental poisoning in children, as these cases normally present early enough for the adsorbent to be effective.

ANTIDOTES There are direct antidotes only to about 5% of poisons, so supportive therapy remains the mainstay of treatment for

1

CASE STUDY 1.1 DOSULEPIN (DOTHIEPIN) OVERDOSE A 50-year-old man was admitted to hospital 2 hours after taking 750 mg dosulepin (dothiepin) (conventionalrelease form) and, possibly, 100 mg diazepam. He was very drowsy (Glasgow Coma Scale 9) and tachycardic (pulse 120 bpm, regular). He had dilated pupils (responding slightly to light), exaggerated limb reflexes and bilateral extensor plantar responses. His respiratory rate was 15 per minute. Bowel sounds were present but quiet, and percussion revealed a distended bladder. His blood pressure was 100/70 mmHg. His ECG confirmed sinus tachycardia but showed marked widening of the QRS complex. Questions 1. What other investigations would you ordef ? 2. What treatment would you consider? <

Discussion

Dosulepin (dothiepin) is a tricyclic antidepressant with marked anticholinergic activity in overdose. The clinical features in this patient are consistent with anticholinergic poisoning due to tricyclic antidepressants, although diazepam (a benzodiazepine tranquillizer) could also be contributing to his reduced conscious state. Tricyclic antidepressants can produce cardiac and respiratory depression, with metabolic and respiratory acidosis. Blood gases should be measured urgently and any hypoxia corrected. His temperature should also be checked to exclude hypothermia (which can be caused by a variety of drugs in overdose, including tricyclic antidepressants). Finally, urea and electrolytes should be measured. The presence of significant ECG abnormalities is an indication for intravenous sodium bicarbonate

the vast majority of patients, including those where an antidote exists. Antidotes work in several different ways: • They may speed the metabolism of a toxin, e.g. thiosulphate speeds the metabolism of cyanide by providing sulphur to form non-toxic thiocyanate, which is then excreted in the urine. • If a compound is only toxic when metabolized, antidotes may reduce the rate of metabolism. Ethanol is used in poisoning by methanol and ethylene glycol to reduce the rate of production of toxic aldehydes and acids. • For receptor-mediated toxins, an antagonist that competes for a receptor may be useful, e.g. the use of (3agonists in the treatment of (3-adrenoceptor blocking drugs overdose. • If the toxin competes with a natural substrate, an antidote may increase the natural substrate's concentration, competitively displacing the poison from the receptor site. Inhibitors of acetylcholinesterase reverse some of the features of anticholinergic poisoning in this way. • Antidotes may combine with the poison to form an inactive compound. Thus, specific antidigoxin antibody (Fab) fragments combine with digoxin to produce an inert complex, which can be excreted more rapidly via the kidney. The availability of a specific antidote does not necessarily justify its routine use. Some antidotes are toxic in their

(50mmol), even in the absence of acidosis. Further doses may be necessary, depending on clinical response. Charcoal is of limited value at this stage and may be dangerous if he cannot protect his airway, so it should not be given. Convulsions are normally controlled by diazepam. Flumazenil (a benzodiazepine antagonist) may reverse the effects of any diazepam this patient may have taken, and thus precipitate convulsions and arrhythmias. It should not be given to patients who have taken tricyclic antidepressants. Because of the large volume of distribution of tricyclic antidepressants, forced diuresis, haemodialysis and haemoperfusion are of no proven value in enhancing their elimination. If this patient were to have a cardiac arrest, there is evidence that prolonged resuscitation might be successful.

own right and should only be used if the severity of the poisoning merits their administration. In general, they are most useful early on in the course of poisoning.

ENHANCEMENT OF DRUG ELIMINATION Methods to enhance drug elimination (Table 1.12) are of limited value in the treatment of overdose and are generally only effective when the volume of distribution of the drug is relatively small. This is because drug removal can only occur from the central (intravascular) compartment, which must therefore contain a reasonable proportion of the total body burden of the compound.

Forced diuresis Forced diuresis has been used to enhance the elimination of drugs (such as aspirin) that are excreted predominantly in an unchanged form by the kidney. It acts by increasing the glomerular filtration rate and by reducing the tubular reabsorption of unchanged drug. This is dependent on renal tubular flow, and on the degree of ionization of the drug in the tubular fluid. For weak acids, alkalinization of the tubular fluid by administration of bicarbonate will result in a greater proportion of the drug existing in the

21

TABLE 1.12 Techniques used to enhance drug elimination Enteral adsorbents Activated charcoal Carbamazepine Dapsone Phenobarbitone Quinine Theophylline

Dialysis Barbitone Ethanol Ethylene glycol Isopropanol Lithium Methanol Phenobarbitone Salicylates Haemoperfusion Barbiturates Carbamazepine Glutethimide Meprobamate Phenytoin

Colestyramine (cholestyramine) Digitoxin Phenprocoumon Warfarin

ionized, poorly lipid-soluble form. It is then unable to diffuse back across the lipid membrane of the tubular cell and be reabsorbed. Conversely, acidification of the urine by administration of ammonium chloride, arginine or lysine hydrochloride will increase the ionization of some basic drugs, thereby reducing reabsorption from the tubular fluid. Owing to the risks of fluid overload and electrolyte imbalance, and its relatively limited efficacy, forced diuresis is falling out of favour and is being largely replaced by other, safer, methods of enhancement of elimination.

Dialysis Peritoneal or haemodialysis is useful to remove drugs with low plasma protein binding, poor lipid solubility and relatively low volume of distribution. It is generally reserved for cases where other methods of removal are contraindicated. This process effectively removes salicylates, phenobarbital and barbitone, methanol, isopropanol, ethylene glycol and lithium. Haemodialysis is normally the more effective of the two approaches.

Haemoperfusion Haemoperfusion involves the passage of arterial blood through an extracorporeal column of activated charcoal or ion exchange resin. This effectively removes a number of drugs where the lipid solubility or plasma protein binding reduces the efficacy of removal by dialysis techniques,

1 22

MCQ 1.12-1.14

but a low volume of distribution of the drug is still required. Haemoperfusion is therefore sometimes considered in severe poisoning with barbiturates (including the shortacting barbiturates not removed effectively by haemodialysis) and non-barbiturate hypnotics such as glutethimide, ethcholorvynol, meprobamate, methaqualone and chloral derivatives (e.g. chloral hydrate). Fortunately, these agents are now used less frequently as hypnotics. Haemoperfusion using resin columns is particularly effective in removing theophylline and, to a lesser extent, salicylates. Complications of the procedure include thrombocytopenia, bleeding and possible infection, so haemoperfusion should only be used in patients with severe poisoning who fail to improve despite supportive management and who have developed, or are at high risk of developing, complications of the overdose. Enteral removal Enteral removal is the most recent approach to the enhancement of drug elimination. It relies on the ability of some non-absorbed agents either to remove drugs that have been excreted in the bile but would have been reabsorbed in the gut, or to remove them by 'dialysis' of the splanchnic circulation. Charcoal is the most widely used enteral adsorbent, and markedly enhances the rate of removal of phenobarbitone, digitoxin, quinine, theophylline and dapsone. It is given as an initial loading dose of 50-100 g, followed by repeated doses of 50 g every 4 hours, sometimes with a single dose of a laxative at the beginning to prevent constipation. Oral colestyramine (an anion-binding resin) increases the rate of removal of digitoxin, warfarin and some other coumarin anticoagulants. This non-invasive procedure usually has no major adverse effects, although an antiemetic may be needed in patients who are vomiting as a result of the toxin (e.g. theophylline). 1 SUPPORT SERVICES It is impossible for a clinician to be familiar with all the details of the recommended current management of all toxins. As in other countries, in the UK and Eire Poisons Information Services have therefore been established in several major cities to serve their region(s) (Fig. 1.9). They also contribute to the editing of a database system (TOXBASE), accessible via the Internet, and soon via the NHS Intranet. Its role is to provide health professionals with up-to-date relevant first-line information on the management of poisoning. It can be found on the Internet at http://www.spib.axl.co.uk. TOXBASE also contains advice on holding centres for antidotes, analytical facilities for toxins, slang terms for drugs of abuse, and references on the most important aspects of toxicology. In cases where further advice is necessary, the nearest Poisons Unit in the UK can be contacted via a single national telephone number: 0870 600 6266, or, in Eire, Dublin 837 9964.

National Poisons Information Service Toxbase: http://www.spib.axl.co.uk UK national number 08706006266

SUMMARY 6 Management of benzodiazepine poisoning

1

• Benzodiazepine poisoning is common but death is rare unless other potentiating agents (e.g. alcohol) have also been taken • Flurazepam, tlunitrazepam and triazolam may cause deeper coma than the other agents • Management is generally supportive • Flumazenil, a specific short-acting benzodiazepine antagonist, has been used in the diagnosis of mixed overdose, but may precipitate benzodiazepine withdrawal in dependent individuals, convulsions in individuals with epilepsy and serious arrhythmias in patients who have also taken tricyclic antidepressants

fatal cases each year in which a benzodiazepine is the only drug identified, but they potentiate the effects of other CNS-depressant drugs such as ethanol and can thus contribute to fatal outcome.

FIG. 1.9 Areas served by the UK and Eire Poisons Information Services

On recovery from an overdose, the patient should undergo thorough psychiatric and, if necessary, social assessment (Ch. 8, p. 224). There appears to be a poor correlation between the severity of the overdose and any underlying psychiatric illness. The GP also plays an important part in supporting the patient once he or she has left hospital. Finally, voluntary services often provide useful emotional and practical support to the patient at risk, and details of these local organizations should be made available to each patient.

MANAGEMENT OF SPECIFIC DRUG OVERDOSE The drugs most commonly involved in acute poisoning are hypnotics and tranquillizers, antidepressants and analgesics.

Diagnosis The major effects are on the CNS and include drowsiness, ataxia, dysarthria and nystagmus. Coma then supervenes, although it is rarely deep unless other agents have also been ingested. Recovery is normally within 24 hours, although flurazepam and flunitrazepam may cause deeper and more prolonged coma, and clonazepam has been associated with cyclical coma. Lorazepam causes only modest CNS depression but can be associated with restlessness and hallucinations, particularly in children. Respiratory depression occurs rarely in benzodiazepine overdose, although it may occur in patients with pre-existing respiratory disease, particularly with flunitrazepam. Cardiovascular effects are also generally mild, although slight hypotension may occur. Flunitrazepam may cause more profound hypotension and a sinus bradycardia. Bullous skin lesions have been reported, but are much rarer than after barbiturate overdose. Management Management is supportive: methods to enhance elimination of the parent compound or its active metabolites are of no value. Most patients will recover with no sequelae. Antagonists of benzodiazepines (e.g. flumazenil) have been used in the diagnosis of mixed overdose, or in avoiding the need for ventilatory support in severe poisoning. However, they may precipitate benzodiazepine withdrawal (including convulsions) in benzodiazepine-dependent individuals, convulsions in those with epilepsy, and serious arrhythmias in patients who have also taken tricyclic antidepressants concomitantly. They are also short-acting, so that benzodiazepine-induced coma can recur. They are therefore seldom used.

HYPNOTICS AND TRANQUILLIZERS Barbiturates Benzodiazepines Benzodiazepines are involved in almost half of the drug overdoses in the UK. There are only a small number of

The incidence of barbiturate poisoning has declined markedly over the past 20 years, but this group of compounds is still associated with high mortality.

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SUMMARY 7 Management of barbiturate poisoning • Barbiturate poisoning is now relatively rare but has a significant mortality • Gastric lavage should be performed within 1 hour and activated charcoal left in the stomach. The airway must be protected • Bullous lesions should alert to the possibility of underlying muscle damage (rhabdomyolysis) • Repeat-dose activated charcoal enhances the elimination of phenobarbitone already absorbed, but not of other barbiturates • Charcoal haemoperfusion should be considered only in severe poisoning with barbiturates

Diagnosis In overdose the barbiturates produce an impaired level of consciousness and, in severe cases, hypotension and respiratory depression. Approximately 5% of patients have bullous lesions on the extremities, particularly over the extensor surfaces, but these are not specific to barbiturate overdose and can occur with other agents producing profound hypoxia. Barbiturates can be detected in the urine. Although their plasma concentrations can also be measured, these correlate poorly with the severity of the overdose, partly because of other confounding drugs such as alcohol, and partly because of tolerance, particularly in those taking the drug chronically. Plasma concentrations are therefore of limited value in the management of a particular case, although very high concentrations in the presence of deep coma and other complications of overdose may indicate the need to enhance the removal of the drug. Management Gastric lavage should be performed if tablets have been taken less than an hour previously, or if the time of ingestion in an unconscious patient is unknown. General supportive management is all that is required in most cases, with particular attention to respiration and cardiovascular function. However, even with these measures the mortality in deep coma (GCS 3) is about 5% and procedures to enhance drug elimination may be considered in such subjects, particularly if complications of overdose are already present. Repeated doses of activated charcoal given by mouth through a nasogastric tube can reduce the half-life of phenobarbitone from over 100 hours to less than 20 hours. This procedure is relatively non-invasive and may replace the use of haemoperfusion for phenobarbitone poisoning. Activated charcoal has not yet been shown to enhance the elimination of any of the other barbiturates, and charcoal haemoperfusion may be necessary in such cases who are deteriorating despite intensive management or who have developed serious complications (e.g. pneu-

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24

MCQ1.15

monia, hepatic or renal failure). The blisters should be treated in the same way as burns. 1

Non-barbiturate, non-benzodiazepine hypnotics These were once widely used but have now been largely replaced by benzodiazepines. Isolated overdoses of these agents still occur, however. Specific effects may be seen in addition to CNS depression. Glutethimide may cause fluctuating coma, convulsions and acute respiratory failure. Pulmonary oedema and cerebral oedema may also occur, and papilloedema may be a sign of severe overdose. Charcoal haemoperfusion is indicated in severe overdose, together with management of specific complications. Chloral hydrate and its relatives (e.g. dichloralphenazone) may cause gastrointestinal irritation, haematemesis and subsequent oesophageal stricture. Cardiac arrhythmias are a particular problem with this group of agents but generally respond well to (3-blockers. Haemodialysis may remove the active metabolite, trichlorethanol, but charcoal haemoperfusion is probably more effective and may be helpful in very seriously poisoned patients. Clomethiazole (chlormethiazole) is often used in alcoholic patients, although its value is not proven and it may be dangerous when taken in overdose together with alcohol. Increased salivation is a particular problem which may increase the risk of aspiration pneumonia, and regular oropharyngeal aspiration may be necessary. Meprobamate is still used in the treatment of anxiety, and particularly with muscle spasm. Signs of overdose are muscular incoordination and weakness and CNS depression. In severe cases pulmonary oedema may be seen. Haemodialysis may be useful in severe overdose, but haemoperfusion appears to be more effective.

ANTIDEPRESSANTS Antidepressants, particularly those in the tricyclic group, are still commonly taken in overdose and are particularly dangerous.

SUMMARY 8 Overdose of tricyclic antidepressants • Tricyclic antidepressant poisoning is common and life-threatening • Anticholinergic signs predominate in the early stages but coma may supervene • Direct cardiotoxicity may result in ventricular tachycardia or ventricular fibrillation. The ECG should me monitored until recovery • Arrhythmias and hypotension may respond to correction of acidosis, hypoxia, hypothermia and hypovolaemia. Persistent arrhythmias may respond to sodium bicarbonate, even in the absence of acidosis • Prolonged cardiopulmonary resuscitation has been reported to be successful after cardiac arrest

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CASE STUDY 1.2 BIPOLAR AFFECTIVE DISORDER A 25-year-old woman with bipolar affective disorder presented 4 hours after taking 9g (18 tablets) of paracetamol. Her parents confirmed that she had taken a package up to the bathroom and locked herself in. When she came out there were almost empty paracetamol packages, which had originally contained 20 g of paracetamol. In the emergency department she was vomiting and complained of some epigastric discomfort. She was taking carbamazepine 600 mg daily for her psychiatric condition. Examination revealed no abnormalities. She was 1.55m (5 feet 2 ins) tall and weighted 50kg (110 pounds). Her plasma paracetamol concentration at 4 hours was 150mg/L (normal treatment concentration at 4 hours is 200mg/L). Questions 1. What other investigations would you ask for? 2. What treatment (if any) 1 would you consider?

Discussion Paracetamol can damage the liver and kidney and her INR, U&Es and LFTs should be measured. In some cases the liver transaminase enzyme concentrations (AST or ALT) may rise (as early as 12 hours) before changes in the INR, and can be a useful early marker of hepatotoxicity. In this woman the y-GT and AST may already be slightly raised because of her carbamazepine therapy (this effect is seen in patients on enzyme-inducing drugs). It might also be useful to check her serum carbamazepine concentration to see whether she might have taken these in overdose. Normally, the potentially toxic dose of paracetamol is 150mg/kg or 10 g, whichever is the smaller. This patient weighs only 50kg, so any dose over 7.5 g should cause concern. In addition, carbamazepine is an enzyme inducer and may increase the risk of toxicity at any given dose. In the UK, individuals receiving enzyme-inducing drugs (carbamazepine, phenobarbitone, phenytoin, primidone, rifampicin or St John's

Tricyclic antidepressants The tricyclic antidepressants act by blocking the uptake of noradrenaline (norepinephrine) by neurons both peripherally and in the CNS. They also have an anticholinergic effect and, in overdose, may have direct actions on the heart. Diagnosis The first signs are usually due to anticholinergic effects. Dryness of the mouth and initial stimulation of the CNS are followed by depressant effects. In severe overdose muscle hypertonia, hyperreflexia and extensor plantar responses are followed by hypotonia and hyporeflexia; generalized convulsions may also occur. Other anticholinergic features are warm dry skin, pupillary dilatation, urinary retention and, in severe cases, paralytic ileus. Depression of respiration may be associated with hypoxia and respiratory and metabolic acidosis. Hypothermia may also occur, and respiratory complications such as aspiration and ARDS (p. 697) can further compromise tissue perfusion.

wort) or at increased risk for other reasons (a regular consumer of alcohol in excess, or badly nourished and thus glutathione depleted) are treated according to the 'high-risk' line, which is half the 'normal' treatment line. The timing of the overdose relative to measurement of plasma paracetamol concentration is crucial in informing such treatment decisions. In this case the parents could confirm when the overdose occurred. However, if there is doubt about the timing of the overdose, consider treating the patient anyway. The treatment of choice in the UK is intravenous N-acetylcysteine for 16 hours. Emptying of the stomach is not indicated after 1 hour. Monitor the INR and U&Es at intervals and when the N-acetylcysteine is discontinued. Subsequent psychiatric assessment is also an important part of the treatment of this patient.

The most life-threatening complication is cardiotoxicity. Tricyclic antidepressants resemble quinidine in their action on the heart, producing a decrease in myocardial contractility, prolongation of the PR interval and widening of the QRS complex. In severe cases the T wave may disappear and the ECG may resemble ventricular tachycardia. Severe ventricular arrhythmias occur in some patients (Fig. 1.10), particularly in the early stages, and the ECG should therefore be monitored preferably even before emptying the stomach.

Management If less than an hour has elapsed, activated charcoal should be given by mouth or nasogastric tube to prevent further absorption of drug in those who have ingested more than 4mg/kg, provided the airway can be protected. A second dose of charcoal (50 g) should be considered after 2 hours in patients with features of toxicity who are able to swallow, and multiple-dose activated charcoal may be useful if a modified-release preparation has been taken. Other methods to enhance elimination of tricyclic antidepressants from the body are of little or no value because

25

FIG. 1.10 Rhythm ECG in tricyclic overdose

of the large volume of distribution, with only a small proportion of the drug therefore in the blood compartment. Convulsions may be related to anoxia and will sometimes respond to adequate oxygenation, although they may require treatment with anticonvulsants such as diazepam. The anticholinesterase agent physostigmine has been used to reverse the CNS effects, but it may precipitate convulsions, ventricular tachyarrhythmias and increased salivary and bronchial secretions. It is therefore rarely used. Arrhythmias and hypotension may respond to correction of acidosis, hypoxia, hypothermia and hypovolaemia. Persistent arrhythmias may respond to bicarbonate, even in the absence of acidosis. Sodium bicarbonate (50 mmol) should be given intravenously to an adult with arrhythmias or significant ECG abnormalities. Further doses may be required depending on clinical response. Antiarrhythmic agents should be used cautiously as they may worsen already impaired myocardial contractility, but positive inotropes (e.g. dobutamine) may be necessary to correct hypotension. Prolonged cardiopulmonary resuscitation has been reported to be successful in patients with tricyclic antidepressant poisoning. 1

Monoamine oxidase inhibitors The monoamine oxidase inhibitors (MAOIs) are much less frequently taken in overdose than tricyclic antidepressants. The onset of symptoms may be delayed for up to 12 hours or more after overdose, so observation for this period at least is necessary in those who have taken a potentially toxic dose. They produce features of increased sympathetic activity, with hyperexcitability and hyperreflexia followed by coma and convulsions. Peripheral muscular effects include myoclonus and rigidity leading to hyperpyrexia and rhabdomyolysis. A sinus tachycardia is often present, but the patient may be either hypertensive or, more rarely, hypotensive. Hyperthermia, or more rarely hypothermia, has been reported. Management The agitation, convulsions and hyperthermia may respond to diazepam, and dantrolene may also be useful in controlling muscle rigidity and hyperthermia. Sympathomimetic agents (e.g. dopamine and dobutamine) should be avoided if possible, as they may lead to a severe hyper-

1MCQ1.16 2MCQ 1.17 26

tensive crisis. Severe hypertension should be treated with an a-blocker such as phentolamine.

Selective serotonin reuptake inhibitors (SSRIs) and other antidepressants These agents appear to be safer in overdose than tricyclic antidepressants and their increasing prescription in depression is reflected in an increased use in self-poisoning. Fluoxetine, fluvoxamine, citalopram, paroxetine and sertraline are the agents available in the UK. There is sometimes a latent period of hours before features occur, and alcohol may potentiate toxicity. Drowsiness, nausea, vomiting (particularly with fluvoxamine), abdominal pain, diarrhoea and sinus tachycardia have been reported. Agitation, tremor, dizziness and sweating are also sometimes seen. Rarely, junctional bradycardia, seizures and hypertension have occurred, and influenza-like symptoms may develop after a day or two. In rare instances a condition known as serotonin syndrome has recently been described. Agitation, myoclonus and sweating, shivering tremor and hyperthermia may occur, followed in some cases by rhabdomyolysis, renal failure, disseminated intravascular coagulation and, rarely, death. This condition is similar to, although normally less severe than, neuroleptic malignant syndrome (NMS), which is sometimes seen after therapeutic doses of some antipsychotic agents. Although both syndromes present with varying degrees of mental status changes and autonomic instability, high fever and muscle rigidity predominate in NMS, whereas gastrointestinal dysfunction and myoclonus are more pronounced in the serotonin syndrome. Venlafaxine potentiates neurotransmitter activity in the central nervous system, probably by inhibiting reuptake of serotonin and noradrenaline (norepinephrine). Although probably less toxic in overdose than tricyclic antidepressants, case reports involving seizures, arrhythmias, the serotonin syndrome (alone or in combination with other drugs), rhabdomyolysis and death have been reported in overdose. Nefazodone inhibits reuptake of serotonin and also selectively blocks serotonin receptors. Nausea, vomiting and drowsiness and, on occasion, convulsions have been reported after overdose. Mirtazapine, a presynaptic a2-antagonist, increases central noradrenergic and serotonergic neurotransmission. It may cause sedation in overdose. Reboxetine is a selective inhibitor of noradrenaline (norepinephrine) reuptake. Overdose may be associated with postural hypotension, anxiety and hypertension.

Management Supportive measures are normally sufficient, although activated charcoal will reduce absorption if given in the first hour. Convulsions should be treated with intravenous diazepam if they are frequent or prolonged. Treatment for all these agents is symptomatic and supportive. Management of the serotonin syndrome is also symptomatic and supportive, although drugs with antiserotonin activity, e.g. cyproheptadine, have been advocated in severe cases.

Lithium carbonate Lithium carbonate is widely used in the prophylaxis of manic depressive psychosis. It has a low therapeutic ratio, and signs of toxicity are most often due to excessive therapeutic doses. Diagnosis Nausea, vomiting and diarrhoea are often the first signs of overdose, followed by more severe signs of toxicity, including dysarthria, ataxia, drowsiness, confusion, coma and convulsions. Renal impairment and nephrogenic diabetes insipidus may occur, and liver damage has also been reported. Cardiotoxicity may be first indicated by ECG findings of non-specific ST segment depression, T-wave inversion, atrioventricular block, and prolongation of the QRS and QT intervals. Symptoms and signs may be delayed, particularly in those who have taken a sustainedrelease preparation, so observation for at least 24 hours, with ECG monitoring and 6-12-hourly plasma lithium measurements, is recommended.

Managemenf Consider gastric lavage for non-sustained release preparations if an adult has ingested more than 4g within 1 hour. Sustained-release preparations (the majority) are unlikely to be able to be removed via a lavage tube, however, and activated charcoal does not adsorb lithium. Rehydration is important, but hypernatraemia (which may indicate nephrogenic diabetes insipidus) may require i.v. dextrose until the serum sodium and osmolality become normal. Hypokalaemia should also be corrected. Toxicity correlates relatively well with the plasma lithium level, although there are differences between those who have taken an acute overdose in the naive state and those on long-term lithium therapy. Haemodialysis should be considered in the former situation in patients with signs of severe toxicity, if the plasma concentration exceeds 7.5 mmol/L, but for those with acute-on-chronic overdose or who have chronic accumulation, plasma concentrations above 4.0 mmol/L in patients with severe toxicity indicate consideration of haemodialysis. Because of the relatively large volume of distribution of lithium, plasma concentrations may increase by up to twofold shortly after the end of the dialysis. Repeated dialyses may therefore be necessary to maintain the serum lithium level at concentrations less likely to cause toxicity. 2

ANALGESICS

1

The dangers of analgesics are not widely appreciated. They are the commonest group of drugs involved in overdose in adults, and in children are associated with serious and sometimes fatal poisoning.

Salicylates Salicylate overdose is responsible for approximately 200 deaths each year in the UK. In addition to being acids themselves, salicylates also increase circulating lactic and pyruvic acid concentrations by interfering with normal carbohydrate metabolism. Stimulation of fat metabolism causes increased production of (3-hydroxybutyric and acetoacetic acids, and increased protein metabolism results in increased circulating amino acids. Impairment of reabsorption of these amino acids, by competition with the salicylate for active tubular reabsorption, produces aminoaciduria and increased fluid loss owing to the effect of this solute load. Fluid loss is worsened by the vomiting associated with salicylate overdose, and by the uncoupling of oxidative phosphorylation, which causes hyperpyrexia and increased sweating. Stimulation of the respiratory centre by salicylates causes a respiratory alkalosis, which partly offsets the metabolic acidosis but causes further bicarbonate depletion, electrolyte loss and dehydration. Diagnosis The clinical features of salicylate overdose are agitation, tinnitus and deafness, increased sweating and hyperventilation; nausea and vomiting and epigastric pain may also be present. Respiratory alkalosis may occur initially but is quickly followed, particularly in children, by a metabolic acidosis associated with increased production of lactate, pyruvate and ketones. There may be hypokalaemia and hypo- or, more rarely, hyperglycaemia. Impaired clotting factor and platelet function are sometimes seen, but bleeding is rare. Confusion and coma may occur before death. Patients older than 70 years or younger than 10 are at the greatest risk from salicylate poisoning, and CNS features, the presence of acidosis, hyperpyrexia, pulmonary oedema and salicylate levels greater than 700mg/L, as well as late presentation, are associated with increased mortality. Management Activated charcoal should be administered at the appropriate dose (50 g for an adult, 10-15 g for a child) in adults or children who have ingested more than 250mg/kg body weight of aspirin within the previous hour. Arterial blood gas measurement (in children, capillary gases or venous blood gases would be a suitable alternative) should be performed, and correction of any acid-base abnormalities and rehydration should be sufficient in mild or moderate cases of salicylate poisoning. Urea and electrolytes, international normalized ratio (INR) and blood glucose and plasma salicylate concentration should be measured, and once

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SUMMARY 9 Salicylate poisoning • Salicylate poisoning is very serious because of the derangement of acid-base and electrolyte balance (metabolic acidosis, respiratory alkalosis and dehydration) • Coma is rare except as a terminal event, and agitation and restlessness, tinnitus, deafness and hyperventilation are characteristic • The very old and young, those with metabolic acidosis, hyperpyrexia, pulmonary oedema, coma or high salicylate concentrations, and those who present late are at greatest risk of a fatal outcome. • Correction of acid-base abnormalities and dehydration is usually sufficient in mild to moderate poisoning, but haemodialysis may be necessary in severe poisoning

the serum potassium concentration is within the normal range, sodium bicarbonate may be given intravenously to enhance the urinary salicylate excretion (optimum urine pH 7.5-8.5). This entails giving 225 mL 8.4% sodium bicarbonate over 2 hours (or 1.5 L of 1.26%) if the salicylate level is greater than 500mg/L in an adult, or 1 mL/kg 8.4% bicarbonate diluted in 0.5% dextrose or saline at 23 mL/kg/h if the plasma salicylate concentration is greater than 350mg/L in a child. Potassium supplements may be necessary to achieve adequate urinary alkalinization, but if this cannot be attained without increasing the blood pH to greater than 7.5, haemodialysis is treatment of choice. It is indicated for severely poisoned patients (generally with salicylate concentrations greater than 700mg/L, although the threshold may be lower in children under 10 years or the elderly, or those with severe acidosis or impaired renal function). Pulmonary oedema may occur as a result of fluid overload or as a direct effect of the drug on capillary permeability. In the former case the pulmonary artery pressure will be raised, but not in the latter. Ventilation with positive end-expiratory pressure may be helpful. 12

Other non-steroidal anti-inflammatory drugs Salicylates form one group of non-steroidal antiinflammatory drugs (NSAIDs) but there are five other groups that can be classified according to chemical structure. These are: • The arylalkanoic acids, which include phenyl propionic acid derivatives such as ibuprofen, naphthyl propionic acid derivatives such as naproxen, and phenyl acetic acid derivatives such as fenclofenac; • The anthranilic acids, which include the fenamates (mefenamic acid and flufenamic acid);

O Case 1.3 O MCQ1.18

28

QMCQ1.19

• The pyrazalone group of compounds, e.g. azapropazone and phenylbutazone; • The cyclic acetic acids, which include indomethacin, sulindac and tolmetin; • The oxicams, at present represented by piroxicam. Diagnosis The arylalkanoic acids, like all NSAIDs, cause headache, nausea and epigastric discomfort, but coma is rare. Gastrointestinal bleeding may occur and, rarely, bronchospasm. Poisoning with anthranilic acids (e.g. mefenamic acid) is more serious and severe haemorrhagic enterocolitis may occur. CNS effects are also commoner and may include convulsions. Overdose with pyrazolones can produce gastrointestinal and CNS toxicity and hepatic and renal damage. The cyclic acetic acids also produce coma, and piroxicam has been associated with coma and convulsions. Management The stomach should be emptied if appropriate. Early administration of charcoal will reduce the absorption of some of the anthranilic and cyclic acetic acids, and may also be of benefit in poisoning with other groups of NSAIDs. Although there is no definite evidence that histamine2-receptor antagonists (e.g. ranitidine) protect against gastrointestinal haemorrhage, they are often administered prophylactically. Convulsions are generally short-lived but can be treated with diazepam. Blood pressure should be measured regularly and hypotension corrected to prevent subsequent acute renal failure.

Paracetamol Paracetamol is a remarkably safe drug in therapeutic doses but in overdose may cause fatal hepatic necrosis and is responsible for approximately 200 deaths per year in the UK. The toxicity of paracetamol in overdose is related to the metabolism of the drug. Approximately 90 % of the drug is conjugated with glucuronide or sulphate in the liver and gut, with only 10% oxidized by the mixed-function oxidase system to a highly reactive intermediate compound (7V-acetylaminobezoneinonimine, or NABQI), which is normally conjugated with glutathione and subsequently excreted as a mercapturate conjugate. In overdose, more NABQI may be produced than can be detoxified, as glutathione stores in the liver become exhausted, and NABQI instead binds to macromolecules in the liver (and sometimes renal tubular) cells, causing necrosis. Patients on enzyme-inducing drugs (see Table 1.5) may produce more NABQI at any given dose of paracetamol and develop liver damage at lower plasma concentrations of paracetamol, and so they are termed 'high risk' and are given antidotal treatment at half the plasma concentrations recommended for patients in general. Other high-risk patients include those with glutathione depletion (e.g. malnourished individuals, including those with HIV, those with pre-existing liver disease and those who consume excess alcohol).

Diagnosis The clinical features are initially mild and consist of nausea, vomiting and epigastric pain. Metabolic acidosis, hypoglycaemia, hypotension and cardiac arrhythmias have been described, particularly with massive overdoses. Incipient liver damage may first be detected by measuring hepatic transaminase enzymes or the one-stage prothrombin time (INR), which may be abnormal even as early as 6-12 hours after the overdose. Liver damage may occur with as little as 12 g of paracetamol and may present clinically with right subcostal pain and tenderness, recurrence of nausea, vomiting, and then jaundice. Loin pain, haematuria and proteinuria after the first 24 hours strongly suggest incipient renal failure. Acute renal failure has also been reported, usually (but not always) in association with severe liver damage. Renal function and electrolytes should be measured daily. A/lanagemenf Activated charcoal should be considered if more than 150mg/kg or 12 g (whichever is the smaller) in total has been taken within 1 hour. The plasma paracetamol concentration should also be checked after 4 hours (earlier concentrations are uninterpretable) and, if it is greater than that on the treatment line (shown in Fig. 1.11), an antidote should be administered. Antidotal therapy should also be used without waiting for the plasma paracetamol concentration if the overdose has been taken at least 8 hours previously, as the efficacy of the antidotes declines markedly with time.

Summary 10 Acetylcysteine and methionine administration

1

Acetylcysteine Dose: by intravenous infusion, in 5% glucose, initially 150mg/kg in 200 ml over 15 minutes followed by 50mg/kg in 500ml over 4 hours, then 100mg/kg in 1000mL over 16 hours. Methionine Dose: by mouth 2.5g initially, followed by three further doses of 2.5g every 4 hours.

Acetylcysteine (see Summary 10) is a glutathione precursor that is usually given intravenously in the UK because, given orally, it can exacerbate vomiting. Acetylcysteine appears to have some efficacy up to 24 hours or even longer after a large overdose. Oral methionine is also used, but is probably ineffective 8 hours or more after an overdose, and the vomiting associated with paracetamol ingestion makes it difficult to retain in the stomach. Anaphylactoid reactions have been reported in around 8% of individuals after the use of acetylcysteine, often during the initial fast infusion. The reaction is probably due to histamine release, and consists of urticaria and bronchospasm, nausea, vomiting, flushing, angioedema, tachycardia, hypotension, respiratory depression and collapse, and in severe cases renal failure and disseminated intravascular coagulation. Death has occurred in patients who have been inadvertently given an overdose (tenfold greater) of acetylcysteine, so the dose of this antidote should be checked carefully. The infusion should be stopped temporarily and an antihistamine given if necessary, with corticosteroids in addition if the reaction is severe. Nebulized salbutamol may be effective in reversing bronchospasm. Once the reaction has settled, acetylcysteine can be infused at a rate of 50mg/kg over 4 hours; further reactions are extremely rare. Blood sugar should be measured and any abnormality treated. The INR should be measured daily. An INR of 4 or more at 48 hours or >6 at 72 hours indicates the likelihood of severe liver failure, in which case the patient should be commenced on a low-protein diet and oral lactulose to help to remove nitrogenous compounds from the gut. A specialist liver unit should be contacted for advice and consideration of possible transfer for management of liver failure. Management of liver failure also includes prophylaxis against infection and peptic ulceration, and management of coagulation abnormalities. Liver transplantation has been successfully performed in some cases, but has a limited role, and patients should be identified and transferred as soon as possible. Factors associated with poor outcome are metabolic acidosis, hypoprothrombinaemia, renal failure and grade 3-4 encephalopathy. Even if acute hepatic failure does occur, the mortality is less than 50% with good supportive management (p. 854). 0

Opioids FIG. 1.11 Plasma paracetamol concentrations above which antidotal treatment is required

Opioids are used not only as narcotic analgesics but also as constituents of some cough suppressants, antidiarrhoeal

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Summary 11 Management of opiate poisoning • Opiate poisoning is a common, serious medical emergency • Naloxone reverses the effects of all opiates (except buprenorphine if given in sufficient dose, since it is a competitive antagonist) • The short half-life of naloxone necessitates repeated doses or even constant infusion in treatment of opiates with long half-lives of elimination (e.g. dihydrocodeine and methadone) • The association between intravenous opiate abuse and infection (hepatitis B and HIV should be recognized and appropriate safeguards taken)

products (e.g. diphenoxylate) and veterinary tranquillizers. The one most often involved in poisoning is dextropropoxyphene, which is combined with paracetamol in compound preparation. Opioids are being increasingly misused in society for their effects on mood, being administered intravenously as well as orally. Diagnosis Respiratory depression is the commonest cause of death in opioid overdose. The pupils are often pinpoint. Depression of the CNS eventually leads to coma and convulsions. The muscles may be hypotonic, but muscular twitching and hyperreflexia have been described. Hypotension is common, but hypertension has been described after pentazocine overdose. Non-cardiogenic pulmonary oedema may occur, particularly in methadone overdose. Management If the opiate has been taken orally activated charcoal may be of value in the first hour, or longer if the preparation is sustained release. Naloxone is a competitive antagonist that is effective in reversing the symptoms of opiate overdose with all compounds except buprenorphine (a partial agonist and not completely antagonized). It is best given intravenously (0.8-1.2 mg for an adult, and 0.01 mg/kg body weight for children), and the dose repeated if there is no response within 2 minutes. Those who have taken very large overdoses, particularly of a long-acting agent such as dihydrocodeine or methadone, may need further doses to competitively antagonize the opioid activity, and continuous intravenous infusion of naloxone, together with intensive monitoring, may be necessary. Assisted ventilation with positive end-expiratory pressure may be required if pulmonary oedema occurs. In buprenorphine poisoning naloxone may have only limited benefit and, if doxapram fails to stimulate respiration sufficiently, assisted ventilation may be necessary. Naloxone may precipitate acute opioid withdrawal, with abdominal pain, diarrhoea and piloerection, but the dan-

1MCQ1.20 2MCQ1.21 30

gers of opioid overdose are greater and life-saving treatment should not be withheld.

RECREATIONAL DRUGS In addition to opioids such as diamorphine (heroin), other drugs are being increasingly widely abused in society and may be dangerous in overdose. Amphetamines are sympathomimetic drugs of abuse. Street amphetamine usually contains up to 5% amphetamine along with inert fillers or other stimulants, but purity varies widely. Initial CNS stimulation (agitation and dilated pupils) may be followed by marked hypertonia and hyperreflexia (>39°C) and generalized convulsions. Hyperpyrexia and rhabdomyolysis may also occur. Sinus tachycardia is usual but supraventricular and ventricular arrhythmias, including ventricular tachycardia, may subsequently occur. Hypertension may be a feature and hypokalaemia may sometimes be profound. The stomach should be emptied within 1 hour and activated charcoal given. Sedation with diazepam may be necessary. Sinus tachycardia with adequate cardiac output is best left untreated, but (3-blockers may be needed. cc-Blockers or labetalol are used to manage hypertension. Diazepam is normally effective in managing convulsions, but if they are more frequent, or if vomiting is also a problem, it may be preferable to paralyse and ventilate the patient. Ventricular arrhythmias occurring in a patient who is having convulsions may respond to disopyramide. Ecstasy (3,4-methylenedioxymethamphetamine, or MDMA) is an amphetamine-like compound with a similar spectrum of toxicity. However, there is marked inter- and intraindividual variability in susceptibility, and deaths have occurred after only a single tablet in those who have previously tolerated similar or greater doses. Signs of severe toxicity include delirium, coma, convulsions, and supraventricular and ventricular arrhythmias. Hypertonia and hyperpyrexia may result in rhabdomyolysis, metabolic acidosis and acute renal failure. Hyponatraemia, disseminated intravascular coagulation, hepatocellular necrosis, adult respiratory distress syndrome and cardiovascular collapse have also been described. Death may occur from intracerebral haemorrhage. Treatment is largely symptomatic and supportive, with correction of metabolic acidosis and dantrolene (or paralysis and ventilation) for the hyperpyrexia. 1 Cocaine may be taken by the oral or intravenous route, or by inhalation. Toxicity is characterized by agitation, tachycardia, tachypnoea, sweating, delirium and hallucinations. Hypertension, hyperpyrexia, generalized convulsions, stroke, cardiac ischaemia, myocardial infarction and arrhythmias, metabolic acidosis, rhabdomyolysis and cardiorespiratory arrest may also occur. Treatment is symptomatic and supportive. Hypertension may best respond to a-blockers or combined a- and p-blockade (e.g. with labetalol). The risk of severe toxicity is particularly high

in 'body stuffers' who, on the verge of arrest, swallow the evidence, rather than in 'body packers', who are hired specifically to smuggle drugs and who have time to wrap them carefully (e.g. in a condom). Lysergic acid diethylamide (LSD) in overdose may cause acute panic attacks, delirium, hallucinations, seizures and coma, respiratory arrest and metabolic acidosis. Treatment is symptomatic and supportive, although features of psychosis may last for several days. Panic often responds to diazepam. Phenothiazines are best avoided in treating the psychosis, as they may reduce seizure threshold. y-Hydroxybutyric acid (GHB),or liquid ecstasy, is a 'psychedelic' agent that has recently become popular. It can cause coma, sinus bradycardia and hypotension in overdose, as well as respiratory depression leading to respiratory arrest. Treatment is symptomatic. The bradycardia may respond to atropine (1.2mg intravenously for an adult, 0.02mg/kg for a child). 2

ANTICONVULSANTS The incidence of psychiatric abnormalities is higher in epileptics than in the non-epileptic population. The availability of anticonvulsants to some epileptic patients results in their being taken relatively frequently in overdose. Barbiturates and primidone, which are converted into phenobarbitone and phenylethylmalonamide in the body, are described on page 23.

Phenytoin Phenytoin is one of the most widely prescribed anticonvulsants. Acute overdosage leads to ataxia, dysarthria, horizontal nystagmus, drowsiness and, in severe cases, coma. Respiratory depression is a rare but potentially serious complication, which is generally only seen after massive overdose. The stomach should be emptied within 1-2 hours of ingestion and activated charcoal will help to prevent further absorption. Because phenytoin is highly protein bound, only charcoal haemoperfusion will effectively remove the drug from the circulation. This should, however, be reserved for patients with severe overdose. Rarely, cases of permanent cerebellar damage with persistent ataxia after phenytoin overdose have been described.

Carbamazepine Carbamazepine is widely used for the treatment of generalized and partial seizures. The drug is structurally similar to tricyclic antidepressants and overdose can be associated with anticholinergic effects, including dry mouth, hyperreflexia and generalized convulsions. Nystagmus, strabismus, diplopia, ataxia, hypotension and respiratory depression have been noted, and cardiac conduction disturbances may also occur. The stomach should be emptied if appropriate, and activated charcoal administered. Repeated doses of charcoal speed the elimination of drug in

normal volunteers and may be effective in severe overdose. Effective removal of the drug by haemoperfusion has also been reported.

1

Sodium valproate Sodium valproate poisoning is associated with coma and respiratory depression. The drug is rapidly absorbed, and supportive measures form the mainstay of treatment.

CARDIOVASCULAR DRUGS Anti hy per ten si ves The major adverse effect is hypotension. With clonidine, hypotension is often associated with bradycardia, but severe hypertension caused by the drug's partial a-agonist activity is sometimes a major problem. Bradycardia often responds to atropine, and a-adrenergic blocking drugs have been used to treat the hypertension. (3-Receptor blocking agents also cause bradycardia and hypotension, and may also cause drowsiness, coma and convulsions in overdose. In hypotension atropine is used to increase cardiac output, but large doses are often required (3mg intravenously in an adult and 0.04mg/kg for a child). Glucagon is used if atropine is ineffective. An intravenous bolus of 50-150mg/kg body weight dissolved in dextrose may be effective but may need to be followed by the same dose or an intravenous infusion of 4mg/h until the patient's condition is satisfactory. Glucagon may induce vomiting and the airway needs to be protected. Pi -Agonists such as prenalterol are also effective, although large amounts may have to be given intravenously to competitively antagonize the (3-blockade. pY Agonists (e.g. salbutamol) may be necessary if bronchospasm is present, and the blood sugar should be monitored to detect and treat hypoglycaemia. Convulsions normally respond to intravenous diazepam (0.1-0.3mg/kg body weight). Calcium antagonists (especially verapamil) may also cause severe hypotension and bradycardia and conduction abnormalities and, in severe cases, asystole. If atropine is ineffective in treating the bradycardia, calcium gluconate (10-20 mL of a 10% solution in an adult) may be required. Pacing may be necessary to treat the bradyarrhythmias, and dopamine and glucagon (and, in resistant cases, insulin and dextrose) have been used to give inotropic support.

Digitalis glycosides Poisoning with the digitalis glycosides is rare but potentially very serious. Nausea, vomiting and diarrhoea are early features, but the major life-threatening complications are hypotension and cardiac conduction disturbances, with brady- and tachyarrhythmias. Hyperkalaemia is often present and mirrors roughly the severity of the overdose. This should be treated with glucose and insulin, or a sodium resonium ion exchange resin, or by haemodialysis

31

SUMMARY 12 Digitalis glycoside poisoning • Cardiac glycosides may cause nausea, vomiting, diarrhoea and generalized malaise • Cardiac effects include bradycardia with PR and QRS prolongation. Sinus arrest and varying degrees of AV block may also occur • Hyperkalaemia and metabolic acidosis may occur in severe cases • Multiple doses of charcoal enhance elimination by interrupting enterohepatic recirculation • Prophylactic pacing should be considered if hyperkalaemia or heart block occur • Severe intoxication is often effectively treated with digoxin antibodies, the dose depending on the amount taken and the serum glycoside concentration

if necessary. Metabolic acidosis may also occur. Both digoxin and digitoxin have enterohepatic recirculation processes and repeated doses of activated charcoal (see p. 24 for dosage) will speed elimination. Continuous monitoring of cardiac rhythm is essential: bradycardia sometimes responds to intravenous atropine (1.2mg for an adult or 0.02mg/kg for a child), repeated as necessary until atropinization occurs. More severe bradyarrhythmias may require temporary cardiac pacing, particularly if heart block or hyperkalaemia are present. Ventricular tachyarrhythmias often respond to lignocaine, but phenytoin and intravenous (3-blockers have both been used in resistant cases. Digoxin-specific Fab antibody fragments may be necessary in the treatment of severe digoxin and digitoxin poisoning. The dose of antibody (Digibind) is about 60 times the estimated body load of digoxin or digitoxin (the amount of drug in milligrams ingested multiplied by 0.8) rounded up to the nearest 40 mg. This can be calculated from the amount taken, or the plasma concentration of the drug.

RESPIRATORY DRUGS Theophylline Theophylline is the respiratory drug most often taken in overdose. Nausea, persistent vomiting and epigastric pain may be followed by agitation, hallucinations and convulsions. Hypertonia may be associated with rhabdomyolysis. Supraventricular and ventricular arrhythmias with hypokalaemia (often profound) may follow a sinus tachycardia. Signs may be delayed for up to 12-24 hours in those who have taken a sustained-release preparation. The stomach should be emptied to prevent further absorption and charcoal (50 g) left in the stomach. The metabolic abnormalities should be treated appropriately, 1MCQ1.22 2MCQ1.23 32

but convulsions and hypertonia may respond to diazepam administered intravenously. Supraventricular and ventricular arrhythmias may respond to the use of adrenoceptor blockers (e.g. metoprolol),but the metabolic abnormalities may only respond to agents that also possess ( 2-antagonist activity (e.g. propranolol). However, (3blockers should not be used in asthmatic patients because of the risk of precipitating bronchospasm. Disopyramide or verapamil have been used successfully to treat arrhythmias in such patients. Repeated oral administration of charcoal has recently been shown to reduce markedly the half-life of elimination of theophylline. Persistent vomiting may mean that an antiemetic such ondansetron (8 mg slowly intravenously in an adult) will be necessary to allow the charcoal to be retained. Haemoperfusion is an efficient way of enhancing the removal of theophylline from the circulation. It should be considered in severely poisoned patients, particularly those with major arrhythmias, hypotension or convulsions, and if repeated-dose charcoal is not feasible. 1

Ephedrine, salbutamol and terbutaline Ephedrine, salbutamol and terbutaline are generally safer than theophylline in overdose, but can cause all the same features in severe cases. Treatment is broadly similar to that of theophylline overdose: again, -blockers must be avoided in asthmatic subjects.

DRUGS WITH ANTICHOLINERGIC ACTIVITY In addition to tricyclic antidepressants many drugs have anticholinergic activity, including some used to suppress gastrointestinal motility (e.g. propantheline), some antiparkinsonian drugs (e.g. amantidine and orphenadrine) and some antihistamines (e.g. chlorphenamine (chlorpheniramine) and promethazine). The effects of these drugs are similar to those caused by overdosage with tricyclic antidepressants, but they are less likely to cause arrhythmias. The anticholinesterase physostigmine is no longer recommended in anticholinergic poisoning because of severe adverse effects. Treatment is supportive and symptomatic.

ANTIDIABETIC DRUGS Poisoning with antidiabetic drugs and insulin produce all the features of hypoglycaemia. The management is described in Chapter 19, page 1020. Sulphonylureas (particularly those with long half-lives of elimination (e.g. chlorpropamide) are of particular concern, as hypoglycaemia may be a problem for several days and they are sometimes resistant to glucose and glucagon. Severe hypoglycaemia has therefore been treated with diazoxide, which

inhibits insulin release and raises circulating plasma catecholamines. At the dose used (5 mg/kg body weight/24 h by mouth in two or three divided doses), it rarely produces hypotension. Diazoxide may be the treatment of choice if there is a risk of hypoglycaemia over several days. Metabolic acidosis may occur after sulphonylurea poisoning, but is more common after poisoning with the biguanide metformin. ©

atrophy. Most patients recover some vision, although some are left with permanent visual field defects. The management of quinine poisoning is supportive. Stellate ganglion block has been advocated in the past but has no proven benefit. As quinine has a large volume of distribution and is predominantly metabolized by the liver, methods to enhance elimination are of limited value, but repeated dose of oral charcoal may be beneficial.

1

Chloroquine ANTIBIOTICS The penicillins and cephalosporins are generally safe in overdose. Sulphonamides may cause bone marrow depression and renal damage (and haemolysis in glucose 6-phosphate dehydrogenase-deficient patients). Maintenance of a high urine output and alkalinization of the urine may prevent sulphonamide-induced renal damage, by preventing crystallization of the drug in the renal tubule. Calcium folinate may help to reverse bone marrow depression induced by sulphonamide or trimethoprim. Isoniazid can cause CNS symptoms with coma and convulsions. Pyridoxine can be used to treat or prevent both convulsions and the metabolic abnormalities: it should be given in a dose of 1 g for every gram of isoniazid ingested. Rifampicin overdose may be associated with orange discoloration of the skin (although this colour can be removed by washing). Treatment is usually supportive. Although most patients recover completely, occasional sudden deaths have been reported, presumably from cardiac arrhythmias. The antileprotic drug dapsone (also used in the treatment of dermatitis herpetiformis) is dangerous in overdose, causing methaemoglobinaemia and sometimes convulsions and coma.

ANTIMALARIALS Quinine Quinine, which is also used to treat night cramps, is the antimalarial agent most often taken in overdose and also the one most likely to cause serious toxicity. Children may take tablets belonging to a family member. Early symptoms of overdose are similar to those of aspirin, with nausea, vomiting, bowel disturbances, tinnitus and deafness. Initial respiratory stimulation may be followed by respiratory depression and respiratory arrest. Quinine can cause brady- and tachyarrhythmias, with death from ventricular fibrillation. Its effect on vision is dramatic. Visual acuity is initially impaired, and this may progress to constriction of visual fields or even complete blindness. Retinal examination reveals constriction of the arterioles initially, followed by retinal oedema and sometimes optic

Chloroquine is widely used as prophylaxis against malaria and can be purchased without prescription. Its toxicity is similar to that of quinine, and visual disturbances are also sometimes seen. As little as 5g may be fatal. Ventricular arrhythmias often occur early (within the first 3 hours) and include intraventricular conduction defects with a wide QRS, and prolongation of the QT interval. Ventricular tachycardia and fibrillation are early arrhythmias, and torsade-de-pointes sometimes occurs later. Very large doses of diazepam (2 mg/kg body weight intravenously over 30 minutes) may reduce mortality, but should be considered only when facilities for assisted respiration are available. Chloroquine is also predominantly metabolized by the liver and has a high volume of distribution; thus, none of the techniques for enhancing removal appears to be effective.

ANTICOAGULANTS The major risk of oral anticoagulant poisoning is haemorrhage: this occurs several days after the overdose because of the delayed effect of these agents. In cases of large overdose, and where the INR is raised at 36-48 hours, vitamin K (10 mg twice daily by slow intravenous injection, 250 g/kg body weight for a child) should be administered and may be necessary for up to a week. Repeated oral administration of colestyramine (cholestyramine) (4 g three times daily) may enhance the removal of warfarin and phenprocoumon, and also reduce the length of time for which vitamin K is required. Rodenticides contain only small amounts of oral anticoagulant and rarely cause toxicity.

POISONING WITH GASES AND VOLATILE SOLVENTS CARBON MONOXIDE Carbon monoxide is still the most common cause of fatal gas poisoning in the UK, despite the substitution of natural gas for coal gas in general use. Deaths occur either accidentally (often by inhalation of fumes during fires) or deliberately, from inhalation of car exhaust fumes in a confined space. Methylene chloride, which is widely used in

33

paint removers, is metabolized by the body to carbon monoxide and causes symptoms identical to those of direct carbon monoxide exposure. Diagnosis The early symptoms of chronic or acute exposure are headache, mental agitation, nausea and vomiting. The characteristic cherry-pink colour of the skin is rarely present during life, but the patient is not cyanosed, despite considerable hypoxia because of the production of carboxyhaemoglobin. Cerebral oedema and myocardial ischaemia or infarction may also occur. Management Oxygen should be given in as high a concentration as possible. There is no clear evidence that hyperbaric oxygen affects outcome, and its use should be discussed with the regional poisons unit. Patients who have been unconscious after exposure, who have a carboxyhaemoglobin concentration over 20% or who have neurological or psychiatric features, are most likely to obtain any possible benefit. Hyperbaric oxygen is not always immediately available, and transfer to such a facility should not interrupt the treatment of severely poisoned patients. Oxygen should be administered until the carboxyhaemoglobin concentration in blood falls below 15%: this may take up to 2 days. Mannitol, Ig/kg intravenously over 20 minutes, may be considered if there is evidence of cerebral oedema. Most patients who die of carbon monoxide poisoning do so before they reach hospital; those who do arrive in hospital usually survive. Unfortunately, permanent neuropsychiatric sequelae may be seen, including intellectual and personality deterioration, parkinsonism and, in rare cases, akinetic mutism. These severely affected patients often show areas of low density in the area of the globus pallidus on CT brain scans. 1

IRRITANT VAPOURS AND GASES

Carbon disulphide, hydrogen sulphide, sulphur dioxide, hydrochloric acid and ammonia are all highly irritant to the eyes and respiratory tract. Cough and chest pain may be followed by dyspnoea, bronchospasm, haemoptysis and pulmonary oedema. Management

Treatment is supportive, with bronchodilators for bronchospasm, oxygen for hypoxia and, in severe cases, assisted ventilation (with PEEP if pulmonary oedema is present). Steroids, diuretics and antibiotics have been used, but because the complications are direct effects of the gas, they

SUMMARY 13 Cyanide poisoning • Cyanide is absorbed through the skin, by inhalation or oral absorption • The clinical features are those related to severe hypoxia and metabolic acidosis • Oxygen in high dose should be given and the metabolic acidosis corrected • Dicobalt edetate is the antidote of choice if the diagnosis is certain • Sodium thiosulphate, together with sodium nitrite, is also an effective antidote

are unlikely to be of benefit. The metabolic acidosis may improve with adequate oxygenation, but if this fails sodium bicarbonate may have to be administered. Ophthalmologic advice should be sought to diagnose and treat corneal abrasions.

CYANIDE Cyanide may be inhaled in the form of hydrogen cyanide, sometimes in fumes caused by burning plastic. Symptoms appear within a few minutes, first with headache, agitation, confusion leading to coma, cardiovascular collapse and respiratory arrest. Cyanide may also be taken orally, in which case symptoms may occur much later, particularly if food in the stomach delays gastric emptying. Management Oxygen in high concentrations should be administered and assisted ventilation performed if necessary. Dicobalt edetate is the most effective antidote, but it may cause hypotension and chest pain on intravenous administration (300 mg intravenously over 1 minute), and should therefore only be used if the diagnosis is certain. It acts by forming inert complexes with cyanide, thereby preventing the cyanide-induced inhibition of cellular oxidizing enzymes. Sodium thiosulphate (25 mL of 50% solution intravenously over 10 minutes for an adult; 400mg/kg for a child) acts as a sulphur donor to allow conversion of cyanide to thiocyanate via the enzyme rhodanase. Subsequent administration of sodium nitrite (10 mL of 3% solution intravenously over 5-20 minutes for an adult; 0.13-0.33mL/kg of 3% solution for a child) converts haemoglobin to methaemoglobin, which chelates the cyanide ion. The two treatments act synergistically. They are generally used if there is doubt about the diagnosis, there is no response to dicobalt edetate, or if the latter is not immediately available.

HYDROCARBONS 1

34

MCQ1.24

Poisoning with hydrocarbons is nearly always accidental, generally from industrial or domestic exposure, but also increasingly from solvent abuse.

Aliphatic hydrocarbons The aliphatic hydrocarbons appear to be less toxic than the aromatic group. The shorter-chain aliphatic hydrocarbons are volatile, so that poisoning is usually from inhalation. High concentrations may cause asphyxia, and the butane in lighter fluid has been used to produce euphoria by solvent abusers. Coma may occur, with death from respiratory depression or ventricular fibrillation. Renal and liver damage may develop if the patient survives. Pulmonary and cerebral oedema have also been reported. Inhaled hydrocarbons may also produce myopathies, neuropathies and permanent neuropsychiatric damage, although some of these effects may be related to additives to the hydrocarbon. Ingestion of liquid aliphatic hydrocarbons can produce effects similar to the above, due either to a systemic effect or, more likely, to aspiration of the low surface tension solvents. Pyrexia, cough and hyperpnoea may be followed by basal crackles in the chest, consolidation, and collapse involving predominantly the middle and lower zones of the lung. Treatment of solvent inhalation or ingestion is generally supportive. Gastric lavage or emesis should not be performed after ingestion because of the risk of chemical pneumonitis. There is no evidence that steroids and antibiotics are effective in the pulmonary complications, but in severe cases ventilatory support may enable the patient to recover.

Chlorinated aliphatic hydrocarbons Chlorinated aliphatic hydrocarbons are widely used as solvents in industry. In addition to the effects described with other hydrocarbons, the chlorinated aliphatics are also more likely to produce hepatic and renal damage (particularly carbon tetrachloride and chloroform), haemolytic anaemia and aplastic anaemia. Methylene chloride is metabolized by the body to carbon monoxide and its systemic toxicity is that of this metabolite, although it is itself locally corrosive. It has been suggested that acetylcysteine may inhibit the metabolism of chlorinated hydrocarbons to reactive intermediate metabolites and thereby reduce hepatotoxicity if given early.

Aromatic hydrocarbons Aromatic hydrocarbons are less often involved in poisoning. Benzene is the most toxic of these agents and, in acute overdose, produces effects similar to those of the aliphatic hydrocarbons. Chronic exposure may lead to aplastic anaemia and leukaemias. Toluene and xylene are similar in structure and effects to, but less toxic than, benzene: any marrow toxicity is probably related to benzene contamination. Benzene contamination is probably also responsible for the haematological problems sometimes seen with chronic petrol inhalation.

1

FIG. 1.12 Blood concentrations after oral administration of ethyl alcohol (2 ml/kg) The concentration declines in a zero-order fashion at an average rate of 190mg/L each hour.

OVERDOSE WITH ALCOHOLS ETHANOL (ETHYL ALCOHOL) (See also ch. 24 p. 1435) Ethanol, present in alcoholic drinks, is the alcohol most often taken in overdose. It is also found as a solvent in some cosmetic and antiseptic preparations. Its major toxicity is related to its central nervous depressant effects. The loss of the gag reflex max result in aspiration of stomach contents. Alcohols inhibit gluconeogenesis and may cause profound hypoglycaemia, particularly in children. Blood ethanol concentrations give a rough guide to the severity of overdose, but may be misleading because of tolerance in chronic alcohol users. Severe intoxication with stupor and marked incoordination is generally associated with blood concentrations above 3000 mg/L. The rate of metabolism is shown in Figure 1.12. Management Because alcohol is rapidly absorbed, lavage is unlikely to be of benefit and the compound is poorly adsorbed by activated charcoal. Metabolism is saturated even at low doses. The treatment is usually symptomatic and supportive, with correction of hypotension and hypoglycaemia. Protection of the airway is paramount. Although haemodialysis will remove alcohol efficiently, it is only indicated in severe and complicated cases of poisoning. Fructose accelerates the metabolism of alcohol, but it can potentiate the metabolic acidosis already caused by the alcohol and should not be used. Intravenous dextrose may be necessary to treat hypoglycaemia. The problems of alcoholism are discussed on page 247.

METHANOL Methanol is much more toxic than ethanol and is widely used as a solvent. Methylated spirit is 5% methyl alcohol

35

and 95% ethanol. The mode of toxicity is not clear, but accumulation of formaldehyde and formic acid is partly responsible. As little as 10 mL of methanol may cause serious illness. The initial features are those of mild inebriation, but 8 or more hours later the patient may develop abdominal pain and vomiting, dilated and unreactive pupils, a metabolic acidosis and, sometimes, signs of cerebral oedema. The optic disc is at first hyperaemic and then becomes oedematous; vision is progressively lost. Management The stomach should be emptied within the first hour of methanol ingestion; activated charcoal does not adsorb significant quantities. Intravenous sodium bicarbonate should be used to keep the arterial pH above 7.2, but metabolic acidosis may be resistant to treatment. Diazepam is indicated if convulsions are a problem. Ethanol competitively inhibits the metabolism of methanol to formaldehyde and formic acid, and is used in less serious poisoning. Haemodialysis may be necessary if the blood methanol concentration exceeds 500 mg/L, or if there is clinical deterioration despite other measures. Haemodialysis also removes ethanol, so that ethanol administration during this procedure has to be increased. Visual impairment is often permanent, although prompt treatment reduces its severity.

ISOPROPANOL (ISOPROPYL ALCOHOL)

Isopropanol is found in rubbing agents, sterilizing fluids and disinfectants, window cleaning fluids and some aftershave lotions. Features of poisoning resemble those of ethyl alcohol poisoning, but because some of it is metabolized to acetone, ketonuria and a characteristic smell of acetone on the breath may be observed. Management

The stomach should be emptied within an hour of ingestion, but treatment is otherwise symptomatic. Haemodialysis will remove isopropyl alcohol but is normally only indicated in severe poisoning.

overdose, but ophthalmoplegias, papilloedema and subsequent optic atrophy may also occur and the patient may become comatose and develop convulsions. After 12 hours respiratory and cardiovascular complications are seen, together with a metabolic acidosis, hypocalcaemia and hyperkalaemia. If the patient survives this phase, he or she may develop acute renal failure after approximately 24 hours. Ethylene glycol is not itself toxic but is metabolized by alcohol dehydrogenase to aldehydes, glycolates, oxalates and lactate, which are responsible for the toxic features. Management The stomach should be emptied within the first hour and arterial blood gases and serum calcium measured. Activated charcoal does not adsorb ethylene glycol. Any metabolic acidosis may respond to intravenous bicarbonate, and calcium gluconate may be necessary to treat hypocalcaemia. Ethylene glycol metabolism can be inhibited by administration of alcohol in doses sufficient to attain blood ethanol concentrations between 1000 and 2000 mg/L. In severe cases (ethylene glycol concentration >500mg/L, or clinical condition deteriorating despite other measures) haemodialysis is necessary to remove ethylene glycol metabolites. Ethanol administration may also be necessary for up to 4 days after the overdose to reduce their production. Dialysis may be required for renal failure. Fomepizole has recently been licensed for the treatment of ethylene glycol poisoning. 1 POISONING WITH CORROSIVE AGENTS

Fortunately, poisoning with corrosive agents is rare, and most incidents are accidental rather than deliberate. The majority of agents produce local tissue damage by protein denaturation, but some (e.g. paraquat) also have serious systemic toxicity. The patterns of damage with acids and alkalis are different and are therefore discussed separately.

ACIDS ETHYLENE GLYCOL

Antifreeze solutions contain ethylene glycol, a solvent that is sweet-tasting and therefore not unpleasant to drink. Death may occur after ingesting as little as 100 mL of ethylene glycol which, like alcohols, is metabolized by alcohol dehydrogenase. CNS toxicity is similar to alcohol

1

36

MCQ1.25

Acids produce severe pain on ingestion. They may cause asphyxia from epiglottal oedema and, although oesophageal damage has been described, they are more likely to cause gastric perforation, particularly in the region of the antrum. Late stricture formation is also a possibility. Lavage should not be performed unless the agents also have serious systemic toxicity. Any metabolic acidosis should be treated with intravenous bicarbonate, but weak alkalis should not be given by mouth. Endoscopy is of limited value in the acute phase and may cause perforation; in later stages, however, it may be helpful in identifying stricture formation. Corticosteroids have been used to try to prevent stricture formation, but their value is unclear.

SUMMARY 14 Acid poisoning • Acid ingestion may cause local corrosion, asphyxia due to oedema of the glottis and perforation of the stomach (less commonly of the oesophagus) • Metabolic acidosis and renal failure may also occur • Lavage should not be performed unless the agent produces severe systemic toxicity • Late stricture formation may occur but the value of corticosteroids in preventing this complication is not proven

Phenol (carbolic acid) can cause systemic toxicity as well as local corrosion, although the latter is normally less severe than with inorganic acids. The urine may be dark brown or black and the breath, urine and blood may smell strongly of carbolic. Haemolysis, renal failure, coma and convulsions, myocardial damage and metabolic acidosis may occur, and early cautious gastric lavage is indicated, provided the airway can be protected. Metabolic acidosis corrected with intravenous sodium bicarbonate and urine output and renal function carefully monitored. Cresols (methylphenols) have similar effects and treatment is therefore as for phenol poisoning. Formic acid is used in kettle descalers and destaining solutions. It too can produce a metabolic acidosis, intravascular haemolysis and renal failure, as well as local corrosion. Gastric lavage is therefore indicated early after ingestion, and any metabolic acidosis should be corrected with intravenous sodium bicarbonate. As with phenols, aspiration into the lung may cause haemorrhagic tracheobronchitis and the airway must therefore be protected during lavage.

ALKALIS Corrosion by alkalis (e.g. drain and oven cleaners) is generally more severe than by acids and is more likely to cause serious oesophageal, as well as gastric, damage. Stricture may develop weeks or months after the initial injury. Treatment is similar to that for acid ingestion; lavage should not be performed. Endoscopy by an experienced operator should be considered to assess the degree of injury and to prevent unnecessary hospitalization. The instrument should normally be passed only to the level of the first area of injury. It may also be useful in identifying alkalis in tablet form, which may adhere to the oesophagus (e.g. Clinitest tablets and some denture cleaners).

BLEACHES Most bleach contains sodium hypochlorite (up to 10%), which may produce corrosion in large or concentrated doses, and laryngeal oedema due to chlorine liberation. The stomach should be cautiously emptied within an hour if more than 300 mL has been ingested in an adult (100 mL

in a child), provided there is no evidence of oesophageal corrosion or severe gastritis. An H2-receptor blocking drug such as ranitidine should be given, and corticosteroids may be of value if laryngeal or pulmonary oedema is present. The sodium load resulting from ingestion of large amounts of bleach can cause hypernatraemia and hyperchloraemic acidosis.

1

DISINFECTANTS Although phenols and cresols (found in Jeyes fluid and some other disinfectants) have been largely replaced by dichlorometaxylenol, corrosive effects may occur after large or concentrated doses. Metabolic acidosis, coma, myocardial and renal damage and laryngeal oedema may also occur after severe overdose, and the stomach should therefore be emptied and the metabolic abnormalities corrected. Some disinfectants also contain isopropanol (discussed on p. 36).

POISONING WITH INSECTICIDES, HERBICIDES, FUNGICIDES AND RODENTICIDES INSECTICIDES The organochlorine group of insecticides (e.g. DDT) have now largely been replaced by compounds that are less persistent in the environment. These include the organophosphorus and carbamate insecticides.

Organophosphates The organophosphates act as inhibitors of cholinesterase in humans, causing symptoms of excessive cholinergic activity, with vomiting, abdominal pain, sweating, constricted pupils and hypersalivation. Muscle spasm, diarrhoea, convulsions and coma follow. Organophosphates can be absorbed from the stomach, skin or bronchial mucosa. Plasma cholinesterase activity, measured in several centres throughout the UK, is useful in the diagnosis of both organophosphate and carbamate insecticide poisoning. Severe toxicity is associated with a reduction in plasma cholinesterase activity to around 10% of normal. Treatment consists of atropine to antagonize the cholinergic (muscarinic) effects. The initial dose is 2 nig for adults and 0.02mg/kg for children, by intravenous injection. Large doses (up to 30 mg in 24 hours in an adult) may be necessary until there are signs of atropinization (dry skin, tachycardia, dilated pupils and dry mouth). Within the first 24 hours the use of an oxime (e.g. pralidoxime mesylate or P2S) will help to reactivate cholinesterase. It can be obtained from holding centres in the UK, details of which can be found on TOXBASE. The normal dose in moder-

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ate or severe poisoning is 30mg/kg by intravenous injection over 5-10 minutes. Benefit should be seen within 30 minutes, but repeated doses at 4-6-hourly intervals may be required. Alternatively, it may be given by intravenous infusion at a rate of 8mg/kg/h. Intravenous diazepam (5-10 mg for an adult; 0.02mg/kg body weight for a child) is helpful in reducing twitching and may improve survival. A clear airway must be maintained and assisted ventilation may be necessary.

the patient presents within an hour of ingestion) with care because of the corrosive effects of the toxin. Charcoal (1 g/kg body weight) is left in the stomach as an adsorbent for paraquat. Oxygen therapy should be avoided if possible as it may enhance the toxicity of these agents. Finally, haemodialysis and haemoperfusion have been tried in an attempt to remove the body burden of drug, but there is no evidence that either has any effect on mortality, particularly when the more concentrated solutions of paraquat (e.g. Gramoxone) are ingested. 2

Carbamate insecticides

Dinitro compounds

Carbamate insecticides produce similar symptoms (CNS signs are less prominent) and atropine is again the treatment of choice. However, because these compounds have a reversible effect on cholinesterase, their duration of action is much shorter and pralidoxime has not shown clear evidence of benefit in poisoning with these agents. O

Dinitro compounds (e.g. dinitro-orthocresol) are generally used in the form of washes for fruit trees. They cause yellow staining of the skin but can be absorbed subcutaneously and produce toxicity by uncoupling oxidative phosphorylation. This results in pyrexia, hyperpnoea and tachycardia, with subsequent sweating, thirst, dehydration and collapse. Treatment consists of preventing severe pyrexia and replacement of electrolytes and fluid. Pentachlorophenol acts similarly to the dinitro compounds but does not produce yellow discoloration of the skin.

HERBICIDES The five major groups of herbicides are: chlorates, triazines, bipyridilium herbicides, dinitro compounds and phenoxyacetic acids.

Chlorates The chlorates are powerful oxidizing agents that can produce haemolysis, methaemoglobinaemia, haemorrhagic gastroenteritis and, in severe cases, renal failure. Treatment consists of emptying the stomach (if appropriate) and methylene blue to reverse methaemoglobinaemia.

Triazines Triazine herbicides (e.g. simazine) appear to be relatively non-toxic, and serious human poisoning has not been reported.

Bipyridilium herbicides (paraquat) The bipyridilium herbicides, particularly paraquat, are extremely toxic. Not only can they cause local corrosion, but systemic absorption leads to renal and liver damage and later progressive pulmonary fibrosis. Diquat, which is less well absorbed from the gut, can cause similar toxicity, although pulmonary fibrosis seems to be slightly less likely to occur. Treatment consists of immediate gastric lavage (if

Phenoxyacetic acids Phenoxyacetic acids are probably the most widely used herbicides. They are relatively non-toxic unless large doses have been ingested; signs of cholinergic hyperactivity are then evident, resulting in coma and occasionally ventricular arrhythmias. Other features in severe cases include hypoglycaemia, metabolic acidosis, convulsions, hypertonia, myoclonus, rhabdomyolysis and renal failure. The stomach should be emptied if appropriate, contaminated clothing removed and the skin washed with soap and water. With 2-4-D and mecoprop urinary alkalinization may enhance their rate of removal, but haemodialysis is more efficient and should be considered in severely poisoned patients.

FUNGICIDES Organic and inorganic mercurials, organotin derivatives and dithiocarbamates are all used as fungicides in industry and horticultural practice. Organotin compounds are poorly absorbed from the gastrointestinal tract and therefore have low toxicity; dithiocarbamates are also relatively non-toxic.

Organic mercurials 1

38

MCQ 1.26, 1.27

2

MCQ1.28

Inhalation or ingestion of organic mercurials can produce severe corrosion and irritation of the respiratory tract. CNS toxicity consists of tremor, memory and psychiatric disturbances, and visual impairment that may lead to blind-

ness. The chelating agents DMSA and DMPS may reduce the systemic toxicity, but dimercaprol is contraindicated.

Inorganic mercurials Inorganic mercurial fungicides (e.g. mercuric chloride) are also predominantly corrosive. Treatment includes gastric lavage, adequate analgesia and treatment of any complications. Mercurous chloride (calomel) and mercuric oxide (the most commonly used agents) are poorly absorbed and, although corrosive, systemic toxicity is unlikely. If albuminuria occurs, however, significant absorption may have taken place and plasma mercury concentration should be measured. Treatment involves the use of the chelating agents. Although dimercaprol is licensed for this use, it has to be given by deep, painful intramuscular injection, and two orally active chelating agents, DMSA (Succimer) and DMPS (Dimaval) have also been shown to be effective. Guidance on administration should be obtained from the regional poisons centre for each individual case.

Metallic mercury Ingestion of metallic mercury is of no major consequence. However, intramuscular injection of metallic mercury may cause systemic toxicity, and intravenous injection has resulted in pulmonary embolus. Inhalation of mercury vapour may produce cough, retrosternal discomfort and breathlessness due to an acute pneumonitis, and flu-like symptoms such as lethargy, fever, aching limbs and arthralgia. High-dose corticosteroids may be useful if signs of lung damage are present. Signs of systemic poisoning may be an indication for dimercaprol, DMPS or DMSA.

cerebral oedema, coma and convulsions and ventricular fibrillation have also been reported. The chelating agents dimercaprol, DMSA and DMPS may reduce the severity of poisoning. Strychnine is sometimes used as a rodenticide, and has been found as an adulterant in some recreational drugs. It is rapidly absorbed by mouth and gastric lavage is contraindicated, as a convulsion may supervene during the procedure or be precipitated by the lavage. The clinical picture is similar to tetanus, with increase in muscle tone in the limbs and facial muscles, with severe spasms, muscle rigidity and exaggerated tendon reflexes. Twitching of muscles precedes the onset of convulsions, which may typically last between 30 seconds and 2 minutes and occur repeatedly. Convulsions may be provoked by any stimulus, including touch, pain and noise. The patient may be conscious and lucid between the convulsions. Cyanosis and death may occur during the convulsions, and most patients do not tolerate more than five convulsive episodes. The increased muscle tone can lead to hyperthermia and muscle damage (rhabdomyolysis) in severe cases. Treatment involves urgently establishing and maintaining a clear airway and ensuring adequate ventilation. This may be difficult if muscle tone is increased or convulsions are occurring, and it may be necessary to paralyse the patient before an endotracheal tube can be inserted and the patient ventilated. The patient should be kept at absolute rest and any stimuli that may precipitate further convulsions should be avoided. Sensory stimuli should be minimized by nursing in a darkened room; convulsions should be treated with diazepam. In severe cases neuromuscular blockers may be needed to paralyse the patient while ventilation is supported mechanically.

RODENTICIDES Many rodenticides contain warfarin or related coumarin anticoagulants and, unless taken in huge amounts, generally cause few symptoms. If the INR does rise, vitamin K should be administered as for warfarin overdose. Alphachloralose is a CNS stimulant that can cause coma, convulsions and rhabdomyolysis in overdose. Treatment consists of managing the complications. Fluoride salts may be associated with severe toxicity, sometimes delayed in onset, including abdominal pain and diarrhoea, with hypotension and peripheral circulatory failure. Hypocalcaemia and hypomagnesaemia cause muscle spasms, weakness, convulsions and cardiac arrhythmias including ventricular fibrillation. Coma and respiratory failure may supervene. Treatment is symptomatic and supportive. Arsenic is sometimes used as a rodenticide as well as a component of some timber (tannalizing) preservatives. Abdominal pain and vomiting precede the onset of profound (sometimes bloody) diarrhoea. Hypotension,

1

POISONOUS PLANTS AND FUNGI Although the number of plants that have been suggested to be poisonous is very great, many of these contain only small amounts of toxins and generally do not cause severe poisoning. They can be classified into those: • • • • • • • • •

producing cholinergic (nicotinic) stimulation producing cholinergic (muscarinic) stimulation with anticholinergic activity with gastrointestinal activity with effects on the heart with convulsant activity with hallucinogenic effects with dermatological effects with toxicity on other organs.

Plants with cholinergic (nicotinic) activity Alkaloids similar to nicotine are found in hemlock (coniine) and laburnum (cytisine). Nausea and vomiting

39

may be followed in severe poisoning by confusion, hallucinations, convulsions, and finally coma and respiratory arrest. Treatment for severe poisoning is as for nicotine. The stomach should be emptied and activated charcoal administered. Monitoring of fluid and electrolytes and adequate replacement therapy, together with measures to assist the respiration and cardiovascular functions, are generally only necessary in severe poisoning (rarely caused by laburnum).

Plants with cholinergic (muscarinic) activity Plants with cholinergic activity include the clitocybe and inocybe fungi. Ingestion produces increased perspiration, abdominal pain and visual disturbances. Treatment is with atropine, 1.2mg intramuscularly, repeated if necessary.

and delphinium may cause bradycardia and muscular weakness.

Plants with convulsant activity Cicuta viirosa (cowbane) and Qenanthe crocata (hemlock water dropwort) contain potent alcohols with effects similar to picrotoxin in antagonizing the CNS inhibitory effects of y-amino butyric acid. In severe cases nausea, vomiting and hypersalivation are followed by convulsions and respiratory failure. Convulsions can be controlled with either short-acting barbiturates or diazepam; respiration may require support until the effects of the toxin wear off. Strychnine is found in the seeds of the tree Strychnos nux vomica, native to India. Features and management are described under rodenticides (page 39).

Plants with hallucinogenic effects Plants with anticholinergic activity Plants with anticholinergic activity include the deadly nightshade (Atropa belladonna}, the thorn apple and henbane. In addition to atropine these plants may contain hyoscine and hyoscyamine. The symptoms are similar to those caused by drugs with anticholinergic activity (e.g. tricyclic antidepressants) and management is supportive.

Plants with gastrointestinal toxicity Oxalates present in some plants can cause local gastrointestinal irritation and painful ulceration of the mouth if chewed by children. These include the household plants dumb cane (Dieffenbachia) and some of the Monstera and philodendron species. Other plants contain irritant resins and saponins (e.g. arum, yew, bryony and Daphne mezereum), which can cause severe vomiting and diarrhoea. The beans of the Abrus species (e.g. Ricinus and Robinia) can cause delayed gastrointestinal symptoms as they contain compounds that can impair RNA synthesis. Solanum species also produce delayed gastrointestinal symptoms: these include potatoes that have been allowed to sprout, and woody and black nightshades. Treatment is supportive, with replacement of fluids and electrolyte loss.

Plants causing cardiovascular disturbances Digitalis glycosides are found not only in the foxglove but also in lily of the valley (Convallarid). Treatment is as for digitalis poisoning. The aconitine present in the monksfoot

1

40

MCQ1.29

In addition to those anticholinergic agents with hallucinogenic effects, there are several other hallucinogens in plants and fungi. These include the psilocin and psilocybin in psilocybes (magic) mushrooms, the tetrahydrocannabinol in cannabis, and the ibotinic acid and muscimol found in Amanita muscaria. Tranquillizers may be necessary if the patient is a risk to himself or to others, and adequate supervision must be given until the hallucinations subside. Table 1.13 lists various plants and their toxicities.

Plants that cause dermatological toxic ity Plants contain substances that can cause either direct chemical irritation (e.g. histamine and oxalic acid) or delayed hypersensitivity reactions (e.g. Primula obconica and the hogweeds, that can produce photoallergic dermatitis and several other species). Treatment is symptomatic.

Plants with toxic ity on other organs The lectins present in the seeds of Ricinus communis cause delayed gastrointestinal tract symptoms. Haemolytic anaemia may also occur, and haemoglobin precipitation in the renal tubules may cause acute renal failure. The principal lectin, ricin, is the most potent toxin known to man. Management is largely symptomatic and supportive. The beans of Ricinus communis are also highly allergenic and may cause anaphylaxis. Severe liver damage can also be caused by the phallotoxins and amatoxins found in Amanita phalloides and some of the other Amanita fungal species. Cooking or drying does not destroy these toxins. Vomiting, abdominal pain and diarrhoea often occur 6-12 hours after ingestion, and albuminuria, haematuria, renal failure and liver failure may occur around 1-3 days later. Treatment consists of emptying the stomach and replacing fluid loss. Specific antidotes are of unproven value, but thioctic acid and high doses of penicillin may be of value in preventing the liver and renal damage.

Blue-green algae are actually cyanobacteria, which grow as blue-green or brown rafts or sediments, usually in stagnant water, and which produce endotoxins. Their disagreeable odour usually prevents human consumption, but deaths have occurred in cattle. In humans local irritation and allergic skin reactions may occur. Consumption of contaminated water by humans may result in acute gastroenteritis, which usually resolves in 1-2 days. Occasionally a hepatitic picture or atypical pneumonia has been reported. Treatment is normally symptomatic and supportive. O

TABU 1.13 Plants and toxicity Plant or fungus

Latin name

Toxic features

Black (garden) nightshade Blue-green algae

Solarium nigrum Microcystis/Anabaena/ Aphanizomenon/ Oscillatoria Bryonia dioica Ricinus communis Clitocybe sp. Cicuta vimsa Daphne mezereum

Gastrointestinal Hepatotoxic Dermatological

Atmpa belladona Amanita phal/oides Dieffenbachia Amanita muscaria Digitalis purpurea Heracleum mantegazzianum Conium maulatum Oenanthe cmcata Hyoscamus niger Inocybe sp. Laburnum anagroides Conva/laria Psilocybes sp. Aconitum nape/lus

Anticholinergic Hepatotoxic Gastrointestinal Hallucinogenic Cardiotoxic Dermatological

Nerium oleander Thevetia peruviana Solanum tuberosum Primula obconica Philodendron Monstera deliciosa Datura stramomium Arum maculatum Solanum dulcamara

Cardiotoxic Cardiotoxic Gastrointestinal Dermatological Gastrointestinal Gastrointestinal Anticholinergic Gastrointestinal Gastrointestinal

Taxus baccata

Gastrointestinal

Bryony (white/red) Castor oil plant Clitocybe fungi Cowbane/water hemlock Daphne/mezereon/spurge olive Deadly nightshade Death cap fungus Dumbeane/Leopard lily Fly agaric Foxglove Giant hogweed Hemlock Hemlock water dropwort Henbane Inocybe fungi Laburnum/Golden rain tree Lily of the valley Magic mushrooms Monkshood/aconite/ wolfsbane Oleander (pink) Oleander (yellow) Potatoes (sprouting) Primula obconica Sweetheart vine Swiss cheese plant Thorn apple Wild arum/cuckoo pint Woody nightshade/ bittersweet Yew

Gastrointestinal Gastrointestinal Cholinergic (muscarinic) Convulsant Gastrointestinal

POISONOUS ANIMALS

1

ADDER ENVENOMATION The adder, Vipera hems, is the only indigenous poisonous snake in western Europe. Only 50% of those bitten develop signs of envenomation, which may occur either immediately, with shock, vomiting and explosive diarrhoea, or several hours later. The initial collapse may be due to activation of the kinin system; the later shock is more often due to hypovolaemia, caused by increased capillary permeability and fluid loss into the swollen limb, and direct cardiotoxicity of the venom (Fig. 1.13). Management Treatment includes reassurance, as shock may be exacerbated by the fear of impending toxicity. The limb should be kept still, but a ligature should not be used unless there is likely to be a delay of more than half an hour between the patient having been bitten and transfer to hospital. If a ligature is used, it should be tight enough to prevent

Cholinergic (nicotinic) Convulsant Anticholinergic Cholinergic (muscarinic) Cholinergic (nicotinic) Cardiotoxic Hallucinogenic Cardiotoxic

FIG. 1.13 Adder bite on the finger of a child A Note the twin puncture wounds and B subsequent oedema involving the hand and arm.

41

venous return but not to obstruct arterial inflow. If there are signs of toxicity the patient should be admitted and observed for at least a day after the bite. Pulse and blood pressure should be recorded, together with urinary output and fluid losses from diarrhoea and vomiting. Local swelling should also be noted, and the white cell count, urea and electrolytes should be measured each day. The use of antivenom should be considered if hypotension persists, ECG signs occur, the white count rises markedly to above 20000/mm3 or, in an adult, severe swelling has extended up the limb within 2 hours after the bite. Anaphylactic reactions to the antivenom occur in 1 % of patients and so antivenom should only be used when the indications described above are present. A history of asthma or allergy is a relative contraindication to its use. Antivenom is given by slow intravenous infusion and is stopped at the first signs of allergic reaction. Adrenaline (epinephrine) solution must be drawn up prior to administration of the antivenom and given intramuscularly if a reaction occurs (intravenously in the case of a severe reaction). Deaths from adder bite are extremely rare but local tissue necrosis may be severe, particularly in adults.

FISH ENVENOMATION

In the UK the only venomous fish regularly found are the Weaver fish (Trachinus vipera), which is found around the coast in the summer months, and the Lion fish (an aquarium species). Both contain heat-labile venom in their spiny dorsal fins, which causes severe local pain. Hypotension, and myocardial and respiratory depression may develop. Management Treatment is to remove any barbs and clean the wound, immersing the limb in water as hot as can be tolerated without discomfort to destroy the toxin. The wound should be examined at a later stage for signs of secondary infection.

VENOMOUS INVERTEBRATES

The Portuguese man of war (Physalia physalis) is the most poisonous jellyfish found around the coasts of the UK. Its sting contains substances capable of releasing histamine and other kinins. Local pain is common, but more serious symptoms include abdominal pain, dyspnoea, hypotension, muscular paralysis and convulsions. Most other jellyfish found around the UK are harmless, but the compass jellyfish (Chrysaora hyoscella), the lion's mane (Cyanea O MCQ1.30

42

capillata) and the sea nettle (Cyanea lamarckii) can cause a sting. Management The wound should be bathed in vinegar solution (4-6% acetic acid), and any tentacles still adherent removed with forceps, a gloved hand or adhesive tape. Treatment is otherwise symptomatic.

ARTHROPOD ENVENOMATION Wasp and bee stings contain amines, kinins, peptides and enzymes that cause local pain, erythema and swelling. Systemic effects are rare unless the stings are numerous or the subject is hypersensitive, in which case even a single sting may kill. Initial symptoms are generalized urticaria, flushing, dizziness, bronchospasm, collapse and coma. Serum sickness may occur after a week or more. Management The sting of the bee should be removed by flicking or scraping, taking care not to squeeze it and inject more venom. Severe pain may respond to local anaesthetic or aspirin. Swelling may respond to antihistamines and corticosteroids. Anaphylaxis should be treated immediately with adrenaline (epinephrine) (0.5-lmL of a 0.1% solution intramuscularly for an adult and 10|ig/kg for a child). The dose may be repeated every 10 minutes if necessary. Stings in the mouth, even in patients who are not hypersensitive, may cause severe respiratory tract obstruction. In allergic individuals, specific venoms have been used in increasing doses to produce desensitization.

POISONOUS SEAFOODS

Seafood may contain bacteria (e.g. Vibrio, Salmonella) or viruses (e.g. hepatitis A); toxicity may also occur as a result of contamination by dinoflagellates or decomposition by bacteria. Antemortem infestation by dinoflagellates of certain subtropical fish (such as groupers and snappers) may occur, but contamination usually involves shellfish, such as mussels, oysters, scallops and clams. The dinoflagellates contain neurotoxins (e.g. saxitoxin) which can cause nausea, vomiting and diarrhoea, followed by circumoral paraesthesiae, ataxia, muscular weakness and, in severe cases, respiratory paralysis. Treatment is symptomatic, with respiratory and cardiovascular support. Postmortem contamination of some oily (dark-meat) fish, such as mackerel, skipjack and tuna, sardines and pilchards, by Proteus bacteria may result in the production of histamine and other unidentified toxins that produce urticaria, flushing, abdominal pain, nausea, vomiting and diarrhoea and, in some cases, bronchospasm. This 'scombroid fish' poisoning occurs around 4 hours after ingestion,

generally lasts only a few hours and is seldom severe. Treatment is symptomatic. Prevention involves keeping the raw fish frozen or on ice to prevent decomposition by bacteria.

POISONING BY METALS IRON Although mortality from iron poisoning has fallen in recent years, it remains one of the most dangerous metals in overdose. Children are particularly sensitive to its effects. Abdominal pain, nausea and vomiting are often followed by gastrointestinal bleeding, encephalopathy, metabolic acidosis, pulmonary oedema, coma, shock, acute renal and liver failure. Doses of elemental iron of more than 150mg/kg body weight produce severe and possibly fatal toxicity. A serum iron level greater than 5mg/L (90 pmol/L) within 4 hours of the overdose is associated with an increased likelihood of severe poisoning. Coma and shock are manifestations of severe toxicity.

Management The stomach should be emptied if more than 60mg/kg has been ingested within the previous hour. Radiography of the abdomen in the first 2 hours may reveal whether or not iron tablets have been taken. Blood should be taken for urgent measurement of serum iron concentration. If coma or shock develop, desferrioxamine should be considered immediately without waiting for the serum iron result. The dose is 15mg/kg body weight/hour for 5 hours. It often causes hypotension if infused more rapidly than this, and can occasionally cause rash and anaphylactic-like reactions. Pulmonary oedema and ARDS have been reported in patients treated with more than 80 mg/kg/day for longer than 24 hours. With prompt treatment the mortality should be less than 5% in severe cases. 1

HEAVY METAL POISONING Heavy metals can cause acute or chronic symptoms,

SUMMARY 15 Iron poisoning • Children are particularly sensitive to the toxicity of iron • Abdominal pain, nausea and vomiting may be followed by gastrointestinal haemorrhage, encephalopathy and renal and hepatic failure • Severe poisoning is normally associated with plasma concentrations around 4 hours after ingestion of more than 5mg/L, with CNS signs and shock • Intravenous desferrioxamine should be given as soon as possible in severe iron poisoning

depending on the dose and duration of exposure. Acute ingestion of most heavy metals will cause gastroenteritis. Generalized convulsions may also be seen, particularly with lead poisoning, and renal failure and cardiac arrhythmias have also been recorded. Inhalation of heavy metal fumes may cause chemical pneumonitis and, in severe cases, pulmonary oedema, and a syndrome known as 'metal fume fever' may occur several hours after the inhalation of some metallic oxides. Chronic effects of heavy metal exposure are similar but milder. Chronic gastrointestinal symptoms and CNS effects occur, particularly after exposure to lead, manganese and mercury. Lead, thallium, bismuth and arsenic can also produce peripheral neuropathy, and gold, lead, cadmium and mercury may cause renal damage. Inhalation of heavy metal fumes can cause pulmonary fibrosis, particularly with beryllium, cadmium, tungsten, titanium and cobalt. An emphysematous picture has been seen with cadmium, and an asthma-like syndrome may occur as a result of sensitivity to chromium, vanadium and platinum. Nickel, chromium, cobalt, platinum and beryllium may also cause skin sensitization and subsequent dermatitis. Taking a full occupational history helps diagnosis. Clinical examination may reveal specific signs of poisoning, such as the blue line on the gums in chronic mercury poisoning or the raindrop pigmentation of the skin in arsenic poisoning. Toxicological examination of the urine, blood, or hair and nail clippings may also help, but this often has to be performed in specialized centres.

1

Management Treatment consists of preventing further exposure to the heavy metal, treatment of the complications of poisoning, and chelation therapy to enhance the elimination of the metal already absorbed. It must be remembered, however, that most chelating agents are toxic and should only be used when their benefits are likely to outweigh the risks of their use. Sodium calcium edetate is the treatment of choice for lead poisoning. It must be given by slow intravenous infusion. Dimercaprol, DMSA and DMPS are effective in severe mercury and arsenic poisoning. Finally, Prussian blue has been used successfully in the treatment of thallium poisoning.

FURTHER READING British National Formulary. British Medical Association and Royal Pharmaceutical Society of Great Britain, published biannually. An excellent reference text and practical guide to prescribing, with useful tables to prescribing in special circumstances and drug interactions. Laurence D R, Bennett P N 1997 Clinical pharmacology, 8th edn. Churchill Livingstone, Edinburgh. Highly readable, with a practical therapeutic flavour. Ritter J M, Lewis L D, Mant T G K 1998 A textbook of clinical pharmacology, 3rd edn. Edward Arnold, London. A practical guide to clinical pharmacology and drug therapy.

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2

Heat cramps

Physicaland

Environmental Disorders

Spasms of painful muscular contraction may occur with sudden rises in temperature during strenuous activities such as long-distance running, or during work in very hot environments. Muscles of the legs and arms are usually affected, typically after the exertion or heavy work is over. There is usually hyponatraemia, and severe cramps may be accompanied by a rise in creatine phosphokinase and evidence of rhabdomyolysis. Part of the pathogenesis appears to be due to replacement of fluid and salt loss by water with too low a salt content; the condition is preventable by drinking fluids containing 0.25% saline.

2

Heat exhaustion John Moxham and Robert L Souhami

Disorders due to heat and cold 45 Whole body radiation exposure 47 Disorders due to extremes of barometric pressure 49

Submersion and drowning 51 Electric shock 53 Smoke inhalation 54 Chemical warfare 54

DISORDERS DUE TO HEAT AND COLD Heat produced by metabolism is lost mainly through the skin and, to a lesser extent, through the gut, urine and breath. Inadequate heat loss leads to sweating and vasodilatation. Cold produces cutaneous vasoconstriction and shivering, which results in increased muscle metabolism and heat production. In moving from a cold to a hot climate, acclimatization occurs over a period of 1-2 weeks; this process is not well understood. There is increased sweating and the salt content of sweat diminishes. Aldosterone secretion increases, at least at first, causing a low urinary sodium with loss of potassium. A progressive rise in temperature above 38-39°C causes irritability and mental confusion. At temperatures above 40-41°C vascular, renal and hepatic damage occur.

HEAT EXCESS Three syndromes due to excess heat occur: heat cramps, heat exhaustion and heatstroke.

Heat exhaustion or heat collapse is the commonest syndrome and is especially likely to occur in individuals exposed to a hot environment for a few days. The very young and the elderly (especially those on diuretics) are particularly at risk. The syndrome is due in part to salt and water loss, and in part to a failure of circulatory adaptation to heat. When water loss predominates, there is intense thirst and weakness, agitation and confusion. Water depletion is more likely to occur in acclimatized people (whose sweat contains less salt). The plasma Na+ and Cl~ rise. With salt depletion, there are muscle cramps, headaches, vomiting and myalgia. Haemoconcentration occurs with a rise in haematocrit and blood urea. Usually, salt and water depletion occur together, and the patient has a normal temperature and appears pale and clammy. The disorder is treated by rest and oral fluids. In water depletion (where plasma sodium is elevated) this should be with water. Typically 5-8 L may be given in 24 hours by mouth or as i.v. glucose. When salt depletion is present the oral fluids should contain salt (e.g. 5L of fluid with 20 g salt).

Heatstroke Heatstroke is a serious and sudden disease which may be fatal unless treated urgently. It is caused by a failure of thermoregulation, resulting in a rapid rise in body temperature. In normal individuals it is usually due to exercise or work in a hot, humid environment. When it occurs in sedentary individuals the patient is usually elderly, often with underlying disease such as cardiac failure, diabetes (with autonomic dysfunction), obesity or alcoholism. Atropine-like drugs, p-blockers, phenothiazines and diuretics predispose to the syndrome. Heatstroke can also occur in fit men working in hot environments, and there are some clinical differences in these cases. Typically the patient develops headache, dizziness and faintness, and abdominal pain and delirium may occur. Sweating stops and the body temperature rises rapidly (and may reach 43°C). Hypotension, renal failure and

45

rhabdomyolysis may occur; the latter is especially common in heatstroke following severe exertion. In this form of heatstroke sweating may continue. On examination the skin is hot and usually dry, and the patient exhibits tachypnoea and flaccidity. Coma and shock are grave signs. The blood shows leukocytosis and respiratory alkalosis (but may be acidotic in the exertional form), the urea is raised, and hypokalaemia and hyperphosphataemia occur. Myocardial necrosis may give ST changes and even an infarction pattern on the ECG. Liver function tests are abnormal, and acute renal failure may occur. Disseminated intravascular coagulation is present in mild degree in the elderly, but may be severe in exertional heatstroke. Management Treatment is urgent. The patient must be cooled as quickly as possible. The most effective way is immersion in cold water, the skin being rubbed to increase the efficiency of cooling. An alternative is to blow cold air over dampened skin. Core temperature must be monitored using a rectal thermometer. Hypotension can be treated with small quantities of saline, taking care to avoid circulatory overload. Hypoglycaemia, if present, can be treated with glucose, and severe acidosis by sodium bicarbonate. More serious complications, such as acute renal failure and disseminated intravascular coagulation, are treated in the usual way (Chs 20 and 23). Cerebellar degeneration may occur, and coma with cortical damage is a terminal event. 1

SUMMARY 1 Clinical features of heatstroke Symptoms • Headache • Dizziness/faintness • Abdominal pain Signs • Increased body temperature • Hot, dry skin (sweating may be absent) • Tachypnoea • Flaccidity • Hypotension • Delirium -> shock/coma Results/complications • Hepatic and renal failure • Leukocytosis, alkalosis/acidosis, hypokalaemia • Rhabdomyolysis • Myocardial necrosis • Disseminated intravascular coagulation • Cerebellar degeneration • Coma, cerebral damage

as 'ecstasy'. Muscle contraction begins after the start of anaesthesia, and body temperature rises rapidly. The anaesthetic must be stopped, the patient cooled and ventilated, and i.v. dantrolene sodium given (2-10mg/kg). Acidosis should be treated. 0

HYPOTHERMIA

Neuroleptic malignant syndrome This syndrome is characterized by muscle rigidity giving rise to hyperpyrexia, tachycardia and impaired consciousness. It is an idiosyncratic reaction to drugs that block dopaminergic transmission, such as phenothiazines and butyrophenones. The increase in muscle tone develops over 12-72 hours. Death from respiratory failure may occur. Treatment is by muscle relaxants, including neuromuscular blocking agents, and ventilation if necessary. Recovery may take several days.

Significant hypothermia is an uncommon problem mainly affecting the elderly, in whom the response to cold may be defective (p. 178). Hypothermia contributes to the excess mortality in this population during winter months. It is defined as being present when the deep body temperature falls below 35°C. As the mouth temperature may fluctuate depending on the ambient air temperature, it is best to use a rectal thermometer when monitoring hypothermic patients. A low-reading thermometer is necessary. The rectal temperature is about 0.5°C higher than oral.

Malignant hyperpyrexia

Aetiology

This is an autosomal dominant disorder in which hyperpyrexia is produced by skeletal muscle contraction following anaesthetic agents such as halothane and suxemethonium and local anaesthetics. It can also occur with drugs such as amphetamines and derivatives such

Hypothermia may be due simply to an age-related impaired thermoregulatory response to a cold environment (Ch. 7, p. 178). In the majority of patients, however, there is an associated underlying pathological cause, including any cause of autonomic dysfunction (p. 178). Hypothyroidism and hypopituitarism are both associated with hypothermia, and the risk is also higher in immobile or demented patients, or in the presence of an acute illness such as bronchopneumonia. There is a clear association between phenothiazines and impairment of temperature regulation, and hypothermia may also be precipitated by sedative drugs, such as hypnotics and alcohol. Although

1

46

Case 2.1

2

MCQ2.1

3

MCQ2.2

a mild drop in body temperature is common, clinically important hypothermia is unusual. However even modest falls in body temperature may produce changes in coagulability, which may predispose to myocardial infarction. Immersion hypothermia is produced by shipwreck. Exposure to cold weather occurs in hillwalkers and climbers, especially if they have not eaten or if they drink alcohol.

Clinical features Hypothermic patients typically live alone in poor housing and have impaired mobility. A typical case would be that of an old person who gets out of bed in the middle of the night to go to the lavatory, falls, and then lies all night on the cold floor in thin nightclothes until discovered the next morning by a neighbour. The skin has a greyish look owing to a combination of vasoconstriction and cyanosis; the face may appear puffy, resembling myxoedema. The diagnosis is often first suspected during examination, when it is found that the patient's skin feels cold in normally warm areas, such as the axilla or the abdomen. There may be ataxia and slow mental response. The patient is often confused when the temperature falls below 35°C, and drowsiness and loss of consciousness occur when the temperature falls below 29-33°C. Shivering is absent below this temperature; instead, there is increased skeletal muscle tone with neck stiffness and abdominal rigidity. The heart rate is slowed and the ECG may show a prolonged PR interval and J waves (Fig. 2.1). Respirations are slow and shallow, and there may be hypoxia and hypercapnia. Hypoxia is exacerbated by a shift of the oxygen dissociation curve to the right, leading to impaired release of O2 from haemoglobin. Acute pancreatitis is often found at necropsy, but this is only rarely diagnosed in life. Impaired renal and respiratory function may lead to a raised blood urea or bicarbonate. Blood sugar levels may be raised, but do not indicate diabetes mellitus, and will fall as the temperature returns to normal. Serum asparate aminotransferase and creatine kinase may be raised due to muscle damage.

Management The lower the deep body temperature, the higher the mor-

SUMMARY 2 Clinical features of hypothermia • • • • • • • •

Contusion/impaired consciousness Cold, greyish skin Shivering absent Increased skeletal muscle tone Slow heart rate, prolonged PR interval and J waves Slow, shallow respiration, hypoxia and hypercapnia Raised blood urea or sugar levels Raised serum asparate aminotransferase and creatine kinase

2

tality (about 50% overall). This is because many hypothermic patients have a serious underlying illness. Patients with mild hypothermia (core temperature 32-35°C) should be wrapped in a space blanket and nursed in a side ward where the ambient temperature is 28-30°C. Their temperature should be allowed to rise gradually, at a rate of about 0.5°C per hour, as fast surface rewarming carries the risk of hypotension. For this reason, the patient's pulse and blood pressure must be monitored. If the blood pressure drops, the space blanket should be removed or the room temperature lowered so that the patient is temporarily cooled. Intravenous fluids are hazardous and may produce acute pulmonary oedema. A broad-spectrum antibiotic is usually given parenterally because bronchopneumonia is nearly always present, even if not clinically apparent. The ECG should be monitored, as both bradyarrhythmias and ventricular fibrillation may occur. The patient is at serious risk of developing a pressure sore and must be nursed on a suitable mattress and turned regularly. When the deep body temperature is below 32°C a more aggressive approach to resuscitation is sometimes advocated, although there is little evidence that this reduces mortality. These measures include positivepressure ventilation to correct hypoxia, measurement of central venous pressure, and active rewarming using a radiant heat cradle over the torso or warmed intravenous fluids.

Thyroid hormones should not normally be given to hypothermic patients. If there is good clinical or laboratory evidence of hypothyroidism, then triiodothyronine (5ug) may be given by slow intravenous injection every 12 hours. A particular problem is presented by patients who have become hypothermic as a result of immersion at sea. They may develop ventricular fibrillation on rescue if they exert themselves. They should therefore be kept still and rewarmed slowly. 3

WHOLE BODY RADIATION EXPOSURE

FIG. 2.1 Electrocardiogram showing J wave (arrowed) in a hypothermic patient

There are two broad types of ionizing irradiation: photons (y and X-rays) and particulate (a and |3 particles). Radiation dose is defined in a variety of ways. The energy

47

deposited in a tissue is measured in grays (Gy; IGy = 1 J/kg). Because different types of radiation have different tissue effects, a unit called the Sievert (Sv) is sometimes used, which weights the radiation dose according to the type of radiation. Particulate radiations are absorbed according to their mass and energy, but do not penetrate deeply into tissues (see also Ch. 6, p. 159). Particulate irradiation transfers more energy and is much more ionizing than Y or X-rays.

EXPOSURE Exposure to ionizing irradiation comes about in three ways: • Background irradiation. We are exposed to approximately 2-3 mSv per year from solar and geological irradiation. Cosmic rays are mostly very high-energy protons. Secondary radiations, from the upper atmosphere, are largely y-rays. Geological irradiation is largely due to radon. • Medical exposure. The therapeutic uses of ionizing irradiation are described in Chapter 6. Accidental exposure of patients or staff has been rare since the advent of stringent precautions following the radiation-induced damage to skin and eyes in the early days of therapeutic and diagnostic radiation. Exposure to whole-body radiation forms part of the treatment of leukaemia and lymphoma. The resulting bone marrow suppression is treated by allogeneic (or autologous) haemopoietic stem cell transplantation. • Military and industrial irradiation. The atomic bombs dropped on Hiroshima and Nagasaki led to numerous cases of acute leukaemia and other cancers. Fallout from nuclear tests has increased annual background radiation by 1%. Industrial exposures also occur, the most dramatic example of which has been the ingestion of radium by radium dial painters from 1916 to 1926, resulting in a great increase in risk of bone sarcoma and cancer of the air sinuses of the skull. The accident in the Chernobyl nuclear power station in 1986 resulted in many deaths due to acute radiation exposure, and an increase in background radiation over a wide geographical area.

TISSUE DAMAGE The tissue-damaging effect of ionizing irradiation is probably related mainly to damage to DNA, leading to strand

1 48

MCQ2.3

breakage and impaired reproductive integrity of the cell. At 0.1 Sv total body exposure there is a slight fall in blood lymphocyte count. At ISv there may be mild radiation sickness with slight nausea and a more profound lymphopenia, and a fall in neutrophils and platelets 2-3 weeks after exposure. Following greater degrees of whole-body exposure certain tissues are damaged acutely by relatively low doses: • Bone marrow. This can regenerate after exposure to 10 Gy, but above this dose permanent aplasia may occur. The white count and platelet count begin to fall within 10 days of exposure. • Intestine. Doses of 10 Gy or over cause severe loss of crypt cells, leading to loss of villi and extensive ulceration. The onset of nausea and vomiting is 1-2 hours after exposure, often recovering a few hours later, but above 10 Gy permanent and fatal damage to the gut occurs, with death in 4-14 days. Death is due to severe diarrhoea, consequent salt and water depletion, and severe Gram-negative sepsis. • Skin. Erythema occurs at doses below 10 Gy. At 20 Gy the skin starts to desquamate and ulcerate. • Lung. Above l0 Gy in a single fraction pneumonitis occurs, and is increasingly severe with increase in dose. Long-term changes include glomerular loss and interstitial nephritis, infertility, pulmonary fibrosis, neuronal loss and gliosis, intestinal stricture and hepatic fibrosis. After acute radiation exposure (such as at Chernobyl and Hiroshima) there is an increased risk of leukaemia at 5-10 years. The safe lower limit is not easily quantifiable but is probably below l0c Gy. Solid tumours may also occur, including bone cancer in radium dial painters, skin cancer, and lung and breast cancer. The risk of solid tumours appears to be 1 in 2000 following total body exposure of 1-2 cGy.

Clinical features After acute whole-body exposure, the clinical features depend on the received dose. Following an initial period of nausea and vomiting (sometimes with parotid swelling), the patient may be relatively well for 7-10 days and then develop a syndrome of haematological failure. There is depression of the white count and platelets, with infection, bruising and bleeding. At the same time skin reactions occur, with desquamation, alopecia and ulceration. If the whole-body dose is above 15 Gy the gastrointestinal syndrome may predominate and be the first sign of toxicity. In a patient with severe leukopenia severe diarrhoea and fluid loss are followed by septicaemia from gut bacteria. This is almost always fatal. Higher doses of whole-body radiation (25-60 Gy) cause cardiovascular collapse and shock.

Management Management is supportive. Antiemetics are given in the acute phase, and fluid losses from diarrhoea are replaced. Transfusion of blood and platelets and intensive antibiotic treatment for gut derived organisms are used during the phase of myelosuppression and infection. Haemopoietic growth factors such as GCSF may be of value. Allogeneic bone-marrow transplantation may help the minority of patients for whom there is a donor, and in whom the haematological toxicity is the major life-threatening complication. It is of no value if the major toxicity is in organs such as the lungs or gastrointestinal tract. Accidental exposure to radionuclides is treated according to the isotope. Potassium iodide is given for I31 I ingestion, and soluble phosphate for 32P overdose. Overdose with bone-localizing isotopes (caesium, radium, strontium) is treated with EDTA and large doses of oral calcium. There has been some interest in drugs that limit damage from radiation: unfortunately, these have to be given before or immediately after exposure. The best known is ethyol, which may also protect normal tissues from cytotoxic drug damage. Late effects occur 3-10 years after exposure. There is an increased risk of acute myeloid leukaemia. The risk of solid tumours is about 1 in 2000. Tumours include cancer of skin, breast and lung. This is a small increase compared to the background incidence in the population.

height. Commercial aircraft are maintained at a pressure equivalent to 2500 metres, so that no additional oxygen is needed unless a patient has severe cardiac or respiratory disease. If there is a loss of pressurization, extra oxygen is made available through masks. Acclimatization to altitude is a complex process. On rapid ascent the relative hypoxia stimulates ventilation, but this stimulus diminishes over a few weeks. This hyperventilation diminishes Paco2, with the consequent development of a respiratory alkalosis. The respiratory centre appears to adapt to a lower Paco2. The acute circulatory adaptation consists of a rise in cardiac output, a fall in renal, cardiac and cutaneous blood flow, and a rise in cerebral blood flow. These changes slowly reverse, and after several weeks cardiac output on exercise is lower than at sea level. The red cell mass increases greatly and with it the total oxygen-carrying capacity of the blood. The oxygen dissociation curve does not shift substantially (as the alkalosis shifts it to the right and the hypoxia to the left). There is an increased formation of tissue capillaries, greatly increasing tissue oxygenation. There are four recognized syndromes of altitude sickness: • • • •

2

Acute altitude sickness Acute pulmonary oedema Acute cerebral oedema Chronic altitude sickness.

Prognosis With adequate treatment, most patients will survive acute exposures up to 10 Gy. Above this dose, bone-marrow failure and the intestinal syndrome are usually fatal. 1

DISORDERS DUE TO EXTREMES OF BAROMETRIC PRESSURE

ALTITUDE SICKNESS The effects of reduced barometric pressure result from the low partial pressure of oxygen and reduced oxygencarrying capacity of the blood. Figure 2.2 shows this relationship. The barometric pressure at sea level is 100 kPa, and the partial pressure of oxygen is 21% of this, i.e. 21 kPa. At 5500 metres the barometric pressure is reduced to 50% (50kPa). The partial pressure of oxygen is, however, less than 20% of this (l0kPa) because the proportion of water vapour rises. Because of the sigmoid shape of the oxygen dissociation curve, oxygen saturation is reasonably well maintained until an altitude of 5000 metres. A precipitous fall in saturation then occurs with increasing

FIG. 2.2 Effect of altitude on alveolar Pao2 and oxygen saturation Because of the steep slope of the oxygen dissociation curve, increasing altitude above 5000 metres causes a precipitous fall in saturation. In an unacclimatized person, acute changes occur at: IT1 3000 metres (10000 feet) - slightly impaired memory and judgement, increased heart rate, abdominal cramps and nausea; [B] 3500 metres (12000 feet) - headache, nausea, diminished visual acuity, and possible pulmonary oedema; [C] 5500 metres (18000 feet) - impaired consciousness after several hours in many people; and [D] 6750 metres (22000 feet) - loss of consciousness.

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Acute altitude (mountain) sickness This syndrome occurs in unacclimatized individuals who ascend rapidly to heights in excess of 2500 metres. People who are unfit, or very young, or those who have respiratory or cardiac disease, are especially prone. The symptoms usually begin at 12-24 hours after ascent. Lightheadedness is followed by lethargy irritability and severe headache, usually occipital in position. Other symptoms include nausea and vomiting, dyspnoea with periodic respiration, and abdominal pain. Physical examination reveals little, although ataxia (shown by walking heel to toe) may be present. The cause of acute altitude sickness is unknown. It is possible that the hypoxia causes mild cerebral and brainstem oedema. This is suggested on MRI scans and by multiple petechiae in the brain in fatal cases. The syndrome is preventable by slow ascent. Individual susceptibility varies greatly and mountainous hikes and climbs should never put pressure on participants to ascend rapidly, especially if they start to feel unwell. When starting an ascent above 3000 metres a reasonable pace is 300m/day, resting for a day every 3 days. Even this may be too fast for some people. Dehydration should be avoided, and a good diet maintained. Treatment is to avoid sedatives, to take mild analgesics for headache, and if the symptoms do not abate, to descend to 1000m to await recovery. Acetazolamide can alleviate the symptoms of acute altitude sickness by acting as a respiratory stimulant, lowering the Paco2 and raising the Pao2. If ascent cannot be made slowly it may be advisable to start acetazolamide (250 mg b.d.) before ascent, and climbers should be warned of the side-effects, particularly paraesthesiae. Acute pulmonary oedema Rapid ascent to heights greater than 3000 metres may provoke the sudden onset of acute pulmonary oedema. Hypoxia is the cause, but the pathogenesis is unclear. The symptoms usually begin 5-36 hours after ascent; acute dyspnoea, haemoptysis and widespread crackles in the lungs occur. Pathologically there is acute oedema and a 'hyaline' membrane in bronchioles. Treatment is with urgent evaluation to a lower altitude, oxygen and diuretics. Nifedipine has been shown to be useful prophylactically in those who have had a previous episode of pulmonary oedema. Acute cerebral and retinal oedema Acute hypoxia increases cerebral blood flow and intracranial pressure, and can cause cerebral oedema. This is asso-

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1

Fig. 2.1

4

Fig. 2.2

2 Case 2.2 3 MCQ 2.4

ciated with headache and brain dysfunction. The patient may be incoherent, drowsy, ataxic, and progress to coma. There may be papilloedema. Deepening coma leads to death. The treatment is urgent descent to a lower altitude and oxygen. Dexamethasone (i.v.) should be given. Cerebral and pulmonary oedema often accompany each other. Many people ascending to high altitude develop asymptomatic retinal haemorrhage.1 Occasionally this may leave a permanent blind spot. Oedema of the retina is assumed to be the cause. Retinal oedema occurs in the absence of cerebral oedema. Pink optic discs and retinal haemorrhage are not in themselves a reason for urgent descent.

Chronic altitude (mountain) sickness Individuals (usually middle-aged men), who have lived for many years at altitudes above 4000 metres may develop polycythaemia and a chronic insensitivity of the respiratory centre to hypoxia. Such individuals hypoventilate and develop a raised Paco2. There is central cyanosis, with cough, headache and giddiness. Patients are cyanosed, with vascular conjunctivae and finger clubbing. There may be RV strain on ECG as a result of pulmonary hypertension. The CNS symptoms are similar to those of polycythaemia rubra vera and are due to decreased cerebral blood flow (a consequence of the raised haematocrit) and hypoxia. Not all people living at high altitude develop this syndrome, which appears in part to be an excessive response to decreased inspired Pao2. The syndrome can only be treated by permanent descent to a lower altitude.

INCREASE IN BAROMETRIC PRESSURE

An increase in barometric pressure is encountered in diving or in mining.

Breath hold diving During a breathhold dive the body directly encounters the increased pressure (1 atm for every 10 metres descent). The breathhold causes a rise in Paco2 and a fall in Pao2. The main respiratory stimulus is the raised Paco2, so that hyperventilation before diving leads to a lack of stimulus to breathe (owing to CO2 depletion). This may cause fatal loss of consciousness from hypoxia (which does not cause an irresistible urge to breathe and thus terminate the dive). As the diver surfaces, decompression lowers Pao2 and again may cause loss of consciousness.

Lung rupture, air embolism, pneumomediastinum During a breathhold dive the air in the lung is compressed and re-expands to its previous volume on ascent, with no risk of lung rupture. If a diver breathes air below the surface he must allow time for the excess air under pressure to be exhaled or the lung may rupture. Divers are taught not to ascend more rapidly than the gas they exhale. A diver breathing air may hold his/her breath while ascending rapidly, without breathing out. This often happens if the diver has accidentally lost the air supply. During the rapid ascent the lung may rupture. Lung rupture may be into the mediastinum or into the pleural space, causing pneumomediastinum and pneumothorax, respectively. The symptoms are breathlessness, cough and haemoptysis during the ascent. Air embolism may occur and cause dysphasia, paralysis, visual disturbance or convulsions. Mediastinal air may cause dysphagia and surgical emphysema in the neck. Treatment is with 100% oxygen to eliminate inert gas, and recompression.

Deep diving, decompression sickness In deep diving the gas must be delivered at the same pressure as the surrounding water. If the gas is air, the high pressure of N2 causes mental confusion below 50 metres. Helium/oxygen mixtures are better tolerated and descents as low as 700 metres can be undertaken. These mixtures must be used below 50 metres. At greater depths than 700 metres neurological disturbances occur owing to the high gas tensions. Very high oxygen concentrations in the inspired gas (even though they reduce inert gas narcosis and the risk of decompression sickness) are toxic to the lung and CNS. This toxicity is related to the level of inspired Pao2 and the duration of the dive, and must be carefully regulated. When breathing air, the nitrogen dissolved in blood (PaN2) increases and, on rapid decompression, forms bubbles, which come out of solution in small blood vessels. Ischaemia results, causing pain in joints, spinal cord injury, chest pain, cyanosis, confusion, visual defects, paralysis and fits. Minor confusion occurs with lesser degrees of compression injury. Treatment is by recompression, followed by very gradual decompression over days. Some instances of air embolization during diving occur in individuals who shunt blood from the right atrium to the left via a patent foramen ovale. About 25 % of the population have minor degrees of patency of the foramen ovale. Figure 2.3 shows the relationship between depth, duration of dive and the need for controlled ascent to the surface. QQ

REFERENCE Bennett PB. Elliott DH (eds) 1993 The physiology and medicine of diving. WB Saunders, London.

2

FIG. 2.3 Relationship between depth, duration of dive and need for controlled ascent to the surface

SUBMERSION AND DROWNING Drowning is a relatively common cause of accidental death, particularly in children, in whom only motor accidents and cancer are more common causes of death. In adolescents and adults, alcohol and drugs are frequently a contributory factor. Spinal injury is a relatively common problem, particularly after submersion following diving. There are considerable differences in the osmotic pressure of salt water (5% NaCl), fresh water (0% NaCl) and plasma (0.9% NaCl). It has been suggested that when large amounts of salt water are aspirated into the lung, water may be sucked into the alveoli from pulmonary capillary plasma, causing death from pulmonary oedema.4 When fresh water is aspirated, however, large volumes may pass into the pulmonary circulation, causing haemolysis and consequent potassium release, which may lead to cardiac arrest. In fact, in both cases death can result from acute reflex laryngospasm, causing asphyxia. The differences between submersion in fresh and salt water are probably trivial; the major factors determining survival are the duration of submersion and the severity of the consequent hypoxia.

RESUSCITATION FROM NEAR-DROWNING A patient who is nearly drowned needs urgent resuscitation. The basic techniques are the same as for any 'sudden death', but the physiology of drowning raises special issues. In both fresh- and sea-water drowning gastric aspiration must be performed once a cuffed endotracheal tube is in place. Large volumes of water tend to be swallowed during submersion, and vomiting during resuscitation is common.

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Similarly, once in hospital, ventilation with positive endexpiratory pressure is required in an attempt to reinflate atelectatic and waterlogged lungs. Acute respiratory distress syndrome (ARDS) is a complication. Hypothermia is frequently an associated problem and septicaemia is a common complication. Defibrillation for VF or VT is less effective in severe hypothermia. Patients who are breathing and coughing have a good prognosis (Table 2.1). Sea-water drowning can be associated with cardiac arrest produced by the rapid absorption of Ca2+ and Mg+ into the blood. Treatment by basic life support is frequently effective in sea-water drowning, if begun within 5 minutes. Fresh-water drowning may produce massive intravascular haemolysis, associated with ventricular fibrillation and

TULEJh Mortality following submersion Mortality (%)

Grade

Definition

1

Normal lung auscultation with coughing Abnormal auscultation, with crackles in some regions Auscultation: acute pulmonary oedema, no hypotension Acute pulmonary oedema, plus hypotension Isolated respiratory arrest Cardiopulmonary arrest

2 3 4 5 6

0 0.6 5.2 19.4 44

93

Modified from Szpilrnan

CASE STUDY 2.1 SUBMERSION AND DROWNING A 26-year-old woman went for a swim with her friend at the local pool. After she had been in the water for some time swimmers at the side of the pool noticed her thrashing around beneath the surface. The onlookers and pool staff pulled her out of the water at the shallow end. She was unconscious, not breathing, and had no detectable pulse. One of the onlookers was medically qualified. Mouth-to-mouth resuscitation and chest compression was initiated and the emergency services were called. On arrival at the scene the ambulance crew documented ventricular fibrillation on the ECG, shocked the patient and restored sinus rhythm. The patient was transferred to the local accident and emergency department. On arrival in A&E the patient was breathing and had a satisfactory blood pressure. There were no signs of external trauma. The axillary temperature was 36.0°C. There was vomitus in the mouth and the patient had obstructed breathing. The Glasgow Coma Scale was 3. The patient became greatly

O MCQ 2.5

52

agitated. Arterial blood gases, breathing supplementary high-flow oxygen, showed ^302 27.3 kPa, Faco2 9.2kPa, bicarbonate 16, pH 7.07. The patient was sedated, intubated and ventilated. She was given intravenous antibiotics and steroids. Additional history obtained from her friend revealed that the patient had been depressed for some time but was not, as far as the friend knew, taking any medication. There was no past history of attempted suicide or epilepsy. Questions 1. Wharf is the prognosA for this patient? 2. On afrival it A&E, fifhat ire the most important management issues? 3. A chest X~fay was performed; what might it show? 4. What is ydur interptetatidn of the arterial blodd gas results? For the next few days the patient was managed in the intensive care unit.

The acid-base status returned to normal. A CT brain scan showed no abnormalities. The chest X-ray initially showed bilaterial patchy air space ©pacification, but subsequently cleared (CASE FIG. 2.1.1). Gas exchange gradually improved and the patient was extubated. Moderate hypoxia persisted; the patient was treated with CPAP and transferred to the high-dependency unit. The patient became febrile, was diagnosed as having a secondary chest infection and treated with antibiotics. One week after admission the patient's jPao2 was within normal limits. The patient was alert, mobilized, and discharged 9 days after admission. She had no recollection of the events that led up to her submersion in the swimming pool. Question 5. What would you regard as being the main factor or ,„, factors that ultimately y resulted in a good outcorne for this patient?

CASE STUDY 2.1

2

CONTINUED

CASE FIG. 2.1.1 Chest X-ray. There is bilateral air space shadowing throughout the lungs, affecting the left lung more that the right Discussion Submersion and drowning is a common cause of death in young people. The most important factor determining outcome is the severity and duration of hypoxia. Clearly, cerebral and spinal trauma may also be critical in patients who, for example, dive into shallow water. Severe hypoxia causes cardiac arrhythmias, cardiopulmonary arrest, brain damage and acute lung injury. Ventricular fibrillation and

cardiopulmonary arrest indicate a poor prognosis (Table 2.1). The most important management issues are to sustain and improve tissue oxygen delivery. This patient's ventilation was inadequate and the upper airway was compromised, hence the importance of intubation and mechanical ventilation. Hypothermia is often a severe problem, but not in this particular case. The patient was treated with steroids, ostensibly to reduce lung

hyperkalaemia, which can be difficult to treat. Survival after prolonged submersion during warm weather is unusual, but survival (with normal cerebral function) has been recorded in children, even after 30 minutes' immersion, particularly in low-temperature water. Sudden death due to a combination of vagal slowing of the heart and intense peripheral vasoconstriction may occur in previously fit individuals who dive into cold water. O

FURTHER READING Szpilman D. Near drowning and drowing classification: a proposal to stratify mortality based on the analysis of 1821 cases. Chest 1997:112:660-665.

injury, but there is little evidence to support such therapy. The chest X-ray showed bilateral airspace shadowing consistent with pulmonary oedema (figure). Hypoxia causes increased pulmonary capillary permeability, alveolar flooding, and can lead to established ARDS. Many patients rescued from submersion vomit and some aspirate, and atelectasis may occur. Acute laryngospasm stops large volumes of water filling the lungs and the hypoxic lung injury is the more important lung insult. The arterial blood gas results show a severe combined respiratory and metabolic acidosis (i.e. the Paco2 is raised and the bicarbonate is reduced). This reflects reduced ventilation and inadequate oxygen delivery to all tissues. Hence the crucial importance of restoring the circulation and ventilation. With appropriate therapy the acid-base abnormalities were rapidly corrected. This patient survived and avoided hypoxic brain damage because of the prompt and effective poolside resuscitation (mouth-to-mouth resuscitation, chest compression and cardioversion). Without such rapid intervention the prognosis would have been very poor.

ELECTRIC SHOCK Injury following electric shock depends on the voltage and current. Below 100 V sudden death is less likely. Alternating current appears to be much more dangerous than direct, as it produces muscle spasm and is more likely to stop the heart. The direction of flow is also important, as flow from hand to hand or hand to foot traverses the heart. At high voltage, the body heats up as the current flows. This heating is much more severe in a small cross-sectional area (fingers) than in a large one (trunk), and burns and charring are thus found mostly in the hands. The upper limbs and trunk are less affected, and deep tissues more damaged than the superficial. The skin burns do not correlate with the level of internal injury. Burns occur at the skin, and arcing of the current may ignite clothing, causing further burns.

53

Clinical features With high voltage, cardiac arrest occurs. Cardiac resuscitation is essential, as is a careful assessment for burns which may manifest themselves later. Arrhythmias may recur for up to 2 days after resuscitation. Intestinal perforation and liver and gallbladder injury may occur. There may be cerebral and spinal cord damage, and peripheral nerves may be permanently damaged. Spinal cord injury may have a delayed onset, with paraplegia or a tabes dorsalis-like syndrome. Acute muscle necrosis may result in renal failure.

Treatment After resuscitation the cardiac rhythm must be monitored for 2 days after the last rhythm disturbance. Hyperkalaemia may occur as a result of acute tissue necrosis, and may need immediate treatment with glucose and insulin or haemodialysis. Renal failure due to rhabdomyolysis must be treated. Intravenous fluids should be used to maintain urine flow, which will minimize the danger of renal failure due to massive myoglobinuria. Mannitol or a diuretic may be needed to maintain urine output. A surgical assessment must be made of burns and charring, and peripheral circulation. Debridement, fasciotomy and even amputation may be necessary. An extreme example of high-voltage injury is a lightning strike. Cardiopulmonary resuscitation is essential, as described above. Rhabdomyolysis and burns are treated in the same way as in other electric-shock injury. With effective resuscitation, over half the victims will survive.

SMOKE INHALATION

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Smoke inhalation causes anoxia, frequently exacerbated by carbon monoxide poisoning and, if plastics are burned, hydrogen cyanide poisoning. Lung and airway injury is mainly chemical rather than thermal. Initial effects are mainly on the airways, including laryngeal oedema and bronchoconstriction; severe pulmonary oedema can develop. Factors predictive of severe injury include fire in an enclosed space, black sputum, burns around the mouth, reduced consciousness, altered voice, and symptoms and signs of respiratory distress. In fires involving plastics, carboxyhaemoglobin levels generally reflect hydrogen cyanide levels. Carboxyhaemoglobin levels should be measured in all cases and levels greater than 10% indicate significant exposure; above 25% indicates severe exposure. High CO levels cause hypoxia; the true arterial oxygen saturation is not demonstrated by pulse oxymetry, and the %CO must be subtracted from the oxymeter reading to give the correct value. Treatment is supportive, including humidified oxygen, bronchodilators and mechanical ventilation in severe cases. Steroids are useful when airways obstruction is severe and persistent. Severe hydrogen

cyanide poisoning requires treatment with sodium nitrite and thiosulphate. In patients surviving smoke inhalation injury the long-term prognosis for pulmonary function is good.

PASSIVE SMOKING Breathing other people's cigarette smoke is a much less serious cause of morbidity and premature death than active smoking, but it does represent one of the most serious causes of indoor air pollution that can affect health. Respiratory symptoms such as wheezing, coughing and the development of respiratory infections are increased in the children of smoking parents. The effect is particularly noticeable in children aged under 1 year. Various international expert committees have concluded that exposure to environmental tobacco smoke increases the incidence of lung cancer in non-smokers, the observed risk being some 30% higher than expected and contributing approximately 300 cases of lung cancer annually in the UK. There is also evidence that environmental tobacco smoke can exacerbate asthma in adults.

CHEMICAL WARFARE Chemical weapons were first used on a large scale during the 1914-18 war, and although a wide range of chemicals were subsequently developed they were not used extensively until the Iran-Iraq war. Their use, but not their possession, is banned by an international treaty. The agents most readily available are nerve gases and mustard gas (see below). Other chemical agents include lewisite, hydrogen cyanide, and riot control agents such as CS gas, phosgene and chlorine. Biological weapons such as anthrax and Botulinus toxin are also potential weapons. When the use of these weapons is threatened, protection of those involved in, or close to, the conflict with respirators and protective clothing is important. Obviously, civilian populations are very vulnerable. Rescue of casualties by medical teams may expose these personnel to risk, so they should also take preventative measures. For all casualties of poisoning by chemical and similar weapons, decontamination is essential, particularly before they are transferred to areas where unprotected staff may be working. Mustard gas (sulphur mustard) is an alkylating agent (as is nitrogen mustard). It is a 'vesicant', causing skin blistering, sloughing of respiratory epithelium, ocular damage and, in a small number of cases, subsequent bone marrow depression. There is no antidote and the treatment is supportive, including careful management of the skin damage, which often takes many months to treat. Overall mortality of mustard gas exposure is only about 2%.

Nerve agents are organophosphorus compounds, closely related to insecticides. They inhibit the action of acetylcholinesterase, leading to parasympathetic overactivity and ultimately neuromuscular blockade. Clinical manifestations are meiosis, bronchoconstriction, hypersecretion and hypersalivation, rapidly progressing to general paralysis (including the respiratory muscles), convulsions and death. These events may occur in minutes, so rapid treatment is essential; this includes the use of atropine and oximes (which reactivate acetylcholinesterase). If there is a risk of nerve gases being used, pretreatment with pyridostigmine, which binds reversibly to acetylcholinesterase and thus 'protects' it from the effects of the nerve gas, is useful. Many armies now equip personnel with individual antidote packs for use in the field.

FURTHER READING

2

Howard J, Tyrer F H 1987 Textbook of occupational medicine. Churchill Livingstone, Edinburgh. A comprehensive and very readable textbook describing environmental and work hazards. Raffle P A B, Lee W R, McCallum R I, Murray R 1987 Hunter's diseases of occupations. Hodder and Stoughton, London. A traditional and comprehensive text covering the entire field of occupational medicine. Skinner D, Driscoll P Earlam R (ed) 1991 ABC of major trauma. BMV Books, London. A concise, practical account of important topics in major trauma. Ward M, Milledge J S, West J B 1994 High altitude medicine and physiology, 2nd edn. Chapman and Hall, London. An excellent book covering all medical aspects of high altitude medicine.

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3

link to form the backbone of each strand, and the bases on each strand face each other and pair by hydrogen bonding. The base pairing is specific: adenine always pairs with thymine and guanine with cytosine. The specific base pairing allows DNA molecules to be copied precisely when cells divide. A sequence of bases coding for a gene is usually divided into coding regions (exons) and non-coding regions (introns). DNA is transcribed by synthesizing a singlestrand ribonucleic acid (RNA) molecule, using one of the DNA strands as a template. The resultant messenger RNA (m-RNA) molecule is processed to splice out the noncoding regions and to modify each end, and then migrates into the cytoplasm, where it directs the synthesis of a specific protein by a process known as translation. This process involves the interaction of the m-RNA with both ribosomes in the cytoplasm and a series of molecules known as transfer RNA (t-RNA) (Fig. 3.2). t-RNA is a specialized molecule to which can be attached a specific amino acid. Each t-RNA carries a three-base coding region which pairs specifically with a corresponding sequence of three bases on the m-RNA. The sequence of three bases is known as a codon and is specific for each amino acid. The sequence of codons makes up the genetic code. There are also three codons which determine the end of a protein; these are known as stop codons. A gene may occupy a sequence of one to tens of kilobases (one kilobase = 1000 base pairs), depending on the length of the resultant protein and the number of introns in the gene. A chromosome consists of a continuous molecule of DNA coding for many thousands of genes. In a chromosome, DNA is intricately coiled and combined with proteins, including histones, which results in a compact structure that can be seen with a light microscope. Often, special stains are used which create a pattern of light and dark bands. These band patterns are specific for each chromosome, and reflect their macrostructure. Figure 3.3 demonstrates the relative size of a gene, in relation to a chromosome band and the chromosome itself.

TheGeneticBasis of Disease Robin M Winter

DMA, genes and chromosomes 57 Ways of looking at genes 58

Loci, alleles and segregation 63 Chromosomal disorders 65 Single gene disorders 69

Types of single gene mutation 60

Multifactorial disorders 72

Chromosome studies 61

Management of genetic disorders 74

Cell division 63

In the western world, chronic diseases with a substantial genetic component occur in 5-10% of the adult population. Furthermore, more than one in 50 babies has a recognizable congenital anomaly at birth, many of which will have a genetic cause. Genetic disorders and malformations account for around 30% of paediatric hospital admissions and up to 50% of deaths under the age of 15 years. The relative frequency of the different types of genetic disorders in the UK is shown in Figure 3.1. In certain populations, specific genetic disorders are of such high incidence as to represent significant public health problems, e.g. the thalassaemias in Mediterranean and oriental populations, and sickle cell anaemia and other haemoglobinopathies in Afro-Caribbean populations. The incidence of affected homozygotes with these disorders can be as high as one in 50 births in some areas.

DNA, GENES AND CHROMOSOMES The basic unit of inheritance is the gene. A gene is a length of deoxyribonucleic acid (DNA) that codes for a specific protein. The DNA molecule is a double helix, i.e. it is formed from two interwoven strands. Each strand consists of a chain of nucleotides, and each nucleotide is made up of a deoxyribose sugar and a nitrogenous base. There are four possible nitrogenous bases: adenine (A), thymine (T), guanine (G) and cytosine (C). The deoxyribose sugars

FIG. 3.1 The relative frequencies of different types of genetic disorder in the United Kingdom

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FIG. 3.2 DNA transcription and translation (After Emery A E H 1984 An introduction to recombinant DNA. John Wiley, London.) See text of details.

FIG. 3.3 The size of a gene relative to a chromosome and chromosome band, illustrated by the b-globin gene This is situated on chromosome 11 in band 11p15.5, which may contain around 4000kb. The gene itself is around 1600 base pairs long and is part of a cluster of similar genes, the (3-like globin gene cluster.

WAYS OF LOOKING AT GENES SOUTHERN BLOTTING There are three basic steps in the process of Southern blotting for the analysis of the sequences of DNA that make up genes (Fig. 3.4):

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1. Use of restriction enzymes. Restriction enzymes, which originate from bacteria, cut double-stranded DNA at

FIG. 3.4 DNA analysis S DNA is cut at specific points by restriction enzymes into different sized fragments. H These fragments are separated by electrophoresis on an agarose gel and blotted onto nitrocellulose paper (Southern blotting). Specific genes cannot be visualized at this stage, [c] A radioactive DNA probe is used to locate a specific gene. The position of the gene on the gel depends on the size of the DNA fragment in which it is contained.

specific base sequences. The distance between such restriction enzyme recognition sites may range from one to tens of kilobases, so that the genome is cut into fragments of differing sizes. 2. Electrophoresis and Southern blotting. Fragments generated using restriction enzymes can be separated by electrophoresis on an agarose gel. The fragments are then denatured (i.e. double-stranded DNA separates into single-stranded DNA) and a mirror image of the pattern of fragments is made on to nitrocellulose paper by a process known as Southern blotting. 3. Use of DNA probes. At this stage, single-stranded fragments of DNA have been separated according to size, and fixed on to the nitrocellulose filter paper. A gene probe must now be used to identify the individual gene sequences present in specific bands. A gene probe is a radioactively labelled single-stranded length of DNA whose sequence is specific for a particular gene, or length of chromosome. It is sometimes made using mRNA coding for a specific protein, by a process known as reverse transcription. The single stranded probe recognizes complementary sequences of DNA on the Southern blot, and anneals to them. Autoradiography can be used to locate the position of the gene probe, which will mark the position of all similar sequences on the Southern blot. If a gene-specific probe has been used, only a few bands will be seen on the autoradiograph, according to how many restriction enzyme recognition sites there are within the gene itself. Different

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restriction enzymes will generate different patterns, using the same probe. The position of the various restriction enzyme cutting sites within the gene can be inferred, and a restriction map produced.

POLYMERASE CHAIN REACTION (PCR) The polymerase chain reaction (PCR) is a way of amplifying specific stretches of DNA so that further genetic analysis can be carried out on them. The revolutionary nature of the technique derives from the fact that large amounts of specific DNA sequence can be copied from only a few (or even a single) DNA molecules. At the start of the process the DNA double helix is denatured by heat to give two single strands. Two specific primers are then needed to amplify the specific sequence of interest. The primers are made up of single-stranded DNA with a specific complementary sequence to the sequences flanking the target DNA sequence (Fig. 3.5). DNA polymerase is then used to copy the target DNA, starting from the primer sequence on both of the original DNA strands. At the end of this process of DNA extension two double helices containing the target sequence will have been made. These double helices are then denatured and the process is repeated several times. At each step the number of copies of the target sequence doubles.

POLYMORPHIC MARKERS Restriction fragment length polymorphisms (RFLP) The restriction enzyme cutting sites in and around genes are variable, as a common, harmless base change may create or destroy a cutting site. Thus, in some individuals, different patterns may be seen on Southern blotting using the same restriction enzyme and the same gene probe. This is because the gene in question will be contained in fragments of different lengths according to the presence or absence of specific cutting sites. Such restriction fragment length polymorphisms (RFLPs) are extremely important because they act as genetic markers, allowing abnormal genes to be tracked through families (Fig. 3.6).

Short tandem repeat polymorphisms (STRPs) The first generation of DNA markers involved RFLPs in known genes or DNA sequences. Use of these markers required Southern blotting. More modern maps use short tandem repeat polymorphisms (STRPs), which are detectable by PCR. The genome contains many stretches of repeated di-, tri- or tetranucleotides of variable length. One of the commonest is the CA repeat. At a specific chromosomal location in an individual there may be (for

FIG. 3.5 Polymerase chain reaction

example) a (CA)10 repeat on one chromosome and a (CA)20 repeat on the other. This length difference can be detected and is the basis of a polymorphism that can be used for linkage studies. Tetranucleotide repeat sequences are easier to analyse and are the basis of the latest generation of genetic maps.

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TABLE 3.1 Molecular mechanisms of single gene mutation, illustrated by the haemoglobinopathies Abnormality of DNA

Effect

Example

Deletion of gene

Diminished or absent protein, depending on the number of genes involved

Most forms of a-thalassaemia

Point mutation (i.e. single base change)

Substitution of a single amino acid in the protein

Sickle cell anaemia, Hb E, C and many other examples Hb McKees Rocks, some forms of (3-thalassaemia Hb Constant Spring (a-chain)

Creation of a stop codon leading to a short protein chain Removal of a stop codon, leading to an elongated protein chain Alteration of splicing signal

FIG. 3.6 Restriction fragment length polymorphism (1) Shows the two alleles E and H of a gene at a specific locus. The alleles are represented by the coloured blocks on each of the two chromosomes. The arrows indicate restriction enzyme recognition sites. In allele A there is an extra site in the middle of the gene, so that when a DNA sample from this individual is cut with the restriction enzyme and a Southern blot made, three bands will be seen (2). The largest band represents allele B and the two smaller bands allele A. (3) Shows a pedigree where alleles A and B are being passed from generation to generation. Allele B causes an autosomal dominant disorder (e.g. neurofibromatosis) in this family so that the RFLP can be used to track the abnormal gene.

Some forms of a- and p-thalassaemia

Insertion or deletion of a number of nucleotides that are not a multiple of three

Frameshift mutation

Hb Cranston, Tak and Wayne Some forms of p-thalassaemia

Fusion of genes

Absence of normal product and presence of a new protein resulting from the fused genes

Lepore haemoglobins involving (3- and 8-globin chains ((3-thalassaemias)

TRINUCLEOTIDE REPEATS Single-nucleotide polymorphisms (SNPs) The most common type of polymorphism in the human genome is a single base pair change known as a singlenucleotide polymorphism (SNP). These SNPs can now be detected by oligonucleotide microarrays (so called 'gene chips'). This will allow for rapid typing of thousands of polymorphic changes in marker loci and known genes that might predispose to disease. A major project is under way to map thousands of SNPs throughout the human genome.

TYPES OF SINGLE GENE MUTATION

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At the molecular level there are many mechanisms that can give rise to a malfunctioning gene (Table 3.1). The haemoglobinopathies best illustrate the full range of molecular defects that can occur. A mechanism of mutation, only recognized in recent years, involves the expansion of trinucleotide repeats.

An unusual form of mutation consists of expansion of a CAG sequence within a gene, sometimes leading to a sequence of polyglutamine within the coded protein. This disrupts its function. Table 3.2 gives details of eight disorders caused by trinucleotide repeat mutations. For reasons unknown, they all involve abnormal neurological function. Trinucleotide repeat mutations often show the phenomenon of anticipation. This means that the severity of disease appears to increase as the gene is passed down the generations of a pedigree. The clearest example is in myotonic dystrophy, where a grandparent may just have cataracts without overt myotonia, a daughter may have the classic 'adult' form of the disease with myotonia, and her child may have the severe congenital form of the disorder with severe early hypotonia and mental retardation. The explanation for this is that the trinucleotide repeat expands (i.e. the number of repeat sequences increases) each time the gene is copied and passed on to the next generation. In fragile X syndrome premutation carriers can occur. These are males or females who have no clinical or cytogenetic abnormalities but who carry an increased number of trinucleotide repeats in the fragile X gene. When passed on by a female such a premutation can mutate to the full

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TABLE 3.2 Triplet repeat mutations and human disease Disease

Clinical features

Chromosome location

Huntington's chorea

Choreoathetosis, dementia

4p16

Spinocerebellar ataxia typel

Cerebellar ataxia

6p21

Friedreich's ataxia

Cerebellar ataxia

9q13-21

Machado-Joseph disease

Cerebellar ataxia, extra-pyramidal signs, ophthalmoplegia

14q32

Myotonic dystrophy

Myotonia, frontal balding, cataracts, diabetes, male infertility

19q13

Dentato-rubropallido luysian atrophy

• Chorea, seizures, dementia

12p12

Chromosome 1

Spinobulbar muscular atrophy (Kennedy's syndrome)

Muscular atrophy/fasciculation, gynaecomastia

Xq21

Fragile X mental retardation

Non-specific mental retardation, fragile X chromosome on cytogenetic examination

Xq28

References Mandel J-L 1993 Questions of expansion. Nature Genetics 4: 8-9 Richards R I, Sutherland G R 1992 Dynamic mutations: a new class of mutations causing human disease. Cell 70: 709-712

mutation (where the repeat is expanded) and a fully affected child can be born.

CHROMOSOME STUDIES Chromosomes are usually visualized during mitosis, at metaphase (p. 63). At this stage the DNA is coiled and condensed, and the chromosomes consist of two identical chromatids, joined together at the centromere (Fig. 3.7). The position of the centromere is specific for each chromosome. In some chromosomes (1-3) the centromere is close to the centre (metacentric); in others (13-15, 21-22) it is near one end (acrocentric), and in the remainder the centromere is somewhere in between these two extremes (submetacentric). By convention, all chromosomes are divided by the centromere into a short arm (p) and a long arm (q).

CHROMOSOME BANDING Like other cell structures, chromosomes must be stained in order to visualize them with the light microscope. Using various methods, a pattern of bands can be produced which

FIG. 3.7 Chromosome nomenclature, using chromosome 1 as an example

is specific for each chromosome. A number of staining techniques are commonly used: • G (Giemsa) banding is the most widely used technique. Light and dark bands are produced. • Q (quinacrine) banding requires a fluorescent microscope. The band patterns are similar to G-banding. Certain chromosome structures, e.g. the long arm of the Y, are particularly well stained. • R (reverse) banding produces a negative image of G-banding. • T (telomere) banding preferentially stains the telomeres (ends of the chromosomes). • C (centromere) banding stains centromeric regions.

Band nomenclature The banding pattern is specific for each chromosome, and a convention exists for labelling each band. The long and short arms are divided into regions by particularly prominent bands (landmark bands) (Fig. 3.7). Within each region, individual bands are numbered from the centromere distally, and landmark bands are included in the distal region they demarcate. Thus, in Figure 3.7 band Iq32 means band 2 in region 3 of the long arm (q) of chromosome 1.

FLUORESCENT IN SITU HYBRIDIZATION (FISH) Fluorescent in situ hybridization (FISH) is an important technique for recognizing very small deletions of chromo-

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Abnormalities in chromosome number The normal diploid number of chromosomes in humans is 46. Individuals with chromosome counts that are not multiples of the normal haploid number (23) are said to be aneuploid. A fetus can receive higher multiples of the haploid number of chromosomes to give 69 (x3) or 92 (x4) chromosomes. Such triploid or tetraploid fetuses usually miscarry early. If individuals carry one extra chromosome, they are said to be trisomic for the chromosome concerned. Very occasionally, an individual can have two extra chromosomes (double trisomy). Monosomy is the situation where one chromosome is missing. In liveborn children it is virtually only seen for the sex chromosomes, giving monosomy X (Turner's syndrome, p. 69).

Translocation, deletion and insertion

FIG. 3.8 Chromosome FISH in a patient with Williams' syndrome One probe (white arrows) identifies the two No 7 chromosomes. The other probe (elastin, black arrow) is missing from one chromosome 7 indicating a microdeletion.

some material. The technique involves preparing a DNA probe, specific for a particular gene or region of the chromosome. This probe is then labelled with a fluorescent tag. A chromosome slide is prepared and the probe is used to label the specific chromosomal region containing the gene under investigation. For a gene on the autosomes, two labelled tags should show up. If there is a deletion on one chromosome, then only one tag will be visible. FISH can detect chromosome deletions that are much smaller than those visible by conventional light microscopic techniques. Another technique involves chromosome painting. In this technique, probes derived from the whole length of a specific chromosome are labelled with a fluorescent dye (Fig. 3.8). If these probes are then used in the same way as the FISH technique, the whole chromosome is labelled with the fluorescent dye. By using different fluorescent dyes and computer image manipulation, each of the 24 chromosomes can be labelled in a different colour. Chromosome painting is useful for detecting subtle or complicated translocations of the chromosomes (see below).

TYPES OF CHROMOSOME ABNORMALITY

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Chromosome abnormalities can be divided into those involving the number of chromosomes, and those involving breakage or rearrangement.

Breakage of chromosomes can result in loss of material (deletion), exchange of material between two nonidentical chromosomes (reciprocal translocation), inversion of a segment of chromosome (pericentric inversions involve the centromere, paracentric inversions do not), and joining of the two ends of the same chromosome (to give a ring chromosome). Horizontal splitting of the centromere can result in a chromosome with identical long and short arms, an isochromosome. A translocation between the long arms of two acrocentric chromosomes, joined at the centromere, is known as a Robertsonian translocation. These possibilities are illustrated in Figure 3.9.

KARYOTYPE NOMENCLATURE The convention in karyotype nomenclature is to give the number of chromosomes first, followed by the types of sex chromosomes, followed by the types of any additional, missing or abnormal chromosomes. Thus, for example: • • • • •

46,XX - normal female 45,X - Turner's syndrome 47,XY + 21- male with trisomy 21 69,XXY - triploidy, XXY sex chromosome complement 45,X/46,XX - mosaic Turner's syndrome.

For inversions or translocations, the numbers of the chromosomes involved are given in brackets (the chromosome with the lowest number being given first). This is followed by the bands or regions involved in further brackets. Symbols are used to indicate the type of rearrangement involved. Thus, 46,XX,t(9:21) (qll :pll) karyotype means that chromosome 9 has broken at band qll and chromosome 21 has broken at band pll. The small letter t (for translocation) indicates that material has been exchanged between the two chromosomes.

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FIG. 3.9 Types of chromosome aberration ffl Two normal non-homologous chromosomes. DEI A reciprocal translocation between the two chromosomes. Note that material has been exchanged between the short arms. Q-] A pericentric inversion of the large chromosome. Breaks have occurred in the long and short arms and the middle segment of the chromosome has become inverted. [B] A deletion. The top part of the large chromosome has been lost. DEI An isochromosome. The small chromosome consists of two identical short arms due to misdivision after replication. DEI A ring chromosome. Both ends of the small chromosome have joined to form a ring.

CELL DIVISION MITOSIS Division of somatic cells is known as mitosis. This is divided into four stages (Fig. 3.10). Between cell divisions, in interphase, the chromosomes are extremely elongated and cannot be seen with the light microscope. 1. Prophase. As a preparation for cell division, the chromosomes replicate to give the classic structure with two chromatids, and they begin to condense. 2. Metaphase. The chromosomes line up at the centre of the cell. 3. Anaphase. Each chromosome separates longitudinally at the centromere, and the two chromatids pass to opposite poles of the cell. 4. Telophase. Two new daughter cells are created by the formation of a nuclear envelope around each new set of chromosomes.

FIG. 3.10 Mitosis and meiosis See text for details.

different gametes of an individual. This is brought about by two separate means: 1. Different gametes receive different combinations of maternally and paternally derived chromosomes. 2. There is an exchange of genetic material between the two members of an homologous pair of chromosomes, known as crossing over. This process results in the creation of a chromosome containing part of the maternal and part of the paternal member of an homologous pair, known as a recombinant chromosome. Without crossing over, alleles on the same chromosome would always be inherited en bloc. Crossing over takes place during the first step of meiosis (meiosis I), which is divided into prophase, metaphase, anaphase and telophase, as in mitosis. However, meiosis I differs in that homologous members of a pair of chromosomes line up and exchange genetic material during prophase, whereas at anaphase each member chromosome passes to an opposite pole without division at the centromere. Meiosis I is known as reduction division, because it results in the formation of two daughter cells containing 23 chromosomes, each of which has two chromatids that may not be identical because of crossing over. The second step, meiosis II, is similar to mitosis except that each 'parent' cell now has only 23 chromosomes (each with two chromatids), and each 'daughter' cell contains 23 chromatids at telophase. Fusion of parental gametes at fertilization restores the diploid number of chromosomes.

MEIOSIS During the production of gametes, the normal diploid complement of 46 chromosomes must be reduced to the haploid number of 23 in the gametes by the process known as meiosis. During meiosis there is the independent assortment of maternally and paternally derived genes in the

LOCI, ALLELES AND SEGREGATION The genes determining a particular trait are situated at identical points or loci on each member of a homologous pair of chromosomes. The two genes on each chromosome

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FIG. 3.11A Inheritance of alleles at autosomal loci

FIG. 3.12A Autosomal recessive inheritance with first cousin parents The boy at the bottom of the pedigree is homozygous for an abnormal gene inherited from the great-grandmother through both parents. The double line indicates consanguineous marriage.

FIG. 3.11B Inheritance of alleles at X-linked loci

at a particular locus may not be identical, and are known as alleles. If two alleles at a locus are identical, the individual is said to be homozygous at that locus; if the alleles are not identical, the individual is said to be heterozygous. The chance of a child inheriting one particular allele from a heterozygous parent is 1 in 2 (50%). For autosomal loci, if both parents are heterozygous, the chance of a child being homozygous for one particular allele is 1 in 4 (25%) (Fig. 3.11A). If a locus is on the X chromosomes, males can only carry one allele (because they only have one X chromosome). They are said to be hemizygous for a particular allele. All daughters of a male hemizygous for an abnormal gene will receive that gene; on the other hand, none of the sons will receive the abnormal gene (because a male must pass on a Y chromosome to his sons, and not an X). Each time a heterozygous female has a child, there is a 50% chance it will be a boy, and if it is a boy, a 50% chance that he will be affected. Likewise there is a 50% chance of a girl and a 50% chance she will be heterozygous (Fig. 3.11B).Q

O MCQ 3.1

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O MCQ 3.2

FIG. 3.126 Autosomal dominant inheritance Note that the disease is passed on from parent to child and that both males and females are affected. There is also transmission of the disease from father to son.

DOMINANT AND RECESSIVE INHERITANCE Disorders where it is only necessary to carry one abnormal allele in order for an individual to be affected are said to be dominant. In autosomal dominant disorders, the abnormal gene is carried on a non-sex chromosome; in X-linked disorders, the gene is carried on the X chromosome. In recessive inheritance an individual is only affected if he or she does not carry a normal allele at all. For autosomal recessive inheritance, affected individuals will be homozygous for the abnormal allele and both of the parents will be heterozygote carriers. In X-linked recessive disorders males hemizygous for the abnormal allele will be affected, whereas heterozygous females will be unaffected. Typical pedigree patterns are shown in Figures 3.12 and 3.13.2

RECENT ADVANCES THE HUMAN GENOME PROJECT

FIG. 3.13. X-linked recessive inheritance Note that half of the sons of a carrier female are affected and half of the daughters are carriers. All the daughters of an affected male are carriers and all the sons are normal, because a male passes on his one X chromosome to his daughters and his Y chromosome to his sons.

NEW MUTATION, PENETRANCE AND GENE EXPRESSION Abnormal alleles have to arise somewhere in a pedigree by the process of new mutation. Sometimes this can be inferred in a case where an affected individual for an autosomal dominant disorder has normal parents. However, many autosomal dominant disorders also display incomplete penetrance or reduced expression. This means the gene carriers sometimes show no signs, or only a few minor signs, of the condition. The two phenomena are therefore important in the context of genetic counselling. If a person has an autosomal dominant disorder but there is no family history, both parents must be examined very carefully in order to determine whether either of them carries the abnormal gene. If they do not, the chance of their having a further affected child will be small (as this would require a second, unconnected, new mutation). On the other hand, if one parent shows very minor signs of the condition the recurrence risk would be 50% for a further affected child.

GENE MAPS AND LINKAGE The presence of loci close to one another on chromosomes leads to the phenomenon of linkage. The closer together loci are on a chromosome, the lower the probability that a crossover will take place between them during meiosis. I, and the higher the probability that two alleles inherited from the parent will be passed on together to an offspring. Linkage between loci can be studied in suitable families by looking at the joint inheritance of specific traits, and an estimate can be made of the distance separating the loci. These family studies are informative for linkage but do not give information about the chromosomes on which the loci are situated. This problem is known as gene assignment and can be tackled by a number of different methods, such as somatic cell hybrids. Using these methods, a human gene map is being constructed giving information about the

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There are thought to be around 100000 genes in humans, and the total number of DNA bases in the haploid genome is around 3000000000 (3000 megabases). The ultimate goal of the human genome project is to locate every gene and to understand its function. It may not be absolutely necessary to sequence all of the 3000 megabases, as genes are known to be separated by large tracts of non-coding DNA sequences that may have no function. The first phase of the project was to create dense genetic maps of polymorphic genetic markers so that genetic diseases and traits can be located by linkage analysis. Markers are evenly spaced every megabase or so. At the same time the genome was broken up into overlapping DNA fragments (contigs) to provide a physical map. Gradually the genetic markers, known genes, and also parts of the coding sequences from expressed genes of unknown function (Expressed Sequence Tags - ESTs), are being located on contigs. This means that if researchers map a disease to a marker by linkage studies they are able to locate the marker on a physical fragment of DNA (the contig) and ask if any candidate genes are present on the same piece of DNA. If a suitable candidate is not found, the overlapping DNA fragments on either side can be examined and so on. The first draft of the entire sequence of the human genome was completed in the year 2000 and contains 90% of the entire sequence. The final sequence, with 99.99% accuracy, is expected to be completed by 2003, or perhaps earlier. The entire gene sequence of model organisms is also being examined. The fruitfly (Drosophila), an important organism in studying the mechanisms of embryonic development, has already been sequenced. Progress is being made in sequencing the genome of the mouse, which provides important models for many medical disorders. assignment of various loci and their distance from others on the same chromosome.

ICHROMOSOMALDISORDERS FREQUENCY OF CHROMOSOMAL DISORDERS About seven per 1000 babies are born with detectable chromosomal anomalies. Of these, three will have sex chromosome anomalies, 1.5 autosomal trisomies (mainly Down's syndrome) and the remaining 2.5 will have chromosomal rearrangements. Most of the latter are balanced, i.e. no genetic material is lost or gained. Of the autosomal trisomies, only trisomy 21 (Down's

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syndrome) cases are likely to survive into adulthood. The sex chromosome anomalies will frequently present with infertility or amenorrhoea. Unbalanced chromosomal rearrangements usually cause severe physical and mental handicap. However, balanced rearrangements have no effect on the carrier, although they predispose to recurrent miscarriage and children with unbalanced chromosome complements. An unbalanced karyotype means that there is duplication or deletion of some genetic material.O

TABLE 3.3 Chromosomal types of Down's syndrome Type of Down's syndrome

Chromosome complement

Comment

Standard trisomy 21

47,XX,+21 or 47,XY,+21

Approximately 95% of Down's syndrome children

Translocation Down's syndrome

e.g. 46,XY,-14,+t(14;21) 46,XX,-21,+t(21q;21q)

In about 2-3% of cases, an extra chromosome 21 is attached to another chromosome. It is essential to examine the chromosomes of the parents, as one may carry a balanced translocation

Mosaic Down's syndrome

e.g. 46,XX/47,XX,+21

Can be demonstrated in about 2-3% of cases

DOWN'S SYNDROME Between one in 700 and one in 1000 liveborn infants have Down's syndrome. The characteristic physical features are well described in paediatric texts and are present at birth, allowing immediate clinical diagnosis in most cases (Fig. 3.14). The head is foreshortened (brachycephaly) and there are usually three fontanelles. The eyes have an upward slant and crescents of skin are present covering the inner canthi (epicanthic folds). Brushfield spots are commonly seen. These are small white spots, situated around the outer third of the iris. The nasal bridge is flat and the tongue protuberant and deeply furrowed. A single transverse palmar crease is present on the hand, together with a short, incurved fifth finger (clinodactyly). A wide gap is present

between the first and second toes, often with a longitudinal plantar crease. Hypotonia and delayed development are universal. Congenital heart defects (particularly A-V canal defects) and duodenal atresia can occur. It is essential that the chromosomal type of a Down's syndrome child is obtained. There are three possibilities (Table 3.3): • In about 95% of cases there is an extra, free-lying chromosome 21. This form of Down's syndrome is associated with increased maternal age. The risk at a maternal age of 37 years is 1 in 250, at 40 years 1 in 100, and at 45 years 1 in 40. • In 2-3% of cases there is a chromosome translocation, usually involving Robertsonian translocation (p. 62). The parents of such individuals must be checked to see whether they carry a balanced translocation. • The remaining cases are mosaic. In these infants the degree of mental retardation can vary according to the proportion of abnormal cells. The recurrence risks for Down's syndrome are set out in Table 3.4.

TRISOMY 18 (EDWARDS' SYNDROME)

FIG. 3.14 Down's syndrome

1

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Case 3.1

This autosomal trisomy occurs in approximately one in 5000 live births. There is usually low birthweight, hypotonia, a prominent occiput, a small chin, a short sternum and characteristic hand and foot abnormalities. The index and little fingers of the hand overlap the middle two and the nails are small; in the feet the hallux is dorsiflexed and the lateral profile of the foot is convex, with a prominent heel (a so-called 'rocker-bottom foot', caused by a vertical talus). Analysis of the dermatoglyphic patterns of the digits reveals an increased number of arch patterns. Internal malformations are common, especially congenital heart defects (ventricular septal defects, patent ductus arteriosus) and renal abnormalities (horseshoe kidney,

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CASE STUDY 3.1 GENETIC COUNSELLING DOWN'S SYNDROME A couple is referred for genetic counselling because they have had a child with Down's syndrome. Question 1. What facts do you need to know before being able to provide accurate genetic counselling? It is crucial to know the age of the parents, particularly the mother. It would also be important to know whether there was any other family history of Down's syndrome. It is essential to know the precise karyotype of the baby. In this case, the karyotype was 46,XY,+t(14;21). This is a karyotype of a male with Down's syndrome, caused by a chromosome translocation of a chromosome 21 to a chromosome 14. Question 2. What further tests would you need to carry out before being able to counsel the parents?

Discussion Most cases of Down's syndrome have standard trisomy 21. In other words, there are 47 chromosomes, and the extra chromosome is a free-lying chromosome 21. The chances of having a baby with this form of Down's syndrome increases with the age of the mother. Recurrence risks after a baby with standard trisomy 21 are mainly related to the age of the mother, although they are slightly increased over the general population risk at any maternal age. Two to 3% of babies with Down's syndrome have a chromosome translocation. In this case it is essential to test the karyotype of the parents. In many cases both parents might have a normal karyotype, in which case the recurrence risk would be small. Nevertheless, one parent can carry a balanced chromosome translocation, as in the current case. Where the mother carries a balanced

14;21 chromosome translocation, the risks of a further baby with Down's syndrome are about 10%. In a future pregnancy an amniocentesis or chorionic villus sample (CVS) can be offered to check the chromosomes of the baby. Serum screening tests for Down's syndrome are not appropriate in this situation, as they do not provide a definitive answer as to whether the baby has Down's syndrome. The balanced translocation may also be carried by other family members. In this family, the wife's parents should be tested if possible, to see whether they carry the translocation. If one of them does, then testing should be offered to other family members, such as the wife's siblings. The other normal children of the present couple should be offered testing when they are of an age to give informed consent.

It is essential to examine the chromosome types of the parents, as one of them may be a translocation carrier. In this case, the mother had a 45,XX, +t(14;21) karyotype. This means that she was a balanced carrier for a 14;21 translocation (Case Fig. 3.1.1). Question 3. What risks would you give for a baby with Down's syndrome in a further pregnancy, and what tests could be carried out in a future pregnancy? 4. What further tests must be carried out?

CASE FIG. 3.1.1 A balanced 14;21 chromosome translocation (arrow) Note that there is only one chromosome number 21 and 45 chromosomes in all. Clinically this is a normal female.

hydronephrosis). Aplasia of the radius, facial clefts and exomphalos each occur in about 20% of cases. Prognosis is very poor, with 50% of cases dying before 2 months, 90% before 1 year and 99% before 10 years; long-term survivors are very severely retarded. Most cases are caused by an extra chromosome 18 (rather than a chromosome translo-

cation) and there is an association with increased maternal age. The risk of recurrence after a trisomic case is about 1 in 100 for a baby with a chromosomal trisomy (not necessarily trisomy 18); however, these risks might have to be modified for older mothers (see section on Down's syndrome).

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TABLE 3.4 Recurrence risks for Down's syndrome Risk to other relatives (excluding offspring of an affected patient)

Type of Down's syndrome

Risk to siblings of affected patient

Standard trisomy 21 Mother <40 years old

1%

Mother >40 years old

Maternal age risk

Translocation (Parents have normal chromosomes)

Maternal age risk

Maternal age risk

10%

Depends on chromosomes of relative Depends on chromosomes of relative Depends on chromosomes of relative

Translocation (One parent carries the translocated chromosome) Mother carries 14:21 translocation Father carries 14:21 translocation Either parent 21:21 translocation

2% 100%

1%

Mosaic

Probably similar to maternal age risk

Maternal age risk

TRISOMY 13 (PATAU'S SYNDROME) This occurs in about one in 8000 live births. There are significant craniofacial abnormalities, with punched-out scalp lesions (aplasia cutis), microphthalmia, and low-set, malformed ears. Many cases have severe bilateral cleft lip and palate and some cases have hypotelorism or cyclopia (a single central eye with a proboscis-like nose), indicating underlying holoprosencephaly of the brain (failure of midline separation of the cerebral hemispheres). In the hands and feet an extra, hypoplastic digit on the ulnar or fibular side is common (postaxial polydactyly). Brain, heart and kidney malformations are very common. Survival past the first year of life is very unusual and retardation is severe. Most cases arise by standard trisomy, but some are the result of a Robertsonian translocation involving chromosome 13. The risk of recurrence after a trisomic case is about 1 in 100 for a baby with a chromosomal trisomy (not necessarily trisomy 13); however, these risks might have to be modified for older mothers (see section on Down's syndrome).

1

68

MCQ 3.3

FIG. 3.15 Turner's syndrome (45,X) Characteristic fades, webbing of the neck, absent breast development and widely spaced nipples.

SEX CHROMOSOME ABNORMALITIES Klinefelter's syndrome Klinefelter's syndrome (47,XXY) occurs in about one in 1000 males. Adult individuals tend to have eunuchoid proportions with female fat distribution and gynaecomastia. The testes are small. Pituitary gonadotrophins are raised and androgen production is low. Affected individuals are sterile, as they produce no sperm. Androgen therapy may help to improve libido and encourage the development of male secondary sexual characteristics. Intelligence is usually normal, although mild to moderate retardation may be seen.

XYY males About one in 1500 males is XYY. Such individuals are physically normal, although they tend to be tall. Although an increased tendency to psychopathic behaviour has been reported, prospective studies have shown that the majority of affected individuals lead normal lives.

Turner's syndrome The incidence of Turner's syndrome (45,X) is one in 5000

births. Affected individuals are short, tend to have a web of skin on the lateral borders of the neck (Fig. 3.15), and may have other physical abnormalities, such as a broad chest with widely spaced nipples and an increased carrying angle at the elbows. Coarctation of the aorta can occur. The vagina and internal genitalia are normally formed, but the ovaries consist of simple streaks of fibrous tissue without ovarian follicles, so that primary amenorrhoea is the rule. Treatment consists of oestrogen replacement around puberty to promote the development of secondary sexual characteristics.

cific oncogenes (see p. 149). In other cases the precise nature of the genetic change is not known. Occasionally, an individual with a specific chromosome abnormality will be predisposed to develop particular types of cancer (see Table 6.3, p. 150). A group of single gene disorders exists that result in an increased tendency to chromosome breakage, owing to abnormalities of DNA repair after damage by agents such as ultraviolet light and radiation. These disorders, most of which are autosomal recessive, also predispose to malignancies (see Table 6.3, p. 150).

3

47,XXX females Females with a chromosome constitution 47,XXX have no physical abnormalities. However, primary and secondary amenorrhoea may occur, and average IQ is 20-30 points lower than in XX females, so that learning difficulties are more common than in the general population. Nevertheless, the majority of affected females (about 70-80%) have normal intelligence. 1

CHROMOSOME DELETIONS AND DUPLICATIONS A large proportion of individuals with chromosome abnormalities have the normal number of chromosomes but a small piece of a specific chromosome is missing or duplicated. Sometimes there may be a combination of a chromosome deletion and duplication. Any part of any chromosome can be involved. Significant chromosome deletion or duplication usually causes a combination of congenital malformations, with developmental delay. It is often difficult to predict the precise clinical picture from knowing the specific chromosome deletion or duplication, but there are a number of specific syndromes caused by particular chromosomal regions being affected. Microdeletion syndromes are also being recognized, where the deleted chromosome material must be detected by FISH (see above, page 61). Any child with a combination of malformations, or an unusual facial appearance, together with developmental delay, should have his or her chromosomes examined.

CHROMOSOME ABERRATIONS AND CANCER Cytogenetic analysis of any malignant cell will frequently reveal a non-specific chromosome abnormality. However, there are certain malignancies where a characteristic abnormality is found; in others, the development of a specific chromosome change can be of prognostic significance. In the case of Burkitt's lymphoma and chronic myeloid leukaemia, the chromosome translocations are known to bring together the loci for immunoglobulin genes and spe-

SINGLE GENE DISORDERS Sir Archibald Garrod first put forward the concept of an 'inborn error of metabolism' in 1908 after studying alkaptonuria, a familial disorder in which patients excrete large amounts of homogentisic acid. This led to the concept that an enzyme controlling a metabolic step can be missing or reduced, leading to failure of production of essential metabolites further down the metabolic chain (e.g. in albinism), or the accumulation of toxic substrates of the enzyme (e.g. in alkaptonuria and phenylketonuria) (Fig. 3.16). Today, McKusick's catalogue of genetic disorders lists over 4000 defects involving every organ system. Only a few important groups of disorders are described here.

AMINOACIDOPATHIES Defects in the metabolism of amino acids include a form of congenital hypothyroidism, albinism, disorders of the urea cycle and organic acid metabolism, as well as the disorders described below.

Phenylketonuria Phenylketonuria is an autosomal recessive disorder affecting about one in 10000 infants at birth. It is usually caused by a defect of the enzyme phenylalanine hydroxylase, which converts phenylalanine to tyrosine. The most common clinical presentation, now rarely seen in developed countries because of screening, is vomiting in early infancy, with eczema, depigmentation of skin and hair, hypertonia, seizures, and mental retardation developing during the first years of life. Fortunately, screening at birth is now widely available, in which a drop of blood, obtained within the first few days of life, is placed on a filter paper and a bacterial inhibition assay used to measure phenylalanine levels (the Guthrie test}. Affected infants can be treated by giving an artificial diet low in phenylalanine until at least 8 years of age. If dietary control is strict the prognosis for mental development is good. Females with phenylketonuria run a very high risk of having abnormal children, unless a strict diet is reintro-

69

FIG. 3.16 Partial metabolic pathway of phenylalanine, tyrosine and related compounds showing position of 'metabolic blocks' caused by enzyme deficiencies DO Deficiency of phenylalanine hydroxylase results in an inability to metabolize phenylalanine, leading to phenylketonuria. E Tyrosinase deficiency leads to an inability to produce melanin, thus causing albinism. [3 Deficiency of homogentisic acid oxidase leads to the accumulation of homogentisic acid, and hence to alkaptonuria. OS Deficiency of any one of several enzymes at this point means that thyroxine cannot be synthesized. The result is familial hypothyroidism.

TABLE 3.5 transport disorders Disorder

Site

Metabolites affected

Clinical features

Inheritance

Intestinal disaccharidase deficiency Hypophosphataemic rickets

Small intestine

Maltose, sucrose, lactose

Autosomal recessive

Renal tubules

Phosphates

Abdominal pain and distension, diarrhoea Rickets (vitamin D-resistant)

Hartnup disease

Renal tubules

Amino acids (mono-aminomonocarboxylic group)

Red, scaly facial rash, ataxia

Autosomal recessive

Cystinuria

Renal tubules, small intestine

Cystine, ornithine, arginine, lysine

Renal stones

Autosomal recessive

Nephrogenic diabetes insipidus

Renal tubules

Insensitivity to ADH

Polyuria, polydipsia

X-linked dominant

duced throughout pregnancy. Their children do not have phenylketonuria themselves, but the abnormal metabolites cross the placenta during pregnancy and affect the developing fetus. Microcephaly, cardiac defects and mental retardation are common. Phenylketonuria is a heterogeneous disorder: the most common form results from a mutation at the phenylalanine hydroxylase locus itself. However, a rarer form caused by a defect in dihydropteridine reductase has been described. This enzyme is essential for the recycling of the cofactor tetrahydrobiopterine.

Homocystinuria Homocystinuria is an autosomal recessive disorder and affects one in 200000 infants. It is due to a defect of cystathionine (3-synthase and leads to the accumulation of homocysteine, methionine and other metabolites. Clinical 1 70

MCQ 3.4

X-linked dominant

manifestations include lens dislocation, mental retardation, osteoporosis, and thrombosis of arteries and veins. Affected individuals tend to be long and thin, making Marfan's syndrome part of the differential diagnosis. Treatment involves a low-methionine diet, and pyridoxine treatment in that proportion of patients who are vitamin B6 responsive.

Cystinosis Cystinosis, an autosomal recessive disorder, should be distinguished from cystinuria (see Table 3.5). There are abnormally high intracellular levels of free cystine, which lead to crystal deposition in the kidneys, conjunctiva, bones and leukocytes. Presentation is in childhood, with photophobia and crystalline deposits in the conjunctiva, and the effects of renal tubular malabsorption (Fanconi's syndrome). Renal failure can occur before the age of 10 years. Alkaptonuria Alkaptonuria is a rare autosomal recessive disorder caused by a defect in the enzyme homogentisic acid oxidase

(Fig. 3.16). Homogentisic acid, a byproduct of the metabolism of tyrosine and phenylalanine, cannot be metabolized and so accumulates in the body tissues and is excreted in increased quantities in the urine. Classically, the urine turns dark on standing and the sweat may be black, but these findings are not invariable. The homogentisic acid and resultant polymers also stain cartilage and other connective tissue; ochronosis is the name given to the generalized blue/grey pigmentation that results and is best seen in the cartilage of the ear and the sclerae. It can also be seen in the tendons of the hands, through the overlying skin, in older patients. The main clinical problem is arthritis, which affects the hips, knees, shoulders and spine. Onset is unusual before middle age. Radiological changes include narrowing and calcification of the intervertebral discs, together with some fusion of the vertebral bodies. Rarer complications include an increased incidence of ischaemic heart disease, calcification of the cardiac valves, and occasionally arterial aneurysms. Treatment is symptomatic.1

TABLE 3.6 Storage disorders Example

Symptoms

Glycogen storage disorders

12 types including: Von Gierke's disease (glucose-6-phosphate deficiency) Pompe disease (acid maltase deficiency)

Hepatomegaly, hypoglycaemia, muscle weakness, cardiac failure (Symptoms vary according to type)

Niemann-Pick disease Gaucher's disease Krabbe's disease Metachromatic leucodystrophy

Hepatosplenomegaly (in some), progressive neurological deterioration

Tay-Sachs disease

Progressive blindness and neurological deterioration

At least 8 types including: Hurler syndrome, Hunter syndrome, MaroteauxLamy syndrome, Morquio's syndrome, Sanfilippo's syndrome

Hepatosplenomegaly, abnormal bones (dysostosis multiplex), corneal clouding, mental deterioration

Sphingolipidoses (p. 1413)

Gangliosidoses (p. 1413)

Mucopolysaccharidoses (p. 1029)

3

The transport of metabolites across cell membranes often involves specific binding sites and transport proteins. Mutations can disrupt these mechanisms and result in a group of disorders characterized by the failure of essential metabolites to enter the appropriate body compartments. Some important disorders are outlined in Table 3.5.

STORAGE DISORDERS Macromolecules in the body are often in a perpetual state of accumulation and breakdown. Thus, if an enzyme needed to break down a macromolecule is deficient, increased accumulation occurs, leading to a variety of symptoms according to the type of molecule and the site involved. Storage material usually accumulates in the lysosomes. Several examples are given in Table 3.6.

CONNECTIVE TISSUE DISORDERS

Type

(p. 1028)

TRANSPORT DISORDERS

TABLE 3.7 Types of collagen and their functions

The main protein of connective tissue is collagen, of which there are at least four different types, each with its own functions (Table 3.7). Defects of collagen synthesis can cause a wide variety of disorders (Table 3.8). Some of these have been characterized at the molecular level, and various collagen probes are available for precise diagnosis. The specific collagen chain abnormality can sometimes be deduced from the clinical features (Table 3.8). Thus, some forms of osteogenesis imperfecta are caused by abnormalities of type I collagen, whereas type III collagen deficiency can result in a form of Ehlers-Danlos syndrome, with thin, atrophic skin and a tendency to spontaneous rupture of

TABLE 3.8 Connective tissue disorders Disorder

Clinical features

Ehlers-Danlos syndrome (At least 8 distinct forms)

Hyperextensible skin, loose joints, 'cigarette paper' scars, easy bruising, rupture of blood vessels, viscera etc.

Osteogenesis imperfecta (At least 4 distinct forms)

Multiple fractures of bones, blue sclerae, hyperextensible skin, easy bruising

Cutis laxa

Loose skin, premature aged appearance, hernias, diverticula and emphysema

(Several different forms)

Type

Function

Marfan's syndrome

I II III IV

Major collagen in skin, tendon, bones, heart valves and scar tissue Major collagen in cartilage Found mainly in blood vessels and intestine; also in skin Found mainly in basement membranes

Tall stature, span greater than height, loose joints, dislocated lens of eyes, aortic and mitral incompetence, dissection and aneurysms of the aorta

Pseudoxanthoma elasticum

Angioid streaks of retina, linear yellow raised skin lesions, vascular disease

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CASE STUDY 3.2 LENS DISLOCATION IN A TALL BOY A 14-year-old boy was referred to the genetic clinic because dislocation of the lenses of both eyes had been diagnosed after an episode of blurred vision. He was also noted to be tall.

Marfan's syndrome. Other physical features of Marfan's syndrome are a high-arched palate, pectus excavatum 1 or carinatum, arachnodactyly (long thin fingers) 2, 3 skin striae (stretch marks), particularly over the shoulders, loins and buttocks, and loose joints. In Marfan's syndrome the lens of the eye classically dislocates upwards, whereas in homocystinuria it dislocates downwards. An echocardiogram should be carried out to look for mitral or aortic valve incompetence and dilation of the aortic root, which precedes a possible dissecting aneurysm of the aorta. Urine should be sent to look for homocystine, although a methionine loading test might be necessary where the diagnosis of homocystinuria seems likely. In the present case, span was 2 cm longer than height, which was on the 98th centile. There was a high-arched palate and significant arachnodactyly. The heart was normal. The patient's father was said to have been tall and had died suddenly at the age of 42 from a ruptured aortic aneurysm. There was no evidence of homocystine in the urine. The diagnosis of Marfan's syndrome

Questions ' What is the differential diagnosis?

What would you ask about inthe family history? What investigation would you carryout? Dislocation of the lenses associated with tall stature suggests a connective tissue disorder. The differential diagnosis lies between Marfan's syndrome and homocystinuria. In the family history, one would ask about tall stature in other family members, and heart defects or sudden death caused by ruptured aneurysms or other vascular problems. The latter would suggest Marfan's syndrome. One would also ask about parental consanguinity, which might suggest the recessive disorder of homocystinuria. In the clinical examination one would measure both height and span. A stature above the 90th centile with span greater than height suggests

blood vessels and other internal organs. Defects of the connective tissue protein elastin are thought to cause the different forms of cutis laxa. Both collagen and elastin are abnormal in pseudoxanthoma elasticum (Ch. 12, Table 12.39). Marfan's syndrome has been shown to be caused by a defect in fibrillin protein.

MULTIFACTORIAL DISORDERS Many common malformations, some diseases and many normal traits are said to have a multifactorial origin, in that both genetic and environmental factors contribute to their O Fig. 3.1 0 Fig. 3.2 3

72

Q Case 3.2 0 Fig. 3.4 6

Fig. 3.3 Fig. 3.5

therefore seemed very likely (De Paepe et al, 1996). Discussion Marfan's syndrome is an autosomal dominant condition caused by mutations in the fibrillin gene on chromosome 15. The gene can be examined to look for mutations in suspected cases, but this is technically difficult because of the size of the gene, and in many cases diagnosis relies on clinical findings. Apart from dislocation of the lens, other clinical complications include joint laxity and associated scoliosis, in addition to mitral and aortic valve incompetence and aortic root dilation leading to aneurysms. Prophylactic p-blocker therapy can be given to alleviate the risk of aneurysms. Regular follow-up is needed for cardiac, orthopaedic and ophthalmological problems. Affected individuals have a 50% chance of having similarly affected children.

Reference De Paepe A, Devereux RB, Dietz HC, Hennekam RCM, Reed E (1996) Revised diagnostic criteria for Marfan syndrome. Am J Med Genet 62: 417-426.

aetiology. Furthermore, the genetic component is thought to be due to several genes acting together - so-called polygenie inheritance. A good example is the inheritance of height. The genetic component is determined by several genes, and final height correlates between parents and children. Nevertheless, environmental factors (such as nutrition) can play an important role. The contribution of the many factors involved results in a gaussian (normal) distribution of height in the general population.

COMMON MALFORMATIONS There are many clues which suggest that a common malformation has a multifactorial origin: • After one affected family member, the risk to other firstdegree relatives is usually in the range 1-5%, depending on the condition.

TABLE 3.10 Some common disorders of multifactorial origin, with possible geneti c markers

TABLE 3.9 Recurrence risk (%) in some common multifactorial malformations Normal parent

Condition

Affected parent Risk of second Risk of third Risk of affected child affected child affected child

Cleft palate alone 2 Cleft lip ± cleft palate 4 Neural tube defect 4 Club foot 3 Dislocation of hip 6 Congenital heart disease 1-4 (varies with type) Hirschsprung's disease (long segment): Male index case 8 14 Female index case Pyloric stenosis: Male index case 3 7 Female index case

8

7

10 10 10 10

4 4 3 12

5-10

1-10

-

-

_

4 13

• The presence of additional affected family members increases the risk to subsequent offspring. • Where a condition can have varying degrees of severity (e.g. cleft lip, with or without cleft palate), risks are higher for relatives of an individual with a more severe malformation. • If there is a sex difference in incidence, risks are greater for relatives of an affected individual of the less commonly affected sex. • The risk declines rapidly as one passes from first- to second-degree relatives. It is thought that everyone inherits a liability to a particular malformation. The degree of liability can vary in different individuals and families, according to the number of adverse genes and environmental factors present. If the liability exceeds a given threshold, the malformation is manifested. Individuals from families where there is more than one affected member will, on average, have a higher liability, as will relatives of more severely affected individuals. Similarly, where a condition is less common in a particular sex, affected persons of that sex must carry a greater liability, as will their relatives. Some common multifactorial malformations with their recurrence risks are given in Table 3.9.O0O

COMMON DISEASES, GENETIC MARKERS AND DISEASE ASSOCIATION Many common diseases, e.g. the common allergies and some forms of epilepsy, have been proposed as candidates for multifactorial inheritance. As more research is carried out into these conditions, heterogeneity is recognized and subtypes are defined. Subdivision is aided by the identifi-

Disorder

Marker

Insulin-dependent diabetes mellitus

HLA haplotypes, e.g, B8, B15, DW3, DW4

Coeliac disease Ankylosing spondylitis Belter's disease Anterior uveitis Peptic ulceration Alzheimer disease

HLA-A1-B8-DW3

3

HLA-B27

Blood group 0 APoE

cation of genetic markers, which may indicate that a major contribution to the disorder is being made by a gene on a specific chromosome. These genetic markers are particular blood groups, tissue types or restriction fragment length polymorphisms (RFLPs) at specific gene loci which are found to occur more commonly in individuals with the disorder (Table 3.10). A good example of the complex interaction between environmental factors and genetic loci is provided by the various possible causes of atheroma. A proportion of patients with early-onset atherosclerosis show abnormalities of lipoproteins or lipoprotein receptors which are determined by various gene loci. In some patients a single gene defect (e.g. of the cell membrane low-density lipoprotein receptors) can strongly predispose to atheroma. In the majority of cases, however, factors such as diet, smoking and high blood pressure may play the predominant role, with minor abnormalities of the lipoproteins merely providing an extra predisposition. The genes that predispose to common disorders are now being sought using genetic linkage techniques.

Linkage disequilibrium and pleiotropy There are two possible explanations for the association of a genetic marker and a specific disease: linkage disequilibrium and pleiotropy. Linkage disequilibrium If a genetic marker (e.g. an SNP, p. 60) is extremely closely linked to a disease locus, specific marker alleles may not be separated from the disease allele by recombination over the generations and an association will be observed in random individuals. This is known as linkage disequilibrium. It should be noted that linkage disequilibrium is a special case, observed only with very close linkage. In most cases of linkage, recombination over many generations will mean that a particular marker allele will not necessarily be associated with the disease in individuals picked at random. Pleiotropy The allele at the marker locus itself may predispose an individual to develop the disease, owing to some function

73

RECENT ADVANCES IN GENE THERAPY Gene therapy, defined as the replacement of a defective gene product, has been carried out for many years, for example in the treatment of haemophilia A and insulindependent diabetes (see Table 3.12). However, recent attempts at gene therapy have involved replacing a defective gene itself, so that it functions in situ to produce the appropriate protein. This approach involves targeting normal genes to a specific tissue so that they are integrated into the genome and function under appropriate regulatory control. At present the accessibility of the affected organ or organs limits the feasibility of this form of therapy to a few diseases only. Genetic disorders affecting the bone marrow are obvious candidates because marrow can be removed and cultured and manipulated in the laboratory before being retransplanted; immunodeficiency diseases and haemoglobinopathies are therefore among the first disorders where attempts at gene therapy have been made. Other organ systems where gene therapy is being tried include the liver and the lungs. Gene therapy for neurological disorders and muscular dystrophies will be more difficult, but is being explored.

of the gene. Some of the disorders associated with specific HLA types may be examples of a pleiotropic effect. For example, a specific HLA type may predispose to infection with specific viruses, leading to some forms of insulindependent diabetes mellitus.

EEIS2 =E :ZZL IE :Z :y 32 SS22 =23 SCREENING

The treatment of many genetic disorders is often most successful if the disorder is diagnosed at an early, presymptomatic stage. In addition, the prevention of genetic disease by genetic counselling and prenatal diagnosis requires the identification of asymptomatic gene carriers. For these reasons, genetic screening programmes have been developed. Depending on the nature and frequency of the condition, screening can involve the entire population, subgroups of the population (for example particular ethnic groups), or specific families in which a genetic disorder is known to be segregating (Table 3.11).

O MCQ 3.5

74

2

Case 3.3

In order to introduce normal genes into the appropriate cells a vector must be used. Vector systems that are being tried include inactivated retroviruses, adenoviruses and liposomes (lipid vesicles containing the appropriate DNA that fuse with the host cell membrane). The Table below summarizes some of the disorders where gene therapy is being attempted. Diseases where gene therapy has been attempted or considered Genetic disorder

Target organ

Adenosine deaminase deficiency (immunodeficiency) Thalassaemia/sickle cell disease Hypercholesterolaemia Phenylketonuria Haemophilia A Cystic fibrosis Duchenne muscular dystrophy

Bone marrow Bone marrow Liver Liver Liver Lung Muscle

TREATMENT OF GENETIC DISORDERS It is still technically difficult to replace missing or defective genes; although it may be possible to isolate and replicate a gene in the laboratory, it is much more difficult to ensure that a replacement gene reaches the correct tissue, and is properly regulated. Efforts are now being made to introduce normal genes into cells to correct genetic defects (see Recent Advances box). There are also a number of treatment strategies for genetic disorders which aim to ameliorate the phenotypic effects. Many common malformations of multifactorial or chromosomal origin can be corrected surgically, and a variety of treatments have been devised for single gene disorders (Table 3.12).

GENETIC COUNSELLING Most doctors will be faced at some stage with questions about the risk of a genetic disorder in patients or their families. Straightforward situations, such as Down syndrome or neural tube defect, can be dealt with by the nonspecialist but complex problems, involving the diagnosis of rare disorders or the use of carrier detection tests and linkage studies, require a specialist opinion.O Whatever the problem, there are a number of essential steps in genetic counselling: 1. Detailed family history. A pedigree of at least three gen-

TABLE 3,11 Screening for genetic disorders Disease

Group screened

Method

Purpose

Phenylketonuria

Total population of neonates

Guthrie test

Early dietary treatment of affected homozygotes

Hypothyroidism

Total population of neonates

TSH levels from dried blood spot

Early thyroxine therapy

Cystic fibrosis

Individuals of reproductive age

Direct DMA analysis of gene mutations

Prenatal diagnosis where both parents are carriers

Sickle cell anaemia and other haemoglobinopathies

Offspring of heterozygote mothers (total population of neonates in some regions)

Haemoglobin electrophoresis

Prophylaxis and early treatment of complications Prevention by counselling and prenatal diagnosis

Tay-Sachs disease

Individuals of Ashkenazi Jewish extraction

Carrier detection by serum enzyme analysis

Prenatal diagnosis where both parents are heterozygous

Adult-onset polycystic renal disease

Relatives of affected individuals

Renal ultrasound, blood pressure, gene tracking in families using DNA probes

Early treatment of hypertension and renal failure

Multiple endocrine adenomatosis

Relatives of affected individuals

Calcitonin, urinary VMA, gene tracking in families using DNA probes

Early treatment of endocrine tumours

Familial polyposis coli

Relatives of affected individuals

Sigmoidoscopy, gene tracking in families using DNA probes, ophthalmoscopy for associated retinal lesions

Identification of gene carriers, early treatment of malignancy

Familial breast cancer

Females in families with multiple affected members

Mutation analysis of BRCA1 and BRCA2 genes

Identification of gene carriers. Prophylactic mastectomy or medical treatment

erations should be taken and details of racial background and consanguinity (i.e. whether parents have common ancestors) obtained. 2. Accurate diagnosis in affected family members. An accurate diagnosis in affected family members must be made. This should include both a pathological diagnosis (established where possible from original notes and investigations) and an assessment of any genetic subgroup of the disorder. 3. Ancillary tests. Chromosome analysis, DNA marker studies or other carrier detection tests may need to be carried out, according to the nature of the problem. 4. Risk assessment. For single gene disorders risk assessment is sometimes straightforward, providing a correct diagnosis is available. For instance, the recurrence of risk for a couple who have had one child with phenylketonuria is 1 in 4, because phenylketonuria is autosomal recessive. Difficulties arise where a disorder has different inheritance types (e.g. retinitis pigmentosa) and with X-linked disorders, where carrier detection tests may need to be applied, new mutations have to be considered and risks must be modified to allow for normal sons in the pedigree. In addition, disorders with a late age of onset (such as Huntington's chorea) or of variable expression (such as tuberous sclerosis) can present problems that may require a specialist opinion. Where linked DNA probes are used, risk assessment can become complex. If a condition is caused by a chromosomal abnormality or is multi-

factorial, empirical risks derived from follow-up studies must be used. 5. Prenatal diagnosis. The availability of prenatal diagnostic tests (Table 3.13) has to be assessed and any possible risks to the mother or fetus weighed against the risk of fetal abnormality.© 6. Communicating risks. Having marshalled all the facts, sufficient time must be set aside to discuss the risks in detail with the patient. A non-directive approach should be taken, whereby objective risks are given and discussed in detail, in the light of the severity of the condition and the availability and reliability of prenatal diagnosis. These factors may be crucial in the final decision of the parents. It is best to give the risks as a proportion (i.e. 1 in 2, 1 in 100 etc.) and to emphasize that a 1 in 20 risk of a child being affected means that 19 times out of 20 the child will not be affected. In order to put the risks into perspective, it is also worth pointing out that over 1 in 50 children are born with significant abnormalities at birth. In comparison to these background risks, a genetic risk of 1 in 20 is generally regarded as low, and those of greater than 1 in 10 as relatively high. However, the perception of an 'unacceptable' risk will depend on a large number of factors. The severity of the condition and the availability of treatment will obviously affect the willingness of a couple to have further children. For example, a 1 in 20 risk of a child with isolated cleft lip and palate will often be seen as acceptable, whereas the

3

75

TABLE 3.12 Therapy for single gene disorders*

TABLE 3.13 Techniques of prenatal diagnosis

Treatment

Procedure

Timing

Types of disorder detected

Villus biopsy

Transcervical 9-11 weeks Transabdominal 12-1 6 weeks

Cytogenetic abnormalities Enzyme defects Single gene defects (DNA probes)

Maternal ct-fetoprotein

16-1 9 weeks

a-fetoprotein Raised: neural tube defects Lowered: Down's syndrome Lowered: Edwards' syndrome (N.B. These are screening tests; diagnosis must be confirmed by further investigation)

Amniocentesis

16-20 weeks

Cytogenetic abnormalities Enzyme defects Neural tube defects Single gene defects (DNA probes)

Ultrasound

From 16 weeks

Anatomical defects Neural tube/hydrocephalus Body wall defects Limb reduction defects Hydrops Major urinary anomaly Bone dysplasias Cardiac defects Craniofacial anomalies

Fetoscopy/ cordocentesis

16-20 weeks

Fetal blood sample Clotting disorders Haemoglobinopathies Cytogenetic abnormalities Fetal skin biopsy Epidermolysis bullosa Ichthyosis Albinism Fetal liver biopsy Urea cycle enzyme defects Fetal visualization Craniofacial defects Digital defects Genital defects

Replacement therapy Replacement of deficient protein Replacement of deficient vitamin or coenzyme: Vitamin B12 Vitamin D Biotin Replacement of deficient metabolite: Cortisone Thyroxine Organ or cell replacement Kidney Bone marrow Blood transfusion Amelioration therapy Restriction of substrates in diet: Phenylalanine Methionine Galactose Drug therapy to remove harmful metabolites: Penicillamine Cholestyramine Iron chelating agents Avoidance of harmful drugs or dietary factors Preventive therapy Removal of potentially malignant tissues Removal of site of destruction of diseased cells (e.g. spleen)

Disorder

Haemophilias Diabetes

Methylmalonicacidaemia (some types) Vitamin D-resistant rickets Biotinidase deficiency Adrenogenital syndrome Congenital hypothyroidism Polycystic renal disease Immunodeficiencies Osteoporosis Thalassaemias

Phenylketonuria Homocystinuria Galactosaemia Wilson's disease Hypercholesterolaemia Thalassaemias G6PD deficiency Porphyria

Polyposis coli Spherocytosis

* After Emery & Malcolm (1995)

same risk for a child with severe, untreatable mental retardation may seem too high. 7. Sympathy and understanding. If a couple have given birth to an abnormal child, the genetic counselling clinic is often the place where considerable feelings of guilt are expressed. Alternatively, there may be an understandable tendency to blame poor medical care or environmental factors for the abnormalities. Time should be set aside to discuss all these feelings in a sympathetic and understanding manner, as they are part of the normal reaction to the birth of an abnormal child. Guilt and blame are usually the result of lack of information. Once a couple have been fully informed of the nature and causes of a child's problems, they can be helped to accept the fact that many genetic abnormalities are unavoidable.

76

Successful genetic counselling requires a combination of

communication skills, detailed genetic knowledge, and a sound clinical background in both adult and paediatric medicine, if couples are to be helped to make the most appropriate decisions about childbearing. It is this combination that makes the practice of clinical genetics so rewarding.

FURTHER READING Emery A E H, Malcolm S 1995. An introduction to recombinant DNA in medicine, 2nd edn. John Wiley, Chichester. A good introduction to the techniques and uses of DNA analysis in medicine. Rimoin D L, Connor J M, Pyeritz R E 1996. Emery and Rimoin's principles and practice of medical genetics, 3rd edn. Churchill Livingstone, Edinburgh. A comprehensive multiauthor text covering most of clinical genetics.

Harper P S 1998. Practical genetic counselling, 5th edn. Butterworth-Heinemann, Oxford. A comprehensive introduction to the problems of clinical genetics.

The UK Medical Research Council Human Gene Mapping Project Resource Centre (MRC HGMP-RC).

Lander E S, Schork N J 1994. Genetic dissection of complex traits.

This Centre exists to provide specialist resources and

Science 265: 2037-2047. An excellent review of the techniques for finding the genes involved in multifactorial inheritance. McKusick V A 1998. Mendelian inheritance in man, 12th edn. The Johns Hopkins Press, London. A catalogue of all known single gene disorders in man. . Mueller R F, Young I D 1998. Emery's elements of medical genetics, 10th edn. Churchill Livingstone, Edinburgh. An excellent

services

introduction to medical genetics.

Worldwide Web computer addresses A vast amount of free information is available through the Worldwide Web (WWW). A few useful addresses are given below:

a

URL: .. http://www.hgmp.mrc.ac.uk/

OMIM (Online Mendelian Inheritance in Man) This database is a catalogue of human genes and genetic disorders authored and edited by Dr Victor A McKusick and colleagues at Johns Hopkins and elsewhere. This is an excellent place to look for up-to-date clinical and molecular information about genetic disorders. URL: http://www3.ncbi.nlm.nih.gov/omim/

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THEIMMUNESYSTEM

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4

INNATE IMMUNITY

Immunological Disorders

The components of the innate immune system provide a constant, unchanging system of protection for the healthy individual (Table 4.1). These physical and chemical barriers are an essential contribution to good health.

David Edgar and Herb Sewell Physical barriers and phagocytes

The immune system 79

Hypersensitivity 96

Immunodeficiency

Immune-suppression 102

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INTRODUCTION This chapter describes the components of the immune system and their interactions in the defence against infection. It is only intended to provide the reader with sufficient basic scientific detail to understand the clinical disorders described. Abnormal or inappropriate immune responses cause the clinical conditions of immunodeficiency and allergy, and these are discussed with an emphasis on clinical presentation, investigation and management. The principles of autoimmunity, along with conventional and novel immunosuppressive therapies, are also discussed. Throughout, the chapter highlights how recent advances in understanding the immune response at a molecular level have had an impact on clinical practice. The human immune system has developed to combat infection by a diverse range of potential pathogenic microorganisms: bacteria, viruses, fungi, protozoa and helminths. It is a complex but effective system comprised of multiple components which have both specific and overlapping functions. The immune system is conventionally subclassified into the innate and adaptive components, the essential functions of which are: • The differentiation of self from non-self; • The recognition of foreign proteins by specific molecules (antibodies, T-cell receptors); • The recall of previous exposure to specific organisms and the production of a rapid, more effective response upon re-exposure. The last two are characteristic of adaptive immunity.

The intact skin and mucous membranes constitute a barrier to the entry of microorganisms. These agents must therefore rely on physical damage, such as injuries or insect bites, to gain access to the body. Numerous natural antimicrobial substances also exist that fatally damage microorganisms. These include unsaturated fatty acids that are secreted on to the skin, lysozyme that is secreted in tears, and others, including gastric acid. Interferons are a further family of molecules (oc,P,y) that block viral replication and promote antiviral immune responses. However, some microorganisms have developed specific attachment and penetration mechanisms to bypass these initial defences. An example is rhinoviruses, which penetrate the respiratory mucosa by first attaching to a cell surface adhesion molecule ICAM-1 (intercellular adhesion molecule-1). If microorganisms are successful in breaching the physical defences, they are usually phagocytosed and killed by polymorphonuclear leukocytes (PMN) or macrophages. Some bacteria (e.g. pneumococci) can resist phagocytosis by virtue of their capsules, whereas others (e.g. staphylococci) release toxins that destroy phagocytes. Whereas some microorganisms can survive within phagocytic cells (e.g. mycobacteria), giving rise to chronic infection, most are killed in the phagolysosomes by a combination of acid pH, oxygen metabolites (e.g. hydrogen peroxide) and various cytotoxic proteins. However, not all killing is intracellular, and macrophages or PMN can secrete toxic molecules in order to kill large targets, e.g. worms (helminths). In the case of viruses and tumours, natural killer (NK) cells also play an essential role.

TABLE 4.1 Innate and adaptive immune systems Innate Physical protection (skin, mucous membranes) Chemical protection (lysozyme, gastric acid) Interferons Phagocytes Complement

Adaptive Antibody Lymphocytes

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complement and phagocytes are recognized as primary immunodeficiency diseases (PID). In addition, individual elements of the innate system are essential in stimulating the adaptive response during antigen presentation. Although classification into innate and adaptive helps our understanding of the immune response, it is important to remember that these elements are interdependent and function as an integrated system.

ADAPTIVE IMMUNITY

FIG. 4.1 Complement activation pathways The central event in complement activation is cleavage of C3 with the subsequent formation of C5 convertase. The generation of cleavage products (indicated by blue lines) augments the inflammatory response by attracting and activating phagocytes and causing activation and degranulation of mast cells. The deposition of C3b on cellular surfaces to promote phagocytosis is known as opsonization. The terminal pathway components (C5-C9) create the membrane attack complex (MAC) which causes osmotic cell lysis.

Complement system A further line of innate defence is the complement system (Fig. 4.1), a cascade of serum proteins which, when activated in succession, mediate three important effects: • Release of small peptides that stimulate inflammation and attract phagocytes; • Deposition of the cleavage component (C3b) on microbial membranes, which promotes phagocytosis via C3b receptors on phagocytic cells; • Assembly of complement components (C5-C9) into lytic complexes which puncture cell membranes, causing osmotic death. This activation 'cascade' is triggered by numerous microbial surfaces, notably the endotoxins of Gram-negative bacteria, by C-reactive protein (CRP) and mannan-binding lectin (MBL). Through interactions with antibody, phagocytes and mast cells, the complement cascade has an important role in integrating the response to infection.

Summary

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The innate immune system is essential in the defence against infection, and deficiency can result in serious clinical consequences. The vulnerability to infection of patients with severe burns emphasizes the protective value of normal skin. As will be described later, specific defects of

The adaptive immune system differs in two important respects from the innate, with its characteristics of specificity and memory. The adaptive system responds to the environment and 'remembers' specific encounters with foreign antigens. The most important cells involved in the adaptive response are lymphocytes (B and T cells). The antigen recognition molecules on the surfaces of B and T cells (antibody and T-cell receptors) confer the specificity of the adaptive system. These molecules recognize and bind to specific antigens through amino acid sequences that are complementary in structure to the target antigen. Immunological memory is generated after the first antigen exposure (primary response) because antigen-specific lymphocytes proliferate and generate an increased pool of cells. These memory cells, responsive to the specific antigen, remain relatively inactive until the same antigen is encountered again (secondary response). Subsequent stimulation of memory cells results in a secondary immune response that is more rapid and quantitatively greater than the primary response (Fig. 4.2).

Lymphocytes Lymphocytes originate from stem cells in the bone marrow. B lymphocytes complete their maturation in the bone marrow, but T lymphocytes require passage through the thymus, where they complete their maturation and education process. Crucially, it is in the thymus that T cells learn to identify 'self proteins', and any autoaggressive T cells are either allowed to die (by apoptosis) or are rendered non-reactive (tolerant). The bone marrow and thymus are referred to as primary lymphoid organs. The secondary lymphoid organs include lymph nodes, the spleen, Peyer's patches, tonsils and adenoids. These are strategically located to encounter microorganisms entering the body through external tissues, blood, gut, and upper airway, respectively. The structure of secondary lymphoid tissue is exemplified by the lymph node, where the cortex contains mainly B lymphocytes and the paracortex T lymphocytes, whereas antibody-secreting plasma cells are found in the medulla. Peripheral blood normally contains 70-90% T cells, 5-10% B cells and approximately 1-10% natural killer (NK) cells. A characteristic of lymphocytes is their ability to 'traffic' from peripheral blood into the tissues and secondary lymphoid organs. This property allows lym-

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FIG. 4.2 Primary and secondary antibody responses Primary and secondary antibody responses to antigen. This demonstrates the characteristics of the adaptive immune response, i.e. specificity and memory. Upon re-exposure to antigen the immune system recognizes the antigen due to immunological memory. The resulting response has a shorter lag time (lag 2) and a quantitively greater antibody response.

phocytes to encounter antigen in almost all physical locations. The lymphoid tissues of the gut, genitourinary tract, breast and lungs behave, to a certain extent, autonomously, in that particular B cells (largely IgAsecreting) and T cells recirculate selectively through them. This recirculation is mediated by the expression of specific homing receptors and is referred to as the mucosal immune system. The result is that primary antigen exposure at one mucosal site will facilitate protective immunity at other mucosal sites. B cells

The main function of B cells is antibody production. Some B cells are stimulated directly by polymeric antigens and these responses are termed T-independent (e.g. bacterial capsular polysaccharides). Most B-cell responses are however T-cell dependent. For T-dependent responses, B cells are triggered to proliferate by interaction between their surface Ig and the antigen, but they require additional signals from T-helper cells in order to differentiate into plasma cells and secrete antibody. These signals consist of non-antigen specific cytokines (particularly IL-4 and -6) and cell-cell-mediated signalling. The interaction of these cell surface molecules, e.g. gp39 (CD40 ligand, CD40L) on T cells with CD40 on B cells, is essential in facilitating effective B-cell antibody production. During T-dependent responses some proliferating B lymphocytes are retained in germinal centres instead of differentiating 'terminally' into plasma cells. These are the memory B cells. Antibodies Antibodies are a family of five major classes of molecule which have a primary role in combating microorganisms free in the blood or tissue spaces, primarily viruses in their

FIG. 4.3 Immunological molecules V = variable, D = diversity, J = joining, C = constant, HC = heavy chain, LC = light chain, VH/L = variable region of heavy/light chain, CH1(2,3) = constant region 1 (2,3) of heavy chain, CL = constant region of light chain.

extracellular stage, and many bacteria. The antibody or immunoglobulin (Ig) molecule is ideally suited to its function of promoting the removal of foreign antigens. Its basic structure is seen in antibodies of the IgG class (Fig. 4.3). The N-terminal half is composed of heavy (H) and light (L) chains and is responsible for binding to antigen (Fab portions). The C-terminal half (Fc), which consists of portions of heavy chains, determines the class of antibody and is responsible for the other biological functions of the molecule. The major role of antibody molecules is to bind to microorganisms via the Fab portion, enhancing phagocytosis, as phagocytes possess Fc receptors. This process of coating microorganisms with antibody is known as opsonization. The basic four-chain structure is preserved in all five classes of immunoglobulin, but each class has certain characteristics that subserve its specific functions. • IgG molecules are involved in the activation of complement, attachment to phagocytic cells, passage into the tissues and transport across the placenta. The four IgG subclasses (IgG1, IgG2, IgG3 and IgG4) vary somewhat in these functions. • IgM is a large molecule with a pentameric structure. It is mainly confined to the bloodstream and is very efficient at activating complement and agglutinating foreign material because of its 10 antigen-combining sites per pentameric complex. • IgA is the predominant immunoglobulin class secreted at mucosal sites. It has a dimeric structure and is protected from proteolytic damage by a special polypeptide, the secretory chain (Sc). Sc is produced by the mucosal epithelial cells and acts as a receptor-transporter, binding to and taking the antibody into external sites. IgA can

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TABLE 4.2 Immunoglobulin structure and function Class & subclass

Structure

Major functions*

Monomer Monomer Monomer Monomer

C&O

Pentamer

c

Dimer

Mucosal protection Mast cell activation Antigen binding

IgG

IgG, IgG2 IgG3 IgG4 IgM IgA

IgE IgD

Monomer Cell surface bound

c C&O 0

*C, complement activation; 0, opsonization.

therefore survive proteolytic attack in secretions of the eyes, lungs, nose, gut and urinary tract. • IgE attaches via its Fc region to receptors on mast cells. When two bound IgE molecules are cross-linked by antigen, intracellular signalling results in the release of mediators from mast cell granules which cause the clinical features of acute allergy. • IgD is found mainly on B-cell membranes and acts as an antigen receptor. Its soluble form is not thought to have a significant physiological role. The properties of the various Ig classes and subclasses are summarized in Table 4.2. Antibody genes Genes on three different chromosomes code for antibody molecules. The genes of heavy and light chains are not continuous in the germline, but consist of separate clusters of gene segments separated by non-informative regions called introns. The clusters are named according to the part of the immunoglobulin molecule that they encode (Fig. 4.3), i.e. V, variable; D, diversity (heavy chains only); J, joining; and C, constant. During the development of a B cell, the germline DNA encoding the heavy-chain genes undergoes somatic rearrangement and recombination such that a complete heavychain variable region gene, V-D-J, is assembled. After transcription, RNA is spliced to link the V-D-J segment with a C segment to encode a complete heavy chain (V-D-J-C). Once this is accomplished, the light-chain genes rearrange to encode a complete light chain (V-J-C). Heavy and light chains then link together to form a complete antibody molecule. If rearrangement is not successful, the developing B cell is aborted. Enzymes (recombinases) encoded by two genes termed RAG1 and

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MCQ4.1

RAG2 largely control the recombination events in lymphocyte progenitors. Defects or mutations associated with these genes can profoundly and adversely affect the development of the immune system. After gene rearrangement, the B cell does not restore the germline configuration and daughter cells will retain this unique rearrangement, ensuring continued antigenic specificity of that clone and its entire subsequent offspring (progeny). This is the molecular basis of immunological memory, thus maintaining immunological specificity in the clonal progeny. The heavy-chain C gene can, however, change to allow class switching (e.g. IgM-IgG) during the immune response, as occurs in moving from a primary to a secondary response. During the life of a B cell, point mutations may occur within the variable regions (somatic mutation), resulting in a change of affinity of the antibody molecule. Increased affinity for antigen confers a selective advantage to any B cell. This phenomenon results in affinity maturation whereby, as an immune response progresses, antibodybinding affinity increases. The huge potential diversity (i.e. the ability of humans to respond to a multitude of different foreign antigens) of antibody binding specificity (up to 108 specificities) is thus achieved by a number of mechanisms: • Association of different heavy chains with either K or X light chains; • Association of V genes with different (D) and J genes; • Genetic joining errors; • Somatic mutation. Genetic differences between antibody molecules are known as isotypic if they occur in the constant region and as idiotypic if they reside in the hypervariable regions (the sites associated with direct binding to antigen; Fig. 4.3). The idiotype of an antibody is the portion defining the uniqueness of that variable region, and may include both the antigen-combining site and the adjacent regions. There are also allelic differences known as allotypes, mainly within the C regions, which enable the antibody molecules of different individuals to be distinguished.1

T ce//s The major effector role of T cells is the elimination of viruses, fungi and protozoa, but they also act as coordinators of the overall adaptive immune response. B and T lymphocytes are impossible to distinguish by light microscopy and therefore more sophisticated techniques are needed (e.g. flow cytometry) which can identify specific cell typespecific surface antigens (CD antigens). All T cells bear the CD3 antigen, which is associated on the cell surface with the T-cell receptor (TCR). Cytotoxic T cells (Tctx) are responsible for killing abnormal host cells (e.g. virally infected, malignantly transformed or transplanted cells) and, in addition to possessing CD3, are also positive for the surface molecule CDS. They destroy target cells by several mechanisms, including cell membrane interactions (such as that of the Fas antigen

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FIG. 4.4 Interaction of T cell receptor and HLA molecules The T cell is 'restricted' in that CD8+ T cells only recognize antigen when it is presented in association with HLA class I molecules. CD4+ cells only recognize antigen in association with HLA class II molecules.

(CD95) with its ligand) and the release of cytotoxic substances: perforins, granzymes and other cytokines. Helper T cells (Th), in addition to expressing CDS, also express CD4. It is helpful to remember some of these more common CD numbers, as these are important in describing primary immune deficiency states and lymphoproliferative diseases.

FIG. 4.5 Antigen processing and presentation 2 = 2 -microglobulin, TAP = transporter of antigenic peptides, class 1, WV = peptide, =C = HLA class II.

= HLA

TABLE 4.3 Major HLA associations The T-cell receptor (TcR, Fig. 4.4) The T-cell receptor is a two-chain (a and , or y and 6) molecule, rather like a shortened immunoglobulin. However, it has a more complicated combining site than antibody, and recognizes linear fragments of small foreign peptides in combination with molecules of the human leukocyte antigen system (HLA). The TcR-associated CD4 or CD8 molecules determine whether the individual T cell recognizes antigen in association with class I or class II molecules. CD8-expressing T cells only recognize antigen when it is presented with HLA class I molecules, whereas CD4-expressing T cells are only stimulated by antigen in association with HLA class II molecules. The human leukocyte antigen (HLA) systems The HLA system is the major determinant of transplant rejection responses. However, its normal physiological function is mainly to control cell-cell interactions, particularly within an individual's own immune response. The HLA genes lie on the short arm of chromosome 6 and are grouped into two major sets, referred to as class I and class II. Each set contains three genetic loci that have a large number of alleles coding for HLA antigens. The genes for some complement components and cytokines also lie within the same region (the class III region), but their products are quite unrelated to class I and class II molecules. Class I molecules consist of a large oc chain, and a small P chain known as pVmicroglobulin. 2-Microglobulin is encoded on a different chromosome and shows no sequence variability. Class I antigens (i.e. alleles at the A, B and C loci) are expressed on all nucleated cells (two from

Disease

HLA-B

Ankylosing spondylitis Rheumatoid arthritis SLE Celiac disease IDDM* Hashimoto's disease

27

HLA-DR

4 3 8 8

3 3,4 5

*IDDM, insulin-dependent diabetes mellitus.

each locus on diploid cells). Class II HLA molecules are two-chain ( and ) structures both chains are encoded in the HLA locus and are polymorphic. Class II antigens (alleles at the DP, DQ and DR loci) are expressed on a more limited range of cells: classic antigen-presenting cells, B lymphocytes and activated T lymphocytes. Class I and II antigens are central to antigen presentation and the generation of an effective immune response. Knowledge of the HLA alleles expressed by an individual is clearly essential for most organ transplantation. In addition, particular HLA types are also known to be associated with certain diseases (Table 4.3). In some circumstances the HLA association is so strong as to be helpful in diagnosis, e.g. HLA B27 and ankylosing spondylitis. Antigen presentation (Fig. 4.5) Antigen-presenting cells (APC) include macrophages, dendritic cells of the spleen and lymph nodes, Langerhans' cells of the skin, and B cells. Antigenic fragments are pre-

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FIG. 4.6 CD4 + cell activation after antigen presentation The binding of cell surface receptors to their cell-bound or soluble ligands results in a series of positive (+) or negative (-) signals transmitted to the CD4 T cell nucleus. Secretion of IL-2 activates both the secreting T cell and its near neighbours. sented to T cells in specialized 'antigen-binding grooves' in HLA class I and class II molecules. Class I molecules present peptides which are endogenously synthesized, e.g. viral proteins in an infected cell, whereas class II molecules present peptides from external proteins (e.g. extracellular microorganisms) which have been engulfed and degraded to peptides by the APC. There are distinct intracellular pathways involved for class I and class II presentation. Class II molecules are synthesized within the rough endoplasmic reticulum (RER) and, bound to a second molecule called the invariant chain, are transported to the endosomal compartment. There the invariant chain is replaced by antigenic fragment and the complex is transported to the cell surface. Class I molecules are also synthesized in the RER and are initially anchored on the inner surface of this organelle. Peptide fragments generated in cytoplasmic proteasomes are transported into the RER by specialized transporter proteins TAP-1 and TAP-2 (TAP = transporter of antigenic peptides). The peptide fragments then bind to the class I molecule and this complex associates with pVmicroglobulin before being transported to the cell surface (Fig. 4.5). * In addition to TcR recognition of the HLA/antigenic fragment, the CD4 molecule binds to a non-polymorphic region of the HLA class II molecule. Several other adhesion molecule pairs (LFA1/ICAM-l, CD2/LFA-3) link together, strengthening the cellular adhesion. The interaction of a T-cell surface molecule CD28 with B7 molecules on APCs is believed to be crucial to T-cell activation, as is the secretion by the APC of IL-1.

1 MCQ 4.2

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Th-cell activation (Fig. 4.6) CD4+ T-cell activation is dependent on a series of 'costimulatory' signals consisting of cell-cell surface binding and soluble cytokines.* The result of these 'positive signals' is the generation of gene transcription factors (such as NFAT - nuclear factor of activated T cells) which 'switch on' genes (e.g. IL-2 gene) within the T-cell nucleus. Once IL-2 is secreted, it acts on both the responding and neighbouring cells. In contrast to CD28, a molecule termed CTLA4 appears to be crucial in donwegulating the T-cell immune response. CTLA4 appears on T cells late in their activation and also binds to B7 molecules (see above), but this binding delivers a negative signal to 'switch off responding T cells. Constructs of CTLA4 have recently been used in clinical trials (phase I and II) to downregulate unwanted T-cell responses in transplantation rejection and in autoimmune disorders. The increase in understanding of the key signalling molecules involved in antigen presentation will undoubtedly result in further attempts at therapeutic manipulation. Regulation of immune responses Both T and B cells are activated by recognition of specific antigens. Effective removal of antigen is therefore an important physiological endpoint for an immune response. However, the immune system has several additional mechanisms that regulate the nature and intensity of the immune response: • Apoptosis (programmed cell death) is now recognized as an important regulatory mechanism for the disposal of immune cells which have completed their function. • Anti-idiotype antibodies are directed against the V region of the Fab portion (idiotype) of other antibody

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TABLE 4.4 The major cytokines aiid their functions Cytokine

Natural source

Functions

Potential clinical uses

TNF-a and p

Macrophages

Antitumour, antiviral, vascular damage, PMN activation, bone resorption, induces IL-1 etc.

Anti-TNF moAb used for rheumatoid arthritis, inflammatory bowel disease

Interferon-

Macrophages

Antiviral

lnterferonInterferon-y

Fibroblasts T eel Is

Antiviral Antiviral, activates macrophages, increases mycobactericidal activity

IL-2 IL-5 IL-6

T cells T cells, mast cells T cells, fibroblasts, ARC, hepatocytes T cells, monocytes Macrophages

Activates T, B and NK cells Eosinophil growth and activation B-cell growth and differentiation; induces acute-phase response Neutrophil activation and chemotaxis Granulocyte growth and maturation

Hepatitis B&C, papillomatosis, Kaposi's sarcoma, hairy cell leukemia, chronic myeloid leukaemia Multiple sclerosis Multidrug-resistant TB, lepromatous leprosy, visceral leishmaniasis, IFNyR deficiency, chronic granulomatous disease, hyper-lgE syndrome, chronic mucocutaneous candidiasis Melanoma, renal cell carcinoma Anti IL-5 moAb in phase II clinical trials for asthma

IL-8 G-CSF

IL-8 receptor antagonist in preclinical trials for airway disease Cyclical neutropenia, chemotherapy 'rescue'

After activation, however, there is a preferential commitment towards either a Thl or a Th2 pattern (Fig. 4.7). Thl cytokines are IL-2, IL-12 and IFN-y, favouring a cellular immune response, whereas Th2 cytokines, favouring an antibody response, are IL-4, IL-5, IL-6 and IL-10. There is mutual suppression between these two dominant patterns of cytokine secretion such that, once a response has become committed in either direction, this pattern will tend to be maintained. It is therefore currently believed that the 'suppression' of immune response seen in certain situations is the net result of a balance in the type of cytokines secreted in the microenvironment, rather than the function of a single cell type. This is important in understanding the influence of the immune response on the pattern of clinical diseases such as leprosy (see hypersensitivity section).1

FIG. 4.7 T cell differentiation The blue lines indicate secretion of soluble mediators, the black lines indicate suppressive activity. For explanation see text.

molecules and may block or modulate antibody function. • A specific T-suppressor cell subset has not been identified in humans. There is, however, increasing evidence, in both animals and humans, that the pattern of cytokines secreted by CD4+ T cells will preferentially induce either a predominantly cellular or an antibody response. The major cytokines, their actions and potential clinical importance are summarized in Table 4.4. Prior to activation, most CD4+ T cells are 'ThO' (i.e. they have the potential to secrete a wide range of cytokines).

IMMUNO DEFICIENCY

Immunodeficiency is classified asprnnory (where the cause is/was previously unknown) or secondary, where there is a recognized cause for the immune defect, such as cancer, infection, drug treatment, radiotherapy or malnutrition.

PRIMARY IMMUNODEFICIENCY Understanding of primary immunodeficiency has increased rapidly over recent years with the identification of specific molecular lesions in a number of these previously poorly understood conditions. Research into these conditions has increased our understanding of the cell biology of the immune response and led to new diagnostic strategies and experimental forms of gene therapy in humans.

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Primary immunodeficiency diseases (PID) are subclassified according to the individual immunological components involved, hence there are antibody, T-cell or combined deficiencies, as well as phagocytic and complement component deficiencies. The defect in each condition leads to preferential susceptibility to certain types of organisms. Typically, antibody deficiency causes susceptibility to bacterial infection: T-cell deficiency to viral and fungal infections; and some complement deficiencies to meningococcal infections. These associations are important in consideration of the initial immunological differential diagnosis.

What are the characteristics of infection in PID? If the clinical history of infection can be described as serious, persistent, unusual or recurrent (SPUR), then immunodeficiency should be part of the differential diagnosis. 'Serious' suggests a potentially life-threatening infection (meningitis or septicaemia). 'Persistent' suggests that an infection is particularly resistant to conventional therapy. Infections may be 'unusual' in terms of site (liver/ brain abscess, or osteomyelitis) or organism (Pneumocystis, Aspergillus, Mycobacteria), and these should always raise the possibility of immune deficiency. Finally, 'recurrent' infection is particularly important. The child or adult who repeatedly presents with infection deserves further investigation of his or her immune status. It is difficult to be specific about how many infections constitute a 'recurrent' problem, and this inevitably involves an assessment of both frequency and severity of infection, evidence of organ damage, impact on systemic wellbeing and normal daily activity. The '10 warning signs of immune deficiency' are by no means exhaustive, but do give practical guidance on the clinical features that should prompt investigation for PID (Table 4.5)

When to suspect the diagnosis? Patients with PID may present with a history of infection or with a family history of an affected relative. More com-

TABLE 4.5 Ten warning signs of immune deficiency

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1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

8 or more new ear infections/year 2 or more serious sinus infections/year 2 months antibiotics without effect 2 or more episodes of pneumonia within a year Failure to thrive Recurrent, deep abscesses Persistent thrush after 1 year of age Need for intravenous antibiotics 2 or more deep-seated infections (sepsis, meningitis, cellulitis) Family history of PID

monly, they may present with the long-term complications of their condition (e.g. bronchiectasis). They may also present with a combination of clinical features and laboratory abnormalities that may not initially alert the non-specialist to the underlying diagnosis (e.g. chronic ill health, autoimmune phenomena). It is very typical for patients with PID to suffer a prolonged delay before the correct diagnosis is made, despite attending many doctors. During this period of delay they suffer significant morbidity and even mortality, and it is therefore essential that there is increased awareness of these conditions to allow earlier diagnosis and treatment. The simple guidelines from the history (Table 4.5) are useful in determining the most appropriate first line of immunological investigation. It is important that investigations are used appropriately and that expert advice is available, both in the selection of tests and in the interpretation of results. The general principles guiding investigation for immune deficiency include determining both that the relevant components of the systems are present, and that they are functionally intact. It is particularly important in the investigation of children that all immunological results are compared to appropriate, age-related normal ranges. Increasingly, specific molecular tests are used to confirm diagnoses, and therefore subtler variant forms of immune deficiency are being recognized.

Primary antibody deficiency diseases X-linked agammaglobulinaemia (XLA/Bruton's type) Clinical features Affected boys usually present between 6 months and 2 years of age. There may be a family history of affected male relatives. The most common complaint is of recurrent bacterial infections (typically Streptococcus pneumoniae or Haemophilus influenzae), usually affecting the respiratory tract, which if untreated lead to bronchiectasis. Boys may present with ear or joint infection and some have a nonspecific arthropathy that responds to the introduction of immunoglobulin replacement therapy. Chronic diarrhoea and a malabsorption syndrome may occur as a result of Giardia lamblia infection. A helpful physical sign is the absence of tonsillar lymphoid tissue or lymphadenopathy. A particular long-term complication in XLA is mycoplasma or ureaplasma arthritis. This is distinct from the more frequent non-specific arthropathy and is difficult both to diagnose and to treat. XLA patients are also susceptible to enterovirus infection (polio, coxsackie or echoviruses). Oral polio vaccine is therefore contraindicated, as it may cause paralysis, and a chronic meningoencephalitis may result from coxsackie or echovirus infection. This latter complication has become rarer since the advent of intravenous immunoglobulin therapy, but it still occurs either as a generalized condition or in a more limited form, causing sensorineural deafness. The prevalence of XLA is thought to be approximately 1 in 100000 in the UK, but

with the advent of molecular testing a milder, previously undiagnosed, form is being identified. Investigation Serum IgG level is usually less than 2g/L, with serum IgA, IgM and IgE being undetectable. Measurement of IgG subclasses is not usually helpful. Isohaemagglutinins are typically absent, as are specific antibodies to previously administered vaccines. Mature B cells are not usually detectable in peripheral blood, but T-cell numbers and function are normal. Neutropenia may be a feature. In the atypical, less severe, cases immunoglobulin levels are more variable and low numbers of circulating B cells are detected (typically in young teenage or adult males). In such cases the diagnosis can be difficult and test immunization responses to protein and polysaccharide antigens (usually tetanus toxoid and pneumovax II) are very helpful. Antigen-specific antibody levels are measured before and 4 weeks after immunization. Results require expert interpretation. The underlying molecular lesion has been characterized as a defect of the intracellular tyrosine kinase 'Bruton's tyrosine kinase' (Btk), coded for at X21.3-22. This kinase is essential for normal B-cell maturation, and B-cell development is therefore arrested at the pre-B stage. Family assessment to identify carriers is possible and should be undertaken, with appropriate genetic counselling. Rare autosomal recessive cases occur. Management of antibody deficiency Replacement therapy with regular intravenous immunoglobulin (ivlg) is now the standard treatment for primary antibody deficiency. This lifelong treatment is extremely effective in controlling infection, improving quality of life and preventing end-organ damage. The usual dose is 400mg/kg, given every 3 weeks. Regular preinfusion serum IgG levels are measured and should be maintained within the physiological range (usually >8g/L). Patients contribute to their own monitoring by completing diary sheets which record their general wellbeing, frequency of infections and antibiotic requirement. Patients must be weighed regularly and appropriate increments in ivlg dose made, because growth (in children) and weight (in adults) often increases significantly after the initial diagnosis and treatment. Various ivlg preparations differ in their con-tent. Once a patient is established on a particular product, it must not be changed without clear clinical indications. The main potential side-effect of treatment is reaction to the infusions. This may be related to infusion rate, intercurrent infection, or anti-IgA antibodies in IgA-deficient patients. Transmission of viral infection is now a very small risk because of careful viral screening and new antiviral steps in the production of ivlg from pooled donor sera. Recent advances include self-administration of ivlg at home and the development of subcutaneous administration (sclg), which is of particular value in the very young. Although immunoglobulin replacement is the mainstay of

treatment for antibody deficiency, there are other aspects of therapy. When respiratory infection occurs, patients should be treated over an extended period (usually 10 days) with high-dose antibiotics, guided by antibiotic sensitivity. Patients should be encouraged to undertake regular breathing exercises to assist with expectoration of sputum, and in those with established lung damage postural drainage should be undertaken daily. Regular assessment of pulmonary function is advised; however, 'routine' use of X-ray and CT examination (e.g. at annual review) is not advised in patients with PID. Many of these conditions predispose to a range of malignant diseases, and 'non-essential' exposure to radiation should therefore be avoided.

4

Common variable immune deficiency (CVID)/ acquired hypogammaglobulinaemla Clinical features This condition usually presents in adults with established lung disease or recurrent pyogenic infections. It is very typical for there to be a diagnostic delay of many years, during which respiratory function has deteriorated. Patients with CVID are at increased risk of autoimmune phenomena, including thrombocytopenia, haemolytic anaemia, malabsorption syndromes and organ-specific autoimmune disease. They have a particular tendency to granuloma formation and may present with lymphadenopathy or hepatosplenomegaly. The finding of typical granulomata on imaging may be helpful in establishing the diagnosis. These are usually non-caseating and steroid responsive, but treatment is not necessary if lesions are asymptomatic. A further characteristic complication of CVID is nodular lymphoid hyperplasia (NLH), in which lymphoid tissue of the gut becomes hyperplastic and produces characteristic filling defects on small bowel radiology series. NLH is thought to be a prelymphomatous condition, but CVID patients without NLH also have an increased risk of malignancy, particularly of lymphoma. CVID prevalence is estimated as 2-4 :100000 in the UK, but is probably underdiagnosed. IgG subclass and specific antibody deficiencies are thought to be related conditions, and some will progress to more typical CVID. Investigation Total serum IgG level is usually less than 3g/L; the levels of IgA and IgM are more variable. The diagnosis can therefore be difficult, and test immunization as described in investigation of XLA is required. In CVID the responses are poor or absent. Measurement of IgG subclasses is not usually helpful. Peripheral blood lymphocyte subset analysis may indicate a reduction in the proportion of CD4+ T cells that also carry the CD45RA antigen. Lymphocyteproliferative responses may be reduced. Unlike XLA, a single genetic defect has not been described for CVID, but B cells from these patients do not develop normally into plasma cells. It is thought that there is an abnormality of T-cell regulation of B cells in CVID.

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Management CVID patients require immunoglobulin replacement therapy as for XLA, with the possible addition of steroids for symptomatic granulomatous disease. CVID patients who are deficient in IgA should always be prescribed an ivlg preparation that is known to be low in IgA in order to reduce the risk of infusion reactions (see below). IgA deficiency Clinical features IgA deficiency is the most common primary immune deficiency in the UK, with a prevalence of approximately 1: 600. Most people with IgA challenge are identified by chance and are asymptomatic. The challenge is therefore to identify those in whom there is a significant immune deficiency. The history is crucial because IgA deficiency is known to be associated with an increased risk of pulmonary/sinus infections, allergy, celiac disease, other autoimmune diseases and malignancy. One must therefore look carefully for any suggestive clinical features in patients presenting with incidentally identified IgA deficiency. Furthermore, IgA deficiency can be a feature of some combined immune deficiencies (e.g. ataxia-telangectasia (page 93) and Wiskott-Aldrich syndrome (page 92)), and there may be clinical features suggestive of these diseases; IgA-deficient patients may form anti-IgA antibodies, which create a high risk of transfusion reactions to IgAcontaining blood products. If immunoglobulin replacement therapy is required, a product containing the lowest possible concentration of IgA must be used. Investigation IgA deficiency is defined by a laboratory measurement of serum IgA <0.05 g/L. The automated methods used in most routine laboratories are not sufficiently sensitive to detect these levels. Therefore, a routine report of 'low' level of serum IgA does not necessarily indicate a diagnosis of IgA deficiency. Once IgA deficiency is established, however, the patient must be fully evaluated to determine whether there is a clinically significant immune deficiency. A number of these patients will have associated IgG subclass deficiency and/or a failure of antibody responses to test immunization. If a combined immune deficiency syndrome is suspected, more extensive investigations are required (see ataxia-telangectasia (p. 93) and Wiskott-Aldrich syndrome (p. 93)).

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Management It is only the minority of IgA-deficient patients who have a significant history of infection, and usually other laboratory evidence of immune deficiency (IgG subclass deficiency, failure of response to test immunization, combined immune deficiency syndromes), who require treatment. Options include prolonged high-dose antibiotics for infectious episodes, prophylactic antibiotics, and immunoglobulin replacement therapy. Very few patients without IgG subclass deficiency or failure of immunization responses require immunoglobulin replacement, which suggests that

isolated IgA deficiency, in the absence of such defects, is a relatively benign condition. IgG subclass deficiency Clinical features IgG subclass deficiency is regarded as a part of a spectrum of conditions, including CVID and IgA deficiency. In common with IgA deficiency, patients may be asymptomatic or give a typical history of recurrent bacterial infection. The simple identification of a slightly reduced level of an IgG subclass is not sufficient in itself to warrant a diagnosis of significant primary immune deficiency. IgG subclass deficiency is usually suspected when the clinical history is suggestive of antibody deficiency, but total IgG (and other immunoglobulin classes) are normal and other primary antibody deficiencies have been excluded. Full immunological assessment is essential before treatment decisions are made. Investigation IgG subclass development occurs slowly during early childhood, and it is therefore important to relate results to the correct age-related ranges. Total serum immunoglobulin levels are usually normal, or may be high if there is a compensatory rise in the level of the non-deficient subclass (usually IgG^. On investigation, T-cell numbers and function (measured by in vitro proliferation assays) are usually normal. A failure of specific antibody response to test immunization would support a diagnosis of clinically significant IgG subclass deficiency. Management Not all patients will require ivlg and a careful assessment of the clinical history and investigative results is required. As discussed under IgA deficiency, several therapeutic strategies may be introduced and monitored for evidence of clinical response. Specific antibody deficiency Clinical features These patients are particularly susceptible to pneumococcal infection, but their total serum IgG and IgG subclass levels are normal. The clinical features are otherwise typical of other antibody deficiency syndromes, except that the diagnostic delay is likely to be longer because of the subtlety of the defect. Investigation These patients fail to mount a specific antibody response to polysaccharide antigens (e.g. Pneumovax II) but respond normally to protein antigen (e.g. tetanus toxoid). By definition, they will have normal total serum immunoglobulin and IgG subclasses. Management As for IgG subclass deficiency, the appropriate therapeutic option for each individual patient is based on a combined assessment of the clinical severity of the defect and the investigative results. The typical clinical features

described will usually indicate a requirement for ivlg; however, equivocal responses to immunization do occur in some individuals who do not require specific therapy. Transient hypogammaglobulinaemia of infancy Clinical features As passively acquired maternal immunoglobulin disappears and the infant begins to produce its own immunoglobulin, there is normally a physiological low level of serum antibody levels between 3 and 6 months of life. In some infants this 'physiological nadir' is profound, prolonged, and associated with bacterial infections. There are no other specific features: this is a diagnosis of exclusion and the clinical priority is to ensure that the child does not have a primary immune deficiency, such as severe combined immune deficiency (SCID, p. 93), X-linked agammaglobulinaemia (XLA, p. 86) or very early-onset common variable immune deficiency (CVID, p. 87). Investigation Serum IgG and IgA levels will usually be below the agerelated normal ranges, but IgM levels may be normal and isohaemagglutinins should be detectable. Differentiation from primary antibody deficiency may be difficult at this stage, but it is essential that a primary immune deficiency be excluded. Close clinical and laboratory monitoring of such infants is required for evidence of emerging antibody production. A diagnosis of transient hypogammaglobulinaemia can only be made retrospectively when antibody levels have returned to normal and the baby is clinically well. Management Decisions regarding treatment depend on the severity of the clinical history. If there are only occasional minor infections, no treatment is indicated. If frequent infection is causing significant morbidity the range of therapeutic options for antibody deficiency should be considered. If immunoglobulin replacement is deemed necessary, despite diagnostic uncertainty, it is essential to observe the patient closely for signs of recovering endogenous antibody production. This may be detected by a rise in IgM or IgA levels in preinfusion testing (intravenous immunoglobulin (ivlg) products do not contain IgM or IgA). Planned withdrawal of ivlg is also possible to allow repeat immunological assessment, including test immunization. Withdrawal of ivlg must, however, be for a prolonged period before immunization, as the half-life of IgG in the circulation is approximately 3 weeks. Immune deficiency with associated hyper-IgM Aetiology This is a disorder of T-cell function which prevents IgMproducing B cells from differentiating into IgG-producing plasma cells. The molecular lesion is of the T-cell surface protein gp39 (CD40 ligand/CD40L) and the gene is located at Xq26-27. The interaction between B cells (expressing CD40) and T cells (expressing CD40L) is crucial in trig-

gering IgM-producing immunoblasts to differentiate into IgG-secreting plasma cells.

4

Clinical features As this is an X-linked condition (although autosomal recessive cases are reported), affected boys present with recurrent pyogenic infections related to their hypogammaglobulinaemia and a commonly associated neutropenia. A typical presentation is with Pneumocystis carinii pneumonia (PCP) in infancy, which is an unusual infection in antibody deficiency and the susceptibility is probably explained by an associated underlying T-cell defect. There is also increased susceptibility to cryptosporidial infection, with ascending cholangitis and chronic liver impairment. There is an increased incidence of malignancy, particularly lymphoma and a range of autoimmune diseases. Investigation Serum levels of IgG are usually less than 3g/L, but IgM levels may be up to lOg/L (normally <3g/L). Neutropenia is common, but T-cell numbers and response to mitogens are normal. The failure of CD40L expression on stimulated T-cells in vitro can help confirm the diagnosis, but mutated forms of the CD40L gene may not be identified without more sophisticated genetic analysis. Management Commencement of ivlg therapy usually results in normalization of both serum IgM and neutrophil counts. The particular susceptibility of these patients to PCP is an indication for primary/secondary prophylaxis with oral cotrimoxazole. Allogeneic bone marrow transplantation is the definitive treatment in childhood. For those (usually older) patients with established chronic liver disease (probably caused by chronic cryptosporidial infection), combined liver and bone marrow transplantation is now considered. Experience to date is too limited to give definitive statements regarding prognosis.

Complement deficiencies The complement system is represented in Figure 4.1. The clinical features of deficiency depend on which part of the activation cascade is interrupted. The major points will be described. Individual complement component deficiency Clinical features Individual complement component deficiencies are rare, and in most cases are inherited as autosomal recessive conditions. Classic pathway component deficiency (Cl, C2 and C4) may present with recurrent bacterial infection or with immune complex-mediated disorders ('lupus-like syndromes'). C2-deficient patients are especially prone to pneumococcal infection. C3 deficiency is very rare; it is associated with recurrent bacterial infection. Deficiencies of properdin (X-linked) or the terminal pathway components C5, C6, C7, C8 and C9 are associated with recurrent neisserial (meningococcal or gonococcal) infection. Any

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CASE STUDY 4.1 RECURRENT INFECTION An 11-year-old girl was referred because of a history of recurrent infection. She had been fully immunized as an infant. At the age of 4 years she had recurrent otitis media and underwent surgical insertion of tympanic membrane vents (grommets). These had required reinsertion the following year. She was well until the age of 9 years, when she presented to hospital with chest pain and pyrexia. Left basal pneumonia was diagnosed and she was treated as an inpatient. Four months later she presented with recurrent symptoms. Chest X-ray again confirmed left basal consolidation. After antibiotic treatment she was discharged and returned to school. However, her parents noted that she suffered from frequent unexplained pyrexias and persisting chest pain. Her school performance deteriorated, she complained of fatigue and withdrew from sporting activities. She had no history of allergy or family history of recurrent infection. Investigations Hb 11.5g/dL, WCC 9.2 x 109/L, IgG 4.59 g/L, IgA < 0.07 g/L, IgM 0.28 g/L. Questions 1. Give two likely explanations for her recurrent symptoms, 2. Do her preliminary investigations establish a diagnosis? 3. What further general investigations are indicated? 4. What further immunological investigations are required?

She was referred to an immunology clinic, where the details of history were confirmed and further investigation undertaken. The history was suggestive of recurrent bacterial infection and, with the suggestion of IgA deficiency, an antibody deficiency syndrome should be considered as the most likely diagnosis.

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Further investigation indicated IgA < 0.05 g/L IgG subclasses: IgGj 4.5 g/L (4.5-9.4); IgG2 0.4g/L (1.6-5.1); IgG3 0.5 g/L (0.3-1.1); IgG4 0.07g/L (0.01-1.2) Classic complement pathway (CH50): normal Nitroblue tetrazolium (NET): normal Lymphocyte phenotype: CD4+ T-cell numbers low. CD45RA expression very low on CD4 T cells Immunization responses: failure to increase specific antibody levels after immunization with tetanus toxoid and Pneumovax II CT scan of chest: no evidence of structural lung damage. A diagnosis of common variable immune deficiency was reached and treatment commenced with prophylactic ivlg (400mg/kg three times weekly) commenced. The girl made a rapid response, with a cessation of her febrile episodes, no further chest infections and a significant improvement in energy levels. Her school performance improved and she re-engaged in her competitive sporting activities. Her weight correspondingly increased, to the extent that her ivlg dose had to be carefully monitored and increased appropriately. After 9 months on hospital-based therapy she opted for a home treatment programme. She and her mother were trained in all aspects of home infusion therapy by an immunology nurse specialist, and home therapy, under the guidance and monitoring of the Regional Immunology Centre, has been successfully established. Discussion The history of recurrent infection in this case was probably not remarkable up to the age of 9 years. It is common for children to present with otitis media, but tympanic membrane vents are usually indicated for chronic secretory otitis media ('glue ear'). There may therefore be

some doubt as to the exact diagnosis at the age of 4 years. The episode of pneumonia at the age of 9 years was significant, particularly because of the recurrence 4 months after initial treatment, and the persisting pleuritic pain and recurrent fevers thereafter. It was therefore appropriate to consider a primary immune deficiency and the initial investigations by the paediatrician were abnormal. The total serum IgG was slightly below the age-related normal range, and although IgA was reported as being, 'low', the level quoted was not low enough to confirm IgA deficiency. The additional investigations undertaken at the immunology clinic confirmed that the total serum IgA was <0.05 g/L and IgG2 subclass was low. The measurement of specific antibody response to immunization confirmed a significant defect in antibody production. Tetanus toxoid is a protein antigen (T dependent), whereas Pneumovax II is polysaccharide (T independent). Thus, these two antigens test the functional integrity of both the Tdependent and the T-independent responses. A healthy response should result in a minimum fourfold (usually much greater) rise in specific antibody level. Because there were low levels of IgG and IgA, low IgG2 and a failure of normal immunization response, the diagnosis was common variable immune deficiency (CVID). The lymphocyte phenotype is not diagnostic, but the relative reduction in CD4 T cells (and the CD45RA subset in particular) is typical of CVID. The clinical presentation described is reasonably typical, with the exception that the diagnosis was made before structural lung damage had occurred. Presentation in the second and third decades of life is common, but can be at any age. Usually there is a delay of many years from the onset of infection to

4

CASE STUDY 4.1 CONTINUED diagnosis, and during this period structural lung damage occurs. Ivlg treatment is proven to prevent infection and its complications, and in this case a specialist immunology service established home therapy for

the child. Home therapy is increasingly seen as a desirable option for patients with primary immune deficiency, as it reduces the need for hospital visits that interfere with normal school or work activities.

patient presenting with a recurrence of meningococcal infection should therefore be investigated for complement deficiency. Investigation Investigation of the complement system is indicated in any patient with symptoms of recurrent bacterial (especially neisserial) infection, 'lupus-like' disorders or angioedema. Total C3 and C4 levels are readily measured, but the most useful screening tests for deficiency are the assays that test the functional integrity of the classic and alternative pathways (known as CH50 and AP50, respectively). If an abnormality is detected, further characterization is necessary to identify the individual component that is defective. Management This is dependent on the clinical presentation. For patients with recurrent bacterial infection, prophylactic antibiotics may be indicated. For those susceptible to pneumococcal and or neisserial infection, immunization with pneumococcal capsular polysaccharide and meningococcal vaccines is often advised. In some cases intramuscular penicillin is kept at home for early treatment of suspected meningococcal disease, and it is advisable for patients to wear a medical warning bracelet. For patients with prominent joint symptoms, further rheumatological assessment may be advised. C1-inhibitor deficiency Defects of the control protein C1-inhibitor (C1-INH) are inherited in an autosomal dominant manner and cause hereditary angioedema. There is a failure of the normal regulation of the classic pathway that results in uncontrolled activation of complement and kinin pathways in response to even minor trauma. Clinical features Patients present with recurrent deep tissue swelling following apparently minor trauma (typically dental treatment). This may affect any part of the body, but is of most concern when the airway is compromised. Symptoms usually begin in early adolescence, although late presentation is increasingly recognized. An interesting feature is that attacks may begin, or become more severe, after commencement of the oral contraceptive pill, hormone replacement therapy, or during pregnancy. Although inherited as an autosomal dominant trait, patients may not give a significant family history as approx-

Integrating treatment into family life also empowers the patient and emphasizes that these conditions, like many other medical conditions, can be prospectively managed, preventing illness and maintaining good health.

imately 20% of cases are caused by new mutations in the C1-inhibitor gene. As with other immune deficiencies, there is often a period of diagnostic delay during which patients will have suffered symptoms, often of a lifethreatening nature. It is typical for children with this condition to suffer recurrent abdominal pain (caused by intestinal wall swelling), rather than swelling at other sites. In one series, 30% of patients had an undiagnosed relative who had died of laryngeal oedema, 34% had had an unnecessary laparotomy and 10% had had endotracheal intubation or tracheotomy prior to diagnosis. Investigation During an acute attack there is a characteristic pattern of serum complement levels which is caused by inefficient and excessive activation of the classic complement pathway. Serum C4 and C2 are low but C3 levels are usually normal. This is a very valuable pointer to the diagnosis hereditary angioedema, and measurement of C3 and C4 in any patient with angioedema will help differentiate this from allergic angioedema. In 85% of cases there is a low level of C1-inhibitor level (usually less than 50% of the lower limit of normal) but in 15% of cases the enzyme level is normal. This latter group have 'functional Clinhibitor deficiency', the enzyme being present but nonfunctional. Management Prophylactic treatment with androgenic steroids (danazol 200-400 mg daily, stanozolol 2.5-10 mg/day - alternate-day dosage may be possible) or antifibrinolytics (tranexamic acid up to 4g/day) is usually effective. Antifibrinolytics are the preferred alternative for female patients because of the androgens' virilizing side-effects. If laryngeal oedema occurs (e.g. after dental extraction) it is life-threatening and requires emergency intravenous administration of Cl-INH concentrate (1000-1500 units i.v). Patients are advised to wear a medical warning bracelet. C1-inhibitor concentrate should also be given prior to surgical procedures, and routine dental work should only be undertaken in hospital, where laryngeal oedema can be dealt with effectively. Cellular immune deficiency Because of the central role of T cells in coordinating the immune response, isolated T-cell deficiency is rare. The following will first consider those conditions in which the T-cell defect is the major feature, and then those in which a combined defect is more prominent.

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DiGeorge's syndrome This is a rare syndrome associated with a developmental abnormality of the third and fourth pharyngeal pouches. The full syndrome consists of: • Abnormal facies with low-set ears, 'fish-shaped' mouth, hypertelorism, notched ear pinnae, micrognathia and a downward slant of the eyes;1 • Hypoparathyroidism (often presenting with neonatal hypocalcaemic tetany); • Congenital heart disease (particularly aortic arch defects: truncus arteriosus, interrupted arch or Fallot's tetralogy); • Cellular immune deficiency. Not all of these clinical features are present in every case, and the immune function usually improves with time. DiGeorge's syndrome is now recognized as one of a group of related disorders that share a common genetic lesion. This is usually a deletion at 22qll, and the group of conditions is referred to as the CATCH 22 syndrome (cardiac anomalies, abnormal facies, thymic hypoplasia, cleft palate and hypocalcaemia). Other clinical syndromes in this group include velocardiofacial syndrome, Kallman's syndrome and Schprintzen's syndrome. Not all the CATCH 22-associated conditions include immune deficiency. Investigation Diagnosis is based on the typical morphological features, associated with recurrent viral or fungal infections such as oral and perineal candidiasis and viral pneumonia. Chest X-ray may show an absent thymic shadow with an abnormal cardiac outline (Fig. 4.8). It is usual to find a reduced number of circulating T cells, but the degree of immunological deficiency is variable and is probably only significant in approximately 20% of cases identified by other criteria. Lymphocyte proliferation in response to mitogens (PHA and PMA) may be reduced. Antibody deficiency is rare. It is now possible to detect the chromosome 22qll lesion by fluorescent in-situ hybridization (FISH). However, as the range of clinical associations with 22q11 lesions is wide and the degree of immunodeficiency variable, the simple demonstration of a 22qll deletion does not necessarily imply that there is clinically important immune deficiency. Management Awareness of the features and early recognition of DiGeorge's syndrome is important, particularly as these infants may be subjected to neonatal cardiac surgery. Calcium levels must be monitored and supplemented as necessary. All blood transfusions must use X-irradiated (25 Gy/unit) blood only, and live immunizations are con-

FIG. 4.8 Di George's syndrome

Chest X-ray of a one-week-old female infant with hypocalcaemia and Fallot's tetralogy. Note the abnormal enlarged cardiac outline and absent thymic shadow consistent with her diagnosis of Di George's syndrome.

traindicated (MMR, oral polio vaccine). Antibiotic prophylaxis to prevent PCP should be considered. In our unit this is instituted if the absolute CD4 count is below 0.4 x 109/L or if there is reduced T-cell proliferation to phytohaemagglutinin (a T-cell mitogen). In cases with severe cellular immune deficiency, bone marrow transplantation is suggested. The place of fetal thymus grafting is still experimental, although there have been some recent encouraging results showing reconstitution of T cells. Other cellular deficiencies Isolated T-cell deficiencies occur but are very rare. The diagnostic approach involves recognizing a suggestive history and undertaking both quantitative and functional assessments of lymphocytes. Chronic mucocutaneous candidiasis (CMC) affects both males and females and presents with chronic candidal infection of skin and mucous membranes.2There may be an associated endocrine deficiency which may precede the immune deficiency, most commonly hypoparathyroidism or Addison's disease. There are normal T-cell responses to non-specific mitogens but a specific failure of proliferative response to Candida. NK cell deficiency is also reported; patients have an increased susceptibility to herpesviruses. Functional studies of NK cells are only performed in specialist centres.

Combined immune deficiencies Wiskott-Aldrich syndrome

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1

Fig. 4.1

2

4

Figs 4.6, 4.7

Figs 4.2, 4.3, 4.4

3

Fig. 4.5

5

6

MCQ 4.3

Figs 4.8,4.9

Clinical features This X-linked disorder presents in young boys with a typical triad of eczema, thrombocytopenia and recurrent

infection.3 Immune deficiency may be mild. There is a high frequency of malignant lymphoma in the second and third decades of life, and severe autoimmune vasculitis or glomerulonephritis may occur. If untreated, death from one of these causes is usual in the second or third decade. Investigation Platelets are small and have abnormal expression of surface glycoproteins (CD43 and gpIb). There are defects affecting the cytoskeletal proteins, including actin, and associated defects of T-cell proliferation. The molecular defect is mutation of the WASP gene at Xp11.22. Characteristically there is a failure of response to polysaccharide antigens and progressive lymphopenia. Management These patients require careful clinical and laboratory assessment to establish optimum management. Increasingly, affected males are offered bone marrow transplantation in early childhood in order to reduce the risk of long-term complications and increase life expectancy. Ataxia-telangectasia (AT) Clinical features This progressive neurological and immunological disorder presents in early childhood with neurological manifestations, including cerebellar ataxia, nystagmus and oculomotor dyspraxia. Telangiectases are typically seen on the elbows, conjunctivae and ear lobes. 4 There is a progressive, combined immune defect that is variable in its immunological features. Patients ultimately develop lymphoid leukaemia/lymphoma in the second and third decades and this, combined with progressive combined immune deficiency, is the usual cause of death. Investigation The fundamental lesion is defective DNA repair leading to increased radiosensitivity (such as is seen in other disorders, e.g. Bloom's syndrome, xeroderma pigmentosa, Nijmegen breakage syndrome). Chromosomal breaks, inversions and translocations are commonly seen at the T-cell receptor, and immunoglobulin gene complexes on chromosomes 7 and 14, respectively. The serum afetoprotein is often raised. Heterozygotes for the AT gene mutations have an increased risk of developing a number of malignancies (including breast cancer), and family members need to be aware of this. Patients with AT gradually develop immune deficiency and, after comprehensive immunological investigation at diagnosis, this is confirmed and monitored by regular review of the clinical and laboratory features. Management Careful, continuing immunological assessment is essential in these patients, and treatment is dependent on the degree of immune deficiency. Patients commonly require ivlg by late childhood. There is no corrective treatment available for the underlying chromosomal instability.

Severe combined immune deficiency (SCID) Clinical features This group of conditions has a number of causes but the clinical features are similar in most cases. By definition, both humoral and cellular responses are impaired or absent. SCID typically presents early (in the first weeks and months of life) with a history of failure to thrive (FTT), unexplained diarrhoea, and recurrent bacterial, viral or fungal infection. Unexplained lymphopenia (<2.8 x 109/L) is often present and should always prompt investigation. Total lymphocyte counts may, however, be apparently normal in B-cell-positive variants, T-cell activation deficiencies and graft-versus-host disease (GVHD). GVHD may be related to maternofetal transfusion, where normally functioning maternal lymphocytes attack the immunodeficient child. If present, GVHD occurs in the first month of life with jaundice, typical skin rash 5and diarrhoea. It may also occur as a complication of blood transfusion, and all transfusions to potentially immunodeficient individuals should be irradiated (25Gy/unit) to eradicate immunocompetent lymphocytes, the potential inducers of GVHD.

4

Investigation When SCID is suspected, immunological advice should be sought urgently, with regard to both investigation and immediate management. In general, serum immunoglobulins are low and there is a low lymphocyte count, with diminished proliferative response to mitogens. Lymphocyte subset analysis is essential and a range of other investigations is needed to exclude SCID. The molecular basis of many variants of SCID is now recognized: each has a particular pattern of abnormalities and some of the more common are summarized in Table 4.6. Molecular characterization allows greater precision in diagnosis and carrier detection. Management Early diagnosis, prevention of infection and rapid bone marrow transplantation (BMT) are all crucial to ensure ultimate survival. Delay in making the diagnosis allows complications to occur (such as disseminated CMV infection), which reduce the chance of survival. BMT can be curative and, in the UK, is currently performed at two supraregional centres. With increasing characterization of the molecular basis of immune deficiency, it is hoped that gene therapy will become a practical possibility in this group of disorders.6

Phagocytic disorders Phagocytes may be defective in numbers or function. Table 4.7 summarizes the main disorders, the commonest of which are described below. Chronic granulomatous disease (CGD) Clinical features CGD typically presents in childhood with recurrent, deep abscesses caused by catalase-positive organisms (Staphy-

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TABLE 4.6 The major features of some combined immunodeficiency syndromes Syndrome

Major immunological features

Molecular defect

Inheritance/associated features

X-linked SCID

Immunoglobulin low; T cells low, B cells normal/increased Immunoglobulin, T and B cells all low Immunoglobulin, T and B cells all low Immunoglobulin low. Progressive fall in T and B cell numbers IgG low, IgM high, T cell numbers normal Immunoglobulin normal/low, B cells normal, reduced CD4+ cells Immunoglobulin normal/low, B cells normal, reduced CD8+ cells.

IL-2 receptor y chain

(XL)

Mutation in RAG1/2 genes Stem cell defect Accumulation of lymphotoxic metabolites Mutation in CD40L gene Mutations in MHC II regulator genes TAP-2 gene mutation

(AR)

T-B- SCID Reticular dysgenesis Adenosine deaminase deficiency X-linked hyper-IgM MHC class II deficiency TAP-2 deficiency

(AR): Anaemia, granulocytopenia, thrombocytopenia (AR): Progressive onset, diagnosis may be delayed into childhood: flared ribs (XL) Neutropenia, thrombocytopenia, haemolytic anaemia, (AR) (AR) MHC class I deficiency

(XL), X-linked; (AR), autosomal recessive.

TABLE 4.7 Examples of phagocytic disorders Phagocytic defect

Clinical disorder

Numbers Adhesion

Cyclical neutropaenia Leukocyte adhesion defect (LAD-1) Schwachmann's syndrome

Chemotaxis

Intracellular killing

Chronic granulomatous disease G6PD deficiency IL-12R & IFNyR deficiency

Inheritance/associated features (AR) See text (AR) See text (AR) Anaemia, thrombocytopenia, pancreatic insufficiency, chondrodysplasia (XL/AR) See text (XL) Anaemia (AR) Susceptibility to mycobacteria and salmonella. See text

lococcus aureus, Aspergillus, Serratia, Nocardia).1 Presentation may be with osteomyelitis, unexplained granulomatous lesions, malabsorption or recurrent pneumonia. New cases have been diagnosed in adulthood. Inheritance may be X-linked or autosomal recessive. Investigation The diagnosis rests on the demonstration of a failure of the neutrophil respiratory burst. The most common screening test of neutrophil function is the nitroblue tetrazolium test (NBT) test, in which normal neutrophils reduce the yellow dye formazan into blue intracellular crystals. 2 This test

1 94

Fig. 4.10

0 Fig. 4.11 3

Fig. 4.12

may not be abnormal in all cases, and more sensitive screening techniques have been developed. The molecular defect is a deficiency of the 91 kDa chain of cytochrome b (X-linked CGD) or the 22 kDa chain of cytochrome b, or of p47 or p67 cytoplasmic factors (autosomal recessive CGD). These proteins are all involved in the energydependent process of intracellular killing. The definitive test is to demonstrate a failure of neutrophil-mediated bacterial killing. Management Antimicrobial prophylaxis (usually with co-trimoxazole) is the mainstay of therapy. Prophylactic interferon-y (IFNy) is not useful prophylactically, but may be a useful adjunct to conventional antibiotic and surgical management of abscesses. Allogeneic bone marrow transplantation, before the development of complications of infection, is now the treatment of choice for CGD if a suitable donor can be found. Cyclical neutropenia Clinical features This condition, which may present in childhood or adult life, is characterized by recurrent abscesses, usually occurring at intervals of approximately 3 weeks, although the periodicity can vary greatly. The neutrophil count is typically <1 x 109/L at times of infection, and the diagnosis should be suspected if there is clear periodicity to the history. Alternatively, the neutrophil count may be incidentally noted as low on a blood count during acute infection. Investigation Neutrophil counts should be measured on alternate days for a 4-week period and carefully analysed for any evidence of a cyclical pattern. A cyclical pattern may also be detected for other elements, including platelets, and other leukocytes.

Management This is dictated by the clinical severity of the condition. Prophylactic antibiotics may be adequate during times of low neutrophil numbers. In more severe cases, treatment with granulocyte colony-stimulating factor is considered. Leukocyte adhesion deficiency (type 1)

heterozygous for the genetic lesion, but this is clinically expressed as a dominant susceptibility. This is in contrast to most autosomal genetic disorders, in which the normal allele dominates, so that heterozygotes only show a minor clinical abnormality. The prevalence of these conditions is not yet established.

Clinical features This is typically a disorder of infancy and childhood. Chronic/recurrent skin ulcers and periodontitis are common. There is characteristically little pus formation and an associated peripheral blood neutrophilia. There is likely to be a neonatal history of delayed separation of the cord (>10 days).

Investigation Cell surface expression of IFNyR and IL-12R is detected by flow cytometry. Specialist functional assays of lymphocyte signalling are necessary to confirm and characterize the defects. Histologically, complete IFNyR deficiency is characterized by a failure to form granulomata, whereas partial deficiency is associated with good granuloma formation.

Investigation There is defective expression of the CD18 (B chain) of the adhesion molecules LFA-1, Mac-1 and CR4. The absent expression is demonstrated on both lymphocytes and phagocytes by flow cytometry. A second variant, LAD-2, is associated with defective expression of CD15.

Management Once the diagnosis is established, appropriate antimycobacterial therapy must be commenced. Experience with adjunctive IFN-y treatment in the partial forms is increasing and discussion with specialist centres is advised.

Management Antibiotics are the mainstay of therapy. Drug choice should be guided by antibiotic sensitivities. Prophylactic therapy may be necessary, depending on the frequency of infection. Bone marrow transplantation is necessary for severely affected individuals. /nferferon-y receptor (IFNyR) deficiency Clinical features Defects in the IFNyR (and IL-12 receptor) systems have recently been identified as important susceptibility factors for mycobacterial infection. These conditions have been identified in both children and adults. They typically develop infection with poorly pathogenic mycobacteria, salmonella, or the live vaccine Bacille Calmette-Guerin (BCG). There are three types of IFNyR defect identified. Complete deficiency determines a phenotype that is characterized by severe and fatal susceptibility to either BCG or disseminated non-tuberculous mycobacterial (NTM) infection. Partial IFNyR-1 deficiency is associated with a less severe clinical defect that may allow disseminated BCG infection with tuberculoid granulomata or clinical tuberculosis. Both complete and partial IFN-y deficiencies are inherited as autosomal recessive traits. A functional defect of the IFNyR has also recently been described which is characterized clinically by susceptibility to nontuberculous mycobacteria (NTM) and variable granuloma formation.3 A notable feature of the cases described to date is that a significant number are initially misdiagnosed as suffering from Langerhans' cell histiocytosis (LCH), because of the association of fevers, lymphadenopathy, granulomatous ulcers and lytic bone lesions. The condition is caused by a premature stop codon in the intracellular signalling domain of IFNyR that reduces the mycobactericidal properties of macrophages. Inheritance of this last type is 'dominant negative'. The affected individuals are

a

SECONDARY IMMUNODEFICIENCY Secondary immunodeficiency is much more common than primary immune deficiency in clinical practice. It may occur as a result of systemic disease, including diabetes mellitus, chronic hepatic and renal failure and systemic malignancy. Autoimmune disorders may be associated with immune deficiency as a consequence of both disease and treatment. Specific infections are also associated with secondary immune deficiency. The best known of these is human immunodeficiency virus (HIV), which leads to the acquired immune deficiency syndrome (AIDS; Chapter 11). HIV causes a progressive loss of CD4+ T cells and thus disrupts both antibody and cellular responses. Several other infections are associated with immune suppression. Measles predisposes to bacterial infection partly through its disruption of phagocytic function. Epstein-Barr virus may occasionally cause hypogammaglobulinaemia. Immunosuppressive drugs are widely used in the treatment of cancer and autoimmune disease and are an important cause of secondary immunodeficiency. When using these agents it is essential to monitor treatment carefully and maintain the lowest level of immunosuppression compatible with effective treatment. Malnutrition, infection and other iatrogenic causes, including radiotherapy, are also important causes of secondary immune deficiency. The mechanisms of secondary immunosuppression are usually multifactorial: specific intervention is not usually indicated, but susceptibility to infection must be recognized in patients who are at risk. Secondary antibody deficiency may occur in lymphoproliferative disorders such as multiple myeloma and chronic lymphocytic leukaemia, or in protein-losing states such as nephrotic syndrome or intestinal lymphangectasia. In the

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lymphoproliferative disorders, where there is a failure of antibody synthesis, there is often a history of recurrent bacterial infection, and in these cases ivIg has been demonstrated to be beneficial. Interestingly, in the protein-losing states, recurrent infection is not usually a significant clinical problem, and antibody replacement therapy is the exception rather than the rule. Splenectomy is an important cause of secondary immune deficiency. These patients have a lifelong risk of suddenonset overwhelming sepsis caused by encapsulated organisms. This is related to the important role of the spleen in the immune response to polysaccharide antigens. Patients in whom Splenectomy is planned should be immunized with pneumococcal, meningococcal and Haemophilus influenzae type b vaccines. Annual flu immunization is recommended, and travel to malarial endemic areas should be avoided if possible. Patient education regarding the risks of splenectomy is very important, and they should be provided with warning cards or bracelets and advised to take penicillin early if they develop cough and fever. Prophylactic penicillin V (250 mg b.d.) should be given for the rest of the patient's life. Penicillin-allergic individuals should take erythromycin (250mg b.d.). Long-term follow-up is recommended both to monitor the need for repeat immunization and to reinforce medical advice. There are also a number of inherited syndromes, many of which are rare, associated with secondary immune deficiency.

HYPERSENSITIVITY

IMMUNOLOGICAL MECHANISMS In contrast to immunodeficiency syndromes, where the immune system is underactive, clinical disease may result from inappropriate overactivity. Overactivity of the immune system is referred to as hypersensitivity. The immunological mechanisms that cause hypersentivity were described and classified by Gell and Coombs (Table 4.8). Four types of hypersensitivity are described, each involving different immunological components. In some cases the hypersensitive response is directed at a foreign antigen (e.g. reactions to allergens, blood transfusions, transplanted organs or infectious agents) and in others it is directed at known 'self-antigens' (e.g. in autoimmune diseases). Finally, some hypersensitivity reactions appear to be directed at unknown antigens (e.g. Wegener's granulomatosis). The term hypersensitivity applies to all four types of reaction in the Gell and Coombs classification, whereas

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Fig 4.13

2

Case 4.1

TABLE 4.8 Classification of hypersensitivity reactions (Gell and Coombs classification) Type of reaction

Effector mechanism

Clinical disorders

I

IgE, mast cells

Allergic rhinitis, urticaria, angiodema

II

IgG directed at cell surface antigens

Transfusion reactions, acute graft rejection, Graves' disease, myasthenia gravis, Goodpasture's syndrome

III

Immune complexes

Cryoglobulinaemia, SLE, post streptococcal glomerulonephritis

IV

CD4+ lymphocytes,

Delayed type hypersensitivity, contact eczema, granulomatous reactions

the term allergy is used in a more restricted sense to describe type I hypersensitivity reactions. In this section, we will use the Gell and Coombs classification to illustrate and explain the important clinical conditions associated with hypersensitivity reactions. In addition to allergy and autoimmunity, the hypersensitivity mechanisms involved in the response to infectious agents can influence the clinical manifestations of disease. Furthermore, the manipulation of the immune response (e.g. in mycobacterial disease) offers new possibilities for therapeutic intervention.

Type I hypersentivity Type I hypersensitivity reactions (the major mechanism in allergy) are the result of the immune system reacting to otherwise apparently innocuous antigen (allergen). The mechanism involves: • Formation of IgE antibody specific to the inducing antigen or 'allergen'; • Binding of this antibody (via Fc receptors) to mast cells and basophils; • Cross-linking of at least two cell-bound IgE molecules; • Degranulation of mast cells, with release of preformed mediators and the generation of late-phase mediators.

Type II hypersentivity Type II hypersensitivity involves the reaction of antibody with cell surface-bound antigen. This reaction then causes downstream activation of the complement system, and attraction and activation of phagocytes and mast cells. The effect is to focus inflammatory damage at the site of antibody binding or, in the case of receptor-binding antibodies, to modulate the function of the target organ. This mechanism is especially important in organ-specific

autoimmune disease (Graves' disease, myasthenia gravis, autoimmune haemolytic anaemia, Goodpasture's syndrome), but also in blood transfusion reactions and hyper acute graft rejection.

Type III hypersensitivity Type III reactions involve the formation of soluble immune complexes that circulate in the blood and cause damage at many sites. Formation of immune complexes is part of the normal immune response, and these are normally disposed of via the complement and reticuloendothelial systems. Complexes remain in the circulation if they are produced persistently or are inadequately disposed of. Such pathological complexes become deposited, typically in the renal glomerulus, in joints and the skin, causing inflammatory reactions at these sites. The experimental model for immune complex disease is serum sickness, in which nephritis, arthritis and rash typically occur 7-10 days after the injection of foreign protein. The best examples in human disease include chronic infection (e.g. hepatitis, malaria, streptococci), systemic lupus erythematosus (SLE), inhalation of antigens (e.g. farmers lung) and cryoglobulinaemia. 1 2

Type IV hypersensitivity This is also known as delayed-type hypersensitivity (type IV hypersensitivity) because in experimental systems signs develop 12 or more hours after antigen exposure. Importantly, the major immunological effectors of type IV reactions are T cells, instead of antibody, which mediates the reaction in types I-III hypersensitivity.

CLINICAL DISEASE ASSOCIATED WITH HYPERSENSITIVITY REACTIONS Allergy Clinical allergy is becoming increasingly prevalent in western societies: it is estimated that up to 20% of the UK population is now affected by allergy. The symptoms depend mainly on the nature of the allergen and the site at which mast cell degranulation occurs. The common clinical syndromes are of seasonal or perennial rhinitis, allergic asthma, urticaria, oral allergy syndrome, angioedema and anaphylactic reactions. The term atopy is used to describe a genetic susceptibility, expressed in the clinical triad of eczema, allergic rhinitis and asthma, which are commonly associated in many patients. Diagnosis The diagnosis of allergy is often thought to be difficult, but in the majority of cases a thorough clinical history combined with relatively simple investigations will prove adequate. The history is the most important component, and

one looks for typically allergic symptoms occurring consistently after exposure to the same agent, and improvement of symptoms during periods of avoidance. Where doubt remains, further investigation by skin-prick testing and/or the detection of allergen-specific IgE (e.g. by radioallergosorbent test - RAST) is necessary. Skin-prick testing is preferred, as it is a rapid, cheap and painless form of in vivo challenge. There are, however, limitations to its use, as it should only be undertaken by trained individuals in an environment with full resuscitative facilities available. Specific IgE testing using the RAST test has the advantage of easy accessibility. Although results correlate well with skin testing for most allergens, they are not directly comparable for every allergen. RAST testing should not be used as a screening test for allergy. Its use should be guided by careful clinical assessment.

4

Allergic syndromes Rhinitis Clinical features Seasonal or perennial rhinitis usually presents little diagnostic difficulty or need for specific investigation. The symptoms of a red, itchy, runny nose with associated swelling and itchy watery eyes are easily recognized. A history of seasonality and/or key triggering factors will usually indicate the offending allergen. Investigation This is required when the provoking allergen is not clear from the history, or when another cause is suspected (Table 4.9). Management The important elements in management are the avoidance of, or reduction in exposure to, the allergens and the use of nasal steroid inhalers, with or without oral antihistamines. The latter are particularly useful in young children, who may find the use of inhalers difficult. For perennial symptoms caused by house dust mite patients need to be advised on how to reduce exposure by modifications to floor coverings, bedding, and cleaning and laundering procedures. There is increasing evidence that effective control of nasal

TABLE 4.9 Differential diagnosis of rhinitis Allergic (aeroallergens) Drug induced (decongestant sprays, cocaine, antihypertensive) Vasomotor Infectious Irritant Vasculitis Hormonal (pregnancy) CSF rhinorrhoea

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allergy in asthmatic patients can improve their overall airway disease. Desensitization is returning to clinical practice for grass and house dust mite allergy, but only specialist units should undertake it.

Urticaria/angioedema Clinical features Urticarial lesions are raised red itchy weals (often described as 'like nettle stings') caused by epidermal mast cell activation. Angioedema is non-itchy, non-dependent swelling which occurs in the deep dermis. Activation of the kinin system is important in causing angioedema. It is common for both symptoms to occur in the same patient. However, when angioedema occurs in the absence of urticaria, hereditary or acquired deficiencies of Cl-esterase inhibitor (Cl-INH) should be considered. A number of specific triggers for both urticaria and angioedema may be identified (Table 4.10), but in the majority (89-90%) of cases referred to clinics no specific allergic cause is identified. If symptoms persist for more than 6 weeks, this is defined as chronic idiopathic urticaria/angioedema. The natural history is quite variable, with many patients experiencing prolonged remissions between relapses. Investigation A thorough clinical history is essential to determine the pattern of symptoms and any associated trigger factors. Screening tests for allergy are not recommended; however, the wide variety of disorders associated with combined urticaria/angioedema (Table 4.10) may justify further investigation, including thyroid function tests, full blood count, CRP and complement levels. Skin biopsy is helpful in confirming urticaria pigmentosa and urticarial vasculitis. Management If an associated medical condition is identified (e.g. hypothyroidism, infection), the urticaria should respond to management of that disorder. In other patients, if attacks are only infrequent oral short-acting antihistamines (e.g. acrivastine 8mg t.i.d.) will be adequate. In most cases, however, daily non-sedating antihistamines are necessary (e.g. fexofenadine, loratadine and cetirizine). If necessary a sedating antihistamine can be added at night (e.g. hydroxizine hydrochloride). Experience with oral disodium chromoglycate has been disappointing, with the possible exception of urticaria pigmentosa, in which it has an important role in management. H2 antagonists (cimetidine and ranitidine) are often tried for refractory cases, as is doxepin (an antidepressant with potent antihistamine effects). Urticarial vasculitis often responds to NSAID therapy. The relapsing, remitting nature of urticaria makes it difficult to be certain of the efficacy of some of these interventions,

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Fig. 4.14

TABLE 4.10 Causes of urticaria/angioedema Idiopathic Allergic (foods, drugs, hymenoptera venom, contact) Physical (pressure, heat, solar, aquagenic, vibratory) Cold induced (autosomal dominant, cryoprotein) Cholinergic (exercise or heat induced) Adrenergic (stress induced) Vasculitis (hypocomplementaemic urticarial vasculitis) Autoimmune (SLE, antibodies to lgE/FceR1/C1q) Infection (hepatitis B, Helicobacter pylori, EBV, Lyme's disease, cutaneous larva migrans, larva currens) Insect bites (papular urticaria) Drug induced (aspirin, ACE inhibitors, opiates, muscle relaxants, and radiocontrast media) Hypothyroidism Urticaria pigmentosa Systemic mastocytosis Angiodema/deafness, urticaria (Muckle-Wells syndrome) Malignancy

and it is essential that once regular therapy is commenced the dose is periodically reduced or withdrawn to determine whether continued treatment is necessary. Food allergy IgE-mediated allergy to food has been described since the 1920s but remains a source of controversy. This is probably because there are exaggerated claims made for both the prevalence and the effects of food allergy, and the diagnostic tests that are available have not been reliable. There is also confusion between food allergy (an IgE-mediated phenomenon) and food intolerance, which may have many causes. For patients in whom food allergy is suspected a double-blind placebo controlled food challenge (DBPCFC) is the only reliable investigation, but this is available in only a few specialist centres at present. Selfreporting of food allergy is common. In one large study the self-reported prevalence was 20%, but actual prevalence was only 1-2% when confirmed by DBPCFC. Food allergy is often invoked as a potential cause for complex multisystem disorders or obscure symptoms. This is unlikely to be the case, and in the absence of clear evidence of allergy patients should be encourage to eat a normal diet. IgE-mediated food allergy may cause symptoms including urticaria, angioedema, rhinitis, asthma, oral allergy syndrome, anaphylactic reactions and some gastrointestinal symptoms (chiefly acute vomiting and/or diarrhoea). Common food allergens include milk, eggs and seafood. Affected children typically become tolerant to these foods by mid-late childhood. Currently, the most important food allergy is to peanut - a relatively unknown condition until the late 1980s, the prevalence of which has increased considerably. Among the UK preschool population it is now estimated to be as high as 1:50-100. Nut allergy is different in many important respects from other food allergies:

• It appears to develop in very young children. • Reactions characteristically cause angioedema, often affecting the larynx, with airway restriction. • Anaphylactic reactions may result from exposure to even trace amounts of nut. • Indirect exposure may cause life-threatening reactions in highly sensitive individuals. • Nut allergy appears to be a lifelong problem in the majority of cases. Nut allergy is a major challenge facing the medical profession and others who look after children. Successful management requires the complete avoidance of all nut-containing foods, and teaching family, friends and school staff the symptoms and signs of allergic reactions. An emergency medication kit should be available which includes both oral antihistamines and injectable adrenaline (epinephrine) (for life-threatening reactions), and patients are encouraged to wear a medical warning bracelet. Nut allergy has now overtaken bee/wasp sting allergy as the most common cause of anaphylactic reactions occurring outside hospital.

Development of autoimmunity The occurrence of hypersensitivity reactions directed against self-antigens implies a breakdown in the body's normal tolerance mechanisms. A number of factors are implicated in the development of autoimmune reactions, including infection, drugs and chemical exposure and HLA type. The influence of the hormonal state is undoubted and is exemplified by the increased autoreactivity seen in women and the effect of hormonal change (pregnancy and lactation, hormone replacement therapy) on the clinical manifestations of disease. Several cellular and molecular mechanisms are recognized as contributing to autoreactivity. These include 'cross-reactivity', where a pathogen is sufficiently similar to self-antigen that it induces an autoimmune response, e.g. group A B-haemolytic streptococcus cross-reacts with cardiac muscle, causing acute rheumatic fever: 'Molecular mimicry', wherein a short genetic sequence of a pathogen is identical to a selfantigen, has long been postulated as a mechanism for autoimmunity. Mathematical modelling, however, suggests that molecular mimicry is likely to be so common as to be the rule rather than the exception, and thus unlikely to be important in disease aetiology. 'Provision of foreign T-cell epitopes' implies that foreign antigens containing T-cell epitopes bind to host proteins and stimulate an autoimmune response. This may be one of the mechanisms through which drug and chemical exposure causes autoimmune reactions. The important HLA disease associations have been summarized in Table 4.3. It should be remembered that T cells learn to differentiate self from non-self antigens during their maturation in the thymus; thus the occurrence of autoreactive antibodies or lymphocytes represents a breakdown in the normal mechanisms of selftolerance. One of the crucial mechanisms for eradication of self-reactive T cells is through programmed cell death

or apoptosis. Patients deficient in the Fas antigen, an essential signalling molecule in normal apoptosis, develop characteristic clinical features dominated by lymphoproliferation and autoimmunity,1 emphasizing the importance of central (thymic) deletion of autoreactive cells.

4

Autoimmune diseases: classification and diagnosis Human autoimmune diseases are classified according to whether predominantly a single organ is affected (organ specific) or whether there is multiple organ involvement (non-organ specific). As with any classification system, some conditions fall between these two extremes. Table 4.11 lists some common autoimmune diseases in these two categories. Autoantibody detection is frequently requested in the investigation of suspected autoimmune disease. Autoantibodies may be primary and directly cause disease (e.g. antiglomerular basement membrane antibodies in Goodpasture's syndrome, antiacetylcholine receptor antibodies in myasthenia gravis and anti-TSH receptor antibodies in Graves' disease), but more commonly they are secondary and are formed as part of the disease process itself (e.g. antinuclear, anti-dsDNA, antismooth muscle, antimitochondrial antibodies). Detection of a secondary autoantibody does not necessarily indicate that the patient has an autoimmune disease. 'False positive' autoantibodies are associated with, for example, infection, female gender, increased age and surgical procedures. Determining the significance of autoantibody results requires careful clinical assessment. It is also important to know the exact pattern of autoantibody detected, its titre (or strength) and

TABLE 4.11 Autoimmune diseases and their associated autoantibodies Disease

Autoantibodies directed against

Hashimoto's disease Graves' disease Pernicious anaemia

Thyroid peroxidase TSH receptor Intrinsic factor Gastric parietal cells Steroid-secreting cells of adrenal cortex Islet cell Smooth muscle Acetylcholine receptor Voltage-gated calcium channel

Addison's disease Type 1 diabetes mellitus Chronic active hepatitis Myasthenia gravis Lambert-Eaton myasthenic syndrome Pemphigus Goodpasture's syndrome Sjb'gren's syndrome Primary biliary cirrhosis Systemic lupus erythematosus (SLE) Rheumatoid arthritis

Desmosomes Basement membrane Nuclear antigens (Ro/La) Mitochondria Nuclear antigens (ds DNA, Ro/La, Sm) Phospholipid IgG (rheumatoid factor-IgM class)

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CASE STUDY 4.2 ACUTE ONSET OF SWELLING A 15-year-old girl presented to her local accident and emergency department with an acute onset of swelling that affected her face. Her eyes were closed, she had swelling of the lips, but neither tongue swelling nor difficulty in breathing (Case Fig. 4.2.1). She reported eating a chocolate bar that contained peanuts 4 hours earlier, and a provisional diagnosis of nut allergy was made. She was immediately treated with i.v. chlorpheniramine and hydrocortisone. Adrenaline was not administered but she was admitted for observation and remained in hospital for 4 days, until her symptoms had completely resolved. She was discharged home with an adrenaline (epinephrine) selfadministration kit and told to read the package insert to explain its use.

Questions 1. How common is peanut allergy in the UK? 2'. Was her presentation typical of nut allergy? 3. If she did have peanut allergy was her treatment optimal?

Further history Her GP referred her for further investigation as he felt that she might have more than just nut allergy. A detailed history revealed that she had suffered recurrent swelling of her hands since the age of 4 years. She also had been investigated for intermittent abdominal pain and painful knees. She had eczema affecting her face and wrists, mild asthma and hay fever. She had previously had positive skin-prick tests to house dust mite and dog and cat dander. She was unable to wear cheap jewellery as this caused a rash. On examination she was obese, she 100

Further investigation The disparity between the low C4 and normal C3 levels prompted measurement of Cl-esterase inhibitor levels. These were normal (Clesterase inhibitor 0.52 g/L (0.28-0.5)); however, functional assessment of Cl-esterase inhibitor activity was 0% (70-140), indicating a functionally defective molecule and confirming a diagnosis of Cl inhibitor deficiency (type II).

CASE FIG. 4.2.1 Facial angioedema that is preventing the patient from opening her eyes or speaking had eczematous patches at her right wrist, marked dermographism, and respiratory examination confirmed scattered inspiratory wheeze. Investigations indicated: total IgE 731 kU/L, specific IgE to house dust mite (strongly positive), grass pollen (moderately positive), peanut (negative). Autoantibody screen negative, rheumatoid factor negative, C3 1.38g/L (0.7-1.7), C4 < 0.1 g/L (0.13-0.43), CRP 1.5mg/L (<6mg/L).

Questions 4. How does this further history affect the differential diagnosis? 5. Do the investigations rule out nut allergy? 6. What other condition(s) should be considered? 7. Do any of these have significantly different therapeutic implications?

Discussion This case demonstrates an important differential diagnosis that must be considered in anyone presenting with angioedema. Although the common causes of urticaria/angioedema are as listed in Table 4.10, Cl-esterase inhibitor deficiency (Cl-INH deficiency) typically causes angioedema but not urticaria. This presentation is typical in a number of respects of the experience with ClINH-deficient patients. She was symptomatic as a child, with some hand swelling and prominent abdominal pain. In her case this was diagnosed as abdominal migraine, but the more likely cause was Cl-INH deficiency-related abdominal pain, which is thought to be caused by angioedema affecting the bowel wall. The development of facial swelling as a teenager is also typical. Attacks commonly become more frequent and severe after puberty (and during pregnancy), the explanation for this being the relative changes in hormonal balance affecting Cl-inhibitor synthesis from the normal allele. Interestingly, however, the patient did have an atopic background with eczema and asthma, as well as a history of nickel sensitivity. On examination she also had dermographism. Thus she was demonstrating conditions characterized by types 1 and 4 hypersensitivity reactions, and this undoubtedly contributed to the initial

4

CASE STUDY 4.2 CONTINUED clinical diagnosis in the A&E department of probable allergic angioedema. The importance of the complement investigations in angioedema cannot be overestimated. Cl-INH deficiency, cryoglobulinaemia or genetic deficiency of C4 usually explains the finding of very low C4 despite normal C3. Thus measurement of complement levels is an extremely useful investigation, and a normal C4 during an attack of angioedema virtually excludes the diagnosis of Cl-INH deficiency.

The treatment of acute lifethreatening angioedema in this condition is very different from that required for allergic angioedema. Life-threatening attacks commonly occur after dental work that precipitates laryngeal angioedema and respiratory obstruction. Emergency treatment consists of 1000-1500 units Cl-INH concentrate intravenously, with close clinical observation in hospital. Prophylactic therapy is also considered for patients with frequent attacks. In this

whether it is of the IgG or the IgM isotype. For example, a significant antinuclear antibody (ANA) would be of high titre (>1:80) and IgG class. If the ANA pattern was not homogeneous (e.g. speckled or nucleolar) this might indicate specific subsets of connective tissue disorders (mixed connective tissue disease, systemic lupus erythematosus, scleroderma). Once an antinuclear antibody is detected, specialist immunology laboratories will further characterize it according to which nuclear antigen is targeted (Table 4.11). Again, this is helpful in the subcategorization of connective tissue disorders and the recognition of susceptibility to specific complications (e.g. anti-Ro antibodies and neonatal congenital heart block).

Diseases associated with type IV hypersensitivity Contact eczema The most common clinical example is nickel hypersensitivity. Affected individuals develop an eczematous reaction to nickel-containing jewellery, watches, buttons etc. that are in prolonged contact with the skin. The reaction is usually confined to the area of contact. Although sometimes referred to as 'nickel allergy', IgE mechanisms are not involved in the pathogenesis of this condition. Nickel is absorbed directly through the skin and binds to selfproteins (haptenization).This stimulates CD4+ T cells, which are recruited to the area, and there is associated oedema of the epidermis. This reaction occurs over 24-48 hours and is artificially recreated during 'patch testing', which is widely used to investigate type IV hypersensitivity. Granulomatous hypersensitivity Granulomatous reactions represent the full development of type IV hypersensitivity reactions, in which antigen persists and a focus of inflammation is established. The tuberculin reaction is a modified, self-limiting form which occurs, for example, with the Mantoux and Lepromin tests.

case the patient was commenced on cyclokapron 500 mg q.i.d., in preference to androgenic steroids, because of the potential virilizing effects of the latter. She was also provided with a warning bracelet that gave details both of her diagnosis and the necessary treatment in case of an emergency. Family studies confirmed that her biological parents were not affected and that this was one of the significant minority of cases caused by a new mutation.

These involve the intradermal injection of M. tuberculosis and M. leprae extracts. The local skin reaction is characterized by an area of induration and swelling which is mediated by sensitized lymphocytes. CD4+ lymphocytes predominate and accumulate, along with macrophages around blood vessels, with a maximum infiltration at about 48 hours. This reaction is focused at the site of foreign antigen in the dermis and is self-limiting, as antigen is progressively degraded and removed. Where antigen persists, however, granulomatous features can develop. Granulomas are collections of macrophages, some of which form giant cells; others appear as epithelioid cells. A cuff of small lymphocytes surrounds these. Granulomas may develop in response to foreign antigen (Mycobacterium infections) or as part of a presumed autoimmune response (Wegener's granulomatosis, sarcoidosis or CVID). The clinical effects of granulomas depend on the underlying cause, and the number, size and location of the lesions. They may cause significant destruction and morbidity, e.g.TB in the lungs, or they may be an incidental finding, e.g. in CVID in the liver. In mycobacterial infection it is recognized that the immunoregulatory Thl/Th2 response influences the degree of granuloma formation and indeed the individual's clinical manifestation of infection. If the response is predominantly of the Thl phenotype, with activated T cells producing IFN-y and IL-2, there is marked granuloma formation and, in the case of leprosy, the clinical pattern is tuberculoid. Tuberculoid leprosy is characterized clinically by localized granulomatous lesions which may be asymptomatic and which contain few viable organisms. In lepromatous leprosy there are widespread skin lesions containing numerous bacilli but few lymphocytes. These patients have a predominant Th2 phenotypic response to the organism (Th2 cells secrete IL-4, IL-5 and IL-10) and no clear granuloma formation. Consequently, M. leprae are able to proliferate and disseminate more freely in lepromatous leprosy, and the patient suffers the systemic effects

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of the infection. Host response in the form of hypersensitivity may therefore be advantageous under certain circumstances, and modification of the response by the administration of exogenous cytokines (e.g. interferon-y) can change the pattern of disease. 1

IMMUNOSUPPRESSION The rapid development of organ transplantation has been dependent on the availability of effective immunosuppressant drugs. An ideal immunosuppressant would be antigen specific and free of side-effects, but none of the currently available drugs meets these criteria. The clinical use and relative merits of the major immunosuppressant drugs are outlined below, as are some newly emerging immunomodulatory strategies. Corticosteroids These drugs have been widely used in the treatment of autoimmune diseases, malignancy and graft rejection for many years. The immunosuppressant action is difficult to separate from other potent anti-inflammatory actions of steroids. In humans it is mediated mainly through an inhibitory action on monocytes and macrophages, with reduced phagocytic function and diminished IL-1 secretion. Although in animals there is a marked lymphocytotoxic effect, in humans this is only significant against abnormal lymphocytes, for example in lymphoproliferative disorders, and when used at very high doses. Corticosteroids are potent immunosuppressants but their major disadvantage is multiple side-effects; these include weight gain, hirsutism, hypertension, diabetes mellitus, recurrent infection, growth retardation, osteoporosis, and reduced response to physiological stress. The appropriate dose of corticosteroid is determined by the individual clinical situation. For the long-term control of autoimmune disorders an oral dose of <10mg/day prednisolone would be appropriate. In the acute management of autoimmune haemolytic anaemia, acute glomerulonephritis or immune thrombocytopenic purpura, l-2mg/kg/day is indicated. In very severe life-threatening situations, such as systemic vasculitis, pulsed high-dose regimens of l0mg/kg are used (maximum 1000mg).

CYTOTOXIC DRUGS (see Chapter 6) This group of drugs kills cells capable of self-replication and they were initially introduced in the treatment of cancer. Their introduction into the management of trans1

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MCQ 4.4

2

Case 4.2

3

MCQ 4.5

plantation and autoimmunity enabled reductions in the doses of corticosteroids required (in this situation they are often referred to as 'steroid-sparing agents'). The major complication of long-term use is myelosuppression and immunosuppression, and a long-term increase in susceptibility to malignancies. Azathioprine Azathioprine is an analogue of the cytotoxic drug 6mercaptopurine (both are thiopurines) and was originally introduced in the 1950s for renal transplant recipients. It now has a major use as a steroid-sparing agent in the management of many autoimmune disorders. Thiopurines block the synthesis of inosinic acid, the precursor of adenylic and guanylic acids, and thus impair DNA synthesis. Their major cytotoxic effect is on developing T and NK cells, and thus there is a delay before clinical onset of action. The most important side-effect is bone marrow suppression. Weekly monitoring of full blood count (FBC) is advised during induction, with 3-monthly FBC during maintenance therapy. The patient must be warned of potential susceptibility to infection, and any unexplained illness or clinical suggestion of infection requires thorough investigation and, potentially, withdrawal of treatment. The usual maintenance dose range is l-3mg/kg daily. 2 Cyclophosphamide This is one of the most widely used drugs in cancer chemotherapy and is now frequently used in combination with corticosteroids in the management of severe autoimmune conditions, especially systemic vasculitis. As an alkylating agent it acts by cross-linking DNA strands, thereby preventing normal mitosis. It is particularly toxic to B cells. Side-effects include a dose-dependent neutropenia and lymphopenia, alopecia and infertility (especially in males) and, infrequently, haemorrhagic cystitis. Cyclophosphamide is typically used in combination with prednisolone in either oral or intravenous protocols to control severe systemic vasculitis. Dosage is determined by disease severity and according to renal function, bone marrow function and the patient's age. Mycophenolate mofetil Mycophenolate mofetil is used in combination with corticosteroids and ciclosporin in the prophylaxis of renal transplant rejection. Mycophenolic acid (MPA) is the active metabolite and is rapidly produced by hydrolysis after ingestion of the drug. MPA selectively inhibits inosine monophosphate dehydrogenase (IMPDH), which prevents lymphocyte purine biosynthesis. The inhibition of IMPDH causes a depletion of guanine nucleotides, inhibition of DNA synthesis, and prevents clonal expansion of both T and B cells. Close monitoring is necessary with weekly full blood counts (FBC) for the first month of treatment, 2-weekly for the next month, and monthly for the first year of treatment. Its use is currently limited to specialist transplantation units.

Methotrexate This drug is used in maintenance treatment of childhood leukaemias and is increasingly used in the control of a number of inflammatory diseases, including rheumatoid arthritis, polymyositis, psoriasis, Reiter's syndrome and graft-versus-host disease following bone marrow transplantation. It also appears to have a role in steroiddependent asthma, although the exact mode of action in this condition is unclear. Methotrexate inhibits dihydrofolate reductase, thus preventing the conversion of folic acid to its active form, tetrahydrofolate. This prevents normal thymidine synthesis and cell division. Side-effects include bone marrow suppression, megaloblastic anaemia, pneumonitis and mucositis. Long-term drug toxicity is increased in hepatic impairment. Acute side-effects are partially reversible by the administration of folinic acid.

NON-CYTOTOXIC IMMUNOSUPPRESSION Ciclosporin This relatively recently introduced drug has revolutionized the management of post-transplantation patients and is also finding a place in the management of some autoimmune disorders. A fungal metabolite with a cyclic undecapeptide structure, it acts to selectively inhibit T-cell activation. The drug binds to cytosolic proteins, called cyclophilins, which prevent calcium-dependent activation of the IL-2 gene. IL-2 transcription is a crucial event in T-cell activation and thus cyclosporine is a relatively selective immunosuppressant. Ciclosporin does not cause myelotoxicity but does cause a dose-dependent reduction in renal function that must be carefully monitored and differentiated from renal transplant failure or rejection. Monitoring of therapeutic plasma levels is essential. Other side-effects include hirsutism, gingival hyperplasia and seizures. In common with other immunosuppressants there is an increased long-term risk of lymphoma and skin neoplasia. Tacrolimus (FK506) This macrolide is not chemically related to ciclosporin but has a similar mode of action. Its use is currently limited to hepatic and renal transplant patients, although there is evidence to suggest it will have significant clinical impact in autoimmunity. Tacrolimus binds to the cytosolic FK506binding protein (FKBP), preventing IL-2 gene activation. It has a similar range of side-effects to ciclosporin. 3

NEWER IMMUNOSUPPRESSIVE STRATEGIES In addition to the pharmacological immunosuppressive drugs, a number of new immunological therapies are emerging in clinical practice.

Plasma exchange has been available for many years and continues to be of value in the acute management of some severe autoimmune conditions, including Goodpasture's syndrome, myasthenia gravis and rhesus disease, in which autoantibodies are demonstrated to be pathogenic. Plasma exchange allows the removal of these autoantibodies acutely but has no proven role in the long-term management of these conditions. High-dose ivIg therapy (l-2g/kg) is of proven benefit in autoimmune thrombocytopenia and Kawasaki's and Guillain-Barre syndromes. Its mode of action is incompletely understood, but may involve blockade of Fc receptors, disturbance of anti-idiotypic networks, or suppression of macrophage and/or T-cell activation. This therapy has specific side-effects, including aseptic meningitis, acute haemolysis (when ivIg is uncross-matched) and acute deterioration in renal function. It should therefore only be used for conditions in which clinical benefit is proven by properly controlled studies. Monoclonal antibody (moAb) therapy has shown encouraging results in a number of areas of clinical practice. CAMPATH-1 is a humanized mouse anti-CDw52 moAb, an antigen which is present on all leukocytes. It has proved to be of particular value in the treatment of acute graft rejection and graft-versus-host disease following bone marrow transplantation. More specifically, anti-CD25 moAb (basiliximab), which prevents T-cell activation, has been introduced for the prophylaxis of acute renal rejection. Antitumour necrosis factor (anti-TNF) moAb has recently shown promising results in the control of disabling rheumatoid arthritis (RA) and in severe inflammatory bowel disease, especially Crohn's disease. TNF is believed to have a central role in the pathogenesis of these diseases. Future clinical developments in this area may follow from current preclinical studies. 'Biological immunosuppressive agents', including antibodies directed against cell surface molecules of T, B and antigen-presenting cells, are being studied in models of transplantation and autoimmunity. These models may indicate new modalities for controlling undesirable immune responses through modulation of the function of the cell surface signalling molecules. Antibodies directed against gp39 (CD40 ligand) and CD28 have been demonstrated to overcome renal allograft rejection in a primate system. Human clinical trials (phases I and II) of these agents are currently under way. Anti-LFA-1 moAb has also been used to control transplant rejection. The cell surface molecule CTLA-4, which is known to downregulate T-cell responses, also has the potential for therapeutic manipulation. CTLA-4 linked to immunoglobulin molecules (to prolong its half-life in the circulation) has been successfully used in clinical trials to treat psoriasis. In respiratory medicine, IL-8 receptor antagonists are being evaluated in airway disease, and antiIL-5 moAb is under investigation in the treatment of asthma. These experiences of 'biological immunosuppression' suggest that this will be a major area of therapeutic development in the coming years, with novel drug devel-

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opment for a wide range of disorders associated with inappropriate or excessive immune activation.

FURTHER READING Chapel H M 1994 Consensus on diagnosis and management of primary antibody deficiencies. British Medical Journal 308:581-585. Chapel H, Heaney M, Misbah S, Snowden N 1999 Essentials of clinical immunology, 4th edn. Blackwell Science, Oxford. Conley M E, Notarangelo L D, Etzioni A 1999 Diagnostic criteria for primary immunodeficiencies. Clinical Immunology 93(3):190-197.

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Janeway C A, Travers P 1997 Immunobiology - the immune system in health and disease, 3rd edn. Churchill Livingstone, Edinburgh. Primary immunodeficiency diseases. Report of an IUIS scientific group. 1999. Clinical and Experimental Immunology 118 (suppl l):l-28. Reeves W G, Todd I 1996 Lecture notes on immunology, 3rd edn. Blackwell Science, Oxford. Rosen F S, Cooper M D, Wedgewood R J P 1995 The primary immunodeficiencies. New England Journal of Medicine 333(7):431-440. Stites D P, Terr A I, Parslow T G 1997 Medical immunology, 9th edn. Appleton and Lange, Connecticut.

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Nutrition in Clinical Medicine Michael E J Lean

Food and its use 105

Overweight and obesity 128

Assessment of nutritional status 115

Nutrition support 132

Dietary intake assessment 117

Nutrition as a cofactor in disease and in therapy 136

Nutrition and feeding practices for growth 119

Food sensitivity and intolerance 140

Malnutrition 120

Nutrition in health promotion: current diet and proposals for change 141

Vitamin deficiencies and excesses 122 Trace elements 127

FOOD AND ITS USE FOOD CHOICE AND FOOD COMPOSITION There is no doubt that diet has profound influence on human health, at all ages and affecting all medical subspecialties. Defining and influencing nutritional status is, however, very complicated. Although we customarily summarize the diets of individuals and populations in terms of nutrient exposure, there are many steps in establishing this exposure, each subject to substantial variability, both within individuals over time and between population subgroups. The general scheme (Table 5.1) may seem mostly self-evident, but indicates the scope for error in research and the need for clarity of thinking. The source of variability which may affect the evaluation of the diet of an individual or a population extends well beyond those that can be established either by retrospective questionnaires (depending on memory) or by prospective food records (depending on representativeness). Most of these influences are beyond the control of individuals, and so may tend to confound efforts to change diets.

As well as variations within the population, many of the components in Table 5.1 are also subject to fluctuations over time. Meal and snack patterns have changed dramatically over the last 10-20 years, with 'grazing' now being the norm in young people. Likewise, a generation has now emerged without experience of traditional meals or home cooking, using almost exclusively pre-prepared foods eaten in 'non-meal' situations - e.g. in front of the television, or on public transport. Increasingly homes do not have conventional kitchens, and people rely on microwaves and freezers. Although daily food shopping is still usual in Mediterranean countries, where fresh foods predominate, the steady trend in UK is towards weekly shopping, and this has profound effects on the need for long-life foods and preservatives. Retailers have progressively selected smaller ranges of foods, for shelf-life, appearance and taste, but disregarding nutrient composition. The dominance of major multiples (supermarkets) has significantly reduced biodiversity and driven farmers to produce highly stylized products. The 'added-value' food processing industry is now the major profit source, such that the most heavily advertised and promoted foods are those with the poorest nutritional value. Individual food choice is very complicated, but essentially demands a mix of the known and safe with a little of something new. Over recent decades there have been progressive trends to increase the sweetness and saltiness of foods. This has created a taste expectation, such that home-prepared foods can taste unpleasant if they contain less (i.e. normal amounts) sugar or salt. On a more positive note, the quest for 'health' by consumers is becoming a major driver for food choice and for reformulation of products. Globalization and sophisticated trading and transport have introduced unfamiliar foods, but also a new layer of uniformity which makes change difficult. The influence of season has all but disappeared, to the extent that many people are suspicious of seasonal foods - even locally grown ones, such as soft fruit. The nutrient composition of foods, catalogued in food tables and databases, is drawn up from analyses of a few examples of each food. One or two (e.g. potatoes) take account of seasonal variations in composition, but not the other factors outlined above. These tables provide only a broad guide as to the nutrient composition of the foods consumed by an individual or in a particular survey. Dietary analysis is imprecise, with scope for serious error. For some foods, similar varieties can contain up to 100-fold differences in specific nutrients, e.g. flavonols in lettuces. One way to resolve this is to assess diets, and to construct dietary advice, in terms of food groups consisting of broadly interchangeable foods - bread/cereal/pasta/rice; fruit and vegetables; spreading fats and oils; meat/cheese/ eggs; sweets, cakes and confectionery. This type of grouping has some limitations, but serves to remind us that diets, and foods, are consumed in meals. The meal is the smallest unit of nutrition, and it is the 'eating episode' which provides a focus for individual planning.

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TABLE 5.1 Influences on diet composition and nutrient exposure with food choice and variability Diet composition

Source of variability

Meal and snack pattern Meal structure Cooking methods Home food storage methods Shopping and catering patterns Food choice of individuals Purchasing policies of retailers Farming methods Seasonal

Age, ethnicity, culture Culture, occupation, family Family structure, housing Housing, finance Socioeconomic, ethnic Age, gender, socioeconomic Profit-driven, convenience Profit-driven, subsidies Latitude, transport Analytical rigour

Nutrient composition of food groups Nutrient composition of specific food varieties

Plant breeding, health concerns

NUTRITION AND NUTRIENTS Nutrition is the process by which food is eaten and utilized by the body. More broadly, the principles of nutrition nutrient supply, storage, requirements, consumption and metabolism - can be applied at many levels. Nutritional balance, which incorporates all these factors, should therefore be considered at the levels of the cell, of organs, of the whole body and of populations. For all the processes that define nutritional balance, there are ranges within which balance can be achieved at a level compatible with health. Outside these ranges malfunction and disease will result from deficiencies, toxicity or competition between nutrients. Within 'normal ranges' of nutrition, research is beginning to define levels which may determine optimal long-term health, and which may differ between individuals according to genetic background. In the presence of disease, nutrient requirements, supplies and metabolism are altered. Nutritional status may be a cause, or part of a cause, of disease, and may in turn be altered by disease. This chapter is concerned with the ways in which nutrient supplies - especially energy - are utilized, and how dietary factors and deficiencies may produce specific clinical syndromes or contribute to the development of disease.

DIETARY REQUIREMENTS AND REFERENCE VALUES

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Defining the nutritional requirements of individuals, or of groups or populations, is one of the most important aims of nutritional science. Information of this kind is essential for designing food supplies, and therefore it has major economic and political implications.

Certain nutrients are essential, i.e. they are necessary components or precursors of human biological pathways, that cannot be synthesized by humans. Essential nutrients include energy (provided by carbohydrates, fat and protein, together with oxygen and water), essential amino acids and fatty acids, and vitamins and essential trace elements. Foods also contain large numbers of other biologically active compounds which can modify metabolism and function. These are not 'essential', but may have beneficial actions for current or long-term health. Finally, there are compounds in foods which are not nutrients. These include environmental contaminants and inert or non-absorbable compounds. They may still affect health through toxic or allergic mechanisms, so the quantity present in foods may be important. Living cells require a continuous balanced supply of nutrients. However, food and nutrient supply is intermittent, and the body must also accommodate periods of nutrient deprivation, whether through famine or illness. The relationship between storage and tissue requirements determines survival time during nutrient deprivation. For oxygen (with only limited local capacity for anaerobic respiration and no storage), survival is measured in minutes. For carbohydrates and water, a clinical problem may occur in hours or a few days. For most water-soluble vitamins and some minerals (e.g. zinc), nutrient status also declines in days of deprivation. In contrast, in the case of the fatsoluble vitamin B12 and iron, full stores can permit many weeks of dietary deprivation. Traditionally, dietary nutrient requirements have been established for the essential nutrients on the basis of the amount per day which is sufficient to prevent a clinical deficiency syndrome developing, with a margin between 30 and 100% to produce a recommended daily amount, or RDA. This safety margin will depend on the nature of the nutrient. Fat-soluble vitamins, which tend to accumulate in the body and can be toxic, have a lower safety margin than water-soluble vitamins, which are rapidly excreted if consumed in excess. For many nutrients, deficiency syndromes develop slowly and isolated deficiencies are rare, so it has been hard to define RDAs. The 'safe intake' is often quoted. These are intakes which are customarily consumed by apparently healthy people. However, there are variations within the range of intakes in the general population. At a cellular level, most nutrients required for normal metabolism are synthesized. In some situations - in illness when supply is limited or demand is increased - there may be a conditioned deficiency of 'non-essential' nutrients which take on the role of 'conditioned essentials'. It appears that, for some nutrients (notably the antioxidant vitamins), there are levels of intake, well above those needed to prevent deficiencies, which are associated with optimal long-term health. Higher intakes than the RDA of vitamin E, for example, appear to have some protective effect against heart disease and some cancers. The RDA for folate, sufficient to prevent folate deficiency, is insufficient to prevent neural tube defects in susceptible women. Furthermore, within the recommended or 'normal' range

a

FIG. 5.1 Dietary reference values - definitions 95% of people would be adequately nourished if they consumed the RNI, and 95% would be deficient at LRNI.

FIG. 5.2 Dietary intakes and risk of deficiency with and without adaptation The risk of clinical deficiency is reduced when there is adaptation to low intake as it falls below the LRNI.

TABLE 5,2 Criteria for defining dietary reference values of folate intakes there is an inverse correlation with plasma homocysteine, a risk factor for heart disease. For most vitamins and minerals the average intakes in western countries are well above the RDAs, but some - e.g. iron, thiamine, folate, vitamin D, vitamin E - are marginal in certain population groups In 1991, the UK Committee on Medical Aspects of Food Policy, published a new approach to dietary reference values for a total of 40 nutrients. The reference nutrient intake (RNI) is defined as 2SD (standard deviations) above the estimated average requirement (EAR), and the lower reference nutrient intake (LRNI) as 2 SD below it (Fig. 5.1). Thus 95% of people would be adequately provided for by consuming the RNI and, assuming no adaptation to low intakes, 95% would be deficient if they consumed the LRNI (Fig. 5.2). The exception to this general rule is the energy requirement. Assuming the need to maintain a constant weight, only an EAR is quoted. The evidence used included not only the classic clinical deficiency evidence, but also data on blood or tissue saturation and on nutrient-dependent enzyme function (Table 5.2). For a number of nutrients adequate scientific data are still not available, and so 'safe intakes' are quoted. The questions surrounding optimal intakes for future health are still unresolved, apart from fatty acids, which follow the recommendations for cardiovascular health. Dietary reference values (DRVs) are determined for healthy people, and assume normal status for other nutrients. The factors affecting requirements are summarized in Table 5.3.

• • • • •

Amount taken without deficiency developing Amount needed to cure deficiency Amount needed to maintain blood or tissue concentration Amount needed to maintain enzyme saturation Amounts associated with appropriate biological marker of adequacy

TABLE 5.3 Factors which affect requirements of nutrients 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

Size Age Growth Sex Physical activity Pregnancy Lactation Availability from specific foods Illness Deficiencies of other nutrients

ENERGY Energy, utilized over time to produce work or build body tissues, is expressed as kcal or kJ (1 kcal = 4.18kJ). It is supplied by fat (9kcal/g), ethanol (7kcal/g), protein (4kcal/g),

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carbohydrates (3.75kcal/g) and dietary fibre (2-3kcal/g). Because energy cannot be created or destroyed, energy intake always equals energy output, plus or minus changes in energy stores. The body stores some energy as carbohydrates, in the form of glycogen (mainly in the liver), which provides a source of glucose. Total glycogen stores contain about 250 g, or 1000 kcal. The remaining energy stores are as triglycerides in adipose tissue. An average person with 20kg of adipose tissue has energy stores of 20 x 7000 = 140 000 kcal, enough to provide for 70 days' starvation at 2000 kcal/day. Carbohydrate cannot be synthesized from fatty acids. There are no specific stores of protein, but during starvation protein is metabolized from the destruction of muscle and connective tissue. This, and the glycerol from triglycerides, provides some glucose for organs dependent on glucose. Energy is necessary for the maintenance of all metabolic processes, physical activity and growth. Most dietary energy is needed to maintain oxygenation, blood supply and ionic gradients across membranes in all tissues. This is termed the basal metabolic rate (BMR). Energy expenditure can be measured by indirect calorimetry, usually in the early morning in a resting state, the subject having last eaten the previous evening. This resting energy expenditure (REE) is close to the BMR. BMR can be estimated with reasonable accuracy from the sex, age and body weight (Table 5.4). More recent 'doubly labelled water' methods measure energy expenditure in free-living adults using the different excretion rates of the stable isotopes deuterium (3H) as water, and 18O as water and CO2, to obtain an estimate of CO2 production and hence total energy expenditure (TEE). The difference between TEE and BMR measures the energy expenditure in association with feeding and from physical activity (Table 5.5). The energy requirement of an individual subject, which is equal to TEE if weight is to remain constant, depends primarily on body size and composition. Age, physical activity, environmental temperature and physiological state (whether pregnant, lactating or suffering from sys-

SUMMARY 1 Factors affecting basal metabolic rate and total energy expenditure Factors affecting basal metabolic rate • body weight • age/gender

relative proportion of lean body mass to adipose tissue recent weight change or energy imbalance

• thyroid function

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Factors affecting total energy expenditure • basal metabolic rate • physical activity and body weight (work output) • diet composition (carbohydrate, protein, fat proportions) • inflammatory conditions, altitude

TABLE 5.4 Equations for estimating basal metabolic rate (BMR) BMR (MJ/d)

Males

10-17 yr 18-29 yr 30-59 yr >60yr

BMR = 0.074 W + 2.754 BMR = 0.063 W + 2.896 BMR = 0.048 W + 3.653 BMR = 0.049 W + 2.459

SEE = 0.44 SEE = 0.64 SEE = 0.70

Females

10-17 yr 18-29 yr 30-59 yr >60yr

BMR = 0.056 W + 2.898 BMR = 0.062 W + 2.036 BMR = 0.034 W + 3.538 BMR = 0.038 W + 2.755

SEE = 0.47 SEE = 0.50 SEE = 0.47

W = body weight (kg), SEE = standard error of estimate

TABLE 5.5 Calculated physical activity level (PAL) of adults at three levels each of occupational and non-occupational activity Occupational activity Light

Non-occupational activity Non-active Moderately active Very active

Moderate

Moderate/Heavy

Male

Female

Male Female Male

1.4 1.5 1.6

1.4

1.6

1.5

1.5

1.7 1.8

1.6 1.7

1.6

1.7 1.8 1.9

Female

1.5 1.6 1.7

temic infection) are also important. BMR is determined by the size and metabolic activity of organs in a resting state, and so it has a major component from organs such as the heart, lungs, kidneys and brain. Skeletal muscle is relatively less important in determining BMR than it does in TEE. TEE has a very close relationship to body weight because the energy cost of physical activity depends closely on weight. Variations in BMR for a given weight can reflect metabolic factors such as thyroid function. Energy expenditure may be considerably increased in situations of metabolic stress, such as pyrexia and burns. The factors that control metabolism physiologically and modify it in disease include catecholamines, thyroid hormones, insulin, cortisol and cytokines (e.g. tumour necrosis factor-a). Energy requirements are highest - on a body weight basis or per unit 'lean body mass' - in infants and young children. Energy expenditure starts to fall in the 20s and declines steadily thereafter into old age, principally because of declining physical activity, with consequent reduction in muscle mass. Because the factors affecting energy requirement vary considerably between individu-

TABLE 5.6 Average daily energy expenditure In various lifestyles

a

24-hour energy expenditure in kcal (MJ) Occupation (age in years)

Men

Retired elderly (65+) Housewife (25-45) Office worker Laboratory technician (20-50) Factory worker (20-45) (heavy industry) Labourer (20-45) (heavy physical work)

2300 2500 2800 3200 3600

Women (9.5) 1900 2200 (10.4) 2100 (11.7) 2200 (13.2) 2400 (14.8)

(7.8) (9.0) (8.6) (9.0) (9.9)

TABLE 5.7 Average energy expenditure of an adult in various degrees of physical activity Degree of activity

Expenditure (kcal/min)

Minimal (e.g. sitting, slow walking) Moderate (e.g. walking, gardening) Intermediate (e.g. swimming, brisk walking) Heavy (e.g. digging, squash, running)

1 5 7 10

als, it is impossible to give an exact ideal nutrient intake, but there are clearly differences in daily energy expenditure between adults with different lifestyles (Table 5.6) and at different ages (Fig. 5.3). The energy expenditure for physical activity depends on body size, so it is convenient to express the energy costs of different activities as functions of BMR. Table 5.7 shows the energy required for various physical activities. As the total time in each 24 hours spent in strenuous activity is often rather short, significant increases in energy expenditure are difficult to sustain. Weight reduction by increasing physical activity is therefore hard to achieve. In adults the main indicator of energy balance (and often of overall nutritional status) is change in body weight. Weight varies by up to 1-2 kg from day to day in healthy adults, and is more affected by fluid balance over the short term. Weight change due to altered energy balance is usually accounted for by fat stores, at 9000kcal/kg (75% of weight change), and lean body mass, at l000kcal/kg (25%). Thus each 1kg change in adipose tissue reflects about 7000 kcal shift in energy balance. Although metabolic rate is governed principally by body weight, the alterations in metabolic rate from weight changes are relatively small: a 1kg weight change alters metabolic rate (and thus energy requirement for weight stability) by only about 15kcal/day. In children energy is required for growth, and measurements of weight gain or height gain are useful indicators

FIG. 5.3 Estimated average requirements for energy intake [A] at different ages, and B during pregnancy and lactation for women.

of dietary insufficiency. During the first few weeks of catchup growth from severe malnutrition, the energy cost of weight gain is about 5kcal/g. Thereafter, it becomes more energy expensive to lay down tissue, as fat rather than lean tissue is laid down. Energy balance can be maintained from a wide range of nutrient origins. In the UK, fat and carbohydrate each provide between 40 and 50% of dietary energy, whereas in developing countries the proportion from fat may be less than 15% and from carbohydrates more than 75%. Protein provides 10-15% of energy in most diets, in both western and developing countries.

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Dietary energy deficiency is that amount which results in negative energy balance. This results in immediate mobilization of energy stores from glycogen and fat. As underfeeding continues a greater proportion comes from protein, principally through muscle atrophy. Excess energy intake will be stored as glycogen if the limited capacity of the liver permits, or as fat in adipose tissue. Gross excess will lend to storage in tissues such as liver, impairing liver function. Minor imbalances of energy balance occur between meals and from day to day. Energy imbalances insufficient to be detected in body weight will have metabolic effects, e.g. on insulin sensitivity and serum lipoprotein.1

PROTEIN Most major human foods include protein, in an amount equivalent to 5-50% of food energy (Table 5.8). Mixed diets usually supply 10-20% of energy as protein. The requirement for dietary protein is determined by tissue growth and repair. The healthy body is efficient in the utilization of amino acids. Total body protein in an adult is about 16kg, which has accrued over 15-20 years of growth. Healthy protein is constantly being broken down and resynthesized in the process of protein turnover, but the amino acids are mostly reutilized. Losses from skin, hair and gut mucosa contribute to an absolute requirement of about 0.6g/kg/day for adults, or about 8% of dietary energy. Although humans cannot incorporate inorganic nitrogen, colonic bacteria can. It is therefore possible for some nitrogenous waste in the bowel to be rescued by bacterial amino acid synthesis and subsequent absorption. There are no body stores of protein or amino acids, but periods of low intake can be tolerated by metabolism of tissues such as muscle, gut mucosa and skin. However, atrophy of these tissues is more likely to reflect total energy deficiency, not specifically protein. The maximal protein requirement for optimal growth in infancy is about 1.5g/kg/day. This is amply provided by human milk, whose protein content is 130g/L, 7.5% energy.

SUMMARY 2 Protein requirements in health • • • •

Protein deficiency impossible with normal food provision Most dietary protein is metabolized like carbohydrate Minimum safe consumption (about 8% dietary energy) Requirements for essential amino acids virtually always met by 1 g/kg/d (= 10% dietary energy)

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MCQ 5.1

TABLE 5.8 The protein content of some foods which are often major protein sources Protein source Cassava Cooked bananas (plantains) Sweet potatoes Human milk (4.1 % fat) Rice (brown or white) Millet flour Potatoes (old, main crop) Maize (sweetcorn kernels) Wheat flour (wholemeal) Groundnuts (peanuts) Cows' milk, full fat (3.9% fat) Beans and peas Lentils

Eggs Cows' milk (skimmed) Fish (fatty) e.g. mackerel Soya (tofu) Meat (lean) (beef) Fish (white)

Proportion of energy as protein (%) 2 3 5 7 7 7 11 15 16 18 19 31 34 34 40 42 45 50 94

It is assumed that human milk contains the amino acids required for growth in optimal proportions, and this is likely to be similar for other milks, and eggs. There are nine amino acids which are not synthesized in the body, and are thus 'essential' nutrients. Others are needed in the diet to optimize utilization, although they are not technically essential. The ability to synthesize specific amino acids may be compromised during illness, such that 'conditioned essentiality' may develop, e.g. for glycine in infants. The metabolic requirement for amino acids is a separate consideration from dietary requirement. Essential amino acids thus form a small part of metabolic requirement, whereas non-essential amino acids (normally readily synthesized in the body) may be required in large amounts. To some extent alterations in colonic bacterial amino acid synthesis may modify essentiality. Because certain foods are deficient in essential amino acids (cereals, for example, are deficient in tryptophan, methionine and cysteine) an optimal amino acid balance can only be achieved by combination with other foods (such as legumes, which are rich sources of tryptophan and methionine). Thus a diet based on maize and beans is consumed by millions of healthy people all over the world. Most mixed diets contain much more protein than is required for health, and the excess is metabolized, mainly as carbohydrates, allowing the correct balance of amino acids to be extracted for protein synthesis. Protein is absorbed in the small intestine as amino acids and small

peptides, after the action of luminal peptidases such as trypsin. Isolated dietary protein deficiency is extremely rare outside famine situations. Low-protein foods such as cassava or plantains are not otherwise eaten in isolation. Even when intakes of ethanol or fat and sugar are extreme, protein requirements in western societies are usually met. There is considerable debate as to how much protein we require. The usual calculation, which has been applied to all nutritional states, is expressed as nitrogen balance - the difference between the dietary intake and the losses of nitrogen in the urine, faeces and sweat. A positive balance is achieved when intake exceeds losses, such as occurs in normal infant and child growth, or during recovery from malnutrition in adulthood. Negative balance occurs when losses exceed intake, as in systemic infection or diarrhoea, or when dietary intake is reduced. The greatest requirements for protein (relative to body weight) occur in young infants. Those less than 3 months of age require about 2.5 g protein/kg body weight/day, and the older infant (9-12 months of age) requires 1.5g protein/kg body weight/day. Children need less than infants but more than adults. Rates of protein synthesis vary with age, being highest in the newborn and declining with time (Table 5.9). Unfortunately, nitrogen balance measurements are difficult to conduct, particularly in the ill or deprived. The main problem is that they depend on having a complete 24-hour urine collection to estimate output. If urine collections are incomplete, as is very common, the results are biased towards an apparently positive nitrogen balance. Thus, improbable claims of positive nitrogen balance have even been made for subjects on very low-calorie diets and evidently losing weight. Nitrogen balance in adults to some extent changes with the customary diet. There is adaptation to low intakes, so that nitrogen balance has apparently been achieved with 0.2g/kg/day after several weeks. However, it is not certain that this is indefinitely sustainable in health. During illness, both protein synthesis and protein degradation are increased, so that total protein turnover is elevated non-specifically and irrespective of whether total body protein content changes. In general, there is net protein loss during disease, with wasting of muscle, and the losses are restored during recovery. The 'ebb and flow'

TABLE 5.9 Variation in rate of protein synthesis with age Age group

Body weight (kg)

Newborn (premature) 2.0 Infant 9.0 Young adult 70.0 Elderly 55.0

Total body protein synthesis (g/kg body weight/day) 15.0 7.0 3.0 2.0

phases of energy and protein balance after metabolic stress relate to the release of metabolically active compounds such as cytokines, and cannot be corrected by increasing the supply of amino acids or dietary protein. There is no simple biochemical test to estimate amino acid or protein status. Plasma amino acids and proteins all reflect stress non-specifically. Serum albumin falls with any stress or inflammatory condition - e.g. myocardial infarction, malignancy or infection - and is not a marker of nutritional status. Serum albumin may, however, be of some value in distinguishing disease-related cachexia from starvation. Low albumin in the presence of starvation is a worrying prognostic sign, usually indicating the presence of infection. This is the case in oedematous malnutrition (kwashiorkor).

a

CARBOHYDRATES There are three major groups of carbohydrates in the diet: sugars, starches, and the plant wall materials that comprise 'dietary fibre'. All carbohydrates are polymers of monosaccharides, with the common formula (CH2O)n. They are almost completely absorbed from the gut, either as monosaccharides in the small intestine after hydrolysis by amylases and mucosal disaccharidases, or (5-10%) as short-chain fatty acids following fermentation by large bowel bacteria. The main absorbed sugars, glucose and fructose, are ultimately metabolized in the Krebs cycle to release energy through oxidation. Each carbon atom combines with two oxygen atoms to produce H2O and CO2 and release 3.75 kcal/g. Of relevance to the management of diabetes and hyperlipidaemia is the 'glycaemic index' of foods. This is the incremental rise (i.e. subtracting this baseline value) in blood glucose over 3 hours after eating 50 g carbohydrate from a food, expressed as % of the rise after 50 g carbohydrate from bread, which is used as a standard. It is possible to predict the glycaemic index of a whole meal from those of its component parts. Low glycaemic index foods, reflecting the content of fat and dietary fibre, consistency, cooking or processing and other undefined factors, are associated with lower blood glucose and insulin (i.e. increased insulin sensitivity) and with improved serum lipoprotein profiles. • Sugars. Sucrose and its components glucose and fructose are the sugars most used as sweeteners. Lactose (glucose-galactose) is the main sugar in milk. Fructose is the sweetest. The monosaccharides glucose, fructose and galactose are readily absorbed at the jejunal surface. The disaccharides sucrose, maltose and lactose are equally well absorbed as the monosaccharide component parts, provided that there has been effective hydrolysis by the intestinal disaccharidases. Sucrose intolerance and lactose intolerance, leading to watery diarrhoea, may occur during starvation or any diarrhoeal disease, as a result of mucosal atrophy and secondary

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disaccharidase deficiency. This is a strong argument for maintaining gut function by enteral feeding in postoperative and intensive care patients. • Starches. These comprise a group of polysaccharides containing large numbers of glucose units linked together to form branched chains. They are variably hydrolysed as a result of cooking, and are then further hydrolysed within the intestine. The commonest are the dextrins amylose and amylopectin. About 90% of starch is rapidly hydrolysed and absorbed in the small intestine. The remainder (some altered by processing or cooking to become hydrolysis resistant) passes with non-starch polysaccharides to the colon. • 'Dietary fibre' - non-starch polysaccharides. Plant walls contain a range of lignins, celluloses and hemicelluloses that are not digested in the intestine, and which are variably degraded by intestinal bacteria in the colon. Dietary fibre can be measured in a variety of ways in foods, but its function in maintaining healthy colonic flora - an essential function - can be performed differently by the different subclasses, and by other compounds, such as lactose in breastfed infants. Different dietary fibres have important physiological functions in influencing the absorption of sugars and the regulation of serum lipoproteins (soluble and gum-forming fibre from vegetables, fruits, legumes and oats) and in contributing to intestinal bulk and large bowel health (cereal fibre such as bran). Dietary reference values for carbohydrate are shown in Table 5.10. 'Extrinsic' sugars are those outside intact cells in foods. Several varieties of non-sugar sweetener exist. Sorbitol is a sugar alcohol; however, its energy value is similar to that of other carbohydrates. Saccharine has no chemical or nutritional relationship to sugars and provides no energy; it is about 500 times as sweet as sucrose. Aspartame is an amino acid-based non-nutritive sweetener. EU regulations control the amounts of sweeteners that are permitted in foods. None have been shown to be hazardous to humans, but the recommended limits can be exceeded by individuals with unusually repetitive food habits, and by diabetic children who consume large amounts of highly sweetened foods. Very high consumers should vary the types of artificial sweeteners used.

FAT

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Fatty acids provide the chief store of energy in the body. They are important in the development of all cell membranes and some tissues, and are essential components of some hormones. Dietary fatty acids are mainly supplied as triglycerides. These are esters of glycerol and three fatty acids. Fatty acids are characterized by the chain length, expressed as the number of carbon atoms (short chain C2-C4, medium chain C6-C12, long chain C20-C24), and by the number and position of double bonds (one double

TABLE 5.10 Dietary reference values as percentage of total energy* Population average Saturated fatty acids cis-polyunsaturated fatty acids of which essential fatty acids

10(11)

cis-monounsaturated fatty acids frans-fatty acids Total fatty acids Total fat Non-milk extrinsic sugars Intrinsic and milk sugars and starch Total carbohydrate

12(13)

33 (35)

Non-starch polysaccharide (g/d)

18

6 (6.5) 3(3)

2(2)

30 (32.5)

10(11)

37 (39) 47 (50)

*The average percentage contribution to total energy does not total 100% because figures for protein and alcohol are excluded. Protein intakes average 15% of total energy, which is above the RNI. It is recognized that many individuals will derive some energy from alcohol, and this has been assumed to average 5%, approximating to current intakes. However the Committee on Medical Aspects of Food (COMA) allowed that some groups might not drink alcohol and that for some purposes nutrient intakes as a proportion of food energy (without alcohol) might be useful. Therefore average figurers are given as percentages both of total energy and, in parentheses, of food energy.

bond monounsaturated, two or more polyunsaturated). Most unsaturated fatty acids are cis isomers, but some, mainly synthetically hydrogenated, are trans isomers. Vegetable oils have a greater proportion of polyunsaturated fats and are more fluid than the more saturated fats from animal sources, which are often hard at room temperature (Fig. 5.4) although liquid at body temperatures. Fish oils need to remain liquid at temperatures down to freezing point, and so contain large amounts of long-chain n-3 fatty acids. Dietary fats are normally almost 100% absorbed as they pass through the small intestine, after emulsification through the action of bile salts, and de-esterification of triglyceride by pancreatic lipase. Most dietary triglyceride is absorbed as monoglyceride and free fatty acids. The triglyceride is thus reassembled by re-esterification in the mucosal cell, and secreted by the mucosal cell with the addition of a lipoprotein as chylomicron. Most reaches the circulation via the chyle and the thoracic duct. Some, particularly short-chain fatty acids, are preferentially released discretely into the portal vein. Dietary reference values are included in Table 5.9. Phospholipids - esters of glycerol with two fatty acids are important for the stability of cell membranes, and deficiency may affect satisfactory psychomotor development. Cholesterol is the most important sterol. It is the precursor of the bile acids (which are essential for mixed micelle formation in the intestinal absorption of fat) as well as of adrenal and sex hormones and vitamin D.

FIG. 5.4 Fatty acid composition of some major sources of saturated, mono, and polyunsaturated fatty acids

of carotenoids (the precursors of vitamin A found in vegetables) and other fat-soluble vitamins. The position is more serious when there is intestinal malabsorption of fat (Chapter 15), as fat-soluble micronutrients are excreted in the faeces, dissolved in the malabsorbed fat. In this situation the dietary fat requirement to maintain dietary needs is greatly increased and may need massive supplemental dosages of essential nutrients. Fats provide over twice as much energy per unit weight as protein or carbohydrate, as each carbon atom of the (CH2) chain combines with three oxygen atoms to produce CO2 and H2O, and 9cal/g. Fats are thus useful sources of energy in diets designed to increase the rate of weight gain, e.g. in malnourished children. Conversely, a reduction in the fat content of the diet is a relatively efficient way to lose weight and to maintain weight loss. The intestinal lipase inhibitor drug orlistat utilizes this principle by introducing malabsorption of 15% of dietary triglyceride. With a low-fat diet (<30% energy) this degree of malabsorption is usually asymptomatic. Long-term use permits maintenance of 12-15% weight loss in the 40% of patients who respond to this drug. These findings remind us that patients may lose weight as a result of asymptomatic fat malabsorption from conditions such as coeliac disease or chronic pancreatitis.

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ALCOHOL Lipoproteins are the chemical complexes, formed by the triglycerides, phospholipids and cholesterol with apoproteins, that circulate in the blood and which transport cholesterol and other fat-soluble compounds such as tocopherol. Lipoproteins can be separated by electrophoresis or according to density on ultracentrifugation, to demonstrate the classes (chylomicrons, VLDL, LDL, HDL) and their subtractions, which are familiar through their roles in atheroma formation. Triglycerides enter the bloodstream via the lymph, as chylomicra, and are converted in the liver muscle and adipose tissue to VLDL and LDL (see Ch. 17). The body is efficient at synthesizing triglycerides, sterols and phospholipids. Many populations whose diet provides only 15% of total energy as fat are able to lay down good stores of subcutaneous fat, reflecting the high capacity for synthesis of fatty acids from carbohydrate (lipogenesis) in liver, muscle and adipose tissue. Lipogenesis occurs whenever a meal provides more carbohydrate than can be stored immediately, but net lipogenesis is relatively unusual with the relatively low carbohydrate intakes in western diets. Most fat storage is from fat. Requirements for essential fatty acids are rather low (under 3% total energy) and deficiency is therefore uncommon. When diets are low in fat the high carbohydrate and protein content satisfies appetite more effectively. This may limit dietary intake and contribute to weight loss and the thinness of populations with lowfat diets. Low-fat diets may also limit the availability

There is no physiological requirement for dietary alcohol (ethanol). However, most adults have sufficient enzymatic capacity to absorb and metabolize much larger amounts than would have been met during evolutionary adaptation. Alcohol contributes 7kcal/g and tends not to satisfy appetite or to stimulate its own oxidation, and so energy from alcohol tends to be additive to the energy balance of the other proximate nutrients (fat, carbohydrate, protein). Alcohol has obvious immediate effects on the central nervous syndrome: it is a diuretic; in excess, alcohol alters lipoprotein metabolism to produce hypertriglyceridaemia; it inhibits folate absorption; and, in excess, supplants other energy sources, leading to multiple micronutrient deficiencies. The most important is thiamine (vitamin B1) deficiency. This constitutes the only true nutritional emergency. Without thiamine, disordered carbohydrate metabolism leads to Wernicke's encephalopathy and Korsakoffs psychosis (Chapter 24 p 1439). Alcoholics are also prone to scurvy because of neglect of their diet.

MICRONUTRIENTS There are large numbers of bioactive compounds in foods. A small number of these have been found to be essential for humans, who lack the ability to synthesize them. This is the basis for the definition of vitamins and essential trace elements. It is not known why nutrition has evolved in this

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CASE STUDY 5.1 ALCOHOLIC DIETARY DEFICIENCY A 42-year-old professional violinist is admitted following a witnessed grand mal seizure in a hotel bar following a performance. He gives a history of some weight loss, with anorexia and diarrhoea for 10 days. He is a smoker and admits to intermittent heavy drinking, including over the last months. There is no previous history of seizures, but some altered sensation in the feet for several months. A CT scan is reported as normal. A relative expresses concern over excessive and prolonged drinking since the death of his father 18 months previously, related to impaired performance and loss of employment.

Questions 1. What biochemical abnormality could explain the seizure? 2, What emergency nutritional therapy should be initiated on admission?

3. What is the cause of altered sensation in the feet? 4. What long-term management is appropriate?

Discussion The seizure threshold is lowered in alcoholics for several reasons, including head injuries, B vitamin deficiencies and cerebral atrophy, presumed to be a toxic effect of ethanol. In this case 10 days' diarrhoea is likely to have depleted magnesium status as a cause of seizures. There are no body stores of magnesium, which is plentiful in many foods, particularly cereals. Serum magnesium gives a good indication of magnesium status. Low levels block the secretion of parathyroid hormone and thus cause hypocalcaemia. Thiamine replacement should be

way. Humans have the genetic potential to synthesize ascorbic acid (in common with most other species), but the genes are not expressed. Certain micronutrients, e.g. metals such as iron, or fat-soluble vitamins, can be toxic in excess, and their absorption and transport are highly regulated. The absorption of metallic trace elements is generally low (15-30%), but can increase through adaptation to low intakes, or when requirements increase in pregnancy. Dietary reference values for mineral micronutrients are shown in Figures 5.5a and b and 5.6a and b, and 'safe intakes' for those whose true requirements are not known in Table 5.11. Deficiencies of individual vitamins result in specific biochemical and clinical responses, but vitamins are also involved in metabolism in more general ways. Folate, for example, is necessary for cell division and the transfer of

1

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MCQ5.2

started without waiting for biochemical confirmation of deficiency. Thiamine is particularly rich in cereals and grains, but not in alcoholic drinks. Peripheral neuropathy is a feature of several B vitamin deficiencies, but also of ethanol toxicity with inadequate antioxidant status, and of secondary diabetes when alcoholinduced pancreatic damage is severe. It seldom responds well to B vitamin replacement. Alcoholics are prone to multiple micronutrient deficiencies. Weight loss, often reflecting loss of lean body mass, indicates reduced total food consumption and may point to other chronic complications, e.g. tuberculosis. A multivitamin prescription is appropriate, but most preparations contain insufficient thiamine, and virtually none contain adequate folic acid. Alcoholics may benefit from greater intakes of antioxidant vitamins (C and E) than healthy people, but evidence is lacking.

methyl groups in protein synthesis; thus, a deficiency may impair tissue repair or growth, even if dietary energy and protein are adequate. Thiamine is important in carbohydrate metabolism, and lactic acidosis may occur in deficiency states and result in the brain damage of Korsakoff s psychosis. Ascorbic acid deficiency leads to scurvy, but it is also one of the hierarchy of antioxidant defences, so low vitamin C status reduces defences against free-radical damage (e.g. from smoking) without any signs of scurvy. A number of trace elements, such as zinc, are important in protein metabolism; deficiency of zinc is associated with an increased energy requirement for deposition of lean tissue. Children receiving nutrient supplements for proteinenergy malnutrition grow more slowly relative to the number of calories given, if they are not also supplemented with zinc. Severe individual micronutrient deficiencies may have recognizable clinical features, but even marginal deficiencies may affect metabolism of protein and energy, and the immune system. A variety of non-essential bioactive nutrients are relevant to human health. For example, flavonoids in fruits and vegetables are potent antioxidants, and may contribute to protection against coronary heart disease and cancers.

a

FIG. 5.5 Reference nutrient intakes for consumption of minerals These amounts will be sufficient for the needs of 95% of people.

Some related flavones in legumes are oestrogenic, and may modify the risks of heart disease, osteoporosis and breast cancer. Dietary carnitine may become important in facilitating fatty acid oxidation if carnitine synthesis is impaired during illness. Caffeine and theobromine in coffee, tea and chocolate have several properties, including central nervous system stimulation and diuretic actions.1 NON-NUTRIENT DIETARY COMPONENTS Within foods there are some compounds which are either not absorbed (e.g. the fat substitute olestra) or which are absorbed but not metabolized (e.g. the sugar inulin). Occasionally the presence of such compounds leads to an important difference between the chemical analysis and the nutritional value of a food. It is important to consider the nutrient availability of foods, as well as their chemical composition. Certain plant sterols, particularly stanol esters, inhibit the absorption of dietary cholesterol, although they themselves are not absorbed. These compounds are marked for cholesterol lowering, on average by about 10%. ASSESSMENT OF NUTRITIONAL STATUS BODY COMPOSITION In weight, the composition of the body is about 16% protein, 10-25% fat in men (15-30% in women), 5% min-

TABLE 5.11 Safe intakes of micronutrients where dietary reference values cannot be defined. Nutrient Vitamins Pantothenic acid adults infants Biotin Vitamin E men women infants Vitamin K adults infants Minerals Manganese adults infants and children Molybdenum adults infants, children and adolescents Chromium adults children and adolescents Fluoride (for infants only)

Safe intake

3-7 mg/day 1.7 mg/day 10-200 jig/day above 4 mg/day above 3 mg/day 0.4mg/g polyunsaturated fatty acids 1 ug/kg/day 10 ug/day

1.4mg (26(umol)/day 16ug(0.3umol)/day 5-400 ug/day 0.5-1.5ng/kg/day 25ng(0.5nmol)/day 0.1-1 .0ug (2.20 nmol)/kg/day 0.05mg(3umol)/kg/day

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Functional measures, such as grip strength, are valuable to complement measures of muscle bulk. Given the wide ranges of normality, changes in repeated measures are more valuable (for example by showing falls, or a reduction in growth velocity in children). Estimation of body composition is a critical factor in human nutrition, both in clinical situations and when the nutritional status of populations is considered. A large number of indirect methods are available, varying in cost and complexity. The situation is complicated by the lack of any true 'gold standard', even for major components such as fat or muscle. For research purposes, estimates can be made from MRI, CT scanning or dual-energy X-ray absorptiometry (DEXA). These approaches can also characterize the physical distribution of tissues. Total body water (found only in non-fat tissues) can be accurately measured from dilution of deuterium-labelled water, and this is probably the most reliable guide to fat mass. Estimation of fat mass or lean body mass in clinical practice and epidemiology has to rely on well-conducted anthropometric measurements (skinfold measurements and waist circumference), either for static measurement or for detecting changes over time. These methods have been validated against underwater weighing (employing the principle of Archimedes) as an independent reference method. A variety of commercially promoted methods (e.g. bio-impedance) generally perform less well than simple anthropometry in estimating body composition.

Anthropometry

FIG. 5.6 Reference nutrient intakes for dietary vitamin consumption These amounts will satisfy the requirements of 95% of people.

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erals, 1% carbohydrate and the rest water (about 60%). This total body water is either in the cells (intracellular water, 35%) or in the vascular system and tissues (extracellular water, 25%). The most important static measures to assess nutrition are the height, weight, body fat content (usually expressed as percentage of body weight) and fat distribution (specifically the intra-abdominal fat mass). Lean body mass (bones, muscle, brain and other organs) is estimated by difference between weight and body fat.

The key measurements for anthropometry are height and weight, measured under standard conditions (e.g. fasting, without shoes, in light clothes and with an empty bladder). Height and weight are combined in the body mass index (BMI: weight (kg)/height2(m)) as an estimate of body build or fatness which does not depend on height. The 'normal range' for adult BMI is 18.5-25 kg/m2, with BMI <18.5 indicating chronic energy undernutrition and BMI >25 usually indicating increased medical hazards from overweight. The conventional cut-off of BMI >30kg/m2 is used for epidemiological classification of obesity. The normal range of 18.5-25 kg/m2 applies at all adult ages, although the medical hazards change. These criteria do not apply to children under 16, whose BMI is usually much lower than that of adults. Mid upper arm circumference reflects both muscle mass and subcutaneous fat and has been widely used to indicate overall nutritional status. Mid upper arm circumference below 23cm in men or 22cm in women is a guide to the possibility of chronic energy undernutrition. A variety of anthropometric approaches have been used to predict body fat (and hence, by difference, lean body mass). The simplest approach, which gives a high prediction and low error through bias, is measurement of the waist circumference at the level between the lowest ribs and the iliac crest when the patient is standing.

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TABLE 5.12 Influence of inflammation on biochemical nutritional analyses Analytes

Reference range

Minor inflammation (CRP<15mg/L)

Iron Zinc Selenium Copper Vitamin A Vitamin E Vitamin C Vitamin Eh Vitamin B2 Vitamin B6 Vitamin B12 Folate Lycopene B-carotene a-carotene Lutein

8-30umol/L 12-18n.mol/L 0.8-2.0 umol/L 11.5-23.5 umol/L 1.0-2.8 umol/L 15-40umol/L 10-115nmol/L 280-540 ng TDP/gHb <70% activation* 18-135nmol/L (PP) 188-1059 pg/mL 3.5-16.0 ng/mL 100-300 ug/L 92-312 ug/L 14-60ug/L 82-202 ng/L

Decreased by 40% Decreased by 10% Decreased by 10% Increased by 10-15% Decreased by 30-40% Negligible No data No data No data No data No data No data Decreased by -50% Decreased by -50% Decreased by -50% Minimal change

Major inflammation (CRP~ 100-200 mg/L)

Comments

Decreased by 60-90% Decreased by 40-60% Decreased by 40-60% Increased by 30% Decreased by 30% Decreased by 20-30% Minimal to >75% dec. No change No change Decreased by 40-50% No change No change Decreased by >90% Decreased by >90% Decreased by >90% Decreased by >70%

Liver uptake Liver uptake ? Redistribution ? Liver extraction Probable redistribution More data needed More data needed More data needed More data needed More data needed More data needed More data needed More data needed More data needed More data needed More data needed

An approximate guide to the extent of change seen in analytes with different degrees of inflammation. The figures quoted are collated from disparate sources and the effects of diverse factors in different pathophysiologies may be important. TDP = thiamine diphosphate: * = of red cell glutathione reductase; PP = pyridoxal phosphate.

Body fat percentage (men) = (0.567 x waist in cm) + (0.101 x age in years)-31.8 Body fat percentage (women) = (0.439 x waist in cm) + (0.221 x age in years) - 9.5 Because the waist circumference incorporates a measure of the internal fat mass as well as of total body fat, it has recently found a place in health promotion to alert people to the need for weight management. Health risks start to develop when the waist circumference exceeds 80cm (32 in) in women or 94cm (37 in) in men. Cardiovascular risks are approximately tripled, and most subjects have symptoms from overweight when the waist exceeds 88cm (35 in) in women or 102cm (40in) in men. Waist circumference does not depend on height.

Biochemical nutritional assessment Biochemical measures are of relatively limited value in nutritional assessment. Blood or plasma is seldom the appropriate compartment to detect functional nutritional abnormalities, and extracellular fluid nutrient contents give only a crude (and sometimes misleading) indication of nutrient status. For some nutrients, e.g. zinc or amino acids, the plasma concentration may actually increase in starvation, reflecting tissue destruction. Abnormal plasma vitamins or trace elements are most frequently found when there is clear clinical evidence of malnutrition. An exception to this generalization is the measurement of haemo-

globin and the nutritional haematinics - transferrin iron, folate and vitamin B12 - where subclinical deficiencies are relatively common and demand treatment. Clinical biochemistry services now offer assays for vitamins (commonly vitamin A and carotenoids, B1, B2, B6, B12, folate, C, D, E) and trace elements (e.g. iron, copper, zinc, selenium). These are used mainly to confirm clinical suspicion of deficiency, and to monitor artificial feeding. Results always have to be interpreted in relation to clinical condition, and to indicators of stress or acute-phase reaction, such as C-reactive protein. Many vitamin measurements, e.g. vitamin C, are strongly influenced by inflammatory states (Table 5.12). Several proteins produced by the liver may be used in association with nutritional assessment, namely albumin, prealbumin, transferrin, retinol-binding globulin and thyroid-binding globulin. Plasma levels are of limited value on their own because they are affected more by short-term energy intake and by stress or inflammation.

DIETARY INTAKE ASSESSMENT Estimation of dietary intake, both of individuals and of groups or populations, is critically important to ensure health. It should not be considered an assessment of nutritional status but it complements nutritional status assessment. Dietary intake can be assessed in terms of eating

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pattern, foods, food groups and nutrients. All of these elements are important to different aspects of health by reference to standard recommendations or to dietary prescriptions for individuals. The dietary assessment of individuals is a specialized activity which needs to be conducted by trained dietitians.

Dietary intake of individuals The habitual eating pattern of an individual undergoes great variation from day to day. It is therefore usually inadequate to base any judgement on the eating habits of a single day, or even a small number of days. Certain foods are often consumed on only one day per week or less (e.g. fish on Fridays in some communities, carrots as the major contributor of B-carotene on Sundays, and liver as the major source of vitamin A much less frequently). The dayto-day variability of major nutrients is often of the order of 30-50%. Two dietetic approaches are used:

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• Retrospective dietary assessment This approach relies on the skill of the dietitian in establishing eating habits, depending on the memory of the subject. Retrospective approaches are sometimes used for a single 24-hour period or for a week, or through questionnaires to estimate habitual intake over a much longer period, perhaps 1 year. As a general rule, the more questions asked and the longer the interview, the more foods are remembered and a greater value is obtained for food intake. Cross-check questions should be employed in the dietary history in order to remind subjects of foods that may have been omitted (for example, asking how often milk is purchased may show a disparity from the answers to a question about the amount of milk consumed). The latter approach, which gives some indication of the nutritional quality of the diet, is usually employed to express the fat, carbohydrate and protein intake as percentage calories. Retrospective dietary assessment has a place in clinical practice when there is an interest in the consumption of individual foods, and learning about an individual's meal patterns is often more valuable than attempting to establish nutritional adequacy, which can often give misleading results. Patients currently referred for dietary intake assessment are mostly overweight or obviously undernourished. In both contexts misreporting is common. Overweight people, and those with restrained eating, systematically under-record or underreport by up to 50%. Brief questionnaires attempting to estimate the intake of individual nutrients, e.g. calcium, have been developed, but give rather poor results compared to fully quantitative methods. • Prospective dietary assessment. This approach does not rely on subjects' memories but does rely on a high degree of cooperation over several days, during which they are asked to complete a full inventory of all foods and drinks consumed, together with details of cooking methods and portion sizes, which may be weighed using food scales or again related to household measures.

The 'gold standard' for dietary intake assessment is the 7-day weighed intake. This approach is often impossible to apply to children, to busy working people, to the confused or demented, and to those who are socially deprived or have literacy problems. For this reason, dietary assessment is often problematic in sectors of the population where nutritional problems are most prevalent. Records over 3-4 days, including weekends and weekdays and appropriately adjusted to estimate 7-day intake, are often used. A dietitian compiles a list of foods consumed by the individual and then makes some assessment of the portion sizes and quantities eaten, usually by reference to simple household measures. Standard food tables (for example McCance & Widdowson's Composition of Foods) are now available on computer databases, so the foods can be identified by code number, and the nutrient composition per 100 g is then available for 40-60 nutrients. Nutrient intake data can be extracted in absolute amounts (in g or mmol per 24 hours), or in nutritional terms, expressed as % energy mg or mmol per l000kcal of food energy. It is helpful to be able to evaluate nutrient intake by meal type, in order to identify meals (e.g. lunches) which are the cause of suboptimal total diet composition.

Dietary assessment of populations and groups Several levels, of differing complexity, cost and precision, are available. The best plan is usually to use more than one approach and to check that the results corroborate each other. • Food disappearance rates. The food and agriculture organization of WHO compiles food balance sheets for each country annually. If the total food supply (commercial production, home production, importation) and the population base are known, then an estimate can be made of food consumption per head of population and therefore of nutrient consumption. Data of this kind are often incomplete, particularly with reference to home food production. A number of assumptions have to be made about the ways in which foods are used, wastage in preparation and cooking, etc. This approach gives no guide at all to the intake of individuals or of population subgroups which may be of concern. On the other hand, broad generalizations about dietary adequacy can be made, and comparisons between countries with different disease patterns. • Household food purchasing. The National Food Survey of the United Kingdom, established in 1945, set up a model which has been employed in many countries: a random selection of households is taken every year and their total food purchases surveyed for 1 week. Analysis requires a knowledge of the numbers of individuals within the household. Knowledge of the social setting may also be of value in establishing the eating patterns

of population subgroups. Assumptions still have to be made about the uses to which food purchases are put. The biggest problem in the past has been that household food surveys have not included any measure of foods purchased and eaten outside the home, or of home food production. Therefore, for a number of nutrients diet intakes are spuriously low. This applies particularly to nutrients such as fat and saturated fat, which are present in high concentrations in foods consumed as meals and snacks outside the home. • Food frequency questionnaires. A number of questionnaires have been validated to estimate the food and therefore the nutrient consumption of groups by enquiring about the frequency of consumption of a range of foods. In the computer analysis, standard portion weights are applied to enable estimation of per capita nutrient consumption. Food frequency questionnaires are not sufficiently precise to be used in the assessment of food intakes of individuals, but they are relatively cheap to use. Inevitably, they address only a limited range of major foods and will therefore tend to underestimate food intake, particularly in individuals whose range of food choices is wider. • Prospective dietary intake. Epidemiological approaches have employed the same prospective weighed intake methods used in the assessment of individuals. Although arguably the most reliable approach, this is an expensive and professionally intensive method, and problematic to more deprived sectors of the population. In clinical practice, all methods of dietary intake assessment tend to underestimate the habitual food intakes by 20-50%, particularly those who are overweight. The reason for this is uncertain and there may be selective misreporting (e.g. for high-fat foods). During the assessment period of prospective methods, overweight people tend to cut down on their usual food intake. There is also an element of self-deception and an unwillingness to reveal true eating habits. It is interesting that in many cultures high social status is associated with a denial or minimization of a number of vegetative and physical bodily functions, including food intake.

NUTRITION AND FEEDING PRACTICES FOR GROWTH Standards for child growth - compiled from subjects living in a clean environment with an abundance of food - show a considerable range in rates of gain in weight and stature. There are also differences in dietary intake in such children, which is also true in healthy adults who are not excessively over- or underweight. A man in his 30s who continues to eat the same amount of food that he ate in his late teens is likely to become overweight. In each case, the difference in nutritional status is the result of the balance between energy intake and energy expenditure.

Early infancy In the young infant nutritional requirements are particularly high in relation to body weight. Breast milk certainly provides enough energy and appropriate nutrients for at least the first 4 months, and has psychosocial and immunological advantages over artificial formula feeds. Recent evidence also points to better brain development in breastfed infants, related to essential fatty acid intake. Artificial formulae are frequently dangerous when prepared under unhygienic conditions, as in the homes of many poor families in the developing world. Cows' milk contains a dangerously high sodium content and should not be given before 1 year. Weaning should be gradual from 4-6 months: overfeeding in infancy may programme an excessive appetite.

a

Later infancy and early childhood Nutritional requirements are also high in infants over 4 months of age, when children can begin to receive solid foods in addition to breast milk. In developing countries the growth rate frequently falters at this stage, either because the energy given is not sufficient (the energy density of weaning foods in traditional societies is often low) or because of gut infection, so that food is not so well absorbed. Specific nutrient deficiencies (e.g. zinc, amino acid, folate) may also play a role. Cows' milk consumption in young children has been associated with bleeding into the bowel and anaemia, leading to the development of 'follow-on' formula feeds for use in the first year of life. There is very weak evidence that exposure to common dietary allergens in infancy may provoke allergies so foods with low allergenic potential (e.g. rice rather than wheat) are preferred.

Later childhood and adolescence Nutritional requirements for protein and energy are usually met in older children, but micronutrient deficiencies (e.g. of iron, folate and zinc), which may lead to anaemia, impaired intellectual performance and short stature, are relatively common even in western populations, and easily go unnoticed.

Pregnancy The nutritional stress of pregnancy is created by the need to produce both an infant and a placenta, plus some maternal fat stores. A 12.5kg weight gain in pregnancy would require a total of about 7000kcal (Table 5.13). There are also increased demands on maternal stores, especially of iron, zinc and folate. On the other hand, carefully conducted studies have not shown a greatly increased food intake in pregnancy. For some nutrients, e.g. calcium and iron, the efficiency of intestinal absorption is increased during pregnancy. Energy intake often falls in the first trimester, and then needs to increase to about 200kcal/day

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above non-pregnant intakes. The additional energy requirements of pregnancy are met from reduced physical activity and greater resting in the later stages. Fetal growth certainly depends on maternal nutritional status, both from starting weight and from weight gain, and may be specifically reduced by physical exertion in late pregnancy. Intriguingly, it has recently been shown that food deprivation in late pregnancy leads not only to smaller babies, but also to these offspring having smaller babies themselves. Good fetal growth is important for later, adult, health (to protect against diabetes, heart disease, stroke), and so maternal nutrition is doubly important. The Institute of Medicine recommends that, at term, women with BMI <19.8 should have gained 12.5-18 kg, those with BMI 19.8-26, 11.5-16kg, and those with BMI 26-29, 7-11.5kg. A BMI 28kg/m2 is a reasonable target at term. Table 5.13 summarizes the extra nutrient requirements of pregnancy, and suitable sources.

Lactation Babies should be exclusively breastfed for 4 months, and according to WHO recommendations breastfeeding should be continued for 12-24 months. The need to produce breast milk (up to 800kcal/day) for many months has obvious nutritional implications. Some of this can be provided from maternal stores laid down in pregnancy, but an additional 500kcal intake and extra protein are often

TABLE S.13 Summary of special nutrient requirements in pregnancy 1. Energy - an increase of 200kcal/day is required in the 3rd trimester. Aim to reach BMI 28 kg/m2 at term (2310kcal for women aged 15-18) (2140kcal for women aged 19-50) 2. Protein - an increase of 6g per day throughout pregnancy (51 g per day) Two small/moderate portions of protein-rich foods, plus milk, bread, pulses, etc. 3. Iron - 14.8mg per day required throughout adulthood. No extra routinely needed during pregnancy: absorption increases 4. Calcium - 100mg per day (19-50) 800 mg per day (15-18) No extra routinely needed during pregnancy: absorption increases Throughout life - half a pint of milk daily as a good insurance 5. Vitamin D-10ug per day Supplement. Encourage women to go outdoors Use fortified foods, e.g. margarine, and vitamin D rich foods, e.g. oily fish 6. Folic acid - supplement from before conception up to first 12 weeks (0.4 mg routinely, 4mg if previous neural tube defect) 7. Vitamin C - increase intake by 10mg to 50mg per day More fruit and fruit juice 8. Vitamin A - increase vegetables, increase intake by 100ug to 800jag

120

9. Dietary fibre - to avoid constipation of pregnancy, increase by 10g/day More vegetables, wholemeal bread

recommended. Many women are able to produce adequate volumes of breast milk despite poor dietary intakes. However, when maternal nutritional status is severely decreased, there is a corresponding decrease in the volume and nutritional content of the milk. It is thus essential to improve the diet and lifestyle of women in developing countries if breastfeeding is to be promoted. When there has been substantial fat accumulation during pregnancy, as is usual in western countries and where obesity is more of a problem than undernutrition, prolonged breastfeeding (4-12 months) helps with weight loss.

MALNUTRITION MALNUTRITION IN CHILDREN The term protein-energy malnutrition (PEM) was used historically to describe a variety of clinical syndromes believed to result from a diet inadequate in both energy and protein. The term is misleading, since dietary protein deficiency is virtually never seen, and low serum proteins in malnutrition are not caused by dietary protein insufficiency. Undernutrition of energy is often accompanied by micronutrient deficiencies, electrolyte imbalance and metabolic disorders. When it occurs in the UK it is usually precipitated by a severe illness (e.g. gastrointestinal disease, surgery). In developing countries it is the result of a poor diet, often exacerbated by the added stress of infection (especially diarrhoea and measles). The term malnutrition/infection syndrome may be used to describe this situation. Classification of the severe clinical syndromes (Table 5.14) depends on the child's weight calculated as a percentage of the median international standard for a child of the same age. Milder grades of malnutrition also exist according to weight/age. Undernourished children may be further classified according to whether, or to what degree, they are short for their age (stunting); alternatively, they may be underweight and thin, i.e. a low weight/height (wasting) (see Table 5.14 and Fig. 5.7). The inference is that children who are stunted are likely to be chronically

TABLE 5.14 Classification of stunting and wasting Degree

Malnutrition (weight/age)

Stunting (height/age)

Wasting (weight/height)

Normal

Over 80%

Over 95%

Over 90%

Mild Moderate Severe

60-80%* Less than 60%*

87.5-95% 80-87.5% Less than 80%

80-90% 70-80% Less than 70%

* Defined as kwashiorkor if oedema present

FIG. 5.7 Growth chart of a severely malnourished child A Start of nutrition rehabilitation. B After discharge from nutrition rehabilitation.

infected or have been deprived of an adequate diet, usually for many months (sufficient to cause linear growth retardation). The child who is wasted but not stunted has usually lost body tissues because of a recent infection or poor diet, for example due to harvest failure.

Marasmus In marasmus (weight for age <60% without oedema), which is usually seen in older, fully weaned children, there is loss of both lean tissue and subcutaneous fat, with characteristic wrinkling of the skin. This is sometimes difficult to differentiate from dehydration. The child is usually very cachectic, and has long eyelashes and lanugo hair on the forearms despite loss of hair on the head. However, the child is generally alert and keen to eat. The plasma albumin is usually maintained, but plasma sodium and potassium levels are often low. Marasmus describes the result of dietary energy shortage, but specific nutrient deficiencies commonly coexist, as in anorexia nervosa.

Vitamin A becomes sequestered in the liver because of insufficient synthesis of the transport protein, retinolbinding protein, and patients are consequently more prone to infection. Plasma albumin is low, as are plasma sodium and potassium. The low plasma potassium indicates a reduction in the total body potassium, owing to the loss of muscle mass. The low plasma sodium, however, is misleading, as it is due to an excess of body water: the total body sodium is in fact elevated. Several factors contribute to the development of oedema. A decrease in plasma albumin decreases colloid osmotic pressure, whereas an increase in the generation of free radicals by infection (from systemic or intestinal pathogens, or toxins, such as aflatoxin) can damage the capillaries sufficiently to cause them to leak fluid into the tissues. The deleterious effects are greatest in children with impaired scavenging mechanisms for free radicals, owing to a relative excess of iron and copper but a deficiency of vitamins C, E and carotenoids.

5

Associated deficiencies Zinc deficiency is common in severe malnutrition, and may account for the skin lesions and impaired cellular immunity. Vitamin A deficiency is frequently precipitated by malnutrition, probably because of lack of synthesis of retinol-binding globulin by the liver, and anaemia often occurs as a consequence of folate and/or iron deficiency and systemic infection (especially malaria). Cellular immunity is frequently depressed, permitting infections such as tuberculosis to become rampant. Antibody production is also impaired, but to a lesser extent, so that even severely malnourished children generally produce satisfactory levels of antibodies following immunization. However, the general reduction in immunity is a key factor in the development of bacterial overgrowth syndromes in the intestine, pneumonia and septicaemia. The decreased heat production in malnutrition is often severe enough to cause hypothermia and prevents a pyrexial response to infection.

Specific organ changes Kwashiorkor The main feature of kwashiorkor, which usually affects infants at the time of weaning, is oedema, which conceals the loss of lean tissue. There is little evidence that dietary differences explain why some children develop kwashiorkor and others become marasmic; kwashiorkor is often precipitated by measles and intestinal and other infections. These children are ill and anorexic, and have very high mortality. Weight for age <60% indicates marasmic kwashiorkor. The oedema usually starts in the legs but may extend to the trunk and head. There is often an associated scaly cracking of the skin, and some children have discoloured or orange hair (caused by associated zinc deficiency). The liver is sometimes enlarged, as it becomes infiltrated with fat which cannot be removed because of inadequate production of lipoproteins (see Ch. 19).

There is atrophy of all organs, including alimentary tract mucosal atrophy, which causes hypochlorhydria and flattening of the intestinal villi with secondary malabsorption. Nearly all children are heavily colonized by intestinal parasites and bacteria. Renal function is often impaired, leading to difficulties in excreting sodium and water. Experimental studies show effects of childhood malnutrition on brain size and psychomotor development, but longitudinal studies of severely malnourished children show that the social environment is more important than nutrient deficiency in determining subsequent intellectual achievement.

Management The following principles should be followed:

121

TABLE 5.15 Predicted rate of weight gain* in malnourished child weighing 7kg Total intake (kcal/day)

Excess (kcal/day)

Weight gain (g/day)

Days to gain 300 g

0

0

-

760

60

10

300

820

120 240

20 40

150

480 960

80 160

700

940 1180 1600

75 38 19

* Assuming maintenance requirements of 100kcal/kg/body weight

• The child requires resuscitation for dehydration and electrolyte restoration (in most cases using oral rehydration therapy). • Antibiotics (this is still an indication for chloramphenicol) should be given for systemic infections, together with treatment for malaria where appropriate. It is wise to assume that all children with severe malnutrition have bacterial infections, tuberculosis and intestinal infestation, even when classic signs of infection are absent. • Nutritional therapy, which depends on the introduction of special feeds providing maintenance requirements (100-150kcal/kg body weight, including 10% energy as protein, and avoiding lactose), should be accompanied by mineral mixes (especially potassium and zinc). In children with kwashiorkor, maintenance requirements are given until the oedema is cleared and then energy intakes are increased. In marasmic children the intake can be increased earlier until, ideally, about 200 kcal/kg body weight/day are given (Table 5.15).

CACHEXIA AND MALNUTRITION IN ADULTS Cachexia of dietary origin, or malnutrition in adults, is surprisingly common in medical and surgical practice. A recent survey in the UK found that 13% of admissions to general medical and surgical wards had malnutrition according to BMI criteria. Higher figures have been found using other criteria. Malnutrition was only recognized in a small proportion, and most patients lost more weight during their admission without any nutritional action being taken. Inadequate intake is the most important cause,

owing to psychological factors (such as depression, isolation or anorexia nervosa), immobility and social deprivation, pain, oral or intestinal cancer, arthritis, nausea/ vomiting, liver metastases, chemotherapy, gastrointestinal disease, fever or postoperative complications (which often cause anorexia). Nutrient intakes are often reduced drastically in those who can only take fluids. 1 Requirements may be considerably increased by sepsis. Energy expenditure increases by at least 10% for every 1°C rise in body temperature, and muscle protein is mobilized to provide amino acid precursors for the inflammatory response. Infection also increases the production of acute-phase proteins such as C-reactive protein, but levels of plasma albumin may decrease as a result of decreased synthesis by the liver and increased catabolism of circulating albumin. Any cause of malabsorption may cause a serious decrease in absorption of protein and energy. Disease of the lower small intestine and colon may cause serious leakage of endogenous protein and protein loss from blood. To produce cachexia, these factors must be chronic, or relapsing without adequate periods of remission, and often more than one factor is operating at any time. The classic causes of malnutrition in adults are cancers, tuberculosis and gastrointestinal problems, including short bowel syndrome and fistulae. Depression is another important cause, but organic disease should always be excluded. More recently AIDS and chronic obstructive airways disease (COAD) have become familiar as causes of apparently intractable cachexia. The most consistent finding is the dominance of anorexia during acute infective episodes, leading to stepwise weight loss. In HIV, as in inflammatory bowel disease, there is also a background of steady weight loss through malabsorption diarrhoea. Elevation of metabolic rate in these conditions plays only a small part in producing weight loss. The most important single manoeuvre in preventing and managing malnutrition is to have good measurements of the weight of every patient at every contact with health services (inpatient and outpatient). The diagnosis must be recorded, as it has profound medical implications, and failure to diagnose malnutrition might incur medicolegal problems. Dietetic intervention, social support and artificial feeding where necessary are much more effective if used early in the process of weight loss. Even with AIDS or COAD, effective nutritional interventions which lead to weight gain will improve muscle function, improve quality of life and reduce susceptibility to infection. Correction of malnutrition takes time, so management started in hospital must be continued after discharge. ©

VITAMIN DEFICIENCIES AND EXCESSES 1 Fig. 5.1 122

0 Case 5.1

A checklist for the methods of assessment of vitamin deficiencies is given in Table 5.16. The important food sources

SUMMARY 3 Vitamin deficiency syndromes Vitamin Syndrome A Thiamine Niacin Riboflavin Pyridoxine Folate B12

C D K

Night blindness, xeropnthalmia Wernicke's encephalopathy, Korsakoff's psychosis Pellagra Mucosal lesions Glossitis, neuropathy Megaloblastosis, villous atrophy Megaloblastosis, neuropathy Scurvy Rickets, osteomalacia Hypoprothrombinaemia

TABLE 5.16 Assessment of nutritional deficiencies: vitamins* Vitamin

Method

Comment

A

Clinical

Infections common Night blindness is a good indicator Corneal lesions are very late-stage findings

• Plasma carotenoids • Plasma retinol Thiamine

Clinical • HPLC • Erythrocyte transketolase

Sensitive indicator of liver stores but reduced in infection Neuropathy and optic atrophy are late-stage findings Specific Sensitive but rapidly altered by amount of dietary thiamine

of the various vitamins are shown in Table 5.17, and their roles in the body in Table 5.18. A table of recommended daily intake of vitamins is given in Table 5.19.

Riboflavin

Clinical • Erythrocyte gluthathione reductase

Mouth lesions are non-specific Assay related poorly to clinical state

VITAMIN A DEFICIENCY

Niacin

Clinical • Urinary n-methylnicotinamine/creatine excretion

Glossitis, stomatitis, dermatitis Sensitive. Difficult assay

Folate

• Serum folate • Erythrocyte folate

Marked changes after dietary intake Sensitive assay of body stores

B12

• Plasma vitamin level

Sensitive assay of body stores

C

Clinical • Plasma or leucocyte ascorbate (HPLC)

Specific but occur at late stage only Sensitive. Rapid response to diet, Falls non-specifically in illness

D

Clinical • Plasma alkaline phosphatase • Plasma 25hydroxycholecalciferol • Bone marrow histology

Rickets, osteomalacia Non-specific. Sensitivity may be improved by isoenzyme analysis Very specific

E

• Plasma or erythrocyte tocopherol (HPLC)

Sensitive and specific. Must be corrected for plasma LDL

K

• Prothrombin time

Non-specific, as it is influenced by hepatocellular dysfunction

Vitamin A (retinol) can be synthesized within the liver from several carotenoids (cc-carotene, B-carotene, lutein) which occur in a variety of vegetables and certain fruits. Vitamin A deficiency leads to night blindness and xerophthalmia (damage to the conjunctiva, the major cause of blindness in children). It also affects the immune system - increasing the severity of respiratory infections and diarrhoea - and the formation of epithelium in the sweat glands, lung and gut. It contributes to the high rates of child mortality in certain populations, particularly among poor communities, where dietary intakes of carotene are low and where the availability of the nutrient may be further reduced by intestinal parasites and diarrhoea, and where undernutrition suppresses the synthesis of retinol-binding protein, preventing utilization of hepatic retinol stores. Vitamin A deficiency sometimes complicates inflammatory bowel disease, coeliac disease and cirrhosis. Measles is an important contributory factor in xerophthalmia because of its direct effect on the conjunctiva, where it increases the local requirement for vitamin A to repair the damaged conjunctiva, and also by its effect on synthesis of retinol-binding protein, which normally carries vitamin A from the liver stores to the eye. Supplementation with vitamin A reduces the mortality from measles in malnourished children, even when their liver contains vitamin A (because its transport to other tissues is inhibited). Night blindness alone is easily reversible, but xerosis (the dry appearance of the conjunctiva) and Bitot's spots (heaped-up desquamated cells causing flecks on the conjunctiva) are signs that, unless treatment is started soon, the lesion may progress to irreversible corneal ulceration. In areas where dietary vitamin A intake cannot be increased by horticulture and nutrition education pro-

5

Specific

* Pyridoxine is omitted as this is not a routine assay

grammes, the administration of vitamin A capsules (100 000 IU every 4 months) will largely prevent xerophthalmia. In established xerophthalmia, retinol palmitate (100 000 IU) is given intramuscularly. Vitamin A should not, however, be given to pregnant women because of its teratogenic effect. Breastfeeding tends to prevent vitamin A deficiency.

123

TABLE 5.17 Vitamins and their important food sources

TABLE 5.18 Major roles of vitamins in the body

Vitamin

Food sources

Vitamin

Function

A

Carotenoids (esp. p-carotene), in carrots, dark green leafy vegetables, pumpkin, mango Preformed vitamin A in fish oils, liver, eggs, margarine

A

Maintenance of mucosal surfaces; production of mucus; immune system and retinal function; fat soluble

Thiamine (B1)

Thiamine (B1)

Fortified wheat flour (much of the thiamine in flour is removed by milling, but is then replaced in most flours), fortified breakfast cereals, milk, eggs, yeast extract, fruit

Metabolism of carbohydrate to provide energy; maintenance of cardiac muscle and peripheral nerves

Riboflavin (B2)

Control of intracellular oxidation; maintenance of skin, especially around the mouth

Riboflavin (B2)

Milk, cheese, eggs, fortified breakfast cereals, liver, kidney, whole grain cereals

Nicotinic acid

Utilization of energy from food; maintenance of skin, especially in light-exposed areas

Niacin

Liver, kidney, milk, cheese, eggs, beef, chicken, pork, yeast extract, instant coffee, peas, beans

Pyridoxine (B6)

Metabolism of amino acids, especially tryptophan to nicotinic acid

Pyridoxine (B6)

Liver, meat, fish, whole grain cereals, milk, peanuts

Folate

Cell multiplication, in the blood and mucosa

Folate

Liver, kidney, green leafy vegetables, peas, beans, oranges, bananas

Cobalamin (B12)

Cell multiplication, especially blood cells; control of fatty acid synthesis in myelin sheaths of nerves

Cobalamine (B12)

Liver, kidney, fish, beef, pork, lamb, eggs, cheese

Ascorbic acid (C)

Ascorbic acid (C)

Oranges, lemons, potatoes, green vegetables, fortified fruit drinks

Maintenance of connective tissue; stimulates iron absorption

D

D

Fortified milk (e.g. evaporated), fatty fish, fortified margarine, eggs, liver

Maintenance of calcium and phosphate levels in the blood; control of absorption of dietary calcium and movement of calcium between blood and bone; fat soluble

E

Vegetable oils, wholegrain cereals, eggs, margarine

E

K

Vegetables, peas, beans, liver

Contributes to antioxidant capacity of body; important in maintenance of erythrocyte membranes in neonates; fat soluble

K

Control of blood clotting; fat soluble

Thiamine deficiency

124

Thiamine is an essential factor in many glycolytic pathways and is especially important for normal function of the peripheral nervous system and the heart. Deficiency can cause a peripheral neuropathy, especially in the legs, ataxia and optic atrophy. Most cases in the UK occur in malnourished alcoholics. Such patients may develop two additional syndromes. In Wernicke's encephalopathy nuclear or supranuclear ophthalmoplegia occurs with nystagmus, pupillary abnormalities, aphasia and mental confusion. In Korsakoffs psychosis a permanent confused state, characterized by short-term memory loss and confabulation, develops (see Chapter 24, p. 1439). In beriberi, a highoutput cardiac failure develops (wet beriberi) and may accompany the peripheral neuropathy (dry beriberi). Deficiency is more common in populations which change to eating highly milled rice, as this process removes the thiamine. Curiously, Korsakoffs psychosis does not seem to occur commonly in populations prone to beriberi, suggesting that in alcoholics an additional factor may be acting. Diagnosis is usually made on clinical history and examination, but subclinical thiamine deficiency should always be suspected in alcoholics, and supplements given prior to feeding carbohydrates. If carbohydrate (e.g. dextrose infusion) is given without thiamine, then lactic acidosis can

rapidly lead to brain damage. Elevated levels of erythrocyte transketolase activity and blood pyruvate occur. Thiamine (100 mg) should be given intravenously (a multiple B vitamin parenteral infusion is appropriate), followed by repeated doses of 20 mg three times daily. Cardiac beriberi and ophthalmoplegias improve rapidly, but Korsakoffs psychosis tends to recover only partially. Many routine vitamin supplements do not contain enough thiamine to correct a deficiency. Long-term oral thiamine supplementation is a reasonable preventative strategy for alcoholics.

Niacin (nicotinic acid and nicotinamide) deficiency Nicotinic acid occurs in many plant and animal foods and can also be synthesized from tryptophan. Nicotinic acid deficiency tends to occur in those who eat a monotonous maize diet (which is low in tryptophan), such as is often supplied to refugees. The resulting deficiency syndrome is pellagra. Pellagra often starts with either a sore mouth, mild diarrhoea or confusion. The full clinical syndrome of 'dermatitis, diarrhoea and dementia' is not common, except in well-established cases. The skin lesions are initially erythe-

TABLE 5.19a Reference nutrient intakes for vitamins Males over 11 years Thiamin (mg/d) Riboflavin (mg/d) Niacin (nicotinic acid equivalent) (mg/d) Vitamin B6 (mg/d) Vitamin 812 (ug/d) Folate (ug/d) Vitamin C (mg/d) Vitamin A (ug/d)

1.0 1.2

17

Females over 11 years

Lactation (0-4 months)

0.8 1.1 14

1.4

1.2

1.5

1.5

+0.2 +0.5

+2

+0.5

200

+60

40

40

+30

700

600

+350

* no increment

TABLE 5.19b Reference nutrient intakes for minerals (SI units)

Calcium (mmol/d) Phosphorus (mmol/d) Magnesium (mmol/d) Sodium (mmol/d) Potassium (mmol/d) Chloride (mmol/d) Iron (umol/d) Zinc (umol/d) Copper (umol/d) Selenium (umol/d) Iodine (umol/d)

Females over 11 years

Lactation (0-4 months)

25

20

+14.3

25

20

+14.3

12.3

12.0 70

70 90 70 180 140

16 0.9 1.0

+2.1

90

* *

70 260**

* *

140 16 0.9 1.0

a

*

200

Males over 11 years

thus accompany general malnutrition or alcoholism and is especially liable to occur during pregnancy. The main lesions are mucosal dryness and cracking around the mouth, ears and eyelids, with the genital region also affected. Red blood cells are affected, causing a normochromic anaemia. Diagnosis is usually on clinical grounds but can be confirmed by reduced glutathione reductase activity in red blood cells. Lesions respond rapidly to riboflavin (6mg daily).

+90

+5 +0.2

*

*no increment ** 160 for females over 50 years

matous, but dry, cracked appearances then occur, especially in areas exposed to the sun, producing 'Casal's necklace' around the neck. There may be villous atrophy in the small intestine and malabsorption. If untreated, later-stage deficiency may cause severe encephalopathy and spasticity. Pellagra is rare in the UK, but may occur in malabsorption syndromes such as coeliac disease, in patients treated with isoniazid, in Hartnup's disease, in the carcinoid syndrome, in patients with very low-protein diets, or in conditions giving rise to considerable loss of protein such as the nephrotic syndrome. Deficiency responds rapidly to daily doses of nicotinic acid (500 mg).

Riboflavin (vitamin B2) deficiency Riboflavin deficiency occurs when a diet is continually deficient in legumes, pulses and animal products. It may

Pyridoxine (vitamin B6) deficiency Pyridoxine deficiency occurs in malabsorption syndromes, alcoholism and secondary to drug toxicity (especially isoniazid), but rarely as a primary deficiency disorder. Clinically, there is mental confusion, glossitis, dry skin lesions and peripheral neuropathy. Pyridoxine deficiency has rarely been associated with infantile convulsions and sideroblastic anaemia. Pyridoxine deficiency is popularly believed to be a cause of premenstrual syndrome but there is little evidence for this. Treatment of deficiency in adults is by 5-20 mg daily. Excess intake can lead to neurotoxicity.

Folate deficiency Folate deficiency occurs in those whose diet lacks fresh vegetables, or in which the vitamin is destroyed by cooking or lost through canning. It may also occur secondary to upper small bowel malabsorption, in situations of increased requirements (i.e. pregnancy or haemolytic conditions), or in patients taking anti-folate drugs (e.g. methotrexate, trimethoprim). Alcohol inhibits the absorption of folate, then aggravating the effect of poor diet in alcoholics. Clinical features, diagnosis and treatment are described in Chapter 23. As well as the megaloblastic anaemia and pancytopenia, depression has been consistently associated with folate deficiency. Folic acid supplementation 400ng/day is recommended for all women who may become pregnant, to prevent neural tube defects (spina bifida, anencephaly). This is not to treat a deficiency, but a pharmacological effect to overcome defects in folate metabolism present in a minority of women. Availability of folate from foods is lower than that of folic acid from supplements.

Vitamin B ]2 deficiency Vitamin B12 deficiency is described in Chapter 23. Dietary deficiency is rare, but can occur in strict vegans.

Vitamin C deficiency The clinical features of scurvy have been identified as part of general malnutrition for centuries, but the specific features of scurvy and its cause only became apparent after it decimated crews on long-distance sea voyages after the discovery of America. In the 18th century, Lind carried out a controlled trial, treating two cases of scurvy with oranges

125

and lemons and using mouthwashes of dilute vinegar or sea water for four other patients. Complete recovery occurred in the treated patients but none in the other patients. Today, deficiencies occur in the elderly - especially those on 'tea and toast' or 'tinned spaghetti' diets - in alcoholics and in food faddists. It may also occur in young children when requirements are high, and in smokers, as ascorbate is consumed in removing the free radicals from smoke. Low ascorbate levels are found in diabetic patients. The clinical features of tiredness, hyperkeratosis of the hair follicles, petechial haemorrhages and bleeding gums are only present in severe deficiency; bleeding gums are more usually due to poor oral hygiene than to vitamin deficiency. The classic features of infantile scurvy - irritability, pain on moving the legs, and tenderness and enlargement of costochondral epiphyses, together with megaloblastic anaemia - are now rarely seen. Diagnosis is by measurement of plasma ascorbate or leukocyte ascorbate content. Ascorbic acid is the antioxidant vitamin whose plasma concentration correlates best with diet. Low concentrations are very common in hospitalized or ill patients, and this is in part an acute-phase response. Ascorbic acid 100 mg three times per day is rapidly effective in clinical deficiency. There is limited evidence that large doses of vitamin C may reduce symptom severity in common cold but this does not point to an underlying nutritional deficiency.

Vitamin D deficiency Vitamin D deficiency occurs in those who fail to produce enough in their skin (from the precursor 7dehydrocholesterol in response to UV light), or who have inadequate dietary intake. In the UK, the high-risk group is immigrant vegetarian Asians, who tend not to expose themselves to the limited sunlight available. Although they do eat fatty fish (a good source of vitamin D), their consumption of vitamin D-fortified foods, e.g. margarine, is low, and the high phytate content (in chapatti flour) of the diet decreases its bioavailability. The result of vitamin D deficiency is rickets (in children) or osteomalacia (in adults) (see Ch. 18, p. 962). 1

Vitamin E deficiency Vitamin E deficiency can occur in low-birthweight infants and in children with malabsorption syndromes (especially cystic fibrosis). It is very rare in adults but has been reported on inadequate total parenteral nutrition, following gastroplication surgery for obesity and in abetalipoproteinaemia, as tocopheral absorption and transport depend on low-density lipoprotein (LDL). Deficiency

1

126

Fig. 5.2

2

Fig. 5.3

permits free radical damage to a number of membranes, such as red blood cells (causing haemolytic anaemia) and nerve cells (causing ataxia and peripheral neuropathy, which is usually permanent). These conditions are exacerbated if extra nutrients, such as linoleic acid and iron, are given without vitamin E. There is no consistent scientific evidence of any effect of vitamin E on athletic success, sexual potency or atheroma. The only indication for therapy is if the level of plasma tocopherol is shown to be low in an appropriate clinical setting. Plasma concentration needs to be adjusted for LDL concentration for interpretation. Deficiency can be treated by 200 mg daily doses in adults, but much larger doses (parenterally) are needed to overcome the effects of abetalipoproteinaemia.

Vitamin K deficiency This may occur in neonates because placental transfer is limited and breast milk is often deficient. It also occurs in obstructive jaundice and certain malabsorption syndromes. The result is hypothrombinaemia and bleeding, which is rapidly reversed by injections of vitamin K (phytomenadione). The prolonged prothrombin time associated with liver disease seldom responds to extra vitamin K.

Fluoride deficiency Dental enamel has a specific requirement for fluoride, whose deficiency in drinking water (under Ippm) is the main cause of dental caries in children. Where fluoride consumption is high - e.g. from tea in Ethiopia - dental caries is rare even with high sugar consumption. Fluoridecontaining toothpaste virtually abolishes the problem in areas of fluoride deficiency. To reach children who do not brush their teeth, successful strategies include fluoride normalization of water supplies to 1 ppm, or fluoridization of salt (Switzerland). Most of the UK is fluoride deficient.

VITAMIN EXCESS SYNDROMES Toxicological syndromes associated with vitamin excess (Table 5.20) are mainly found with fat-soluble vitamins (A, E, D, K) which accumulate in the body.

Vitamin A Toxicity occasionally occurs acutely in children given large doses (e.g. 200000IU) of vitamin A intramuscularly. It takes the form of irritability, and even convulsions, as a result of increased intracranial pressure. Recovery occurs within a few days. Excessive self-medication is the usual cause. Levels of vitamin A in the livers of farmed animals have risen in recent years because of feeding practices. It is quite possible to consume, in a single meal containing liver, much more than the maximum permitted of 10000IU per day for

TABLE 5.20 Main consequences of vitamin toxicity Vitamin

Symptoms of toxicity

A

Headache, convulsions, muscular stiffness, hepatomegaly, teratogenic effects Not described Not described Vasodilatation Peripheral neuropathy Not described Not described Increased urinary oxalate Hypercalcaemia, renal failure Nausea Hyperbilirubinaemia

Thiamine (B1) Riboflavin (B2) Nicotinic acid Pyridoxine (B6) Folate Cobalamine (B12) Ascorbic acid (C) D E K

a woman during pregnancy. Large doses of vitamin A are associated with an increased prevalence of craniofacial abnormalities in the infant. For this reason it is recommended that pregnant women do not eat liver, which used to be encouraged for pregnant women to provide iron and other nutrients.

Pyridoxine (vitamin B6) Pyridoxine toxicity has been occurring more frequently in recent years owing to its use - successful or otherwise - in attempts to alleviate premenstrual syndromes (depression and fluid retention). A peripheral neuropathy is likely if the daily dose exceeds 500 mg, and has been reported at lOOmg/day. Some cases have neurological abnormalities which persist even after stopping the drug.

Vitamin C Toxicity occurs among those who take enormous doses of vitamin C in the unfounded belief that it will prevent the common cold or cancer. Doses above 2g/day may cause abdominal discomfort and osmotic diarrhoea. There is increased urinary oxalate excretion - which may dispose to oxalate stones - and some evidence of damage to the intestinal epithelium.

Vitamin D Vitamin D toxicity occurred in the UK after World War II in some children given too much fortified milk. (The quantities added are now more strictly controlled.) Mild forms of vitamin D toxicity are characterized by weakness, weight loss and growth failure. Severe forms cause nephrocalcinosis, radiological changes in the epiphyses and mental retardation.

TRACE ELEMENTS

a

The clinical relevance of trace elements in health is limited, but zinc deficiency appears important. Zinc, and probably also copper, is important in protecting cell membranes against free radical damage. Zinc is a cofactor in over 100 enzymes, and there are no body stores. Absorption from the diet is about 30%, but adapts to needs in health. Deficiency is seen most clearly in the congenital disorder aerodermatitis enteropathica, which is characterized in infants after weaning by a scaly skin rash, secondary bacterial and fungal infection, diarrhoea and severe growth faltering. All are rapidly reversed by zinc therapy. Deficiencies are also seen in children with severe malnutrition, and were formerly seen in patients receiving parenteral nutrition without sufficient trace element mixes. © Selenium deficiency can cause a cardiomyopathy, although its main role is as a cofactor in the antioxidant enzyme glutathione peroxidase. The selenium content of plasma falls during stress or illness as part of the acutephase response.

Iodine deficiency Most iodine deficiency is due to low levels in the soil and water. There are many regions in the world, e.g. Nepal, Peru and Bangladesh, where iodine intakes are so low (<50-75 mg/day) that thyroid function is impaired. There is a high prevalence of cretinism in neonates in these regions, which may present as deaf-mutism, mental retardation and ataxia, with the characteristic morphological features of thickened facial appearance, stunted stature and enlarged tongue. The brain damage is irreversible if not treated early. It is now also realized that the poor intellectual performance and deafness (without any unusual morphological features) found in many children in iodine-deficient areas is due to marginal iodine deficiency. This may be partially reversible. In some areas an already limited iodine availability is made worse by the consumption of goitrogens, e.g. in certain brassicas, cassava or soya beans. The extent of the problem can be assessed by measuring the prevalence of goitre (enlargement of the thyroid gland), which is particularly common among adolescents and pregnant women. Measurements of urinary iodide and iodine/ thiocyanate levels can determine whether the problem is primary dietary iodine deficiency (low iodine) or the result of a dietary goitrogen. Richer people in goitrous areas generally obtain enough iodine by eating food (e.g. fish) brought in from other areas, but the main strategy is to iodize salt. Where this is impractical, injections of iodized oil (lipiodol) may be given, especially to women of childbearing age. A single dose (5ml) will usually last for up to 5 years. Oral doses (400 mg) of iodine preparations may provide enough to last for 2 years.

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OVERWEIGHT AND OBESITY Obesity is the accumulation of excess fat with multiple organ-specific pathology. The disease and its clinical consequences are obviously progressive, but for epidemiological purposes cut-offs of BMI 25 and 30kg/m2 are used, corresponding with the clinical hazards increasing and becoming frequent. Alternatively, waist circumference can be used as a simple indicator of total body fat, which is largely independent of weight.

Causes Obesity is due to an interaction between genetic constitution and the environment. The genetic component is clear, as is shown in studies of families and twins. The genes involved are not identified but are probably multiple, and they provide only the predisposition to more or less rapid weight gain. They may affect appetite regulation or metabolic efficiency. Together, genetic factors account for about 30% of predisposition to weight gain. The remainder comes from environmental influence - food attractiveness and availability, need for exercise etc. The fat accumulation itself can of course only come from excess energy consumption above needs over a prolonged period. 1 Obesity may be precipitated by an obvious decrease in energy expenditure due to a change in lifestyle (e.g. to a more sedentary job), or an injury or arthritis which limits mobility. However, in most obese individuals it seems that intake and expenditure problems occur together. Many people admit to eating excessively. A sympathetic request for a confidential 2-week diary of everything the patient eats may be very revealing, but most obese people underestimate their intake. Depression and psychosocial problems are common, so a brief history in the outpatient clinic will usually fail to give an accurate assessment. The metabolism of food energy has been studied in detail over the last 20 years, and the evidence gives some clues as to how some individuals are more prone to weight gain than others with a similar energy intake. • People with a high fasting respiratory quotient (RQ) (CO2 production divided by O2 utilization) are most prone to weight gain. • When volunteers are given extra calories, some put on weight faster than others. • Dieting leads to an adaptive decrease in energy expenditure, and this may vary between individuals. • Obese people have a decreased thermogenic response to stimulation by noradrenaline (norepinephrine) or food, and this persists even when they have lost weight.

1 128

Figs 5.4, 5.5

2

Fig. 5.6

There are well-described genetic obesities in experimental animals, but the mechanisms appear to be different in humans. To cause obesity there needs to be an increase in appetite without a compensatory rise in energy expenditure. The ob gene codes for a peptide hormone, leptin, which is released from adipose tissue as a long-term signal of fat storage. Leptin signals satiety via hypothalamic receptors modifying neuropeptide Y activity, and as a signal to other functions, such as the onset of puberty, and tends to downregulate energy expenditure. Overweight humans have high circulating leptin concentrations and may therefore be resistant to it, although a complete absence of leptin, usually from a very rare defect in the ob gene, results in colossal childhood obesity. Several other genetic obesities are known, such as the Prader-Willi syndrome, with a defect on chromosome 15. No common gene defect has yet been discovered in the general population of obese patients. Studies of families, twins and adoptees all point to a strong genetic influence, accounting for about 30% of variability in weight gain. Multiple genetic factors are involved, with no single common pathway controlling energy balance yet identified.

Consequences It is often overlooked that overweight people start to develop symptoms (Table 5.21) as BMI increases above 25kg/m2. Most people with BMI >30kg/m2 are chronically troubled by symptoms, including tiredness, breathlessness, sweatiness, low back pain, and hip and knee pain. Depression is a common complaint but is unlike typical endogenous depression, and is probably due in part to fatigue. Obesity is associated both with functional difficulties in simple domestic activities and with discrimination in every walk of life. This poor quality of life is only exceeded by the worse quality of life for an obese patient on a protracted diet without visible results. The metabolic effects of overweight, leading to increased risks of heart disease (hypertension and hyperlipidaemia) and cancers (related to increased adipose tissue aromatase and increased free sex hormone) are well documented. These metabolic hazards of being overweight are exaggerated in those who also have a central (appleshaped) fat distribution, with a high intra-abdominal fat

TABLE 5.21 Symptoms of overweight • • • • • • •

Tiredness Sleeping poorly Sweating Breathlessness Snoring Low back pain Hip and knee pain

• Hirsutism • Menorrhagia • Amenorrhoea • Stress incontinence • Angina • Depression • Infertility

TABLE 5.22 Medical consequences of overweight and obesity Physical symptoms

Metabolic problems

Social problems

Anaesthetic/surgical problems

Endocrine problems

Psychological problems

Tiredness Breath lessness Varicose veins Back pain Arthritis Oedema/cellulitis Sweating/intertrigo Stress incontinence

Hypertension NIDDM Hepatic steatosis Hyperlipidaemia Hypercoagulation IHD and stroke

Isolation Agoraphobia Unemployment Family/marital stress Discrimination

Sleep apnoea Chest intections Wound dehiscence Hernia Venous thrombosis

Hirsutism Oligomenorrhoea/ infertility

Low self-esteem Self-deception Cognitive disturbance Distorted body image Depression

Metromenorrhoea Oestrogen dependent cancers: breast, uterus, prostate

a

IHD, ischaemic heart disease; NIDDM, non-insulin dependent diabetes mellitus

mass shown by high waist circumference. Table 5.22 shows the range of metabolic and mechanical consequences of being overweight. They have an impact in virtually every branch of medical practice. © The extra medical costs of the overweight are estimated to account for an astonishing 2-80% of total health service budgets. For this reason the UK Government Health of the Nation White Paper made the prevention and correction of obesity one of the highest priorities for the health service in the 1990s. Most Local Health Authorities have programmes for weight management. The World Health Organization has included obesity as a worldwide epidemic needing coordinated preventive measures, as well as a disease in its own right which requires treatment to relieve distress.

Criteria for treatment The management of weight problems should address the process of weight gain. Many people say they want to lose weight: most are able to do so using a variety of approaches, but many are not prepared to adopt the permanent lifelong change in diet and lifestyle needed to prevent regain. The groups of patients who need professional (medical) weight management are those who are unable to control a weight problem using self-help methods, who are prepared to make substantial lifestyle and diet changes for relatively modest cosmetic gains, and those who should be advised on medical grounds to lose weight. People with BMI below 25kg/m 2 cannot be considered overweight, and so weight loss is usually inappropriate. A request for help from these people may indicate an underlying eating disorder, such as anorexia nervosa. There may be patients with BMI a little under 25 when some weight loss could be valuable, for example those with metabolic syndrome or non-insulin dependent diabetes. Advice on weight management should be offered to all patients whose BMI exceeds 25kg/m2, aiming first at restricting further weight gain and second at a period of weight loss, followed by a period of supervised weight maintenance. Between BMI 25 and 30, the principal aim

should be the further weight gain. Those who wish to lose weight or those who have a high risk (e.g. through family history) of developing diabetes, heart disease, hypertension or hyperlipidaemia, and those who already have these conditions, should be given advice on how to lose weight. Above BMI 30, where disease risks are high, weight loss will bring benefits in relation to metabolic and cardiovascular problems and, more importantly in older patients, from the point of view of symptoms and impairment of quality of life. With a view to health promotion for the general public the waist circumference provides more accessible criteria for treatment. Above waist 80cm (women) or 94cm (men) the risks are increasing and people should avoid further gain. Above 88cm (women) or 102cm (men) health impairment is almost universal, and professional help should be offered (Table 5.23).

WEIGHT MANAGEMENT Recognizing the aetiology of obesity, and its major medical consequences, it is vital that doctors take a leading role in advising patients about the need for and methods of weight management. The skills of several professional groups can be valuably employed, including nurses, dietitians, clinical psychologists, physiotherapists, and even commercial slimming and exercise clubs. Weight management is best conducted in the primary care and community environment, but up-to-date training should be provided for all those involved. All patients with weight problems require assessment for other related and compounding risk factors, such as smoking, blood pressure, lipids and blood glucose. Although many smokers gain some weight when they stop, this weight is usually lost over the subsequent year or so and the gain can be prevented by simple dietetic advice. The medical hazards of smoking are only equalled by weight gain equivalent to a doubling of body weight, but the combination of smoking and overweight has multiply

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TABLE 5.23a Waist watchers - Men Action level 2 Action level 1 <94cm >102cm 94-102 Increasing health High health risk Green zone risk -aim for - seek advice - no need to green zone to lose weight lose weight Prevalence (%) of Type 2 diabetes Cardiovascular risk factors Shortness of breath Poor physical functioning Chronic low back pain

0.6

1.8

26.0 10.4

47.4

4.5 64.2

17.1 10.2

31.5 17.5

19.5

21.1

4.8 14.1

TABLE 5.23b Waist watchers - women Action level 1 Action level 2 <80cm 80-88 >88cm Green zone Increasing health High health risk - no need to risk - aim for - seek advice lose weight green zone to lose weight Prevalence (%) of Type 2 diabetes Cardiovascular risk factors Shortness of breath Poor physical functioning Chronic low back pain

0.4 13.6 17.4 7.1 16.5

active effects on risks. Serum y-glutamyl transferase (y-GT) should be checked, as alcohol consumption is often an important component of weight gain in men, and it is often difficult to identify overweight drinkers. It should be remembered that y-GT will be elevated in untreated non-insulin dependent diabetes mellitus or metabolic syndrome with fatty liver. Serum TSH is useful, as subclinical hypothyroidism is common and greatly impairs ability to lose weight. Treating hypothyroidism does not automatically lead to weight loss.

Diet modification

130

A first step towards weight management is healthful balanced dietary advice. Many of the features of current health promotion dietary advice are highly appropriate to weight loss or weight maintenance. Even during slimming, patients should eat at least five portions of fruit and vegetables daily. Extra helpings, and even snacks of vegetables, can be encouraged. This will help to reduce fat intake. Fat is the nutrient with the highest energy content (kcal/g), so its major dietary origins need to be restricted, particularly full-fat milk and dairy products, processed meat products such as sausages and pies, and biscuits and baked

0.5 26.0 25.5 10.0 18.0

2.7

42.5 39.4 19.7 24.1

food. Bulky and relatively nutritious foods such as bread, potatoes and pasta can still be taken in reasonable amounts to satisfy appetite; it is the spreads or sauces that go with them that tend to contain unnecessary calories. The style of eating recommended for weight management should be continued for life. It should be explained to patients that they have a metabolic profile which will present a problem if they revert to eating a diet high in fat. Alcohol contains 7 kcal/g, so alcohol restriction is directly valuable, but alcohol consumption rapidly leads to non-compliance with diets. It is best avoided during periods of weight loss, particularly by drivers.

Eating behaviour Many patients with weight problems have a rather undisciplined eating pattern, often skipping meals such as breakfast, and even lunch, and then eating large amounts later in the day and at night. A useful management strategy is to concentrate on shopping, to advise patients not to buy what is not needed. It is helpful to plan eating patterns in advance, based on three meals a day and complete avoidance of all snacks. A breakfast which is filling and nutritious but low in calories, such as porridge, is effective.

SUMMARY 4 Practical advice for weight management • • • •

Become a non-smoker (top priority) Eat at least five portions fruit and vegetables daily Eat fish at least twice a week 20-30 minutes moderate activity daily (to breath hard or break sweat) • Avoid future weight gain (before and after loss) • Achieve weight loss 5-10 kg in 3 month stages • Feel proud to have done each of these

Porridge and 'breakfast cereals' are useful as standbys for energy-saving evening meals, and are preferable to lowcalorie commercial meal replacement products, which are often expensive and unpalatable. Individual strategies can be discussed, negotiated and used with patients. 'Rules', such as only eating off a plate, never eating with the fingers, or never eating with the television on, may be helpful.

Physical activity It is extremely difficult to lose weight simply by increasing exercise and physical activity. Each kilogram of adipose tissue (fat) contains about 7000 calories, so 7kg (a stone) contains 50000 calories. Sustainable increases in physical activity would need to be maintained for well over a year to lose this amount of weight. On the other hand, physical activity can be enormously valuable in improving quality of life and helping people to feel better, and in reducing blood lipids, blood pressure and the risks of diabetes. Increased physical activity is vital for weight maintenance to avoid regain, and it is essential to protect muscle from wasting during weight loss. Regular physical activity may help regulate appetite. The metabolic rate of a patient who has lost 7kg (one stone) will be reduced by about 120kcal/day. This can be matched by 20-30 minutes of brisk walking daily if the patient were to continue to eat the previous intake. It is useful to advise the patient to trade food at snack time for activity, even of a very limited extent. Negotiated plans should be agreed, for example to walk all journeys which are less than one mile. Organized physical activity is helpful for many patients but seldom conducted on a daily basis. For those unable to take some exercise daily, it is acceptable to undertake longer blocks of exercise less frequently (e.g. 1 hour three times a week). In addition to taking specific exercise, the avoidance of complete inactivity is important. Television watching (average 29 hours per week in the UK) relates closely to weight gain and to difficulty in slimming, even in people who take some exercise.

Drugs The main function of drug therapy for obesity is to restrict long-term weight gain below the untreated rate. Weight loss is a brief (3-6-month) phase, but no available drug can produce major weight loss alone, and a drug that did would

be dangerous. Initial weight loss is probably most efficient using a very low-calorie diet, under supervision, with drugs for the long-term maintenance phase. No drug therapy can achieve weight loss or maintenance at a lower level without dietary and physical activity changes, and so drugs should not be prescribed unless patients are achieving success with dietary and lifestyle modification as an indication of motivation. One of the main aims of using drugs for weight management is to reduce the need for drug therapy for complications of obesity, such as antihypertensive drugs or hypoglycaemic agents, lipid-lowering drugs and analgesics. These preparations are usually taken indefinitely and often in combination. There is no place in weight management per se for the use of diuretics: oedema is usually a local problem, not the result of sodium retention, and responds poorly to diuretics. Thyroxine does not produce weight loss except in large doses with dangerous cardiac side-effects, and should not be used for obesity. With recent recognition of the extent of pathology and healthcare costs attributable to obesity, there has been intense research interest in developing new drugs for weight management. Drugs may affect appetite or satiety and energy intake, or energy expenditure. Because of the physiological complexity of energy balance, no single drug is likely to have profound effects, and responsiveness varies widely between subjects. Ideally, to reduce body weight, energy intake must fall and energy expenditure must rise. Most effective agents have some effect on both sides of the energy balance equation, but pharmaceutical management will always rely on dietary restraint. The old appetite suppressant drugs, based structurally on amphetamines and sharing noradrenergic releasing activity (e.g. phentermine), have fallen out of favour, largely because of the historic association with amphetamine, despite their lacking addictive or mood-altering actions. They were never subjected to long-term clinical trials, but undoubtedly led to substantial weight loss in patients otherwise unable to achieve it. These drugs are still available in the USA and elsewhere. Sibutramine, available in most of America and Europe, has both noradrenaline and serotonin reuptake inhibition activity. Patients who respond (2 kg weight loss in 4 weeks) can expect to lose about 10 kg on average over 3-6 months, and to maintain the differences from placebo for at least 2 years. Greater weight loss, achieved by an initial period on a very low calorie diet can also be maintained. The main side effects are increase in pulse rate and in blood pressure. In patients who fail to lose weight blood pressure tends to rise, but blood pressure falls with weight loss on sibutramine, particularly in hypertensive patients. About 10% of patients do not lose weight with sibutramine. They were included in the clinical trial results, but should be identified early in a therapeutic trial in routine practice. Orlistat aids weight loss and maintenance by inhibition of intestinal lipase, leading to 30% fat malabsorption. Patients who lose 5% body weight after 3 months treat-

131

ment, together with a 30% fat diet, can expect 10-15% weight loss, maintained for 2 years. However, only 30-40% of patients are able to pass this hurdle. The main sideeffects are symptoms of fat malabsorption if patients eat too much. The drug is not absorbed. A wide variety of other weight loss agents are prescribed in other countries, or sold over the counter in pharmacies and supermarkets. For none of these is there evidence of safety or efficacy, with the possible exception of an ephedrine and caffeine combination, widely used in Europe, but not in UK.

Surgery In patients with BMI above 35kg/m2 and where metabolic or other complications are crippling or life-threatening, surgery is sometimes justified. The most widely used, operations at present are vertical banded gastroplasty and laparoscopic gastric bonding which reduce the size of the stomach to only about 50ml. Gastroplication requires the backup of a high dependency unit, but has a relatively low complication rate in experienced hands. Following operation, patients need to follow a liquid-only diet for 3 months, otherwise the staple line is likely to rupture and the surgery will be ineffective. It is a good plan to insist that all patients spend 3 months on the liquid-based diet before operation; during this time they should be expected to lose approximately 15kg in weight. Supplementation with iron and vitamins is necessary, and long-term medical nutritional and dietetic supervision is required. This form of operation usually results in a deranged eating pattern for life. For this reason psychiatric or psychological assessment and subsequent supervision should be available. Weight loss of 30-100 kg can be achieved but because regain after 2-3 years is so common gastric bypass with Roux-en-Y is becoming preferred. Long-term weight loss is more assured, but at the cost of chronic loose stools.

1 kg of fat in a week through strict dieting, but to gain the same amount temporarily from water, and this can be demoralizing.

Weight maintenance Very few patients can continue to lose weight beyond 3 months, and it is unreasonable to ask them to attempt more. Any result other than weight gain should be regarded as successful at 3 months, and then a weight maintenance programme introduced to prevent regain. This follow-on programme should include active support and lifestyle and psychological counselling for a further 3 months. Commercial and lay slimming groups may provide valuable support. Where the medical risks of weight gain are specially high (e.g. active, or family history of diabetes, hypertension, coronary heart disease), long-term medication may be considered. 1 2

NUTRITION SUPPORT Malnutrition delays wound healing and the recovery of muscle tone after an injury or operation, and may increase susceptibility to infection. Adults with a BMI below 16 have three times the postoperative mortality of betternourished patients. The striking changes in body composition from partial starvation in illness are shown in Figure 5.8. It is better to avoid malnutrition than to treat it, and it is essential to make a nutritional assessment of every patient. If the patient is already underweight, or if there is weight loss and the clinical condition gives concern, some form of nutrition support - such as dietetic supplements, enteral feeding or parenteral feeding - can be used to prevent further deterioration (Table 5.24). Every hospital should have a nutritional assessment and support policy, with a nutrition team comprising a physician and/or sur-

Expected rate of weight loss Many patients, and indeed health professionals, have unrealistic expectations during weight loss. Following a strict dietary restriction of 500 calories a day below normal maintenance, patients will lose about 0.5kg (1 Ib) per week or 7kg (1 stone) in about 3 months. More restricted diets and faster weight loss can only be achieved by a minority and for a fairly short period. More rapid weight loss may be dangerous, as it implies excessive loss of muscle or other body tissues. Weight loss of 0.5-1 kg per week should be expected and encouraged. Patients should not weigh themselves more often than every 2-4 weeks, as bathroom scales give a poor guide to body weight. It is also possible to lose

1

132

Case 5.2

2

MCQ 5.3

FIG. 5.8 Body composition of a man in health and after partial starvation

TABLE 5.24 Examples of conditions in which nutrition support may be necessary Illness associated with nausea and abdominal pain Gastrointestinal disease Malignancy Chemotherapy

Inability to eat Coma

Weakness Bulbar/pseudobulbar palsy

facing malnutrition, a formal prescription process for nutritional supplements may be as important as that for drug administration.

a

Intestinal disease

Enteral feeding Maiabsorption Inflammatory bowel disease Fistulas Thoracic duct damage Ischaemic colitis Short bowel syndrome Increased requirements Burns Sepsis Trauma

geon with special experience in clinical nutrition, a nutrition nurse/technician and a dietitian, together with strong support from the pharmacy, biochemistry and pathology laboratories.

Food and sip feed supplements Many patients find hospital food unappetizing even when they feel relatively well. In such cases, it may be possible to increase energy and nutrient intake by snacks provided by the diet kitchen between main meals. Attractive food and company can contribute greatly to maintaining nutrition; impersonal meal delivery and having to eat in bed have negative influences. If solid food is not well accepted, it is often possible to give liquid feeds for sipping but energy intake can be compromised. Semi liquid feeds can be prepared for patients with swallowing difficulties. A considerable range of commercially prepared feeds are available, presented as 200ml cartons. Some are complete feeds, containing a balance of all essential nutrients in proportion to requirements; others are incomplete, such as flavoured sugar solutions. Palatability is very variable. Sip feed supplements and enteral feeds are available in a vast range of compositions. For virtually all patients, the macronutrient contents should be similar to that of a healthy balanced diet, i.e. about 10-15% energy from protein, 50-60% from carbohydrate and 30-40% from fat. There is no clinical indication for high protein feeds: preparations with up to 40% energy as protein are available but should not be used as they suppress appetite and may lead to impaired renal function. Evidence is very limited to justify the use of 'elemental' feeds containing pre-digested peptides or oligosaccharides, or for feeds enriched with particular amino acids such as glutamate. Sip feed supplements should be served chilled and their volumes recorded accurately. They must be taken as supplements to an optimized food intake, not used as meal replacements. Patients often need a nurse to help and encourage supplement consumption. For patients

If oral intake is not satisfactory usually because of swallowing problems, a fine-bore silastic nasogastric tube may be passed. Because the enteral route should always be used when the gastrointestinal tract is intact, surgeons should also be encouraged to place a feeding nasogastric or nasojejunal tube at the time of any upper gastrointestinal surgery, or to leave a feeding jejunostomy. Even very limited enteral feeding after surgery or in the ITU nourishes the intestinal mucosa, reducing bacterial overgrowth and translocation, and permits more rapid weaning on to full enteral feeding. Enteral feeding solutions are passed down the tube at controlled rates. Small battery-operated pumps can control the exact flow rate, but they are not essential. The feed should be started in small volumes, and no more than 1000 mL given in the first 24 hours, otherwise diarrhoea may develop. The volume is then increased to the desired amount (probably a maximum of 2500mL/day). When patients are beginning to take food, the feed should be stopped for 1 hour before meals. Overnight enteral feeding may usefully supplement a limited oral intake, but care must be taken to avoid aspiration of gastric contents. A semirecumbent position is advisable. A large range of commercially available enteral feeds are available, made up from a variety of protein sources, including casein, soya and mixtures of amino acids, with glucose polymers and triglycerides added to increase the energy content. Most feeds provide about Ikcal/mL and have an osmolality of 280-420 mmol/kg. Low-lactose and cows' milk-free feeds are available. The commercial preparations have micronutrients in amounts that match dietary reference values, and so additional vitamins and minerals may be needed for patients whose micronutrient status is poor, or who have increased losses, utilization or malabsorption. Biochemical monitoring is required. Energy provision should match the metabolic rate, measured by indirect calorimetry or predicted from standard equations (Table 5.4) (BMR x 1.3 for a bedbound patient, plus 10-50% according to degree of illness or need for weight regain). It is impossible to overcome the increased metabolic rate of an ill, infected patient and to promote muscle regrowth at the same time. Protein should account for 10-15% of energy, the remainder coming in approximately equal amounts from carbohydrates and fat. The use of oligosaccharides or polydextrose may reduce the osmotic effects of glucose delivered enterally, but the evidence for using expensive peptide feeds is scanty. Enteral feeding can be performed at home; the reservoir bottles and lines should be changed every 24 hours to avoid the risk of contamination of feeds, but the silastic tubes can remain in situ for several weeks. Even so, complications of enteral feeding occasionally occur and should be anti-

133

cipated. Some patients prefer to use enteral feeding intermittently and become expert at introducing nasogastric tubes. Oesophagitis caused by the tubes is rare with modern silastic tubing, but the tube may be misplaced and a clinical check (aspiration of gastric fluid, or detection of bubbling with a stethoscope) should be carried out before feeding is commenced. When enteral feeding needs to be continued beyond a few weeks, gastrostomy feeding is usually easier and more acceptable to the patient. Percutaneous endoscopic gastrostomy is now a simple and safe procedure, increasingly used in a range of medical conditions, including pseudobulbar palsy following stroke, advanced multiple sclerosis or other neurological disorders. The most common complications of enteral feeds are diarrhoea, abdominal distension and pain, all of which relate to excessive infusion; the volume infused should then be decreased. More protracted diarrhoea can be controlled by codeine phosphate (30-60 mg t.d.s.) or imodium (2-4mg t.d.s.). Aspiration pneumonia is relatively frequent in debilitated patients (especially those with swallowing disorders) receiving enteral feeding when lying flat. Such patients should be fed sitting, if possible.

Parenteral feeding If enteral feeds cannot be given, parenteral feeding is an option; however, the dangers of infection, thrombosis and metabolic problems with this method are considerable. Enteral feeding should be commenced as soon as possible (even if very limited) to prevent mucosal atrophy. Parenteral feeds are ideal culture media for bacteria. They must be made up under sterile laminar flow conditions by specialist pharmacists (the vitamin and mineral preparations have limited stability, so feeds must be made up shortly before use). A dedicated intravenous line must be inserted under sterile conditions and only handled by trained staff. -Long-term parenteral nutrition requires a central line, as the high osmolality (often l000mmol/L) causes thrombosis in slow-flowing peripheral veins. For shorter-term feeding (up to 10-14 days), perhaps before it is ascertained that long-term parenteral nutrition will be required, peripheral veins can be used. Sterile techniques should still be used, and blood flow can be increased by a distal GTN patch. A lower glucose content allows reduced osmolality and so reduced thrombosis: a limited energy supply is often acceptable for 10-14 days for peripheral line feeding. Some commercial peripheral feeds are incomplete in terms of micronutrients, and so monitoring is important. The energy requirement for a malnourished patient receiving nutritional support is often difficult to assess. For long-term feeding, energy requirements can be estimated from standard equations published by the WHO (Table

1

134

MCQ 5.4

5.4). For ill patients and the malnourished, measurement of resting metabolic rate by indirect calorimetry is valuable, largely to avoid overfeeding, which causes a fatty liver. The amino acid content should be 10-15% of energy, and the remainder given as glucose or lipid emulsion (which permits a lower volume and lower osmolality than with glucose alone). A standard single 24-hour bag (2-3 L) containing 1500-2500 kcal is available. Parenteral feeds can be given either continuously over 24 hours, or over 12-18 hours to allow a daytime period off feeding, when the line is sealed and the patient can be mobile. Micronutrient requirements depend on clinical condition. All the essential nutrients (amino acids, fatty acids, vitamins, trace elements) are required. The matching of provision to need is more critical than with enteral feeding, because the 'buffering' influence of absorption in the gut does not apply. If the patient is malnourished and tissue growth is required, a greater than normal provision of phosphate, potassium and zinc will be needed to avoid 'refeeding syndrome' deficiencies. Because it is difficult to exclude subclinical vitamin B1 deficiency, extra thiamine should be given to patients when starting parenteral nutrition. For some, the intravenous delivery results in more rapid renal excretion, and so greater than normal dietary amounts are needed. Many patients receiving parenteral nutrition have tissue damage, and renal failure is relatively common, demanding special consideration. A number of metabolic complications may occur in patients receiving parenteral nutrition: • Hyperglycaemia is common in patients with severe surgical stress (e.g. burns and intravenous trauma) and sepsis, but plasma glucose can be controlled with carefully monitored insulin, adjusted to maintain plasma glucose 4-8mmol/L. Rebound hypoglycaemia may occur if intravenous feeding is abruptly halted. • Metabolic acidosis is rare if fructose and excessive quantities of amino acids are avoided. • Parenteral feeding, especially with lipid solutions, may cause hepatic abnormalities. The commonest reason is overfeeding, leading to fatty liver, which responds to a reduction of energy in feeds. However, most patients receiving parenteral feeding have many other potential causes for hepatic damage, and there is rarely any indication for parenteral nutrition to be stopped on account of mild biochemical changes. • Fat is metabolized more favourably than glucose by patients with sepsis. • Patients with respiratory failure should not receive large glucose loads because of their impaired ability to excrete the extra CO2 produced. • Mineral and electrolyte abnormalities occur variously according to the underlying disease processes. Fortunately, deficiencies can be made up relatively easily during preparation of the bag that contains the feeding solutions. • The stability of feed constituents is precarious, and problems have arisen with 'home-made' feeds and with

CASE STUDY 5.2 POSTOPERATIVE MALNUTRITION A 54-year-old man, height 1.75m, weight 65kg (BMI 21kg/m2) underwent a revision of a mitral valve replacement. His postoperative course was complicated by mediastinal wound infection and he had an episode of pneumonia, hypotension and acute renal failure, necessitating prolonged ventilation. During recovery the question of his nutritional status, complicated by 7 days of infection is raised at a caseconference, 10 days postoperatively, at which stage feeding had not been commenced. His weight has fallen to 60kg. Questions 1. What nutrient deficiencies are likely to be present? 2. How could management be optimized? Discussion Failure to eat for 10 days postoperatively, when metabolic rate is elevated about 50%, will have resulted in negative energy balance of about 10 (days) x 1.5 (increased metabolic rate) x 1600 (minimum daily requirement) = 24000k/cal. This would be equivalent to almost 4kg adipose tissue, but excess lean tissue is lost in infection, at about l000kcal/kg. The weight

measurement is likely to be seriously confounded by oedema, and changes in fluid balance (which may not be dependent). The patient's 'true' BMI may therefore be as low as 16kg/m2, making death from malnutrition likely. Specific deficiencies of many micronutrients are likely. Blood biochemistry is likely to be difficult to interpret owing to acute changes in protein and electrolyte balance. Deficiencies of nutrients which do not have body stores will be particularly depleted (e.g. vitamin C, B complex, magnesium, zinc, selenium). Preoperative status of thiamine, selenium may have been marginal thereby potentially impairing cardiac function. Immune function may have been impaired by a variety of nutritional factors, including a deficiency of essential fatty acids, vitamin A and zinc. Preoperative nutritional assessment and optimization should be routine. Common hazards with late, and inexperienced, nutritional support include inadequate thiamine to overcome a deficiency state, and the overprovision of energy. During illness the capacity to utilize nutrients and to synthesize body tissues is reduced, partly from cytokine action, partly from secondary nutrient deficiencies and altered nutrient essentiality. Excess energy supply

storage. Micronutrients should be added shortly before infusion. Home parenteral nutrition is occasionally necessary for patients with postsurgical short bowel syndrome and other conditions. It represents an enormous undertaking, but with family, social and medical support can be continued satisfactorily for many years. Commercial organizations exist to deliver supplies and to provide nursing and pharmacy support. In many cases total parenteral nutrition is not necessary - more limited feeding, e.g. 3 or 4 nights per week, may be sufficient. 1

Monitoring nutrition support The measurements available for monitoring support are shown in Table 5.25.

nutrition

leads to acute hepatic steatosis and impaired liver function. Measurement of metabolic rate is possible using a ventilated hood calorimeter, but it is more difficult when the patient is on a ventilator. Using estimated BMR is usually adequate. At this stage this patient requires assessment and management by a multidisciplinary Hospital Nutrition Support Team (including representation from specialist trained nursing, pharmacy, dietetic, biochemical and clinical staff). Biochemical nutritional data should be assessed at least weekly, with daily weight and assessment of state of hydration and for oedema. If the GI tract is accessible and intact, then this route is preferable to intravenous feeding. Because of mucosal atrophy after 10 days without feeding, enteral feeding will need to commence at low rates, increasing to approach energy requirement after 2-5 days. A nutritionally complete feed is required. Evidence does not support enrichment with individual amino acids. An approximate breakdown of energy 15% protein, 55% carbohydrate, 30% fat is appropriate. If increased CO2 production is clinically problematic, then higher fat, lower carbohydrate feeds might be considered.

a

TABLE 5.25 Measurements for monitoring nutrition support • Anthropometric: weight, mid-arm muscle circumference (MAC) • Minerals and electrolytes: uric acid, phosphate, sodium, potassium, zinc, magnesium, iron • Resting metabolic rate • Plasma vitamin concentrations • Nitrogen balance: corrected 24 hour urinary urea excretion • Glucose

Regular measurements of weight are necessary but are difficult to perform in the very sick without special bed balances. Changes in body weight may indicate alterations in fluid balance rather than an increase in lean body mass.

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Skinfold thicknesses and mid upper-arm circumference are valuable but affected by oedema. Plasma proteins (CRP, albumin) are useful indicators of progress in treating the underlying disease processes. Glucose should be measured regularly. Plasma phosphate and potassium levels may decrease rapidly and even precipitate cardiac arrhythmia if nutrition support is given rapidly in large quantities to a severely malnourished subject who has previously received very little dietary intake. Most modern amino acid solutions, however, have sufficient phosphate to avoid this. A low plasma sodium is often present in severely malnourished subjects. Total body sodium, however, is often high, and extra sodium should only be given with great caution. An approximate assessment of urinary nitrogen loss can be obtained by measurement of the 24-hour urinary urea excretion, corrected according to the formula: Nitrogen (g/24h) = urinary urea (mmol/L) x urine volume (L) x 0.028 x 6/5 This formula allows for the conversion of mmol of urea to g of nitrogen, and corrects for the fact that urea accounts for approximately five-sixths of total urinary nitrogen loss. Parenteral feeding solutions are ideal culture media. The previously high prevalence of infection has been reduced by the single-bag system, but a high standard of nursing and medical care of the lines is essential if sepsis is to be prevented. Different types of intravenous catheters are available - the best are those that are tunnelled subcutaneously. The feeding line must not be used for any other purpose. If other infusions are required a multilumen Hickman line may be used, keeping one lumen sterile for parenteral feeding. Hickman line insertion requires skill and experience. Complications include pneumothorax, central vein thrombosis, nerve injury, haematoma and arrhythmias. Similarly, only staff trained in the care of central venous feeding lines should be allowed to touch them, and the need for aseptic changing of sets and meticulous care of the catheter entry site should be emphasized. Feeding line infection should be suspected if fever develops, and is confirmed by cessation of fever when feeding is withheld and by a drawback blood culture (conducted under sterile conditions). Infected feeding lines can often be rescued by stopping feeding and by infusing vancomycin for 4-5 days. Central vein thrombosis can be treated by streptokinase infusion, but complete sterility must be maintained if the line is to be reused for feeding.

Refeeding syndrome

136

A lesson learned from work in the developing world, and now applicable in western hospitals, is that refeeding of severely malnourished and ill patients can often precipitate rapid decline and death. The 'refeeding syndrome' relates to the dynamic changes induced by introducing nutrition support. Metabolism is reactionary to rapid shifts from

extra- to intracellular spate of potassium, magnesium, zinc and phosphate. Low plasma levels can then lead to cardiac and central nervous system problems. These shifts need to be anticipated, and clinical problems can be avoided by careful monitoring and extra provision of these nutrients during early refeeding.

NUTRITION AS A COFACTOR IN DISEASE AND IN THERAPY

Hypertension There are direct relationships between BMI, sodium intake and blood pressure. Humans evolved on very low-sodium diets. The main effect seems to be a programming effect from exposure to high sodium intake in infancy. Most patients with 'essential hypertension' are in fact obese, and the increased sodium intake is secondary to increased food intake. There is a threshold effect of additional salt in adult volunteers, with those on very high doses showing an increased blood pressure. However, there are also important cofactors, including family history, stress, obesity and potassium, calcium and magnesium intakes, which may obscure the relationship in an individual. In the UK the average daily salt intake in adults is 5-10 g, i.e. sodium intake (150-250mmol). This is more than twice the amount associated with lower rates of hypertension experimentally, and 10 times more than is required daily. Salt restriction and weight loss should always be the first steps in hypertension management. Halving sodium intake to 80-100 mmol/day has an effect similar to that of routine antihypertensive drugs (5-10mmHg) in hypertensive patients, but without the side-effects. This reduction would lower blood pressure by 25mmHg immediately for normotensive people, and would prevent a l0mmHg rise 30 years later. A weight loss of 5-10 kg will also reduce blood pressure by 3-5mmHg. Greater effects are seen during acute energy restriction, but blood pressure tends to return to pre-weight loss figures over a period of years.

Atheroma International comparisons of mortality rates from coronary heart disease (CHD) show that these are highest in populations with the highest saturated fat intakes. This is true even when the effects of obesity, hypertension, cigarette smoking, diabetes, stress and family history are allowed for. The dietary factors leading to coronary heart disease are shown in Figure 5.9. The major lipid risk factors for the development of atheroma are high levels of plasma cholesterol and lowdensity lipoproteins (LDL), and low HDL. The pattern of high triglycerides, small dense LDL and low HDL is particularly atherogenic, and is associated with insulin resistance and non-insulin dependent diabetes in the 'metabolic syndrome', characterized by a high waist circumference

Environmental factor

Metabolite or process affected

Pathophysiological change

Pathology

Disease

FIG. 5.9 Factors leading to coronary heart disease

and intra-abdominal fat accumulation. Consumption of saturated fatty acids is particularly likely to increase both LDL and cholesterol. Diets low in saturated fatty acids lower these levels. Saturated fats are prominent in butter, lard, sausages, meat pies, pastries and chocolates, whereas unsaturated fats predominate in oils or margarines prepared from olives, rape seed, maize, sunflower or soya. Not all margarines are unsaturated - those that contain coconut oil (used in many hospital canteens in the UK), for example, are highly saturated. Synthetically hydrogenated fats

contain high amounts of trans isomer fatty acids, which behave like saturated fats. Plasma cholesterol mainly indicates the production of cholesterol by the liver. Cholesterol-containing foods (such as eggs) do not necessarily increase the synthesis of cholesterol in the liver. Cholesterol absorption can be reduced 10% by plant sterols (sitosterol and sterol esters) used in non-functional foods. Dietary antioxidants (e.g. vitamins A, C, E, flavonoids in fruits and vegetables) reduce atheroma by protecting LDL from oxidation. Fibrinogen is elevated in the overweight, as are coagu-

137

lation factor VII and plasminogen activator inhibitor (PAI-1). These are all predictors of thrombosis, and other dietary factors also have an influence (e.g. dietary fat on factor VII). Certain n-3 polyunsaturated fats - such as eicosapentanoic acid, present in cod liver oil, mackerel and pilchards - tend to inhibit thrombosis and should be particularly encouraged. People who eat a lot of fish have less heart disease. Major dietary changes in the population of Finland between 1970 and 1990, increasing fruit and vegetables and fish, and reducing sodium and saturated fat, together with reduced smoking, have been accompanied by 60-70% reductions in CHD. Intentional weight reduction in overweight or obese subjects, particularly in diabetic patients, is followed by a reduced risk of mortality from CHD and an increased life expectancy.

Diabetes Insulin-dependent diabetes is not principally linked to diet in its aetiology, although prolonged breastfeeding seems to be protective. The major need in management is to provide regular meals and snacks, every 2 hours or so, to match the profile of insulin action and to avoid hypoglycaemia. Alcohol impairs glucose release from the liver and thus potentiates any risk of hypoglycaemia. Non-insulin dependent diabetes (type II) is closely linked to diet. In nearly every society, those who are overweight and whose diet is high in fat and low in soluble dietary fibre have a significantly increased risk of diabetes. The greatest risk is in those who were born small for dates and show poor growth in the first year of life. They seem specially prone to weight gain and diabetes. The major hazard in non-insulin dependent diabetes is premature heart disease and stroke. Weight loss improves the prognosis for the overweight, and physical activity probably plays a major part. For all patients with diabetes, the need to follow a low saturated fat diet, with a high fruit and vegetable intake, is even more pressing than for people without diabetes. Sugar avoidance is no longer considered necessary, but general recommendations for a healthy diet apply (Table 5.26). There is sufficient circumstantial evidence to urge high intakes of antioxidant-rich fruits and vegetables to protect against microvascular disease. There is no benefit from the use of so-called 'diabetic' foods, which exploit a vulnerable group.

The metabolic syndrome

138

The 'metabolic syndrome' describes a clinical context which predisposes to premature CHD and stroke by a variety of coexisting abnormalities, including hypertension, dyslipidaemia (low HDL, high triglycerides, high small dense LDL), type 2 diabetes and hypercoagulability. The clinical syndrome is characterized by a predominantly central fat accumulation (intra-abdominally) even in those

TABLE 5.26 Summary of nutritional recommendations for people with diabetes compared with current average UK diet Approximate content of usual UK diet

Recommendations for diabetes

Energy

maintains BMI 25 kg/m2

to approach BMI 22 kg/m2

Carbohydrate (% energy) Added sucrose or fructose (g/day) Dietary fibre (g/day) Total fat (% energy) Saturated fatty acids Monounsaturated fatty acids Polyunsaturated fatty acids Protein (% energy) Salt (g/day) normotensive hypertensive So-called 'diabetic' foods

45 50-100

50-55* <25

19-25 40

>30g 30-35* <10 10-15 <10 10-15

17 11

6 12-15

10 -

None

<6 <3 None (avoid)

* Lower amounts of energy from carbohydrates and up to 35% from fat may be acceptable provided that most of the fat derives from monounsaturated fatty acids such as olive oil in 'Mediterranean-style' diets.

who are thin - with a high waist circumference. The unifying biochemical feature is probably early insulin resistance, at least in tissues other than the intra-abdominal fat mass, and there seem to be a reduced activity of PPAR (peroxisome proliferator-activated receptor-y) enzymes. The metabolic syndrome is at least partly genetic, but is precipitated by weight gain and physical inactivity, by smoking and by high alcohol consumption. Another key element is related to poor fetal and infant growth (low birthweight and size at 1 year of age). This may relate to under- or imbalanced nutrition at critical stages of fetal organ development the 'Fetal programming' hypothesis.

Cancers It is estimated that malnutrition and cachexia play a part in 70-80% of all cancer deaths, and diet contributes to 35% of all cancer development. Obesity is associated with the development of colonic cancer and also the sex hormonerelated cancers (breast, endometrium and prostate). The WHO produced a summary of dietary influences on different cancers, revealing a rather consistent pattern among major cancers of associations with dietary fat and alcohol, and with protection from fruits and vegetables. There is some suggestion that high intakes of meat perhaps burned meat containing cyclic hydrocarbons may be hazardous. It is not certain which factors in fruits

and vegetables are protective, but antioxidants probably play a part. It is possible that vitamin E supplementation may help reduce cancers. On the other hand, studies with P-carotene supplementation have actually shown increases in lung cancer in smokers, especially if they are also heavy drinkers. Vitamin tablets should therefore not be taken, or prescribed, in doses far exceeding healthy dietary intakes. It is better to promote fruits and vegetables, which also contain other bioactive compounds, such as carotenoids and flavonoids, that probably also help to protect against cancer when consumed throughout life. Advice for cancer prevention is thus essentially the same as for reduction in heart disease.

Gallstones The deposition of cholesterol to form gallstones depends on the relative concentrations of total bile salts, lecithin and cholesterol. The fine balance between these is affected by obesity and low dietary fibre intake, but the precise mechanisms of the imbalance or of the formation of gallstones are not clear. Rapid weight loss may precipitate biliary colic.

Liver disease The most important association between dietary factors and liver disease is that between alcohol and cirrhosis. However, mycotoxins may also affect the liver: aflatoxins, which are widely prevalent in cereals kept under poor storage conditions, may be a factor in causing primary liver cell cancer and may also contribute to the development of the fatty liver in kwashiorkor. Malnutrition in children does not account for the high prevalence of cirrhosis in developing countries: hepatitis B infection seems to be the major cause.

Pancreatic disease Chronic pancreatitis is frequently found in populations where malnutrition is rife. Periods of undernutrition may cause stasis of the exocrine juices within the pancreas, leading to acinar cell destruction and loss of digestive function. Pancreatic calcification often follows, with secondary diabetes. However, in western societies alcohol excess seems more important than undernutrition as a cause of chronic calcific pancreatitis.

Respiratory disease Being overweight, and particularly having a central (intraabdominal) predominance of fat, causes breathlessness, and also aggravates symptoms in patients with COPD. Sleep apnoea and hypoxia is a potentially serious consequence, with snoring as an early symptom. Weight loss is very effective. A proportion of patients with COPD and chest bellows disease become severely cachectic. The chest problem is

aggravated by wasting of the respiratory muscles, and by malnutrition-related immunosuppression. The main cause is suppression of appetite by recurrent infection exacerbations. Hypermetabolism is a lesser factor. Weight gain is extremely hard to achieve by dietetic means, but can improve respiratory function: appetite is poor, and the effort of feeding worsens hypoxia. Starvation ultimately leads to death by pneumonia in most cases, and it has been suggested that malnutrition may contribute to the development of emphysema.

5

Renal disease Patients with renal failure accumulate potassium, phosphate and nitrogenous products from protein catabolism. Traditional conservative management included a diet restricted in protein potassium (limited meat, dairy products, fruit and vegetables). Former advice to avoid fruit and vegetables is now tempered by anxieties about reduced antioxidant status, as the main cause of death is cardiac disease. A daily limit of three items of fruit and two portions of vegetables (or vice versa) is acceptable for most patients. Most patients with advanced renal diet have poor appetites and tend to undereat. The dietetic emphasis should probably be on increasing starchy carbohydrates, rather than on restricting foods. During dialysis, small molecules including vitamin C are removed, and supplements should be given afterwards. Nephrotic syndrome and proteinuric diabetic neuropathy are aggravated by high protein intakes. Restriction to about 0.8-1 g/kg/day (10% energy) is appropriate and will still allow nitrogen balance. This amount is much less than usual in UK diets.

Dental caries Fluoride is an essential nutrient, required to form healthy dental enamel. Much of the UK, particularly Scotland, has a fluoride-deficient water supply (below Ippm). Dental caries occurs when Streptococcus viridens adheres to teeth with fluoride-deficient enamel and metabolizes sugar into lactic acid. This lowers the pH acutely and erodes the enamel. Low-pH foods can be similarly damaging. All sugars can act as substrate; thus 'natural' sugars such as fructose are just as cariogenic as sucrose. The most important factor is the length of time that sugar-containing foods remain in contact with the teeth; adhesive foods and sugary drinks given in bottles to infants are particularly damaging. The low pH of many fruit drinks and colas leads to rapid enamel loss. There has been a marked decrease in dental caries among children in certain social groups in the UK over the last 20 years, but increased social division within the population reveals very high rates in deprived areas and groups. The fall in caries has been associated with an increase in the use of fluoride (in toothpaste, in drinking water or as tablets), and possibly also an increased prevalence of teeth cleaning. Perhaps paradoxically, sugar con-

139

sumption has increased over this period, although very recently low-sugar products have become more prevalent.

TABLE 5.27 Foods associated with food Intolerance* Food

% of cases

Urinary calculi

Milk

Calcium or oxalate stones are sometimes precipitated in the urinary tract as a result of increased dietary intake. Oxalate stones are those most frequently associated with dietary factors, occurring most commonly in populations with high phosphate intakes. In Thailand, for example, oxalate calculi occur most commonly in the rural populations, where the high phosphate intakes, associated with a predominantly vegetarian diet, contrast with the lower phosphate intakes of the better-off urban families. Oxalate stones may also be precipitated by dehydration in extremely hot climates, and by excessive vitamin C consumption. 1

Egg

25 22

Nuts/peanuts Fish/shellfish Wheat/flour Chocolate Artificial colours Pork/bacon Chicken Tomato Soft fruit Cheese (but not milk)

12 12

6 5 3 3 3 3 3 3

*From. Truswell AS 1986 ABC of nutrition

FOOD SENSITIVITY AND INTOLERANCE

The clinical importance of food allergy is difficult to assess as little is known of the scientific basis for hypersensitivity to food, there have been few controlled clinical trials of exclusion diets, and the mechanisms by which they work are not understood. A variety of foods have been implicated in food intolerance (Table 5.27). There has been considerable public interest in peanut allergy. Reports of food allergy can lead to needless anxiety. Parental concern can lead to poorly designed exclusion diets and nutrient deficiencies. The great majority of self-diagnosed food allergies or food intolerances turn out to be erroneous when professionally assessed. However, dramatic, even life-threatening allergies do occur. The major clinical symptoms associated with food sensitivity are shown in Table 5.28. A number of food allergies are associated with immunological reactions - usually an IgE response. A radioallergosorbent test (RAST) may detect antibodies in plasma against a specific food protein, but there is little correlation between the clinical features and the results of a variety of RAST tests. Skin tests of purified antigens may detect an urticarial response within a few minutes of intradermal inoculation, but positive skin tests do not correlate well with sensitivity reactions in other organs, such as the lungs and the gastrointestinal tract. In short, there is as yet no defined mechanism in most cases of food sensitivity, and very few laboratory tests are of any use. Management therefore depends on careful history-taking and a critical approach to elimination diets.

1

140

MCQ 5.5

TABLE 5.28 Symptoms in 100 patients with food intolerance* Symptom

Number of patients affected

Asthma Gastrointestinal Eczema Urticaria Rhinorrhoea Angioedema

58 41 37 35 31 8

* From: Truswell AS 1986 ABC of nutrition

Eczema Exacerbations of eczema are frequently associated with reactions against eggs and milk. Infantile eczema is sometimes improved by withdrawing eggs and cows' milk products; families with a strong history of eczema are advised to breastfeed as long as possible and to delay the introduction of eggs and cows' milk. Dietary manipulation in older children and adults is also worth trying but is often disappointing, and must be supervised to ensure nutritional adequacy.

Gastrointestinal symptoms The best-defined gastrointestinal hypersensitivity syndrome is to gluten in coeliac disease (see Ch. 15). Onset is sometimes precipitated by a gut infection, especially in children. Transient gluten intolerance following mucosal damage from giardiasis or rotavirus infections may occur in other patients. Secondary lactose intolerance may occur

in untreated coeliac disease through mucosal atrophy and loss of lactase. A more frequent problem is cows' milk protein intolerance. Here, mucosal damage permits access to mucosal lymphocytes, which become sensitized to the dietary protein. Subsequent exposure then produces a severe response in which lymphokines are released, damaging enterocytes. Villous atrophy occurs and malabsorption develops. There is also some evidence of exacerbation of the symptoms of ulcerative colitis by cows' milk; it is sometimes suggested (though reliable evidence is lacking) that infantile colic is caused by dietary factors transmitted in breast milk or contained in cows' milk. Early exposure to cows' milk in infancy has been related to gastrointestinal blood loss and anaemia, but the mechanism is obscure. The principal carbohydrate in milk is lactose. The expression of lactase in intestinal mucosa varies widely in adults, and in some races (particularly eastern) it is virtally absent, leading to lactose intolerance. Fermented milk products are preferred and are less liable to be malabsorbed. The very rare genetic fructose intolerance syndrome is usually identified by patients who develop symptoms after sweet foods.

Management of suspected food sensitivity If the patient suffers a reaction each time exposure to the allergen occurs, the latter should be easily identifiable. However, in the case of the general systemic symptoms described above, identification of the allergen is more difficult. There are two approaches:

5

• Exclude a suspected allergen for at least 4 weeks and then reintroduce it (this is mostly satisfactory where the condition is mild); or • Work out an elimination diet (one based on lamb, rice and pears is a classic starting point) as advised by a dietitian which ensures full nutritional adequacy. Then reintroduce a potential allergen every 2 weeks and observe the response. It is important to monitor body weight regularly and be alert to the possibility of an underlying eating disorder. Multiple food 'allergies' are less likely to have organic origins, and multiple exclusion diets can be dangerous. Restricting food choices for growing children is particularly hazardous, and needs careful supervision and counselling.

Migraine Migraines sometimes appear to be precipitated by foods such as chocolate, cheese, red wine, nitrates, cows' milk and wheat. Some of these contain amines or stimulate histamine release, which may produce an effect on cranial arteries.

NUTRITION IN HEALTH PROMOTION: CURRENT DIET AND PROPOSALS FOR CHANGE Health promotion

Respiratory tract responses Respiratory tract responses - including excessive production of tears, nasal secretions, sneezing and asthma are usually related to environmental factors, e.g. chemical sprays, cosmetics and food or plant pollens, but eggs, cows' milk and chocolate may also precipitate symptoms. Recent studies suggest that a variety of food preservatives, including tartrazine and sulphur dioxide, may also be responsible.

Urticaria and angioedema Most cases of urticaria or angio-oedema do not have dietary orgins. Acute or chronic urticaria may occur in response to eggs, nuts, fish (particularly shellfish) and cows' milk, as well as certain fruits, wine and cheese. Angioedema is a feared and potentially lethal complication.

Neurological and behavioural symptoms A range of syndromes of 'hyperactivity' in children and tiredness in adults are commonly attributed to intolerance, especially to tartrazine. Although some cases may occur, social factors are probably more important.

The promotion of good health (physical, psychological and social) incorporates an increasing emphasis on disease prevention through dietary change. Many of the major disabling illnesses and causes of premature mortality in western societies - heart disease, stroke, cancer - are progressive, not amenable to cure by drug therapy, and to a substantial extent preventable through dietary change. Two approaches are possible: • High-risk screening strategy. This approach requires a screening procedure to identify individuals at high risk, who then receive specific dietary advice and professional follow-up. The screening procedure must have very high sensitivity and must be able to reach high-risk groups, such as those in deprived areas and communities. It is dependent on high levels of professional input and therefore expensive. Such a programme must be sustained indefinitely, as there will always be new individuals entering the high-risk categories. Although this type of approach has been heavily promoted for cholesterol lowering, the principles outlined above cannot in fact be met. In particular, the sheer numbers who would require to be screened and followed up would make the system impractical (almost half the UK population has undesirably high blood lipids), and

141

the low sensitivity and specificity of cholesterol screening means that among those with low serum cholesterol the commonest cause of death is still ischaemic heart disease. The high-risk strategy approach is therefore more suited to less frequent conditions that require specific advice, such as phenylketonuria identified by a Guthrie test at birth, or the identification of women who have had a child with neural tube defect, who need high-risk folate supplementation (4mg daily) in the periconceptional period to prevent a recurrence. • Population-directed strategy. This approach does not involve screening but requires, by a combination of health education and modification of food supply, a change in the nutrient consumption of the whole population or of targeted subgroups. Examples include the abolition of marketing of high-sugar bedtime drinks for infants, as a way of reducing dental caries, and the healthy eating food and health policies designed to reduce major diseases such as ischaemic heart disease, diabetes, cancers and osteoporosis, which have been urged by many governments and umbrella organizations such as WHO. Population-directed programmes do not demand major health service inputs, although high-risk strategies may operate alongside for special groups. Because the diet of the whole population will be modified, it is essential that the changes promoted should be advantageous or safe for everybody. Given the very limited resources of health promotion agencies, effective population-directed nutritional policies must include cooperation from the food production and supply industries.

142

The average dietary intakes in western countries, including the UK, have changed substantially over the last 50 years, with greatly increased intakes of foods of animal origin, and declining intakes of fruits and vegetables and starch-rich staple foods (cereals, potatoes). There is now little scientific argument in opposition to health-directed measures aimed at reducing intakes of total fat (particularly saturated fat), reducing sodium and some increase in potassium and calcium consumption, while promoting increased consumption of fruits and vegetables and, to some extent, unsaturated fats, particularly those from oilrich fish. Although the benefits to any individual from dietary change are relatively small, the burden of disease to whole populations would be reduced substantially, particularly through reductions in heart disease, stroke and diabetes, and in the prevention of obesity and osteoporosis. A comprehensive package of quantitative proposals for dietary change have been made for Scotland, a country which has a very high burden of preventable disease (Table 5.29). To some extent .this has been influenced by the observational evidence from countries such as Norway and Finland, where long-term programmes of dietary change have resulted in major reductions in heart disease, stroke and cancer. It is important to recognize that nutrient tar-

TABLE 5.29 Intermediate nutrient and dietary targets for Scotland for the year 2005 Dietary component Vegetables and fruit excluding potatoes (g/d) Carbohydrates: total % E Starch (% E) Non-starch polysaccharides (g/d) Extrinsic non-milk sugars (% E) Fatty acids (% E): Cis-monounsaturated Cis-polyunsaturated (Total) n-6 n-3 Saturated Trans Total fat (% E) Sodium consumption (mmol/d) Potassium consumption (mmol/d) Alcohol consumption* (g/d) Men Women Dietary cholesterol (mg/d)

1989-91 intake

Targets

181

>400

25.3

>40

10.5 16.3

>16 <10

12.6 6.3 5.2

<10

0.8 16.6

13 <8.8 >1.2

2.1

<11 <2

40.7

<35

163

70

62

80

34.5 11.1*

<24*

-

-

<16*

f

Current intakes relate to estimates derived from a variety of sources. % E signifies the proportion of the nutrient as a percentage of total food energy, i.e. excluding alcohol. Changes in vitamin intakes are those expected from the dietary changes; women of child-bearing age have been recommended to supplement their diet with 400 ug folic acid, * Alcohol is specified for consumers only, intakes from Adult Survey, maximum intakes proposed by Royal College of Physicians (1987).

gets can only be met if there are changes in food choices, and that these must be matched by changes in food supply. Successful intervention programmes thus require multidepartment government action over a long period. For some of the nutritional consequences of dietary change, the benefits would be seen principally in those who are currently consuming very poor diets; however, it is likely that there would be some improvement even for groups with better diets at present. Extensive studies have shown no appreciable health disadvantage in the changes proposed. In particular, the effects of cholesterol lowering, which were disputed for many years, have now been shown clearly not to be harmful. The benefits from sodium restriction had been difficult to quantify because of the variety of research addressing different groups with different levels of blood pressure and different levels of sodium intake. Large meta-analyses have clarified that a major reduction in sodium intake should be made. This would partially benefit those who already have relatively high blood pressure and would be likely to reduce the development of hypertension in younger people.

RECENT ADVANCES IN HUMAN NUTRITION Recent years have seen an important expansion of research in human nutrition, stimulated by recognition that the major sources of illness and premature mortality in the world, and specifically in highly developed Western countries, will not be amenable to cure by drug therapy. If these problems (cancers, heart disease, stroke, diabetes, osteoporosis) are to be alleviated, the answer must lie in prevention, and diet plays a major role. These are the themes that underlie the application of modern nutritional science to medicine. Most diseases develop as a result of interaction between genetic factors peculiar to the individual, and environmental exposure or conditions. Thus within human nutrition the concept of 'gene-nutrient interactions' has emerged. It is very difficult for people to change their diets, and satisfy targets to maintain good health. The science of food choice, which relates closely to food science in the context of functional foods, designer foods and therapeutic foods or diets, has become of major importance. Dietary and nutritional influences operate over a very long timespan in modifying health and disease. Longterm observational follow-up studies from cohorts of relatively young people, are already demonstrating new dietary influences on health in periodic followup surveys. A number of recent advances in human nutrition can be identified as arising from these new understandings: • Importance of fetal nutrition and development for later health: poor fetal growth predicts diabetes, hypertension, heart disease, stroke. • Folic acid supplementation in the perioconceptional period overcomes metabolic abnormalities that prevent neural tube development. • Dietary folate reduces serum homocysteine, a risk factor for CHD. • Antioxidants - vitamins C, E, carotenoids and phenolics - have the potential to be involved at several stages against development of cancers (free radical DNA damage) and coronary heart disease (protection against LDL oxidation). • Vitamin supplements given unphysiologically as tablets may have different effects from giving foods which contain these vitamins. Foods contain many other related bioactive compounds such as flavonoids, carotenoids, etc. This balance is likely to be important for health. • Specific fatty acids have different effects on plasma lipo-proteins and coronary heart disease risk. For example stearic acid, although saturated, does not elevate cholesterol. Trans-fatty acids, found mainly in synthetically hydrogenated fats such as margarine and in baked foods, elevate LDL cholesterol and are linked to heart disease prevention in the same way

as saturated fatty acids. Individuals with different apolipoprotein E subtypes respond differently to dietary fatty acids. • The human placenta can probably transfer fatty acids to the fetus and there may be specific fatty acid transfer proteins. • Immune function appears to be determined to some extent by the balance of fatty acids in the diet. New non-absorbable drugs (e.g. orlistat) or novel food products (e.g. sitosterols and sterol esters) modify fat absorption and consequent health. • The two-way interaction between nutritional status and disease may lead to 'conditioned essentiality' for specific nutrients during illness, e.g. for amino acids such as glycine or glutamine, which are not essential during health.

Some of the dietary changes required to improve health demand action principally from individuals, to select more appropriate foods and to cook and prepare them in more healthy ways. Thus an increased consumer demand for fruits and vegetables and for lower saturated fat food can be encouraged to help health promotion, and is likely to be met by increased provision from the food industry. To reach other nutrient targets, however, there will need to be greater emphasis on programmes of change within the food manufacturing and catering industries: for example, about 80% of sodium intake derives from foods that have had salt added during manufacture or processing. A programme of stepped small reductions in the salt content of common foods is likely to be acceptable and beneficial to consumers. The composition of many foods could be modified with health benefits and without impairing palatability or commercial success. Examples of effective national nutritional policies are available from countries such as Norway and Finland, where substantial changes in average diet composition over a period of 10-20 years have been accompanied by major reductions of the order of 60-70% in ischaemic heart disease and cancers before the age of 65. There are far greater effects that could be achieved by lipid lowering or other drug interventions. The three dietary components with the greatest impact are reduced saturated fat as a proportion of energy, reduced sodium consumption, and substantially increased fruit and vegetable consumption. The success of these programmes has depended on the activities of committed health professionals prepared to take on public positions and to interact with national and local governments and with the food supply industries. Responsible and well-educated media involvement, which does not seek to promote mavericks and sensationalists, has been influential. High levels of general education and minimization of social deprivation are critical for the effectiveness of health promotion.

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FURTHER READING Department of Health. Nutrition: A core curriculum for nutrition in the education of health professionals. London: HMSO, 1994. Department of Health. Nutritional aspects of the development of cancer. Report of the Working Group on Diet and Cancer of the Committee on Medical Aspects of Food and Nutrition Policy. Report on Health and Social Subjects No. 48. London: HMSO, 1998. Dietary reference values for food energy and nutrients for the United Kingdom. Report on Health and Social Subjects, 41 1991. Department of Health COMA. London: HMSO, 1991. Garrow J S Obesity and related disorders. Edinburgh: Churchill Livingstone, 1988. Holland B, Welch A. McCance and Widdowson's compositions of foods, 5th edn. Cambridge: Royal Society of Chemistry. 1991: See also supplements dated after 1991. James W P T, Garrow J S Human nutrition and dietetics, 10th edn. Edinburgh: Churchill Livingstone, 2000.

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Mann J, Truswell A S. Essentials of human nutrition. Oxford: Oxford University Press, 1998. Manual of dietetic practice, 2nd edn, Oxford: Blackwell Science, 1994. National Institutes of Health (NIH) obesity guidelines. Available online at http://www.nhlbi.nih.gov/guidelines/obesity/ob_home.htm The Scottish Office Home & Health Department. The Scottish diet: Scotland's health - a challenge to us all. Report of a Working Party to the Chief Medical Officer for Scotland, 1994. Scottish Office Department of Health. Scotland's Health - A challenge to us all. Eating for health - a diet action plan for Scotland, 1996. Truswell A S ABC of nutrition, 2nd edn. London: British Medical Association, 1992. WHO Diet, nutrition and the prevention of chronic diseases. Technical Report Series 797. Geneva: World Health Organization, 1990.

6

Cancer Medicine Robert L Souhami

Incidence and epidemiology 145 Aetiology 146 Tumour growth and development 149 Pathology 151 Clinical features 151 Staging and investigation 155

Supportive care in cancer management 165 New approaches to management 167 Trials of treatment 167 Care of the dying 168 Alternative therapy 168

Principles of cancer management 157

Each year in the UK there are approximately 220000 new cases of cancer. Almost one-third of the population will develop cancer during their lifetime, and of these 70% will die of the disease - 150000 deaths a year. As a cause of mortality, cancer is second only to cardiovascular disease. It is most common in the elderly: the age-specific incidence rates for men and women are shown in Figure 6.1. The frequency of cancer and the increasing complexity of management mean that every clinician must have a firm grasp of the principles of diagnosis, investigation and management. In recent years, the approach has been changing rapidly as a consequence of fundamental advances in cancer biology, the isolation of genes responsible for hereditary disposition to cancer, increasing accuracy in diagnosis and staging, and major developments in the use of radiotherapy and chemotherapy. At the same time, clinicians have developed a better awareness of the problems faced by patients who are incurable, and professional attitudes have changed in the direction of more open discussion with patients. Cancer medicine therefore demands a combination of a high degree of technical competence and a sympathetic insight into the feelings of the patients. It is this double challenge that makes it a most rewarding part of medical practice.

INCIDENCE AND EPIDEMIOLOGY Incidence means the proportion of a defined population developing a disease in a stated period of time; prevalence

is the proportion which has the condition at a single point in time. Crude incidence or prevalence rates refer to a whole population and specific rates to selected groups, for example those defined by age or sex. The age-specific incidence rates of some cancers are shown in Figures 6.2 to 6.4. It can be seen that adenocarcinomas in women have quite different age-specific incidence rates. Cancer of the breast increases rapidly in incidence before the menopause, and at a slightly slower rate thereafter (Fig. 6.2). Uterine and ovarian cancer also show an increasing incidence premenopausally, but the rate does not rise in later life. Gut cancers (Fig. 6.3), on the other hand, show no relation to the menopause but rise rapidly in incidence in old age in both sexes. The biphasic age-specific incidence of Hodgkin's disease (Fig. 6.4) contrasts markedly with the findings in adenocarcinoma. Lung cancer is at present more common in men, but the incidence in women is rising rapidly, approaching that of breast cancer. Cancer is the second main cause of death in childhood, with acute lymphoblastic leukaemia accounting for nearly half the deaths. The commonest sites of cancer in the west are the lung, skin, large bowel, prostate, stomach and rectum in men; and the breast, large bowel, skin and lung in women. The mortality rates are, however, different from incidence rates (Fig. 6.5), with skin cancer having a low mortality rate and lung cancer a very bad prognosis. However, the relative incidence of cancers is changing with time. For example, the incidence of lung cancer has been rising rapidly since the mid-1960s, especially in women, whereas that of stomach cancer has been falling for both men and women (Fig. 6.6). The rise in incidence of lung cancer is undoubtedly due to smoking, but the reason for the decline in stomach cancer is not clear. Cancer incidence varies in different countries (Table 6.1), and this variation may provide insights into aetiology. Carcinoma of the oesophagus has a high incidence in an area extending from the Caspian Sea to Central Asia and the Far East; it is also more common in the Transkei. In these areas it has an incidence 200 times that found in the UK. In Japan, gastric carcinoma is 30 times more common than it is in the UK, but pancreatic cancer is much rarer. The reasons for these variations are as yet unknown, but dietary and nutritional factors are suspected to play a part. The migration of populations has helped to determine how much of the geographical variation is genetic and how much is environmental. When Japanese people settle in the USA, the incidence of cancers in their offspring resembles that of the adopted country: the high incidence of gastric cancer falls, and the lower incidence of cancers of the breast, colon, ovary and prostate rises. These findings suggest that environmental, rather than genetic, causes account for most of the observed differences between countries.

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FIG. 6.3 Age-specific incidence of adenocarcinoma of the colon FIG. 6.1 Age-specific incidence of cancer (England)

FIG. 6.4 Age-specific incidence of Hodgkin's disease

FIG. 6.2 Age-specific incidence of carcinomas of the breast, ovary and uterus Note change in rate of increase at the time of the menopause.

AETIOLOGY Evidence suggesting aetiological factors in cancer has come from epidemiological and laboratory investigation. 1 It is probable that, for many types of neoplasm, an inter-

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MCQ 6.1

FIG. 6.5 Incidence and mortality of common cancers in men and women in England and Wales Note that whereas skin cancer is common, its mortality is low. Cancer of the lung is common and accounts for a large number of total cancer deaths.

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FIG. 6.6 Cancer of the lung and stomach A Cancer of the lung: age-standardized death rate/10000 in age group 65-74,1905-85 in the UK. B Cancer of the lung: mortality 1941-91 for different age groups. C Cancer of the stomach: change in mortality in England and Wales and in Japan, 1940-1990.

TABLE 6.1 Geographical Incidence of cancer Cancer

High incidence

Low incidence

Ratio (high Mow)

Oesophagus

Iran, Transkei, Kazakhstan Australia Mozambique Far East (China) UK Japan Europe, USA

Holland

200:1

India UK Europe Nigeria UK Japan

200:1 100:1

Skin Liver Nasopharynx Lung Stomach Breast

100:1 35:1 30:1 6:1

action of genetic and environmental factors is responsible for the development of a cancer (Fig. 6.7).

CHEMICAL CARCINOGENS

The frequency of scrotal carcinoma in chimney sweeps was noted by Sir Percivall Pott in 1775, and the high incidence of bladder cancer in dye workers in 1895. The mechanisms

of action of chemical carcinogens have been intensively studied. There are several classes of experimental carcinogens (Table 6.2) which are possible causes in humans: • Polycyclic hydrocarbons are formed from combustion of organic compounds. They are present in cigarette smoke, soot, car exhaust fumes and some foods. Dibenzanthracene was one of the first to be shown to be carcinogenic. The carcinogenic effect results from reaction with bases in DNA. • Aromatic amines and azo dyes, such as B-naphthylamine and benzidine, are metabolized to an active form. (3Naphthylamine is glucuronated in the liver. Glucuronidases in the urine liberate the carcinogen in the bladder. • Nitrosamines are formed when nitrites in food are converted to nitrates, which react with amines in food. The substances can cause stomach cancer experimentally. • Alkylating agents, such as those used in cancer management, bind to DNA. Use of these drugs in cancer treatment has been associated with the development of secondary malignancies, the most important of which is secondary leukaemia, which may also be caused by treatment with etoposide, a widely used anticancer agent.

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FIG. 6.7 The sequence of genetic events contributing to invasive cancer

TABLE 6.2 Chemical carcinogens Class

Example

Source

Polycyclic hydrocarbons Aromatic amines Azo dyes Nitrosamines Toxins Alkylating agents Chromates Asbestos

Dibenzanthracene

Smoke, cigarettes

p-Naphthylamine Dimethylaminobenzene Dimethylnitrosamine Aflatoxin Melphalan

Aniline dyes Butter yellow ?Food Aspergillus flaws Drug treatment of cancer Industrial exposure Insulation and heating installations

• Organic toxins include the best-studied example, aflatoxin, produced by the mould Aspergillus flavus growing on grain. This substance has been suggested as an aetiological agent in liver cancer in Africa. • The most important occupational carcinogen is asbestos, which causes cancer of the pleura, lung and peritoneum in workers exposed to the dust. When carcinogens act on a cell they may cause a permanent change which predisposes to cancer, a process known as initiation. Other agents can then produce transient changes which with continued exposure lead to cancer; this is known as tumour promotion. This multistage process has been shown in some experimental cancers, where mutagens act as initiators and hormones or dietary constituents act as promoters. The more prolonged the exposure to a carcinogen, the more likely the tumour is to develop. Several genetic events in sequence are necessary for the tumour to develop.

IRRADIATION

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The carcinogenic effect of ionizing irradiation was indicated by the skin cancers that developed on the hands

of early radiologists, and by the increased frequency of acute and chronic leukaemia, breast and thyroid cancer in Hiroshima during the 30 years after the atom bomb was dropped. The mechanism of carcinogenesis is probably related to the chromosomal damage caused by X-rays. It seems likely that 'background' ionizing irradiation does not contribute greatly to common cancers in humans. Therapeutic irradiation may give rise to bone and soft tissue sarcoma (after a latent period of 10 years), and possibly to lung cancer. Ultraviolet light probably plays a role in the development of skin cancers. This is seen most clearly in the autosomal recessive disorder xeroderma pigmentosum, where a defective DNA repair mechanism is associated with the early development of skin cancers on skin exposed to sunlight. Malignant melanoma and other skin cancers are uncommon in black people but are particularly frequent in fair-skinned Celts. In Australia, skin cancers are common among the non-indigenous population and increase in incidence in the north nearer the Equator.

VIRUSES Ribonucleic acid (RNA) viruses can cause a variety of cancers in animals. These viruses contain a gene which codes for the enzyme reverse transcriptase, which is produced in the infected cell and results in the cellular synthesis of DNA complementary to the viral RNA and thus to the production of more viruses. For this reason they are called retroviruses. Tumours caused by these viruses include avian erythroblastosis, rat sarcoma, feline leukaemia and murine leukaemia. The insertion of the viral genome into DNA leads to malignant transformation. A growth-factor receptor is encoded by the erythroblastosisB virus (v-erb B), and a phosphokinase by Rous' sarcoma virus (sis). RNA viruses are involved in the development of some forms of T-cell leukaemia and lymphoma (human T-cell leukaemia virus, HTLV types 1 and 2). The human immunodeficiency virus (HIV) is the cause of the acquired

immune deficiency syndrome (AIDS), in which there is a greatly increased frequency of skin sarcoma and B-cell lymphoma. These tumours are probably not caused by the virus but are a consequence of oncogenesis in patients with greatly reduced immunity. Hepatitis C is an RNA virus which is implicated in the high incidence of hepatoma in chronically infected patients. Research into RNA viruses led to the discovery that the viral oncogenes had homologues in normal cellular DNA. These cellular proto-oncogenes appear to code for products very similar to those produced by the equivalent virus. These findings have led to the search for increased expression of cellular oncogenes in human cancers, for the gene products, and for the link between carcinogenesis and oncogene activation. There is strong circumstantial evidence implicating DNA viruses in the pathogenesis of some malignant neoplasms. For example, Epstein-Barr virus (EBV) causes proliferation of normal human B lymphocytes; EBV-coded proteins are found in Burkitt's lymphoma cell lines; and African children with the lymphoma have high titres of antibody to viral antigens. Worldwide, hepatoma is one of the commonest cancers. Infection with hepatitis B virus (HBV) is associated with its development both in Africa and in Europe. Hepatoma is particularly likely to occur in chronic active hepatitis associated with HBV and hepatitis C, and in alcoholic cirrhosis where there is evidence of previous HBV infection. Cancer of the uterine cervix is increasing in frequency in young women. There is strong evidence that human papillomavirus is associated with this disease, possibly as a result of sexually transmitted infection.

GENETIC FACTORS Numerous inherited genetic abnormalities predispose to the development of malignancy (Table 6.3). These syndromes include examples of autosomal dominant and recessive inheritance, and X-linked disorders. Inherited chromosomal abnormalities may also predispose to cancer (Table 6.3). The most common is Down's syndrome (trisomy 21), where there is an increased incidence of acute leukaemia. In some cases the relationship between the genetic abnormality and the induction of cancer has become clearer. In hereditary retinoblastoma the retinoblastoma gene (Rb) acts as a growth suppressor gene. Inherited loss of this gene is followed by mutation in the other allele, which sets the scene for malignant transformation. Germline mutation, followed by loss of heterozygosity of the p53 gene, occurs in the Li-Fraumeni syndrome, in which the families of children with sarcoma show an excess of other cancers. It has become apparent that there may be an important inherited genetic component to many other common cancers. Very recently, two genes responsible for familial breast cancer have been isolated. The first, BRCA1, is prevalent in Ashkenazi

RECENT ADVANCES IN GENETIC DIAGNOSIS OF FAMILIAL CANCER, SCREENING, CANCER PREVENTION

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The cloning of two breast cancer genes that are responsible for early-onset and aggressive breast cancer, the identification of the genes responsible for hereditary colon cancer, and the likelihood that other genes are responsible for some cases of testicular, lung and prostate cancer, will lead to increasing demand for genetic testing for cancer risk. In satisfying this demand it will be necessary to provide counselling and advice to patients and their families. The identification of individuals at especially high risk may allow screening services to be directed more efficiently towards those who have extra need and in whom considerable expenditure will be fully justified. It is now feasible to consider the use of drugs which may prevent cancer developing in those at high risk. An example of such intervention is the use of tamoxifen as a preventative agent in breast cancer.

Jewish women and has an early age of onset. A wide variety of mutations have been detected. BRCA2 predisposes to both breast and ovarian cancer. In hereditary nonpolyposis colorectal cancer the syndrome arises as a result of mutation in one of a family of DNA mismatch repair genes. Acquired genetic abnormalities are frequently found in cancer cells, with mutation, transposition and deletion of genetic material. These abnormalities are sometimes consistent, such as the translocation from chromosome 22 in chronic granulocytic leukaemia, and the reciprocal translocation involving chromosome 8 in Burkitt's lymphoma. In many tumours (lung cancer, leukaemia, hepatoma) there is mutation of the p53 gene, which codes for a growth regulatory transcription factor. In colon cancer a cascade of genetic events is responsible for the transformation of polyps to invasive cancer.

TUMOUR GROWTH AND DEVELOPMENT Some tumours exhibit properties which imply that they have arisen as a result of clonal expansion caused by an oncogenic event in a single cell. Lymphomas, for example, usually show restriction to one type of surface immunoglobulin light chain; and studies in individuals who are heterozygotes for the enzyme glucose-6-phosphate dehydrogenase have shown that tumours contain only one form of the enzyme. Whether all cancer are monoclonal in origin is not known, and the development of some

149

carcinomas in a polyclonal field of premalignant change remains a possibility. Even if most tumours are monoclonal, heterogeneity of structure and function arises during the course of tumour growth. Cells from a tumour are diverse with respect to resistance to damage by irradiation or cytotoxic drugs, surface antigen expression, growth rate, and expression of biochemical markers such as embryonic proteins or peptide hormones. This diversity is due to genetic instability in the cancer cells. Heterogeneity within tumours presents a formidable problem for treatment. In normal tissues, self-renewing stem cells replenish a proliferating population of cells which follow a pathway of differentiation resulting in a mature tissue (Fig. 6.8). Cell death is balanced by the formation of precursors, and the tissue is static in size or else grows and diminishes in response to such external controls as hormonal environment. In cancers the restraint on growth is disrupted, so that sustained expansion of the tumour occurs. For clinically detectable cancers, the kinetics of growth appear to be exponential and the rate of tumour volume doubling varies widely. In Burkitt's lymphoma, the doubling time of visible tumour may be as short as 1-2 days, in contrast to 100-400 days for some squamous carcinomas and adenocarcinomas. It seems unlikely that growth is exponential from the beginning of the cancer, as this would imply very long subclinical growth periods for some tumours (Fig. 6.9). Cancers are clinically apparent after about 32 doublings, and lethal after 36-38. It is possible that tumours grow more rapidly when they are very small and slow progressively as they enlarge (gompertzian growth). If true, this may have implications for therapy, as the more rapidly dividing small tumour might be more susceptible to chemotherapy. During growth, the tumour becomes vascularized and lymphatic drainage is established. Cells more than 150 um from a capillary are relatively hypoxic and resistant to radiotherapy. They are also exposed to a lower concentration of cytotoxic agents. The vascularization may be insufficient to sustain viability, and areas of necrosis and haemorrhage are frequently found in large cancers. The process of vascularization allows tumour cells to penetrate blood and lymphatic channels, and thence to metastasize to regional lymph nodes and distant sites.

Metastasis Metastasis is a remarkable process and one which is still very poorly understood. The risk of metastases increases as tumours become larger. The cells must survive tissue invasion, circulation, passage across the capillary wall, and establishment in tissues. The process of tissue penetration

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150

Figs 6.1, 6.2

Table 6.3 Inherited genetic abnormalities and malignancy Inherited disorder Skin disorders Neurofibromatosis (AD) Tylosis palmaris (AD) (keratosis of palms and soles) Peutz-Jeghers syndrome (AD) Immune deficiency X-linked agammaglobulinaemia (XLR) Wiskott-Aldrich syndrome (XLR) Ataxia telangiectasia (AR) X-linked lymphoproliferative syndrome (XLR) Gut disorders Polyposis coli (AD) Gardner's syndrome (AD) Hereditary non-polyposis Colotectal cancer (AD) Neurological disorders Tuberous sclerosis (AD) Retinal/cerebellar angiomatosis (von Hippel-Lindau syndrome) (AD) Other syndromes Bloom's syndrome (AR) (short stature, telangiectasia) Hemihypertrophy Fanconi's anaemia (AR) (skeletal abnormality, patchy pigmentation, mental retardation) Multiple enchondromata (S) (Oilier syndrome) Chromosomal abnormalities Down's syndrome (trisomy 21) Klinefelter's syndrome (47.XXY) Aniridia - Wilms' syndrome (11pMosaicism (45,XO/46,XY) 13q- (multiple malformations)

Cancer

Sarcoma, phaeochromocytoma, medullary carcinoma of thyroid Oesophageal cancer Intestinal and ovarian cancer

Lymphoma Lymphoma Lymphoma and stomach cancer Lymphoma

Colonic carcinoma Colonic carcinoma Duodenal carcinoma Colonic carcinoma

Glioma Hypernephroma, ependymoma, phaeochromocytoma

Leukaemia Many other cancers Wilms' tumour, hepatoblastoma Acute leukaemia

Chondrosarcoma

Acute leukaemia Breast cancer Wilms' tumour Gonadoblastoma Retinoblastoma

Hereditable component of other cancers Breast cancer BRCA1 BRCA2 Breast cancer Unknown (recessive?) gene Testicular cancer p53 mutation Sarcoma in children Breast and other cancers AD Autosomal dominant AR Autosomal recessive

XLR X-linked recessive S Sporadic

• sarcomas, which arise from mesodermal cells making up bone and connective tissue; • leukaemias and lymphomas, which arise in cells of the bone marrow and immune system.

FIG. 6.9 Diagrammatic representation of exponential and gompertzian growth

FIG. 6.8 Diagrammatic representation of cellular proliferation in a tumour A Pluripotent self-renewing stem cell. B Proliferative compartment in which cell number increases but gradually loses reproductive potential. C Mature tissue.

appears to be by secretion of enzymes known as metalloproteinases (such as collagenase). Inhibitors of tissue metalloproteinases are now in early trials as anticancer agents. The precise location of a metastasis is probably due in part to chance. Nevertheless, clinical patterns of bloodborne metastasis are apparent: gut cancers spread through the portal venous system to the liver; ovarian cancers seed into the peritoneal space; breast cancer has a predilection for bones of the axial skeleton; sarcomas characteristically spread to the lungs.

PATHOLOGY The major categories of malignant tumour are: • carcinomas, which arise from ectoderm or endodermal cells;

6

The distinction between benign and malignant neoplasms is based histologically on the cellular pleomorphism, frequent mitoses and tissue invasion that are characteristic of malignancy. The clinical manifestations of malignancy are tissue infiltration and lymphatic and bloodborne metastases. The degree of differentiation of a tumour is often an important guide to prognosis, and therefore to therapy. Poorly differentiated carcinomas have a worse prognosis than well-differentiated tumours. This is due in part to an association with a more rapid growth rate and more early and widespread metastases. About 5% of cancers present as metastases where the primary site of the tumour is unknown. The histology is usually a poorly differentiated carcinoma, often with features suggestive of adenocaicinoma, but the pathologist may find the tumour difficult to classify. The development of monoclonal antibodies has led to a greater precision in diagnosis by using immunocytochemical methods. Many anaplastic tumours can now be diagnosed as epithelial tumours, melanomas or lymphomas by using antibodies against epithelial antigens, or antigens associated with melanoma, leukocytes or T and B lymphocytes. The correct identification of lymphoma will lead to important changes in management of a patient (Fig. 6.10). Many antibodies will not bind to antigens on formalin-fixed and paraffin-embedded sections, and require fresh tissue. Other specialized investigations can be carried out on fresh tumour tissue - measurement of hormone receptor content (e.g. oestrogen and progesterone receptors) for example, which may be of importance in prognosis and in deciding treatment. Using immunocytochemical techniques, the presence of substances such as oc-fetoprotein can be detected in the tumour. The increasing complexity and versatility of histopathological diagnosis means that it is now essential for there to be close collaboration between clinician and pathologist before specimens are obtained. Ultrasound and CT scanning now allow accurate needle biopsy and aspiration cytology of hitherto inaccessible intra-abdominal and intrathoracic tumours. 1 Cytological diagnosis does have some limitations: in the diagnosis of lymphoma, for example, it may be difficult to distinguish tumour cells from normal reactive lymphocytes. For this reason, histological diagnosis is preferred, especially in situations in which there is clinical doubt about the diagnosis.

CLINICAL FEATURES Cancers cause symptoms due to the local spread of the primary tumour, and as a result of metastasis and of metabolic and remote effects of the malignancy.

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Metastatic disease in bone causes pain which is often intense and distressing. One characteristic feature of malignant bone pain is that it is often worse at night. Bone pain may occur in the absence of a pathological fracture or vertebral collapse, but becomes worse when this occurs. In the liver, metastases cause pain by stretching the capsule. Cerebral metastases give rise to raised intracranial pressure, fits, focal signs and symptoms, and mental confusion. Pulmonary spread may cause breathlessness due to large intrapulmonary tumour masses, diffuse lymphatic permeation (lymphangitis carcinomatosa) and massive pleural effusion.

SYSTEMIC SYMPTOMS Primary and metastatic cancer may cause a variety of metabolic and other disturbances which are important causes of symptoms. In general, these are produced in one of three ways:

FIG. 6.10 Section of nasopharyngeal tumour A Staining with anticytokeratin; the epithelium of normal respiratory gland stains strongly but tumour cells are negative. B Staining with antibody to the leukocyte common antigen reveals that the tumour cells are expressing the leukocyte antigen and that the tumour is a lymphoma.

SYMPTOMS DUE TO LOCAL DISEASE

152

The primary tumour is clinically silent either until it becomes a visible painless lump that the patient notices (this is a common presentation of breast cancer and Hodgkin's disease and other lymphomas), or until it impinges on surrounding tissues. Thus, carcinoma of the lung will cause increasing bronchial narrowing, with breathlessness, cough and collapse of the distal lung; colonic carcinoma may present with disturbed bowel habit and obstruction; brain tumours may cause raised intracranial pressure or focal neurological signs; cancer of the head of the pancreas will cause obstruction of the bile duct, leading to jaundice. As the primary tumour gets larger it may ulcerate and bleed. Haemoptysis is a common symptom of bronchial carcinoma, and chronic blood loss leading to iron deficiency anaemia frequently occurs with carcinoma of the colon. The tumour may infiltrate nerves and bone, leading to pain, or pain may arise from stretching of the capsule of an organ - for example pain over the liver with advanced hepatoma. Nerve entrapment frequently occurs with pelvic tumours, such as carcinoma of the cervix. Similarly, carcinoma of the bronchus occurring in the superior sulcus (Pancoast's tumour) may be accompanied by intense pain in the arm, owing to involvement of the brachial plexus.

• As a result of the tumour mass, both primary and metastatic; • As a result of secretion of hormones by the tumour (Table 6.4); • By ill-understood mechanisms which give rise to specific cutaneous, neurological and other syndromes remote from the tumour and not due to metastasis - paraneoplastic syndromes (Table 6.5). The commonest metabolic disturbance associated with advanced cancer is cachexia. This is a state of profound weight loss, muscle wasting and weakness. Many factors contribute to the state, of which anorexia is perhaps the major cause. Loss of appetite occurs early with tumours of the upper gastrointestinal tract, even before metastases have occurred. For most tumours loss of appetite is an accompaniment of advanced disease, particularly hepatic metastases. Anorexia may be made worse by treatment with radiation and cytotoxic drugs, by psychological factors such as depression, and by unrelieved pain. The tumour may promote weight loss by direct metabolic effects. For example, there may be excess lactate production by the tumour which is recycled into glucose (a process wasteful of energy), and an increased glucose consumption at a time when carbohydrate intake has declined. Some tumours may cause malabsorption (carcinoma of pancreas) or intestinal obstruction (colon cancer), which contributes to weight loss. Unlike patients who are starving, many cancer patients have a normal or high metabolic rate but the reason for this is not clear. Fever may accompany cancer and is not always due to infection, although this must always be excluded. Fever is particularly likely to occur with lymphomas, renal carcinoma, sarcomas, and any tumours that have metastasized to the liver. Both fever and anorexia may be due to cytokine production by the tumour.

6

CASE STUDY 6.1 COUGH AND BACK PAIN A 65-year-old retired warehouseman presented with a 2-month history of troublesome cough productive of clear sputum. One week previously he had had a sudden onset of midthoracic back pain while bending to clean the bath. The pain was worse on moving and on coughing. He smoked 20 cigarettes a day and for 2 years had had intermittent pain in his left calf on walking 500 yards. On examination he looked well but had back pain on undressing. BP 145/90, pulse 76 regular. Foot pulses absent except for the right posterior tibial. Both external jugular veins were distended. The heart was normal and there was no peripheral oedema. Chest expansion was symmetrically diminished, with increased anteroposterior diameter of the chest. There was an expiratory wheeze, more marked on the right. He was tender on pressure over T8, with a suggestion of angulation at this site. The rest of the examination was normal.

Questions 1. What is the probable underlying diagnosis? 2. What might be the cause of the venous distension? 3. What is the probable cause of the back pain? 4. What are the most important diagnostic investigations? 5. What should be the immediate treatment?

Discussion The patient is a cigarette smoker who has a history and signs of peripheral vascular disease in his legs. Any new

symptoms in such a patient should raise the question of whether these might be due to the development of a bronchial carcinoma. The local symptoms caused by a bronchial carcinoma depend on the site of the tumour. At the periphery of the lung it may remain silent until it invades the pleura, causing pain or an effusion, or obstructs a peripheral airway, causing breathlessness or infection. When centrally placed, tumours may obstruct an airway, causing severe breathlessness, wheeze, or an exacerbation of cough. The tumour, or associated lymph node masses, may expand in the superior mediastinum and cause superior vena cava obstruction (SVCO). Bronchial carcinoma typically metastasizes to liver, bone and brain. About 50% of cases present with symptoms or signs of metastasis. Metastasis to bone typically causes pain that may not be alleviated by rest - indeed, it is often troublesome at night. Presentation with pathological fracture may occur. One of the most important sites of bone metastasis is the cervical and thoracic vertebral column, because at this site there is a grave risk of spinal cord compression. In this case the worsening cough might equally be due to an exacerbation of the obstructive airways disease from which smokers suffer. The back pain after minor exertion raises the possibility of a vertebral collapse and therefore of metastasis to the vertebral column. Physical examination further increases the suspicion that there might be an underlying malignancy. The wheeze is more prominent on the right, suggesting a unilateral cause, and there is tenderness over

Anaemia may be due to blood loss, malabsorption, or dietary deficiency of iron or folate. The most common mechanism is a failure of release of iron (stored in macrophages) into the plasma - the anaemia of 'chronic

the spine of the eighth thoracic vertebra. The distended external jugular veins, in the absence of signs of heart failure, may indicate the early onset of SVCO. Investigations are therefore directed to establishing the diagnosis and the cause of the back pain. A chest X-ray may show appearances suggestive of a carcinoma and indicate if this is centrally placed. If a mass is present the involvement of the SVC can be further investigated by CT scan. Sputum cytology may reveal malignant cells. If negative, a bronchoscopy will be necessary provided that the clinical condition permits. A bone scan will show increased uptake in the thoracic spine if there is a vertebral metastasis, and a lateral X-ray may show vertebral collapse. The appearances will be further delineated by a thoracic CT scan. This will also give an indication of incipient pressure on the spinal cord which is the greatest threat to this patient. Routine full blood counts and biochemistry are unlikely to add to the diagnosis but will be helpful in indicating if other complications of malignancy are present, such as liver metastases or hypercalcaemia. The essential initial treatment is relief of early SVCO and treatment of the vertebral metastasis, if present. To some extent the method of treatment will depend on the histological type of lung cancer. Chemotherapy is rapidly effective in relieving SVCO if the tumour is small cell carcinoma. Other types of lung cancer will require radiotherapy treatment. The vertebral metastasis should be treated with radiotherapy, whatever the histology, especially if the CT appearances suggest that the cord may be in danger.

disease' (p. 1226). This anaemia is unresponsive to iron therapy. Chemotherapy and radiation both depress bone marrow function and contribute to anaemia. The hormonal syndromes that accompany cancer (Table

153

TABLE 6.4 Hormonal syndromes in non-endocrine cancers

TABLE 6.5 Paraneoplastic syndromes

Hormonal syndrome

Tumour

Mechanism

Syndrome

Hypercalcaemia

Squamous carcinomas Carcinoma of kidney

Parathyroid hormone related peptide

Neurological Neuropathy (usually sensory)

Hyponatraemia

Small cell lung cancer Lymphoma Pancreatic carcinoma

Ectopic ADH produced by tumour

Small cell lung cancer Bronchial and thymic carcinoids

Ectopic ACTH produced by tumour

Gynaecomastia

Teratoma Hepatoma Large cell bronchial cancer

Excess oestrogen activity

Hyperpigmentation

Small cell lung cancer

Ectopic MSH produced by tumour

Cushing's syndrome

Cerebellar degeneration Eaton-Lambert syndrome Musculoskeletal Clubbing Hypertrophic pulmonary osteoarthropathy Dermatomyositis

Polyarthritis Haematological Multiple venous thrombosis

6.4) are important because they are a cause of symptoms which are frequently treatable. In many patients hypercalcaemia is due to bone destruction by metastases, but some cancers produce hypercalcaemia by a hormonal mechanism. In these cases the calcium level falls if the tumour is removed. The tumour elaborates a peptide (parathormone-related peptide) and other factors (such as growth factors) which can mobilize bone calcium. Hypercalcaemia associated with cancer can be very severe, requiring urgent management (see Ch. 18). Hyponatraemia, caused by the production of antidiuretic hormone (ADH) by the tumour, is a frequent accompaniment of small cell lung cancer. Malaise, fatigue leading to fits, and coma may result. The condition can be reversed by demeclocycline and water restriction (Ch. 21). Adrenocorticotrophic hormone (ACTH)-like peptides may also be produced by small cell lung cancer. In this disease the high levels of ectopic ACTH produce profound metabolic disturbances, with proximal muscle weakness, hyperglycaemia and hypokalaemic alkalosis. These symptoms can be reversed by management of the tumour. The paraneoplastic syndromes (Table 6.5) can cause diagnostic difficulty in two ways. First, the syndromes must be distinguished from other diseases causing a similar clinical picture. For example, the peripheral neuropathy accompanying cancer may be clinically indistinguishable from other causes. Second, the underlying carcinoma may not always be clinically apparent. Tumours such as carcinoma of the ovary or pancreas may be associated with multiple migratory venous thromboses at a time when the primary disease is not detectable. The diversity of symptoms caused by primary and

0 Case 6.1

154

O Fig. 6.8

0 Figs 6.3-6.6

Q Fig. 6.7

Erythrocytosis

Disseminated intravascular coagulation

Associated tumours

Small cell lung cancer Cancers of breast and ovary Small cell lung cancer Small cell lung cancer

Carcinoma of the lung (particularly squamous cell) Lung cancer Oesophageal cancer Other cancers Adenocarcinomas of breast, gut and ovary

Pancreatic cancer Other adenocarcinomas Renal carcinoma Hepatoma Cerebellar haemangioblastoma Uterine cancer Mucinous adenocarcinomas

metastatic cancer, together with the hormonal, metabolic and paraneoplastic syndromes that accompany many malignant tumours, mean that a diagnosis of cancer must be considered in any unexplained illness, particularly in a middle-aged or elderly patient.

METASTASIS FROM AN UNKNOWN PRIMARY SITE From 2 to 5% of patients with cancer present with a metastasis, in lymph nodes, bone, liver, brain or lung, the primary site not being clinically apparent. Usually the histological appearances are of adenocarcinoma or poorly differentiated cancer. This common clinical problem is a considerable test of medical skill, because the patient is understandable extremely anxious and it is probable that only limited treatment will be available if the primary is discovered. The site may suggest the source of the metastasis. Lymph node metastasis in the head and neck will suggest a head and neck or lung cancer. Metastases in the liver commonly arise from the gut. An axillary node containing adenocarcinoma 1 may be due to a primary in the breast. Detailed histological analysis may be necessary to rule out important and curable cancers such as germ cell tumours or poorly differentiated lymphomas. Investigation is directed towards discovering a treatable primary source, for example in breast or prostate, where hormone therapy

may be effective. Multiple invasive investigations seldom produce information that will affect management. In 20% of cases the primary site is never discovered. Empirical treatment with chemotherapy may be given, but the risk of toxicity is considerable and the response rates are poor.

STAGING AND INVESTIGATION Once a diagnosis of cancer has been established, further investigation is usually needed to establish the degree of spread of the primary tumour and to determine whether metastasis has occurred. It has been known for many years that the prognosis of a patient depends, among other things, on the size of the tumour and the presence of metastases. Our ability to locate the tumour and distant metastases accurately has improved immeasurably in recent years with the introduction of radionuclide and ultrasound scanning, CT scanning and magnetic resonance (MR) imaging. These techniques have shown that in many patients the cancer is metastatic at the time of presentation. This realization has led to a greater emphasis on systemic treatments such as hormone therapy and chemotherapy and, in some cases (e.g. breast cancer), a tendency towards less radical surgical procedures for the primary tumour. The determination of the degree of spread at presentation is generally known as staging. The international acceptance of staging systems has meant that, in treatment trials, comparable groups of patients can be treated allowing a comparison between different methods.

TNM CLASSIFICATION

A generally accepted system which is applicable to some (but not all) cancers is the TNM (Tumour, Nodes, Metastases) classification. 0 The T component defines certain characteristics of the primary tumour, such as its size, site or depth of invasion; the defining criteria will be different with each type of cancer. N refers to the presence or absence of involved nodes; the degree of node involvement may be designated as NO (no involved nodes) and Nl, N2, N3 etc. as more nodes are involved. If no metastases are present the designation is MO, and Ml if they are detected. Clearly, the TNM stage assigned to a tumour will depend on the thoroughness of the clinical and radiological investigation, and this will change as new techniques are invented and perfected. The TNM stages can be grouped into categories which have prognostic significance. These categories or 'stage groups' have been of great value in the design of treatment trials. The TNM stages and related stage groupings for carcinoma of the kidney are shown in Table 6.6 and the prognosis related to the stage grouping in Figure 6.11.

TABLE 6.6 Renal carcinoma TNM staging and stage

grouping Stage

Definition

T1 T2 T3 T4

T stage Small tumour surrounded by normal kidney Large tumour with kidney deformity Perinephric infiltration or renal vein extension Invasion of local structures (e.g. abdominal wall)

NO N1 N2 N3

N stage No nodes involved Ipsilateral nodes involved Contralateral nodes involved Fixed nodes

M1

M stage No distant metastases Distant metastases

Stage I Stage II Stage III Stage IV

T1 T2 T3 T4

M0

6

Stage grouping NO NO NO-2 NO-3

MO MO MO M1

The stage grouping refers to the worst prognostic feature of the case: e.g. a T1 N1 tumour would be stage III

The TNM system is not applicable to some tumours and is of limited value in others; it is clearly inappropriate, for example, in acute leukaemias, and prognostic factors in these diseases are based on other criteria (see Ch. 23). Nevertheless, staging classification is possible and useful in diseases such as chronic lymphatic leukaemia and myeloma. The criteria have nothing to do with a TNM system, but are related to tumour mass. In lung cancer the TNM system is useful and widely used in squamous carcinoma, but is of considerably less value in small cell carcinoma. In this disease, a rough categorization is made into limited disease (confined to one hemithorax) and extensive disease (spread beyond one hemithorax, including metastases). There is a clear difference in prognosis in these two categories (Fig. 6.12).

STAGING INVESTIGATION Much information can be obtained from a chest X-ray. © As techniques are developed, the sensitivity (ability to detect an abnormality if it is present) and specificity (ability to distinguish a metastasis from other pathologies) of the investigations changes. At present, radionuclide bone scanning is the most sensitive method of detection of bone metastases (Fig. 6.13A). 4 CT scanners are better than,

155

FIG. 6.12 Prognosis of small cell carcinoma of the lung related to the disease extent at presentation

Limited disease = disease confined to one hemithorax. Extensive disease = more widespread local extent or metastasis.

CT has proved of value in detecting lymph node enlargement in the thorax and the abdomen. Unfortunately, nodes can be replaced by secondary tumour and yet not be enlarged. Lymphography - in which contrast material is injected into lymphatics in the dorsum of the feet can show filling defects in normal size nodes, as well as node enlargement. For tumours that spread transperitoneally, such as carcinoma of the ovary, laparoscopy (peritoneoscopy) is the most sensitive method of detecting spread of tumour if a laparotomy is not carried out. Although invasive, this procedure can also be used to obtain liver biopsy material under direct vision.

TUMOUR MARKERS 4

FIG. 6.11

A Carcinoma of the left kidney. T = degree of local spread; N = involvement of adjacent lymph nodes; M = metastasis to bone or other sites. B Prognosis according to stage grouping.

or at least equal to, ultrasound scanning in the detection of hepatic metastases (Fig. 6.13B), 1 but ultrasound is much cheaper and can be repeated regularly to assess response. CT is the best method of detecting pulmonary metastases and is able to demonstrate metastases of 2-3 mm in size (Fig. 6.13C). MRI is superior to CT in detecting deepseated brain tumours, especially in the brainstem and spinal cord, and is the preferred method for showing brain metastases (Fig. 6.13D). 2 MRI is of great value in demonstrating cord compression (Fig. 6.13E) 0 and the soft tissue extent of tumours such as sarcomas (Fig. 6.13F).

156

1

Fig. 6.9

4

MCQ 6.2

0 0

Fig. 6.10

0 Fig. 6.11

Figs 6.9-6.11

Tumours may secrete substances into the blood which can be used both diagnostically (to detect the presence of disease) and in therapy, to monitor the effects of treatment. A variety of biochemical disturbances may be induced in the body by a tumour, such as the rise in alkaline phosphatase caused by liver or bone metastases, but these are crude and insensitive guides to the effect of treatment. The markers in common clinical use (Table 6.7) are oncofetal antigens, placental products, isoenzymes, ectopic hormones and some cellular antigens, usually derived from the cell membrane. Ideally, the tumour marker should always be produced by the cancer in question. In choriocarcinoma, human chorionic gonadotrophin (hCG) is produced in over 95% of cases; and 75% of germ cell tumours secrete either oc-fetoprotein (AFP), hCG or both. Carcinoembryonic antigen (CEA) (a glycoprotein produced by colonic mucosa) is found in the serum in 65% of cases of colorectal cancer. With some markers, e.g. hCG, AFP and placental alkaline phosphatase (PLAP), the serum level of the marker is a reasonably accurate and sensitive reflection

6

FIG. 6.13 Scanning 0 5] Isotope bone scan showing multiple areas of increased uptake in a patient with bone metastases from lung cancer. B Ultrasound scan of liver showing several metastases (arrowed) in a patient with colorectal cancer. C CT scan of thorax showing a solitary subpleural metastasis in the left lung. D MR scan of the brain showing a left-sided frontal metastasis with some associated oedema. The patient had non-small cell lung cancer. E MR scan of the thoracic vertebrae. A large paravertebral mass is invading the left lateral T9 vertebra. The tumour passes through the intervertebral foramen and is displacing the spinal cord to the right. This was a round cell sarcoma of the chest wall. F MR scan showing a large intraosseous tumour arising in the right tibia. The associated soft tissue mass is clearly shown. This was an osteosarcoma.

of the tumour mass in an individual patient, and can therefore be used as a guide to therapy. Prostate-specific antigen (PSA) is a sensitive marker of early prostate cancer which is now widely used in screening. This has led to considerable controversy over the treatment of early, screen-detected, prostate cancer. The antigen is a serine protease produced at low levels in non-malignant prostate disease. The serum marker may be a valuable guide to tumour recurrence and, in most cases of germ cell tumours (such as teratoma of the testis), is a more sensitive indicator of tumour recurrence than any other technique. There is, of course, little value in knowing when relapse is occurring if there is no effective treatment. However, in the case of early-stage germ cell tumours, the markers have allowed a policy of observation following initial surgery, as highly effective chemotherapy is available for relapse. An example of the use of tumour markers is shown in Figure 6.14.

The tumour marker may be produced in other conditions: for example, serum AFP is raised in early pregnancy, and CEA may be present in inflammatory bowel disease. AFP is produced in the fetal liver, in the malignant yolksac cells in teratoma, and in hepatoma. It has a plasma halflife of 5-7 days. hCG is produced by the placenta and by choriocarcinoma, and by the trophoblastic elements in teratoma. The plasma half-life is 30 hours.

PRINCIPLES OF CANCER MANAGEMENT Surgery and radiotherapy are the principal methods of treating the primary tumour. For many early-stage cancers - e.g. in cancer of the breast, squamous cancer of the lung, and cancers of the ovary, kidney, testis and gastrointestinal tract - surgery alone has a good chance of cure. Unfortu-

157

FIG. 6.14 Tumour markers in management of testicular cancer A Both hCG and AFP markers are elevated before orchidectomy but fall following operation (hCG more rapidly because of its short half-life). B No evidence of recurrence, followed by a rise in marker levels. C Combination chemotherapy for recurrence is followed by a fall in levels to normal. D, E A further rise in marker levels is treated more intensively and the patient is disease-free at 3 years F.

TABLE 6.7 Tumour markers present in blood Marker Oncofetal antigens oc-fetoprotein

Tumour

Carcinoembryonic antigen Pancreatic oncofetal antigen

Germ cell tumours of ovary and testis Hepatoma Gastrointestinal cancer Pancreatic carcinoma

Placental products Human chorionic gonadotrophin Placental lactogen Placental alkaline phosphatase

Choriocarcinoma Teratoma Choriocarcinoma Seminoma

Isoenzymes Alkaline phosphatase Lactic dehydrogenase Neuron specific enolase

Osteosarcoma Neuroblastoma, many cancers Small cell carcinoma of lung

Ectopic hormones (see Table 6.4) Other cellular antigens (defined by antisera) Ca 125 (aglycoprotein) Ca 19-9 (a carbohydrate) Prostate-specific antigen (pSA)

158

Ovarian cancer (also breast, pancreas and gut) Pancreatic cancer (also gut) Prostate cancer

nately, many patients cannot be cured surgically, either because the tumour is so advanced locally as to make resection impossible, or because investigation has revealed metastases. Advances in radiotherapy technique and the recent developments in combination cytotoxic chemotherapy have meant that, for many patients, a combined approach

to management is needed to achieve the best results. This involves close collaboration between surgeon, radiotherapist and medical oncologist. Before treatment begins, it is essential to decide whether there is a possibility of cure or whether the intention should be palliative. Many factors will influence this decision, including the degree of spread of the tumour locally, the presence of distant metastases, and the patient's age and state of health. It may be very difficult to decide on the best policy if the chances of cure are relatively small and the toxicity of treatment considerable. In a young patient the aim of cure would probably overcome doubts about toxicity, but this might not be the case in the elderly. If the clinical evidence makes it quite clear that there is no hope of cure, then investigations should only be performed if they will alter management. Investigation, as previously outlined, will be necessary in all other patients to determine the degree of spread of the disease before deciding on the treatment plan. The principles of surgical management of cancer are beyond the scope of this chapter, but it is important for all physicians to have an understanding of the basis of management using radiotherapy, chemotherapy and hormone therapy.

RADIOTHERAPY Most radiotherapy treatment involves the use of electromagnetic waves with very high energy and short wavelength - gamma rays and X-rays. Some modern radiotherapy machines use 60Co as a source, which decays to a more stable form with a half-life of 5.3 years. The process of decay (with loss of a neutron) is accompanied by emission of gamma rays with a high energy (1.2MeV). X-rays were first produced by Roentgen, who heated an electrode in a sealed vacuum tube. The electrode produced electrons which bombarded a target, resulting in the emission of

TABLE 6.8 Relative radiosensitivity of tumours

Depth/cm FIG. 6.15 Tissue penetration of different types and energies of radiation

electromagnetic waves which were designated 'X-rays' and whose nature was the same as that of gamma rays. By increasing the voltage, X-rays of shorter wavelength and higher energy are produced which have greater tissuepenetrating power than those produced from low-voltage machines (Fig. 6.15). Modern machines accelerate the electrons almost to the speed of light, resulting in a high-energy beam. These machines (linear accelerators) have become standard equipment in most departments. They provide a sharper beam than that obtained from 60Co sources and greater depth doses. When the target is moved out of the path of the electrons, the high-energy electron beam can be used for the treatment of superficial tumours. The tissue-penetrating power of high-energy X-rays and gamma rays means that normal tissues will be irradiated as well as the tumour. With lower voltage X-rays, the penetrating power is less and more energy is deposited in superficial tissues, especially bone. With electrons, the radiation decays rapidly in tissue, the depth of penetration depending on the energy of the beam (Fig. 6.15). The important site of radiation damage is nuclear DNA. The damage appears to be induced indirectly. The radiation first produces highly reactive radicals, which in turn damage the DNA, impairing the reproductive integrity of the cell. The damaging effects of radiation are less marked in cells which are hypoxic. Some areas of tumour may not be well vascularized and these cells are relatively radioresistant. The mechanisms of resistance are not well understood. The amount of cell death following exposure to irradiation is also proportional to the dose administered. At low doses the damage is sublethal. Nevertheless, radiation administered as a few large fractions may not be as effective as multiple-fraction regimens using smaller daily doses. The latter technique may be more effective because it allows the tumour to shrink and become less hypoxic, may be easier to tolerate, and allows normal tissues to recover at a faster rate than the tumour. In treating tumours, multiple fractions are usually employed and the total dose administered depends on what is known of the radiosensitivity of the neoplasm (Table 6.8). The total dose

Highly radiosensitive Lymphomas Ewing's sarcoma Seminoma Wilms' tumour Myeloma

Relatively resistant Squamous cell lung cancer Hypernephroma Bladder carcinoma Rectal carcinoma Soft tissue sarcoma (adults) Cervical carcinoma

Moderately radiosensitive Breast cancer Small cell lung cancer Ovarian cancer Medulloblastoma Basal cell carcinoma Teratoma

Very resistant Melanoma Osteosarcoma Pancreatic carcinoma

received by the tumour is measured in grays (1 Gy = 1 J/kg) orrad (100 rad = 1Gy). The planning of the radiation field is often a highly complex procedure that has been greatly facilitated in recent years by the use of CT scanning and simulators, which allow the fields to be constructed with precision. In planning the fields, the radiotherapist must therefore consider the localization of the tumour, its probable inherent radiosensitivity, the tolerance of the normal tissues in the path of the beam, and the need to include draining lymph nodes in the treatment. Multiple fields may be necessary to achieve the desired dose in the tumour without damaging normal tissues. The fields may be open (or direct}. Here, the radiation beam is applied directly, usually at rightangles to the skin. Alternatively, if several fields are used, the field may be wedged. These wedges, inserted into the beam, alter the dose distribution so that the tumour dose is homogeneous and problems of irradiation of normal tissue where fields overlap are minimized. An example of a multiple field is shown in Figure 6.16. The treatment area is immobilized and, for some tumours, such as head and neck cancers, moulds and shells are used to ensure accurate and reproducible positioning. The radiation source is mounted in a gantry which moves isocentrically about the patient. Radiotherapy may also be given by placing a sealed source containing a radioactive isotope inside a body cavity or in tissues. This is known as brachytherapy. Examples of such isotopes are 137Cs, which is widely used as an intracavity source of radiation in treating carcinoma of the cervix, and iridium wires, which may be placed in breast tissue to provide interstitial irradiation when radical radiotherapy is used following conservative surgery for breast cancer. Unsealed sources of radioactivity may be taken by mouth, e.g. 131I in the treatment of thyroid cancer, or given intravenously, e.g. 32P in the treatment of polycythaemia rubra vera.

6

159

TABU 6.9 Complications of radiotherapy Complication

FIG. 6.16 Radiation planning for carcinoma of bladder The relationship of the three beams to the tumour and the dose levels (% of maximum) achieved within the tumour and surrounding normal tissue are shown.

The complications of radiotherapy depend on the radiation sensitivity of normal tissues in the path of the beam, and may be immediate or delayed. A summary of some of these is given in Table 6.9.

SYSTEMIC TREATMENTS In the last 40 years there has been a dramatic increase in interest in the use of drugs to kill cancer cells. So many cancers are either disseminated at diagnosis or too advanced locally to resect, that a systemic approach to treatment offers the only chance of remission or cure. The two treatments in general use are cytotoxic chemotherapy and hormone therapy.

Cytotoxic chemotherapy The earliest compounds to be introduced were nitrogen mustards, which were shown to be cytotoxic to lymphoid tissue and then to have activity against lymphomas in humans. In 1948, Farber demonstrated remissions of leukaemia using the antifolate aminopterin, and this led to the development of a wide variety of antipurines and antipyrimidines. Antitumour antibiotics were first developed in 1940 (actinomycin A), with a significant step forward in 1963 with the isolation of anthracyclines. The platinum drugs were introduced in the 1970s and proved to have great activity in germ cell tumours. The epipodophyllotoxins were also introduced at that time. Recently the taxoids have been introduced. There are now about 35 cytotoxic drugs of proven value in routine use, and the

1

160

MCQ 6.3

Tissue

Immediate

Delayed

Skin

Erythema, desquamation

Oral cavity Gut Bone Kidney

Mucosal ulceration Nausea, diarrhoea Bone necrosis Acute nephritis

CNS

Radiation myelitis and encephalitis

Eye

Conjunctivitis

Gonads Bone marrow

Sterility Leukopenia

Fibrosis Telangiectasia Squamous carcinoma Loss of saliva Fibrosis and stricture Loss of bone growth in children Chronic nephritis Hypertension Demyelination Possible alteration of personality and intellect Dry eye Cataract formation Sterility Suppression of haemopoiesis in area irradiated

RECENT ADVANCES IN NEW METHODS OF ADMINISTERING RADIOTHERAPY The advent of CT scanning has meant that precise three-dimensional images of the tumour can now be obtained. The radiation can now be channeled with considerable accuracy using new methods of directing the beam ('beam's eye view'). A further development has come from the knowledge that repopulation of tumours with new cells occurs rapidly. This has led to the development of hyperfractionated schedules of radiation, in which two or more treatments are given each day. This, and conventional fractionation, may now be given at the same time as cytotoxic chemotherapy in an attempt to improve local control and to prevent interruption of systemic treatment. These complex procedures are likely to play an increasing part in modern cancer management.

increasing complexity of medical treatment of cancer has led to the development of medical oncology as an important specialty in cancer management. Mechanisms of action Cytotoxic drugs produce their effect mainly by damaging the capacity of the cell to divide, and also by interfering with synthesis of essential proteins. For many of these agents the most important toxicity concerns DNA, with impairment of DNA synthesis, reaction with the DNA helix or damage to DNA repair mechanisms. During cell division there is a phase (G1) which precedes the phase of DNA synthesis (S). Following the S phase

SUMMARY 1 Common chemotherapeutic agents Alkylating agents Nitrogen mustard Melphalan Cyclophosphamide Ifostamide Busulphan Chlorambucil Nitrosoureas Cisplatin

Plant alkaloids Vinca alkaloids Epipodophyllotoxins Taxoids Antibiotics Anthracyclines Doxorubicin Daunorubicin Bleomycin

Anti-metabolites Methotrexate 5-fluorouracil 6-mercaptopurine 6-thioguanine Cytosine arabinoside

there is a postsynthetic phase (G2), which is followed by mitosis (M). The daughter cells then either enter into the cycle of division or remain in a non-reproductive stage (Go). Because of their action on DNA, most cytotoxic drugs exert their maximum effect on replicating rather than resting cells. If, after damage to DNA (e.g. by alkylation), the cell does not divide, there will be time for DNA repair mechanisms to excise the attached alkyl groups and to repair strand breaks. Rapidly proliferating cells are thus more susceptible to cytotoxic damage, but this is not the only determinant of susceptibility since, as with radiation, different tissues and tumours show inherent differences in susceptibility, the biochemical basis of which is poorly understood. Alkylating agents are very reactive compounds which exert their effect by linkage of the alkyl group to DNA bases, particularly guanine. If the drug is bifunctional (having two alkyl groups), inter- and intrastrand crosslinks will form. Nitrogen mustard, phenylalanine nitrogen mustard (melphalan), cyclophosphamide, busulphan and chlorambucil are commonly used alkylating agents. Cyclophosphamide itself is inactive but is metabolized by the liver to 4-hydroxycyclophosphamide, which is transported to the tissue and there releases the active alkylating compounds. Nitrosoureas and cisplatin probably act mainly as alkylating agents. Methotrexate inhibits dihydrofolate reductase, thus preventing the formation of tetrahydrofolate, which is necessary for thymidine synthesis. Other antimetabolites include 5-fluorouracil (5FU), which also blocks thymidine formation; 6-mercaptopurine (6MP), which interferes with purine nucleotide biosynthesis; and 6-thioguanine, which has a similar mechanism of action to 6MP. Several plant alkaloids have anticancer activity. The vinca alkaloids interfere with the formation of the mitotic spindle by blocking the assembly of tubulin. The taxoids interfere with disassembly of the microtubules that constitute the mitotic spindle. The epipodophyllotoxins damage

DNA through topoisomerase II. This enzyme normally allows the unwinding of DNA during DNA replication. Anthracycline antibiotics intercalate between DNA bases, as does actinomycin, which has the additional action of interfering with RNA synthesis. Bleomycin causes DNA strand breaks.

6

Testing a new drug When a new drug has shown activity in the laboratory, it is tested in patients with cancer. At first, it is given in gradually increasing doses to patients with advanced drugresistant cancer. These trials are called phase I studies: the aim is to monitor toxicity and to study metabolism and distribution of the drug, as well as to note any activity. In phase II studies, patients with a wide range of tumours are then treated in order to determine the spectrum of activity of the drug. Later, phase HI studies are performed in which the drug is tested, usually in previously untreated patients, either alone or in combination with other drugs, and often as part of a randomized comparison. Combination chemotherapy In recent years it has become standard practice to use cytotoxic drugs in combination. The aim is to produce a variety of different biochemical lesions in the tumour, if possible without increasing toxicity. It quickly became apparent that quadruple therapy in, for example, advanced Hodgkin's disease, produced a far higher complete response rate (disappearance of all symptoms and signs of the tumour) than did single-agent therapy. Furthermore, many of these complete responses were sustained, about 40% of patients being disease free between 5 and 10 years later. This had not been observed with single-agent therapy. Similar results were reported with non-Hodgkin's lymphoma and, later, with testicular teratoma, Ewing's sarcoma and other childhood tumours. In the common tumours of adults (such as cancer of the breast and small cell lung cancer), an increased response rate is also obtained with drugs in combination, but most of these responses are partial (>50% reduction in size) and not sustained for long. Most of the regimens used today have been derived empirically by oncologists with knowledge and experience. There are, however, some general principles governing selection of the drugs (Table 6.10). Using these general principles, combination chemotherapy has been introduced into the treatment of many cancers and forms the mainstay of management in an important minority of uncommon tumours. Unfortunately, most of the common adult cancers are only moderately sensitive to these drugs, and some are very resistant (Table 6.11). Cancer is a disease of the elderly and many patients are not fit enough to risk the toxicity of chemotherapy, especially if the intention is to palliate rather than cure. Complications of chemotherapy 1 There are both immediate and long-term complications of chemotherapy. Many patients greatly fear chemotherapy

161

TABLE 6.10 General principles governing the selection of drugs used in combination therapy • The drugs are known to be effective when used as single agents. • Where possible, drugs with differing modes of action are combined. • The major toxicity of each drug should be as different as possible from that of other agents. • Pulsed intermittent treatment is used to allow recovery of the gut and bone marrow. • If possible each drug should be used in its optimum dose and schedule, although in practice some reduction in dose is nearly always necessary. • There should be no known synergistic toxicity.

as they have often been told lurid stories about toxicity. However, with many regimens toxicity is very mild. The drugs are not equally toxic and it is incorrect for inexperienced physicians to give patients the impression that they are. Immediate The most troublesome immediate side-effects of some chemotherapy regimens are nausea and vomiting, mucosal ulceration, bone marrow depression and alopecia. Nausea and vomiting are probably initiated by a centre in the medulla. Intravenous alkylating agents tend to produce nausea at 12-18 hours, and cisplatin and doxorubicin typically produce nausea about 6 hours after administration. Many other drugs produce very little nausea. Nausea is often accompanied by vomiting, and the symptoms usually last 12-24 hours. These symptoms can be very troublesome but are tolerated by the majority of patients. Skilled, meticulous and flexible use of antiemetics is essential. 5HT3 antagonists have been a big advance in controlling nausea and vomiting, and are now the mainstay of antiemetic treatment. The most widely used agents are ondansetron and granisetron. These are the antiemetics of first choice for chemotherapy which regularly produces troublesome vomiting,

SUMMARY 2 Complications of chemotherapy Long-term Impairment of fertility Secondary cancers Pulmonary fibrosis Cardiomyopathy Nerve damage Loss of hearing Renal impairment

Immediate Nausea and vomiting Mucosal ulceration Bone marrow depression Immune suppression (opportunistic infection) Alopecia

1

162

Case 6.2

2

Figs 6.12-6.15

3

MCQ 6.4

TABLE 6.11 Relative chemosensitivity of tumours Highly sensitive tumours (which may be cured by chemotherapy) Teratoma of testis Hodgkin's disease High grade non-Hodgkin's lymphoma Wilms' tumour Embryonal rhabdomyosarcoma Choriocarcinoma Acute lymphoblastic leukaemia in children Ewing's sarcoma Moderately sensitive tumours (in which chemotherapy may sometimes contribute to cure and often palliates) Small cell carcinoma of lung Breast carcinoma Low grade non-Hodgkin's lymphoma Acute myeloid leukaemia Ovarian cancer Myeloma Relatively insensitive tumours (in which chemotherapy may sometimes produce palliation) Gastric carcinoma Bladder carcinoma Squamous carcinoma of head and neck Soft tissue sarcoma Cervical carcinoma Resistant tumours Melanoma Squamous carcinoma of lung Large bowel cancer

such as cisplatin (Table 6.12). Piperazine phenothiazines (e.g. prochlorperazine) are of some help when given in full dose, but aliphatic phenothiazines (e.g. chlorpromazine) have less antiemetic effect. Metoclopramide is of some value, and its effect may be increased by giving it in high dosage. Benzodiazepines enable the patient to sleep during the period of maximum nausea. Mucosal ulceration in the mouth and gut is a complication of chemotherapy which is particularly likely to occur following methotrexate and anthracyclines. It is dose related, but some individuals are especially susceptible and the dose may then need to be lower than usual. Alopecia is very common with many drugs especially doxorubicin and cyclophosphamide, and is caused by damage to the proliferating cells of the hair follicle. Although the hair regrows when treatment is finally stopped, many patients find this a distressing side-effect. With anthracycline the hair loss can be minimized by scalp cooling during drug administration. The patient must be warned of the likelihood of hair loss, and a wig ordered if desired. Bone marrow depression results in acute leukopenia

TABLE 6.12 Commonly used antiemetic agents Drug

Usual dose

Side-effects

5HT3 antagonists Ondansetron Granisetron

0.15mg/kg 3mg i.v.

Constipation, headache Constipation, headache

12.5mg i.m. or as suppository

Drowsiness Dyskinesia

Benzodiazepine Lorazepam

1-2 mg p.o, or i.v.

Sedation, dizziness, hypotension

Steroids Dexamethasone

6-8 mg i.v.

Restlessness

Phenothiazines Prochlorperazine

10mg p.o. or i.v., Metoclopramide or 1-2mg/kg i.v. (5HT3 and dopamine antagonist)

Dyskinesias, diarrhoea

and thrombocytopenia and the slower onset of anaemia (because of the greater lifespan of red cells). The nadir of the leukocyte count often comes at 7-9 days after intravenous chemotherapy, and it is at this time that the patient is most susceptible to serious infection. 1 Increasingly, oncologists are adjusting the dosage in each cycle of very myelosuppressive regimens according to nadir counts, even though this involves an extra blood count between visits. Patients must be forewarned of their susceptibility to infection and bleeding, so that they can report symptoms promptly. The commonest infections are of the respiratory and gastrointestinal tracts. Immune suppression is cumulative. Patients become increasingly susceptible to opportunistic infection. These are typically pulmonary (aspergillosis, Pneumocystis), oral and oesophageal Candida, and herpes zoster 2 and simplex, which can be severe, confluent and disseminated. Long-term The long-term sequelae of cancer chemotherapy are now becoming better defined as more children and adults are surviving previously incurable cancers. One in 1000 adults now has been cured of cancer in childhood or adolescence. Although complications may be an inevitable risk of regimens that are potentially curative, they are a reminder of the risks attached to increasing the intensity of treatment. Cytotoxic drugs impair fertility in adults. In men, complete and irreversible loss of fertility occurs with many regimens, particularly those that include an alkylating agent or procarbazine. Prepubertal boys do not become infertile, but Leydig cell function may be impaired and testosterone levels may fall. It is important to inform adolescent boys and men of this risk and to arrange sperm storage before chemotherapy begins. Curiously, in Hodgkin's disease, where there is greatest experience of

this problem, patients are often subfertile even before chemotherapy begins. For women, the problem is more complex. Amenorrhoea is common during chemotherapy, especially if an alkylating agent is used. Menstruation will usually return when treatment is finished, although subfertility is common. Chemotherapy may, however, induce the onset of menopause; this is more likely to occur in older women who are nearer the natural menopause. Even in younger women the period of reproductive life may be reduced. It is essential to discuss this potential problem. In both sexes, patients who are receiving chemotherapy should be advised of possible short-term teratogenic effects and to use a contraceptive during treatment. Second cancers are increasingly recognized as a longterm consequence of chemotherapy, particularly in ovarian cancer or Hodgkin's disease. In both cases the risk is especially of acute myelomonocytic leukaemia. Second cancers are also more common in patients receiving immunosuppressive therapy with cytotoxic drugs, and in these patients there is an increased incidence of brain lymphoma, cervical carcinoma and skin cancer. Pulmonary fibrosis is a complication of treatment with busulfan (e.g. for chronic myeloid leukaemia), and acute pneumonitis leading to fibrosis is a dose-related complication of bleomycin. Other cytotoxic agents rarely produce lung damage, although pulmonary fibrosis is a long-term complication of cyclophosphamide and nitrosourea treatment. Anthracyclines such as doxorubicin cause a cardiomyopathy, the risk being dose related. Above a total dose of 400mg/m2 of doxorubicin about 50% of patients will have measurable impairment of cardiac function, but only 5% will develop cardiac symptoms. Established cardiomyopathy leads to cardiac failure, which is irreversible on stopping the drug. Vinca alkaloids cause damage to peripheral and autonomic nerves. The earliest symptoms are of tingling paraesthesiae. There is loss of tendon reflexes and, later, sensory loss and motor weakness. Autonomic neuropathy produces ileus and postural hypotension. Vincristine and vindesine are particularly likely to produce neuropathy, and vinblastine less so. The neuropathy is usually reversible, is totaldose related and is more common and severe in the elderly. Cisplatin may cause irreversible loss of hearing, particularly of high frequencies, and peripheral neuropathy. Renal impairment is also common and irreversible. These toxic effects are a reminder that the treatment of cancer with cytotoxic drugs is a matter requiring skill and judgement if the benefits are not to be outweighed by the disadvantages. Nevertheless, the improvement in prognosis in some cancers as a result of cytotoxic drug treatment fully justifies the acute and long-term risks involved.

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Hormone therapy3 The growth of many normal tissues is under hormonal regulation, and the cancers that arise in them often retain

163

sensitivity to changes in the hormone environment. Hormone therapy is an essential part of management of cancers of the prostate, breast and endometrium. In these cases, the steroid hormone binds to a hormone-binding molecule (receptor) in the cytoplasm and the receptor/ hormone complex is transported to the nucleus, where it modifies the activity of DNA. There is an increase in RNA polymerase activity, resulting in increasing production of cytoplasmic proteins followed by cell division (Fig. 6.17). In some cases the hormone provokes the increased synthesis of receptors for other hormones; oestrogen, for example, increases the synthesis of progesterone receptor in breast epithelium. Response to hormone therapy is strongly associated with the presence of cytoplasmic hormone receptors. In advanced breast cancer, the presence of oestrogen receptors is associated with a 60% response to hormone therapy but only a 5% response if the cancer contains very low levels of receptor. Response is also strongly associated with the presence of progesterone receptors. The following general approaches are taken in hormonesensitive tumours. Blocking the action of circulating hormones In breast cancer, the use of tamoxifen has been a major advance. It appears to exert most of its effect by binding to the oestrogen receptor, thereby preventing the activity of circulating oestradiol. Paradoxically, the drug is effective in postmenopausal women whose tumours are receptor positive, but in whom circulating levels of oestrogen are likely to be low. A direct growth-regulatory effect of the drug may be responsible. Reduction in concentration of circulating hormones Until recently, this was the mainstay of hormone therapy and was usually accomplished surgically. In breast cancer, oophorectomy was performed, or in premenopausal

164

women a radiation menopause induced. In those who showed an initial response but then relapsed, further responses could be obtained by adrenalectomy, which prevented sex hormone synthesis in the adrenal, and by hypophysectomy which produced a similar effect. The advent of aromatase inhibitors has led to a decline in frequency of these operations. Androstanedione is converted in peripheral tissues (and in the breast itself) to oestradiol by enzymes known as aromatases, and several powerful aromatase inhibitors can now be used to prevent oestradiol formation. In prostate cancer, luteinizing hormone-releasing hormone (LHRH) agonists cause a spurt of LH release followed by a profound fall, which reduces plasma testosterone levels to those seen after castration. Prostate cancer is usually very sensitive to a fall in testosterone levels. LHRH agonists are therefore a widely used medical alternative to orchidectomy.

Addition of hormones The hormonal environment can be altered by the administration of hormones which are judged to provide an unfavourable environment for the tumour. Stilboestrol has for many years been used to produce regression in carcinoma of the prostate, and androgens, glucocorticoids and progestogens may all slow the growth of the tumour in breast cancer. Progesterone derivatives will also produce regression in about 20% of carcinomas of the endometrium. In advanced breast cancer, endocrine therapy has the great advantage of low toxicity and low cost compared to chemotherapy. Tumour responses are often more complete and more durable than those achieved with cytotoxic drugs. On the other hand, the proportion of responding patients is lower (30% with endocrine therapy, 60% with chemotherapy). For these reasons, many physicians prefer to start treatment with hormone manipulation, moving to chemotherapy when the disease becomes unresponsive and progresses.

FIG. 6.17 The mechanism of oestrogen action on cell growth Tamoxifen acts by binding to the oestrogen receptor and blocking its action.

Adjuvant chemotherapy and hormone therapy There are many situations in which a cancer has been removed surgically or treated with radiotherapy, but the risk of local or systemic recurrence is high. Examples include breast cancer, where there is involvement of axillary nodes; gastric and other cancers, where the regional nodes are involved; or Ewing's sarcoma of bone, where the tumour is highly sensitive to radiotherapy but the risk of metastasis is very great. In these situations, advances have been made by the use of cytotoxic drugs or hormones in an attempt to delay or prevent recurrence. Even if these treatments are not very effective against advanced cancer (of the stomach or breast), they may be more so when the residual tumour mass is small, when the penetration of the drugs may be better and the degree of cell kill may lead to cure rather than temporary tumour regression. Many large-scale trials have been undertaken to assess the value of adjuvant cytotoxic or endocrine therapy. For the results to be accepted with confidence, there must be both sufficient numbers of patients in the study, and prospective randomization of the allocation of the treatment policy. (The difficulties involved in these trials are discussed below.) In patients with stage II breast cancer, both adjuvant endocrine therapy (using tamoxifen) and cytotoxic therapy (using drug combinations such as cyclophosphamide, methotrexate and 5-fluorouracil) have been shown to give a survival advantage of about 7% at 5 years and 10% at 10 years (Fig. 6.18). A follow-up overview of all randomized trials now shows that patients with stage I disease also benefit from chemotherapy if they are premenopausal, and from hormone therapy after the menopause. Adjuvant drug therapy after surgery or irradiation has become an essential part of management in most childhood tumours (rhabdomyosarcoma, Wilms' tumour, osteosarcoma, Ewing's sarcoma), and in a number of adult tumours, such as breast cancer, ovarian cancer, and in Duke's C colon cancer. There are many other tumours (gliomas, gastric carcinoma, operable lung cancer) in which adjuvant chemotherapy has not yet been adequately evaluated. As the survival benefit is likely to be small, it will only be demonstrated in very large-scale trials, which are still to be undertaken or in patients data-based metaanalyses. Even a 5 % improvement in survival in colorectal cancer is worthwhile, as the disease affects 1 million people a year in eastern and western Europe.

SUPPORTIVE CARE IN CANCER MANAGEMENT Patients with cancer need supportive care for both the psychological impact of the disease and the physical effects of the tumour and its management. Even if there is no

6

FIG. 6.16 Radiation planning for carcinoma of bladder The relationship of the three beams to the tumour and the dose levels (% of

prospect of cure, the patients' quality of life can be greatly improved by the attitude of the medical staff and by meticulous attention to the management of pain, anaemia, infection, nausea and anorexia.

Psychological support The last 20 years have seen an increasing readiness on the part of doctors to discuss the diagnosis of cancer with their patients and to explain the principles of management. Indeed, the complexities of modern cancer management make it difficult to withhold the facts of the diagnosis, even if it were desirable to do so. Nevertheless, the manner in which the diagnosis is explained and the words used are of great importance, and must be carefully judged in each case. Cancer is the only word that conveys the nature of the complaint accurately; other words used are often misinterpreted by patients as implying a less, or even more, serious condition. The problem is that in the mind of many patients cancer is invariably fatal. Explanation of the diagnosis must therefore be accompanied by an unhurried and easily comprehended account of management and the possibilities of cure. It is nearly always wrong to offer no hope of either cure or a period of normal life. Usually, the physician will need to talk to the patient on several occasions, as their understanding of the problems may be incomplete at the beginning. Time taken in unhurried, private conversation is always well spent and greatly appreciated. One of the advantages of having specialized oncology units in hospitals is that all members of the medical team - nurses, doctors, social workers and counsellors - become familiar with the problems that are associated with malignant disease and skilful in dealing with them. It is important that all members of this team know what has been said to the patient in the way of explanation, in order to avoid conflicting advice. A relapse of the disease or the appearance of a new symptom will often cause a slump in morale and confidence which will require more explanation and reassurance. The emotional demands of this aspect of cancer

165

medicine are considerable, and are one reason why some doctors have been reluctant to spend time in discussion with their patients. Nevertheless, the patient will need the help and support of the doctor at these difficult times. It is an essential aspect of cancer medicine and one of the most rewarding.

PAIN RELIEF This is a very important aspect of management, particularly in patients with widespread disease who are terminally ill. No single analgesic will suit all patients all of the time. A patient will need to change from one to another, depending on the severity of pain. A brief classification of some of the most useful analgesics is given in Table 6.13. When using opiates, the dosage should be adjusted to the patient's requirements. A wide range of dosages is encountered. Long-acting morphine and heroin are especially useful and should be given regularly, rather than 'as required'. The constipating effects of opiates can be partly relieved by regular laxatives. If pain is at a particular site, it may be possible to give relief by local measures, such as radiotherapy to a bone metastasis, a nerve block or a coeliac plexus block. The advice of colleagues specializing in these forms of pain relief is often helpful, and the procedures may allow a reduction in dosage of opiate.

Nutritional support

166

Patients lose weight because of the local effects of the tumour (especially if this is in the alimentary tract), metastases, and as a result of treatment. Successful treatment of the primary tumour (e.g. by surgery) will be accompanied by a return of appetite and weight gain. During radical treatment with surgery, radiotherapy and intensive chemotherapy, weight loss is common. Calorie supplements can be given both in the form of oral supplements and intravenously to patients undergoing cancer treatment. However, the value of nutritional support is difficult to demonstrate. It is usual practice to consider total parenteral (intravenous) nutrition in patients undergoing exceptionally intensive treatment, such as high-dose chemotherapy or total-body irradiation with bone marrow transplantation, or during the intensive phases of chemotherapy for acute leukaemia, where there is prolonged hypoplasia. At these times, mucosal ulceration, nausea and diarrhoea make it difficult to feed the patient by mouth, and nasogastric tubes may produce monilial infection or exacerbate acid reflux and oesophagitis. Parenteral nutrition is also used for patients undergoing extensive surgery, particularly gut resection. The aim is to maintain the patient's weight and nutritional status so that recovery is more rapid, allowing further treatment with chemotherapy or irradiation to begin as soon as possible. There is no evidence that additional enteral or parenteral feeding is of value in the management of advanced

TABLE 6.13 Useful analgesics Drugs Mild analgesics Aspirin Paracetamol Indole derivatives (e.g. indomethacin) Propionic acid derivatives (e.g. ibuprofen)

Duration of action (hours)

4-6 2-4 6-8 4-6

Moderate analgesics Codeine (and dihydrocodeine) Pentazocine Dipipanone Oxycodone

4-6 3-4 6 8

Strong analgesics Morphine sulphate Diamorphine Dextromoramide Pethidine Methadone

4-6 (up to 12 with sustained-release forms) 4-6 4-6 3 12-30

cancer where cure is impossible. It is, however, important to encourage the patient to eat by giving food that appeals (often in the form of smaller, more frequent meals), by controlling nausea with drugs such as metoclopramide, and by the careful use of corticosteroids which improve wellbeing and stimulate the patient's appetite.

Tumour lysis syndrome In some very sensitive untreated cancers, chemotherapy may produce massive tumour breakdown when treatment is first given. This process may be accompanied by severe metabolic disturbances, which constitute the tumour lysis syndrome. The syndrome is usually associated with the early phases of treatment of lymphoma and leukaemia in children and, less frequently, in other chemosensitive childhood tumours. In adults the syndrome is infrequent but may occur with treatment of lymphoma, especially if there is impairment of renal function (such as ureteric obstruction by lymph nodes), which diminishes renal excretion of the tumour products. Tissue destruction releases large amounts of urate, phosphate and potassium. The urate may be deposited in the renal tubule, causing reversible renal failure, which in turn diminishes further urate excretion. Severe hyperuricaemia and renal failure may necessitate dialysis. This complication can be largely avoided by using the xanthine oxidase inhibitor allopurinol (100-200 mg 8-hourly) before and during the early phase of treatment, and by establishing and maintaining a diuresis during the first 24-48 hours.

Hyperkalaemia may be severe, particularly if renal failure occurs, and may need treatment with glucose and insulin (see Ch. 21). Hyperphosphataemia can be partly prevented by hydration and diuresis before and during the initial treatment.

NEW APPROACHES TO MANAGEMENT Progress in cancer treatment is slow, and results usually improve after many small refinements in therapy, rather than by sudden steps forward. Since the late 1970s only modest progress has been made, and the search for new drugs and new approaches continues.

Haemopoietic growth factors (see also Ch. 23) The production of haemopoietic growth factors by recombinant technology has allowed their use in chemotherapy to reduce the period in which the white count is low. Proven advantages are a modest reduction in the period of neutropenia and somewhat diminished antibiotic use. It is possible that the intensity of chemotherapy may be increased by avoiding dose reductions. It has yet to be proved that the routine use of growth factors increases the cure rate of cancer by allowing increasing dose of chemotherapy. They are used if the dose of a curative treatment would otherwise have to be reduced but can be maintained if growth factors are given. Granulocyte colony-stimulating factor (GCSF) is most widely used. It is given for 7-10 days subcutaneously following chemotherapy. It may cause fever and bone pain. It is expensive and should only be given if there is a clear indication, and not if treatment is palliative.

High-dose therapy Allogeneic (from one individual to another) bone marrow transplantation was introduced for the treatment of acute myeloblastic leukaemia in the early 1970s. Allogeneic marrow was infused after an attempt had been made to eradicate the leukaemia by total-body irradiation and high-dose cyclophosphamide. The results (Ch. 23) showed that the leukaemia might be eradicated. This finding led to the consideration of total-body irradiation in the management of other disorders, such as lymphomas and myeloma. More recently, attempts have been made to eradicate leukaemia, lymphoma and some solid tumours with very high-dose chemotherapy (rather than total-body irradiation) using autologous (taken from, and reinfused into, the same individual) bone marrow, harvested just before treatment, as a means of preventing life-threatening myelosuppression. These approaches are based on the assumption that increasing doses of chemotherapy will eradicate residual disease when multiple conventional doses will fail.

This approach has been revolutionized in the last few years by the finding that the haemopoietic progenitor cells appear in large numbers in the peripheral blood following chemotherapy and the use of haemopoietic growth factors. These cells can be 'harvested' by a leukopheresis machine and used, instead of bone marrow, to reconstitute the blood count following high-dose treatment. This is called a peripheral blood stem cell (PBSC) transplant. High-dose therapy and PBSC transplant has now become a safe and much cheaper treatment allowing further exploration of the value of high-dose therapy.

6

Monoclonal antibodies to cell surface antigens Many tumours express oncofetal or differentiation antigens not usually found in the normal tissue from which the cancer is derived. An example are the antigens found on the surface of both acute lymphoblastic leukaemia cells, lymphomas and normal lymphatic progenitor cells. The development of monoclonal antibodies of defined specificity has resulted in the production of monoclonal reagents, which bind preferentially to antigens on the surface of some tumour cells (and to those normal cells that express the antigen). Cytotoxic drugs, radioactive isotopes, and enzymes capable of converting an inactive cytotoxic agent to an active one, can be attached to such antibodies with the aim of selectively destroying the tumour. There are considerable difficulties with this approach: heterogeneity of antigen expression within the tumour; variable uptake and distribution of antibody in normal and malignant tissue; and the production of antibodies by the patient against the foreign (usually mouse) protein. Nevertheless, there are interesting future possibilities for therapy and tumour localization using this approach.

TRIALS OF TREATMENT Many cancers have a long and unpredictable natural history: cancer of the breast, for example, is associated with an excess mortality for over 25 years after diagnosis. If survival is the endpoint of treatment, assessment of therapy in this disease will mean prolonged periods of observation. In small cell lung cancer or acute myeloblastic leukaemia, on the other hand, a majority of patients are dead within 2 years, and relapse in those who survive is less frequent beyond that point. Treatment trials will therefore give answers quickly. In assessment of therapy of a cancer (such as breast cancer), there may be more than one endpoint to be considered: does the treatment give effective local control: does the treatment influence the onset of metastasis; is the proportion of survivors at 5 and 10 years or longer increased? Comparison of a treatment with historical controls is very unreliable, as diagnostic and staging criteria are changing constantly and selection of cases is thereby

167

altered. Randomized prospective studies are now regarded as the only reliable way of making a comparison between two treatments. Such studies must include sufficient numbers of patients to allow the questions to be answered with confidence statistically. The studies require careful documentation and prolonged observation of the patient groups. The treatments being compared must be justifiable ethically and the design of the study capable of giving a clear answer to the central question. These considerations mean that treatment trials in cancer are complex and usually demand collaboration between many different centres: even, in the case of rare tumours, between different countries. To detect a 5 % difference in survival with confidence may require many hundreds or even thousands of patients in a study. Nevertheless, a 5% difference in long-term survival in breast cancer, if achieved by a non-toxic hormonal means, would mean 1000 lives saved a year in the UK alone - more than the number of patients cured of Hodgkin's disease. However, a 5% difference achieved by means of toxic chemotherapy might be regarded with less enthusiasm. At present, because progress in cancer management is slow and achieved only by small improvements, large-scale clinical trials are the only reliable way of validating new treatments.

CARE OF THE DYING

168

Many patients with cancer die from their disease; it is the responsibility of the oncologist to be sure that aggressive management of the tumour is not thoughtlessly continued beyond the point at which cure is possible. This does not mean that treatment is discontinued, but that the aim of management becomes palliative rather than curative. In skilled hands palliative treatment can often give the patient a period of happy life free from distressing symptoms. Palliation may require radiotherapy, e.g. for painful bone metastases or bronchial obstruction; chemotherapy at low dose to suppress constitutional symptoms in lymphoma; aspiration of ascites or pleural effusion; or surgical pinning of a bone weakened by metastasis. There is more to palliative management than pain relief. Nevertheless, relief of pain, control of nausea and treatment of depression become increasingly important as the disease progresses. The most important component of management at this stage is the psychological support of the patient and his or her family. Support comes from the nature of the relationship that the patient has established with the medical team throughout the illness. Extra help may be needed from domiciliary nursing teams, which are increasingly providing expert and readily available advice on symptom control to patients in their own homes. Many patients prefer to remain at home in the last few weeks of life, and the family doctor and specialist nurses can often make this possible. Alternatively, the patient's wishes or family circumstances may make admission to a hospital or hospice necessary.

The nursing practices and the approach to symptom control that have been developed in hospices are now being incorporated into hospital practice. In some hospitals, nurse specialists have been appointed to advise on these aspects of management. The gradual awareness of death produces many different reactions. The patient may become angry and direct this at the medical or nursing staff. Feelings of apathy, hopelessness and fatigue are common, and depression may be severe enough to need treatment with antidepressants. The support of relatives and friends is essential. Meticulous attention to detail and a willingness to take time to talk to the patient are just as important at this stage in management as during the early stages when the intention may have been curative. Even though active management of the cancer has finally failed, this does not mean it was not worthwhile, nor is it a reflection on the abilities of the medical or nursing staff. The fact of treatment failure leads some doctors to avoid seeing their patients at this stage. This is bad practice and increases the patient's feeling of isolation and helplessness. Many non-medical agencies are able to help the patient and his or her family. Patients with religious beliefs may gain great comfort from their clergyman and other members of their local religious community. Counselling and support groups have been set up in many towns to provide help during the illness and to the bereaved relatives afterwards.

ALTERNATIVE THERAPY A multitude of unorthodox approaches to management of cancer have been offered to patients over the years. These usually have echoes of current medical practice. Serotherapy was used after antitoxins were introduced for infectious disease; tooth extraction was practised, based on the interwar notions that dental sepsis was responsible for chronic inflammation. Nowadays, psychological ideas are translated into visualization therapy, and concern over pollution and diet are transmuted into strict vegetarian or fatfree diets. The uncritical assumption that answers will be found in nature has led to a wide range of herbal remedies, some of which (e.g. laetrile) are somewhat dangerous. As with many chronic diseases, the practitioners of homeopathy and faith healing offer their remedies. Most of these approaches share certain recognizable characteristics. These include a tendency to borrow the jargon of medicine without its science; a belief that all tumours can be treated by the same or similar remedies; a tacit or explicit assumption that there exists a medical conspiracy to conceal the truth about the remedy in question; and a complete failure to adopt any of the proven methods of validation of the results of treatment. What these approaches offer distressed and anxious patients is a feeling that they can themselves do something to combat their disease, a glimmer of hope that they might

be cured, and relief from the side-effects of conventional treatment if this is abandoned. These benefits are often a reflection of inadequacy in the relationship of the patient and doctor, rather than a clearly held view by the patient and family. The damaging aspects of these approaches are that they may induce the patient to abandon a worthwhile treatment, weaken the relationship between doctor and patient, and impose unpleasant constraints on the patient's life, such as rigid dietary control. These disadvantages should be discussed with the patient and, if patients are thinking of abandoning a potentially curative treatment, every attempt should be made to persuade them not to do so. Nevertheless, the doctor's role in management is to offer help, advice and expertise; the patient has the right to choose what to do. In many cases no great harm will be

done, and an experienced doctor will make it clear that the patient is welcome to continue under his or her care now and in the future.

6

FURTHER READING DeVita V T, Hellam S, Rosenberg S 1997 Cancer: principles and practice of oncology, 3rd edn. Lippincott, Philadelphia. A comprehensive cancer textbook. Souhami R L, Tannock I, Hohenberger P, Horiot J C 2001 Oxford textbook of oncology, 2nd edn. Blackwell, Oxford. A comprehensive textbook of oncology. Souhami R L, Tobias J S 1997 Cancer and its management, 2nd edn. Blackwell, Oxford. A medium-sized text covering most aspects of cancer treatment.

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7 Ageing and Disease Peter W Overstall

Theories of ageing 172

Altered reactions to disease 189

Sociological aspects 173

Clinical approach 191

Special features of disease in old age 174

Investigation in the elderly 193

Autonomic dysfunction 178

Assessment of fitness for operation 196

Nutrition and ageing 179

Prescribing for the elderly 197

Balance and falls 180

Cholesterol lowering in stroke 200

Urinary incontinence 185 Faecal incontinence 187 Sleep and insomnia 187

Rehabilitation 201 Community care and long-stay care 202

Sexual function 189

Most ill health in developed countries now occurs in elderly persons. Not only are the elderly more prone to illness, but the proportion of elderly people has increased considerably in the last 100 years. The response of an individual to growing old depends more upon the previous pattern of life than upon anything in the ageing process itself, so that one of the features of old age is increased differences between individuals.

LIFE EXPECTANCY Life expectancy is the average observed years of life from birth, or from any stated age. Since 1900, life expectancy at birth in the UK has increased from 49 to 75 years for men and from 52 to 80 years for women (Fig. 7.1). This is mainly the result of reductions in infant mortality from the major

1 MCQ 7.1

infectious diseases. Tuberculosis, acute rheumatic fever, smallpox, diphtheria, tetanus and poliomyelitis now account for less than 2% of the ill health they caused in 1900. These changes are largely due to improvements in nutrition and to public health measures which have reduced water- and food-borne diseases. The influence of immunization and treatment on mortality is comparatively much smaller. Life expectancy may also deteriorate sharply. In the former Soviet Union and eastern bloc countries male life expectancy has fallen since 1980 from 62 to 58 years. This has been blamed on the disruption caused by the transition to market economies and the resulting poverty, unemployment, homelessness, excessive drinking and smoking. Life expectancy in sub-Saharan Africa has also fallen since the 1980s because of HIV/AIDS. Much interest was aroused by early studies in industrialized countries which suggested that there was a connection between income inequality and life expectancy, implying that income inequality is bad for the whole population. It has now been shown that there is no association at the population level, although household income has a powerful effect on mortality. In the UK life expectancy at birth for daughters of semiskilled and unskilled manual workers is 3 years less than for those born to professional and managerial classes. For their brothers there is a 5-year class divide.

CHANGES IN THE ELDERLY POPULATION The age structure of a population is affected by infant mortality and by fertility rates, late-age mortality and migration. Demographic ageing, i.e. a shift towards a larger proportion of elderly people in the population, began in Europe in the early 20th century, as a result of falling fertility. This change has already occurred in the UK, so that during the 1990s there was very little overall change in the population aged 60 years and over, but a rapid expansion of the over-85s. After 2001, the cohort of the post-1945 'baby boom' reaches retirement and there will then be a further rise. The proportion of elderly in the population will not increase thereafter unless there are further substantial falls in both fertility and late-age mortality. Fertility rates are declining worldwide and we can anticipate the most rapid changes in age structure of the population to be in the developing world (Fig. 7.2). Note the narrowing of the base of the pyramids during the 21st century due to lower fertility rates. The population pyramids in Europe and the western Pacific are starting to invert. Already over 60% of older people live in developing countries, and by 2020 this will reach 70%. Absolute numbers of elderly in the world will increase from 385 million now to 1.5 billion in 2050. Most of this increase will occur between 2025 and 2050, as children bom in the 1960s reach the oldest population cohorts. 1

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FIG. 7.1 Life expectancy at birth (both sexes) in WHO regions (weighted by population)

SUMMARY 1 Epidemiology of ageing • In the UK, the increase in life expectancy at birth seen in the early part of the 20th century was due largely to a decrease in infant mortality. • The rising percentage of elderly in the population is due to falling fertility and lower mortality rates, particularly in the very old. • During the 1990s there was a pause in the overall growth of the elderly population in the UK, but the over 85s increased by onethird. • Developing countries face a growing number of elderly in the first half of the 21st century.

FURTHER READING ON LIFE EXPECTANCY Mackenbach JP 2002 Income inequality and population health. BMJ 324: 1-2. FIG. 7.2 Population pyramids of WHO regions

THEORIES OF AGEING

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Ageing is a complex process resulting from intrinsic and extrinsic damage to the organism at a rate dependent on each particular individual's genetic background and environment. The resulting disability is not fixed or inevitable. For example, high-tone deafness and high blood pressure are common in elderly Britons, but are absent among

elderly persons in the Easter Islands. Osteoporosis is common in western Europe and the USA but rare in China. Thus descriptions of physical decline are too variable to be useful for defining ageing. A better approach, which allows populations to be compared and so highlights differences in environmental or intrinsic ageing factors, is to define ageing

as a process which brings about an ever-increasing age-specific mortality (i.e. the older the individual becomes the more likely he or she is to die). In the UK mortality is at its lowest around puberty, and ageing can be said to begin at this point, rising progressively throughout adult life. There is general agreement that ageing is at least partly genetically determined. Each animal species has a specific lifespan: the maximum recorded longevity of Marion's tortoise, for example, is over 152 years, for man 122 years, and for golden hamsters 2 or 3 years. In species of Drosophila, the Fl hybrid has a greater longevity than either parental strain. Female sex also generally confers increased longevity in a number of different species. Individuals whose parents live to the age of 75 years or more live longer than those whose parents died before the age of 60, and siblings of centenarians have a four times greater chance than average of surviving to their early 90s. The mean difference in longevity in dizygotic twins is twice that of monozygotes. Current theory sees the ageing process as non-adaptive, with ageing evolving as a late by-product of processes that benefit the individual during its earlier, more fecund lifespan. With limited energy resources, an organism has to strike the right balance between investing in bodily maintenance and repair, and producing and rearing its young. Oxidative metabolism plays a key role in cellular ageing. Over the years free radicals cause increasing damage to enzymes, structural proteins, and nuclear and mitochondrial DNA. Mitochondria are the main intracellular source of free radicals, and with increasing age more free radicals are generated while at the same time antioxidant production declines. This suggests that defective mitochondria are central to the process of ageing. The only proven way to delay ageing in higher animals is to eat a low-calorie diet. A 50% calorie diet restriction increases the lifespan of mice from 38 to 56 months. Whether humans would show a similar gain is unknown, but restricting calories by onethird results in lower blood pressure, cholesterol, glucose and white blood cell counts.

FURTHER READING ON THEORIES OF AGEING Kirkwood T 1999 Time of our lives: the science of human ageing. London: Orion Publishing.

SOCIOLOGICAL ASPECTS Retirement age is an administrative measure without relation to the capacity of individuals. Most people at retirement can expect good health for several years, and for developed countries the World Health Organization has introduced a new demographic indicator of 'life expectancy without incapacity'. At age 65 this is estimated to be between 8 and 11 years for men, and between 9 and 12 years for women. People in developed countries are main-

taining better health in later life than ever before, and severe disability in older people is declining at 1.5% per annum. For example, it is anticipated that in the USA the number of severely disabled elderly will halve between 2000 and 2050. The notion that the older you get the sicker you get has been challenged by the finding that centenarians appear to have lived most of their lives in good health, with a relatively rapid terminal decline. This suggests that the older you get the healthier you have been, and promises a potential reduction in morbidity and disability as people approach the limits of their lifespan. None the less, medical costs are four times greater in the first decade of retirement than during working life, and by the second decade of retirement they are nine times as great. The top diagnostic categories for healthcare costs for the over-70s are dementia, stroke, musculoskeletal disorders and falls.

7

ATTITUDES TO THE ELDERLY In Europe the falling birth rate, increased longevity and trend to early retirement has reduced the workerpensioner ratio. In 1901 4.7% of British citizens were aged 65 or over; today this figure is 15.6%. This striking change had occurred by the 1980s (since when it has levelled off) and was not accompanied by undue economic strain or intergenerational strife, despite concerns in the 1960s and 1970s about 'dependency ratios' (the ratio of non-working people to those of working age). Discrimination against elderly people springs from three main impulses: a fear of death and dying, a social belief that falsely associates success with productivity, and misconceptions about the inevitability of senility. There is, in fact, little or no sign of a significant decline in happiness or life satisfaction with age. Over 80% of elderly people maintain independent house-holds, three-quarters of those over 85 can wash all over unaided, 95% can go to the toilet alone, and only 5% of people over 75 have significant dementia. It is true that institutionalization rates for the very old have increased considerably in the last 30 years owing to a decline in the amount of family support available to the elderly. Women aged between 45 and 60 have carried the brunt of community care, and since 1900, when there were 83 women in this age group for every 100 people over 65, there are now only 45. None the less, families do still care for their elderly relatives and indeed provide far more support than is available from health or social services. Family support ratios compare the relative sizes of older and younger generations and indicate the availability of family support for the elderly (Fig. 7.3).

RETIREMENT Retirement is now a well established part of life in developed countries and is starting to appear in developing countries among government employees and urban

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FIG. 7.3 Parent support ratio in WHO regions (weighted by population) The increase in the parent support ratio (population aged over 80 divided by the population aged 50-64) is most marked in developed countries, particularly Japan (increase in ratio from 8 to 41 between 1975 and 2025).

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workers (Fig. 7.4). Most people no longer see it as a traumatic event marked by major losses to the individual, but instead prepare for it as a normal and expected part of the life-cycle and welcome it as a time of opportunity and increased leisure. The rate of early retirement is, therefore, rising. Since 1975 there has been a decline in the UK of about one-third in the number of men aged 60-64 in fulltime employment. Of course, not all of these early retirements are voluntary, and there has been a noticeable trend for businesses in economic difficulties to make their older rather than their younger workers redundant. The period of active retirement, in which many take up part-time or voluntary work, ends when the person becomes disabled by declining physical or mental health. The difference between these two stages of old age depends on functional capacity, not on chronological age. Some people do find that retirement produces troublesome stresses. The most frequent problem is adjustment to a lower level of income. Some suffer from a loss of selfesteem, others fear the onset of ill health, or are distressed by their idleness. Most of these problems fade as the new pattern of activity is taken up, and serious depression is not a particular feature of retirement. Claims of large numbers of super-centenarians living in certain geographical regions - such as Vilcabamba in Ecuador, Hunza in Pakistan and Abkhasia in Georgia have been shown to be exaggerated. However, it is true that the inhabitants of each of the above areas are relatively long-lived, and in each case the esteem and merit enjoyed by a person increases with age. There is no retirement age

FIG. 7.4 Percentage of the population aged 65 years and over that is economically active worldwide The developed countries have still to find a satisfactory role for their unemployed elderly.

and old people continue to play an active role in the economic and social life of their communities.

FURTHER READING ON SOCIOLOGICAL ASPECTS Grundy E 1996 Age, 'dependency' and intergenerational relationships. Rev Clin Gerontol 6:303-304.

SPECIAL FEATURES OF DISEASE IN OLD AGE Measurement of physiological functions in healthy young adults gives fairly uniform results, with a narrow range between the upper and lower limits of normal. From about 30 years of age, a functional decline in performance can be detected in most organs and body systems (Fig. 7.5). However, the organs and systems age differentially, so that the variation both within and between individuals increases with age. The chronological age of an old person may therefore bear little relation to his or her functional age (Fig. 7.6), and the response of an old person to the stress of illness will be more unpredictable than that of a young adult. Degenerative changes occur throughout the body with increasing age, but these may become sufficiently marked to constitute a pathological process. The distinction between this and normal physiological ageing is often difficult to make, and there is increasing recognition that so-called normal ageing is the result of occult pathology. These changes have an important bearing on the management of the patient, as will be seen in the examples that follow.

TABLE 7.1 Good practice guidelines in osteoporosis 1. Frail housebound elderly should be prescribed calcium and vitamin D, assessed and managed for falls risk and considered for hip protectors.

7

2. Patients with osteoporosis risk factors should have their bone mineral density measured (DXA at the hip). If their T-score is above -1 they can be reassured. If between -1 and -2.5 they should be given lifestyle advice and osteoporosis treatment if there is a history of a previous fracture. If the T-score is below -2.5 they should have lifestyle advice and osteoporosis treatment.

30

40 Age (years)

3. Patients with a previous fragility fracture should have routine investigations (blood count, ESR, bone and liver function tests, serum creatinine, serum TSH) and, because they are at high risk for a further fracture, should be started on osteoporosis treatment and given lifestyle advice.

FIG. 7.5 Age decrements in physiological functions in males A Fasting blood glucose; B resting cardiac index; C maximum breathing capacity; [6] maximum work rate.

cause of visual impairment is age-related macular degeneration. This is untreatable, but about 80% of patients can improve their reading performance with simple magnifying devices and brighter illumination.

THE AGEING EAR

FIG. 7.6 The relation between resting cardiac output and age in men without circulatory disorders Note that several men over the age of 70 have values similar to men in their 30s.

Impaired hearing increases with age and can contribute to poor health, social isolation, depression and (probably) paranoid psychosis. About 30% of the elderly regard themselves as having a hearing impairment, but audiometric testing reveals a much higher prevalence (60%) in those aged over 70. Presbyacusis is age-related loss of high-frequency hearing, but this cannot be reliably distinguished from the effect of ototoxic drugs, diuretics or vascular disorders. Some of the hearing loss usually regarded as an inevitable part of old age may be due to our noisy environment.

OSTEOPOROSIS (See Table 7.1)

THE AGEING EYE The force required to focus the eye increases considerably at about 40 years of age and, by 45 or 50, accommodation will be so poor that for most persons small print can be read only at arm's length (presbyopia). This is a result of both a reduction in elasticity of the lens capsule and a thickening of the lens, which prevents it adapting its shape to focus on near objects. Opacities and general yellowing of the lens, together with an age-related meiosis, cut down the amount of light entering the eye and reduce visual aculity. A loss of cells in all regions of the visual pathway affects perception and contrast sensitivity. About 20% of those aged 75 and over have a visual acuity of less than 6/12. With continuing advances in the management of cataracts, glaucoma and diabetic retinopathy the main

Postmenopausal (type 1) osteoporosis results from accelerated bone loss due to oestrogen deficiency. There is mainly a loss of trabecular bone, typically resulting in fractures of vertebral bodies and the distal forearm in women in their 60s and 70s. Senile (type 2) osteoporosis is a slower, age-related bone loss that occurs in both sexes. There is cortical as well as trabecular bone loss, which typically results in femoral neck fractures in men and women in their 70s and 80s. These fractures are a serious threat to older people and are associated with a 20% increased risk of either death or institutional care over the following year. Secondary causes of osteoporosis include endocrine (thyrotoxicosis, hypogonadism, hyperadrenocorticism) and gastrointestinal (malabsorption, primary biliary cirrhosis) disorders, rheumatoid arthritis, malignancy, hypertension, and drugs such as corticosteroids and heparin. Other risk

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factors include a strong family history, inactivity, excessive alcohol and smoking. Unfortunately, clinical risk factor profiles correlate poorly with both bone density and fracture risk, and the most useful way of assessing increased osteoporosis risk is to measure bone density by dual energy X-ray absorptiometry. Ultrasound assessment of the skeleton is a promising alternative method. The predictive value of bone density is similar to that of blood pressure in determining the risk of stroke. The relative risk of fracture increases two to three times for each standard deviation decrease in bone density. Definite indications for bone density measurements include fracture after minimal trauma in previously fit individuals, past history of early menopause (<45 years) in women up to the age of 70 years, underlying secondary causes of osteoporosis and apparent osteopenia on X-ray. There is currently no evidence to indicate that routine population screening is valuable, and instead a case-finding strategy is used. Bone density measurements are not needed in patients at greatest risk, such as those over 80 years who are frail and housebound or institutionalized, those with a previous fragility fracture and patients taking prolonged oral steroid therapy (>7.5 mg prednisolone/day), as they should be treated regardless of their bone density. Prevention of osteoporosis depends on achieving the maximum peak bone mass (regular weight-bearing exercise and dietary calcium intake of 1000-1500 mg/day, between the ages of 15 and 25) and reducing the rate of bone loss by encouraging elderly people to keep exercising, maintain a daily calcium intake of 1000 mg, avoid falls (see p. 175), stop smoking and moderate alcohol intake. These are all worthwhile interventions at the population level. For the individual postmenopausal patient at risk, particularly if she has climacteric symptoms such as hot flushes, the single most effective intervention is hormone replacement therapy (HRT). The greatest benefit is gained by starting treatment soon after the menopause. For current users of HRT there is a 65% reduction in hip fracture risk but 5 years after stopping HRT most of the benefit is lost. For optimal protection HRT should be continued for long periods. Long-term use increases the risk of breast cancer; for women aged 50-70 the risk of developing breast cancer increases from 51 cases per 1000 women to 57. HRT reduces the risk of coronary artery disease but the benefit is not as great as early studies suggested. The risks of developing Alzheimer's disease appears to be reduced. Raloxifene is an alternative to HRT for the postmenopausal patient without climacteric symptoms, which can be exacerbated by raloxifene. It appears to be associated with a lower incidence of breast cancer and does not cause

1

176

MCQ 7.2

2

Fig. 7.1

endometrial bleeding, but, like HRT, it can cause deep vein thrombosis. For the elderly patient HRT is rarely indicated and bisphosphonates or calcium and vitamin D are used instead. The best evidence for efficacy in reducing spinal, non-vertebral and hip fractures is for alendronate and risedronate. Calcitonin has proven efficacy for preventing spinal fractures and is also effective in relieving the pain associated with vertebral fractures. Calcium and vitamin D have proven efficacy in preventing non-vertebral and hip fractures, and it has been argued that these supplements should routinely be prescribed for frail housebound elderly persons. Corticosteroid treatment doubles the risk of fractures of the hip and distal radius and quadruples the risk of vertebral fracture. All patients over 65 years taking prednisolone 7.5 mg a day or more should have treatment to prevent osteoporosis: the first choice is a bisphosphonate1212.

FURTHER READING ON OSTEOPOROSIS Royal College of Physicians, 2000. Osteoporosis: clinical guidelines for prevention and treatment. RCP, London.

DEMENTIA AND NORMAL AGEING Cross-sectional and longitudinal studies consistently demonstrate a decline in cognitive function with increasing age. A decline in cognitive ability is not confined to old age, and tests that measure the ability to solve novel problems rapidly (fluid intelligence) show a fall in performance by the late third and early fourth decades. Age-related changes in cognitive function appear to be related to a general decline in the speed at which information is processed. Thus, highly practised skills, such as vocabulary test scores, alter very little with age, but timed novel problem solving, reaction time tests and the ability to learn new material decline with increasing age. Ill health undoubtedly affects cognitive performance, particularly cardiovascular disease. Congestive cardiac failure doubles the risk of cognitive impairment, and systolic hypertension in middle age increases the likelihood in old age of developing white matter hyperintensities (on MRI) and dementia. Other predictors of cognitive decline are increasing age, 'old age forgetfulness', low educational status, lack of social and physical activities and possession of the ApoE-4 allele. The major cause of intellectual loss in old age is Alzheimer's disease (AD), followed by vascular dementia and Lewy body dementia. There is increasing recognition that vascular risk factors are important predictors of AD as well as of vascular dementia. Severe atherosclerosis carries a threefold risk of developing AD, and the Syst-Eur study showed that treating systolic hypertension halves the likelihood of developing dementia. AD is a distinct entity rather than a mere exaggeration of normal ageing, and prevention strategies

17

pathological decrements in SUMMARY 2 Normal vs physiological performance in old age Normal age-related functional decline

pathological process

Impaired sight (presbyopia)

Cataracts, macular degeneration

Impaired hearing (presbyacusis)

Effects of ototoxic drugs, diuretics or vascular disorders

Bone loss

'Accelerated' osteoporosis

Decline in intellectual function

White matter lesions due to hypertension; Alzheimer's disease

Impaired glucose tolerance

Diabetes

Minor gait slowing and balance impairment (increased sway)

Parkinson's, Alzheimer's or cerebrovascular disease; dementia; vestibular lesions; cervical spondylosis; visual problems

Altered sleep pattern

Insomnia due to nocturia (due to detrusor instability); pain, depression, etc.

need to concentrate on 'cognitive impairment, not dementia' in people aged 65 and over. This has twice the prevalence of all types of dementia combined and is associated with functional disability and the need for institutional care, yet little is known of its natural history.

IMPAIRMENT OF BIOCHEMICAL HOMEOSTASIS Most normal old people can, under resting conditions, maintain their internal environment at levels similar to those in the young. When stressed, however, it is apparent that homeostatic mechanisms in the elderly are impaired. Blood glucose control and osmoregulation are two good examples of this.

The control of blood glucose The average fasting blood glucose level increases only slightly with advancing age. When a glucose load is imposed, however, the rise in maximum blood glucose levels is clearly greater, and the return to resting levels slower, in old people (Fig. 7.7). The upward drift of blood glucose with age produces diagnostic difficulties. If criteria used to diagnose diabetes in young populations were applied to the elderly, there would be a considerable increase in the number of those diagnosed as diabetic from the glucose tolerance test. Thus, elderly patients with an impaired glucose tolerance test (i.e. a 2-hour post-glucose blood sugar of 7-llmmol/L) should probably not be regarded as diabetic if they are asymptomatic, but they do carry a

Minutes FIG. 7.7 Mean blood sugar levels after a 50 g oral glucose load in a cross-sectional population study Known diabetics have been excluded.

higher risk of developing frank diabetes. Recent American Diabetic Association (ADA) criteria propose the use of fasting blood sugar, with 6.1-6.9 mmol/L indicating impairment and 7.0 mmol/L as the new diagnostic cut-off (instead of the WHO fasting criterion of 7.8 mmol/L). The fasting ADA criteria are less predictive than the WHO criteria of cardiovascular risk in the elderly, and for older adults a fasting glucose cut-off of 7.8mmol/L is preferable.

Osmoregulation On average, young adults maintain their blood osmolality in the range 280-295 mmol/kg. Although resting plasma osmolality is unchanged in the elderly, the osmoregulatory response to 24-hour water deprivation is impaired, even in good health. Despite developing higher plasma osmolality and sodium concentrations in response to dehydration, elderly subjects do not respond with appropriate thirst and water intake. They do not drink sufficient water to replenish their body water deficit and return plasma sodium levels to normal. Not only is there reduced thirst and water intake following dehydration, but the old person's kidneys are less able to retain water, due to reduced renal responsiveness to arginine vasopressin (AVP). These changes can predispose even healthy old people to fluid and electrolyte disturbances when there is excessive salt and water loss. They are also at risk of overhydration and hyponatraemia because they are unable to excrete excess water, mainly because of a decline in glomerular filtration rate with age. Particular care is needed with intravenous infusion to avoid overhydration and hyponatraemia. Postoperative patients are at high risk, especially if they have been taking a thiazide diuretic and as a result have mild hyponatraemia. Surgical stress causes inappropriate ADH secretion, which increases the hypona-

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traemia. Sympathetic blockade resulting from spinal anaesthesia lowers the blood pressure, and if in an attempt to counteract this large volumes of i.v. 5% dextrose/saline are given, serious hyponatraemia ensues, which carries a 20% risk of brain damage or death. Hypotonic fluids must not be given to elderly postoperative patients.

FURTHER READING ON SPECIAL FEATURES OF DISEASE IN OLD AGE Mosekilde L 1998 Aging of bone. Rev Clin Gerontol 8:281-296. O'Neill P A 1997 Aging homeostasis. Rev Clin Gerontol 7:199-211. Sorlie P, Gordan T, Kannel W B 1980 Body build and mortality: the Framingham Study. JAMA 243:1828-1831. Staessen J A, Fagard R,Tuijs L et al 1997 for the Systolic Hypertension in Europe (Syst-Eur) trial investigators. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 350:757-764.

AUTONOMIC DYSFUNCTION This results from a number of factors: a reduction in nerve density and neurotransmitter concentrations in the autonomic nerves; reduced responsiveness of effector organs, such as blood vessels and stretch receptors in arterial walls; and a decline in cellular p-adrenergic sensitivity. Dysfunction may follow central lesions such as cerebrovascular disease, Parkinson's disease, Shy-Drager syndrome, Wernicke's encephalopathy (due to thiamine deficiency associated with alcoholism) and Alzheimer's disease. Peripheral autonomic neuropathy may occur in diabetes mellitus, chronic alcoholism and malignancy. Autonomic dysfunction may also be caused by drugs such as phenothiazines, tricyclic antidepressants and haloperidol. The important clinical consequences are orthostatic hypotension (Table 7.2), bowel and bladder disturbances, impotence and impaired thermoregulation.

AGEING AND THERMOREGULATION

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Under normal circumstances the body core temperature is about 37°C with, in temperate climates, a skin temperature of 33°C, giving a core-skin temperature gradient of 4°C. Thermoregulatory responses are impaired in old age due to disordered autonomic function. This usually passes unnoticed, but in times of environmental stress the old person is less able to maintain a constant deep body temperature. Surveys of old people living at home in winter show that only 0.5% had frank hypothermia (deep body temperature less than 35°C) but that 10% had a deep body temperature below 35.5°C. The latter had impaired

TABLE 7.2 Orthostatic hypotension • Fall in systolic blood pressure of at least 20mmHg or a fall of 10 mmHg or more in diastolic pressure on standing • Prevalence in elderly between 10 and 24% • Age-related aetiology Impaired baroreceptor response Failure of cerebral autoregulation Increased arterial and arteriolar rigidity Autonomic dysfunction • Cardiovascular causes Low cardiac output (e.g. heart failure) Restricted cardiac output (e.g. aortic stenosis) Absolute hypovolaemia (e.g. blood loss) Relative hypovolaemia (e.g. venous pooling) • Drug causes Centrally acting (e.g. L-dopa, MAOIs, sedatives) Vasodilators (e.g. nitrates, alcohol) Diuretics, calcium channel blockers • Symptoms Typically these consist of faintness, giddiness and blurring of vision, and are precipitated by standing and exacerbated by exertion or a heavy meal. However, if there is a lesion of the parasympathetic system these symptoms may be absent, so that despite a fall in blood pressure on standing there is no warning giddiness. The patient remains upright and experiences symptoms such as profound weakness, falls, confusion and pallor • Management Raise head of bed 15-20°, leg and abdominal compression, 9afludrocortisone 0.1 mg daily initially, increasing by 0.4mg each week. Other drug treatments include mididrone, dihydroergotamine, indomethacin, domperidone (in Parkinson's disease) and octreotide (for postprandial hypotension)

thermoregulation, as shown by a core-skin temperature gradient only half that of normal individuals. The elderly may also suffer impairment of thermal perception. Young persons can detect temperature differences as small as 0.8°C, but old people only perceive differences of 2-5°C. Furthermore, the elderly shiver less efficiently in response to cooling, with little more than half the metabolic heat production seen in young subjects. Old people are thus not only less able to maintain their deep body temperature when subjected to cold stress, but may also be less aware of cold conditions and therefore fail to take the appropriate steps. This may explain why some old people can tolerate cold living conditions without discomfort. Although most British homes now have central heating, hypothermic patients are less likely than controls to have the heating on at the time of collapse. Typically, hypothermia occurring indoors results from a collapse due to illness, when the patient is alone, lightly clothed and not in bed. These conditions cause progressive core cooling. About 80% of the variation in mortality rates throughout the year is associated with changes in temperature

a

FIG. 7.8 Observed and expected deaths in the UK during the cold winter of 1984/5 Note the rise in death rate during the winter months and the excess deaths during the two exceptionally cold periods in early 1985.

FIG. 7.9 Relation of obesity to mortality found in the Framingham study The obesity index is the ratio of the subject's weight to a reference weight obtained from height and frame charts compiled by large insurance studies. Note that the lowest mortality occurs at an obesity index rather above 1.0.

FURTHER READING ON AUTONOMIC DYSFUNCTION (Fig. 7.8). For every degree change in the average winter temperature, the number of annual winter deaths rises or falls by about 8000. Thus, in the UK in the mild winter of 1983/4, about 30000 more elderly people died than during the summer months (a 14% increase). In the cold winter of 1984/5 this figure rose to 46000 (an increase of 20%). However, the majority of these 'excess' deaths are not directly due to hypothermia, but to coronary and cerebral thrombosis resulting from haemoconcentration and hypertension after cold exposure. Over the last 20 years there has been a decline in this excess winter mortality. About half of this decline is the result of non-seasonal factors, such as improved general medical care. The rest is due to improvements in home heating and greater car ownership, which reduces outdoor exposure to cold. The diagnosis and treatment of hypothermia are discussed in Chapter 2, p. 46. The elderly are also less able to cope with excessive heat, and the mortality rate during heatwaves rises with increasing age. In Chicago during the benign summers of 1992, 1993 and 1994 the heat-related mortality was 1, 3 and 9, respectively, but during the exceptionally hot summer of 1995 it rose to 515, with 162 deaths on a single day in July. It has been estimated that on the hottest day of a heatwave there are six extra deaths per 100000 population. There is much unrecognized heat illness and large variations in the mortality rates, as there are no international or even national agreements on the definition of heat-related death. Various criteria have been introduced, such as a core body temperature above 40.6°C at the time of death. Most models of global warming predict an increase in the frequency and intensity of heatwaves. The impact is likely to be greatest in mid-latitude cities with infrequent but extreme heatwaves, so that in cities such as Shanghai and New York there will be several thousand extra heat-related deaths annually by the middle of the 21st century.

Collin K J 1997 Aging, disease and the autonomic nervous system. Rev Clin Gerontol 7:119-126.

NUTRITION AND AGEING At retirement age in developed countries the average person is more likely to be obese than undernourished, but subsequently body weight and nutrient intake fall and, for the very elderly, the main concern is undernutrition. Moderate overweight is not associated with a high mortality in old age (Fig. 7.9), but low body weight is associated with a higher mortality in both fit old people and those admitted to hospital. Nutritional surveys have shown a marked decrease in energy requirements and nutrient intake with increasing age. However, this is due mainly to physical illness and reduced physical activity, which reduce appetite and energy expenditure. With increasing age there is a gradual decline in metabolism at rest, but this is relatively unimportant. For healthy active persons over 60 years of age the energy and nutrient requirements are similar to those of a 30-year-old. Longitudinal studies have shown that nutrient intakes are maintained in old people who remain in good health. Housebound elderly women consume 15% less carbohydrate and 46% less vitamin C than do active age-matched controls.

NUTRITIONAL DEFICIENCIES A survey of old people living at home found that 3% were suffering from malnutrition, including protein-calorie malnutrition, iron deficiency and specific vitamin deficiencies.

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supplement of 800 IU vitamin D and calcium reduces fracture rates and should be widely prescribed to at-risk patients. 1

TABLE 7.3 Risk factors for malnutrition Unexpected weight change of more than 3 kg Physical disability Lack of sunlight Gastrectomy Mental confusion Chewing or swallowing difficulties Fewer than eight main meals, hot or cold, in a week Absence of fruit or vegetables in diet Food wastage Alcoholism Poverty (receiving financial support from state) Depression or loneliness

BALANCE AND FALLS

In most cases this was the result of some underlying medical problem and was only rarely due primarily to economic or social factors (see Table 7.3). Social factors are, however, likely to be important in cases of subclinical malnutrition. For example, 31% of those living alone had leukocyte ascorbic acid levels below 7.0ug/108wbc, compared to 8% of those living with a spouse. Scurvy remains rare even in the most isolated patients. Almost 10% of acute hospital admissions are seriously malnourished and this is associated with a slower rate of recovery, longer hospital stay and increased treatment costs. Patients should be weighed on admission and questioned about their diet. Megaloblastic anaemia due to a folate-poor diet is rare in old people in the UK. However, low serum folate levels are found in about 8% of elderly hospital patients, and often in patients with physical or mental disorders that interfere with shopping and cooking. Osteomalacia may contribute significantly to the skeletal rarefaction seen in old age (although this is more commonly due to osteoporosis). There are many causes of osteomalacia, but two of the most important are reduced vitamin D intake and low exposure to sunlight - two factors often present together in the elderly. More than half of elderly admissions to a general medical ward have 25-OHD concentrations below 37.5nmol/L and nearly a quarter of these have a level below 20nmol/L indicating severe deficiency. The current UK recommended intake of vitamin D for people aged 65 years and over is 400IU (10 ug) daily, and this is not easily achieved without fortified foods or adequate levels of sunlight. A daily

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MCQ 7.2

0 Case 7.1 3

4

Fig. 7.3

0 Fig. 7.4 6

0 Fig. 7.5

Fig. 7.2 MCQ 7.3

During normal quiet standing balance is maintained when the centre of gravity is kept within the support base provided by the feet. Maintenance of this upright position is associated with body sway, mainly in the anteriorposterior (AP) direction, and this sway may be measured either as degrees of angular movement or, using force platforms, as changes in the pressure over the soles of the feet. Threats to balance are detected principally by vision, lower limb cutaneous sensation and proprioception, and to a lesser extent by the vestibular system. Following a pertubation sensory information is centrally processed and corrective responses, such as muscle stiffening and cocontraction, or protective responses, where one or more steps are taken or an arm is thrown out to catch hold of an external support, are triggered. Disease in any part of this system will impair balance. Loss of a single sensory input is rarely completely disabling because of good overall reserve, but closing the eyes always causes an increase in postural sway and it appears that peripheral vision in particular is necessary for normal balance.

CHANGES IN BALANCE IN OLD AGE Both AP sway velocity and area increase in normal elderly subjects (Fig. 7.10), (i.e. those who report that their balance is normal and who are functionally independent). Further increases in AP sway correlate with spontaneous falls, but a better predictor of falls is increased mediolateral sway. Age-related changes occur in all parts of the postural control system. There is reduced visual acuity, contrast sensitivity, depth perception and dark adaptation. There is decreased cutaneous sensitivity in the feet and proprioceptor loss in the ankles and apophyseal joints in the cervical spine. In the vestibular system there is loss of labyrinthine hair cells and vestibular ganglion cells. Centrally there is an age-related loss of neurons, resulting in slowing of information processing and depletion of neurotransmitters such as dopamine in the basal ganglia. The older person has to pay much more attention to their balance, and loss of concentration contributes significantly to the risk of falling. On the motor side there is an agerelated reduction in muscle strength due to decreases in the size and number of muscle fibres and motor neurons. Loss of strength of the ankle dorsiflexors and knee extensors (i.e. quadriceps) is particularly associated with an increased risk ofgn f There has been a long-running debate on what constitutes normal gait in old age and the cause of senile gait

TABLE 7.4 Risk factors for falls

a

More than one previous fall Lower limb disability (including muscle weakness) © Impaired balance or gait Use of sedative drugs Use of more than four drugs Cognitive impairment (mini mental state examination score <26/30) Impaired activities of daily living 0 Visual deficit

FIG. 7.10 Postural sway (measured as movement in the anterior-posterior plane with the subject standing) increases with age At all ages, women sway significantly more than men. 1 unit = 3.5° of angular movement.

disorder. There are undoubtedly some elderly people who maintain a normal gait even in extreme old age. However, gait laboratory studies show subtle changes even in carefully screened healthy elderly subjects. Gait slowing is due to a decreased stride length and cadence (steps per minute) remains unaltered. Stance time and double support time increase and there is a less vigorous push-off. Whether this represents an early degeneration of the balance control system or an adaptation to make the gait safer is unclear. However, it is now apparent that the senile gait disorder, which is characterized by caution and shorter and more frequent strides and is said to occur in about 20% of the elderly, is not due to age but to underlying neurodegenerative syndromes and subclinical cerebrovascular disease. These patients have a twofold increased risk of cardiovascular death, compared to age-matched subjects with a normal gait. 4 FALLS Although falls are the leading cause of death from injury in people over the age of 75, serious injury only occurs in about 5 % of falls in community-living elderly, and a much more common consequence is loss of confidence, a reluctance to go out of doors and reduced quality of life. Thirty per cent of people over the age of 65 give a history of having had a fall in the previous year, and 50% of fallers do so repeatedly. Incidence rates in nursing homes and hospitals are nearly three times the community rate and the likelihood of an injury is more than doubled. Falls increase with age and fall rates in women are twice those in men. The more risk factors a person has (Table 7.4) the more likely they are to fall. Over 1 year 65-100% of people with three risk factors will fall, compared to 8-12% for those with none. The typical frequent faller usually has multiple defects affecting the postural control system.

Clinical or subclinical disease is a far more important cause of falls than environmental factors such as trailing wires and loose rugs. It is therefore no surprise to find that falls, incontinence and functional dependence all share the same risk factors. Increased fall rates in women probably reflect greater muscle weakness and possibly lower levels of fitness: for example, over 50% of women over the age of 55 are unable to walk at 3 miles per hour on the level, and the average healthy 80-year-old woman has to make a maximum quadriceps contraction to rise from a low armless chair or the lavatory. 7

HISTORY AND EXAMINATION It is important to spend time with the patient (and ideally a reliable witness) getting a precise account of the circumstances surrounding the fall. Was it a simple trip or accident, which carries a relatively good prognosis? Or was it a more ominous spontaneous fall (' I don't know what happened, I just went down') (Table 7.5). Some may say that they felt dizzy (particularly if prompted by the doctor). However, only very rarely does the patient experience true vertigo (a sensation of the surroundings or the inside of the head spinning round). They do not so much feel dizzy as unsteady when standing or walking, and are frightened that they are going to fall over. Some of these patients suffer drop attacks. These are falls which occur without warning: the patient suddenly crumples to the ground and there are no neurological sequelae. As with other spontaneous falls their aetiology is multifactorial, although sometimes a specific cause will be found, such as reflex-mediated syncope, normal-pressure hydrocephalus or Meniere's disease. Specific causes of falls such as these are less common than widespread postural defects (e.g. cerebrovascular disease and a diabetic peripheral neuropathy), which result either in spontaneous falls or a fall following a trivial pertubation because of slowing or even loss of the normal corrective responses. These patients are usually older and more frail, their gait and balance are noticeably impaired and their general health poor. Their mortality is about five times that of non-fallers.

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TABLE 7.5 Causes of spontaneous falling

TABLE 7.6 Causes of syncope

Patient usually impaired in more than one of the systems concerned with balance control:

Pathophysiology of syncope is complex in older patients. Orthostatic hypotension, carotid sinus hypersensitivity and vasovagal syncope overlap in 30% of elderly with syncope.

• • • • • •

Vision, e.g. impaired depth perception Impaired cutaneous sensation (e.g. peripheral neuropathy) Impaired proprioception, e.g. cervical spondylosis, peripheral neuropathy Vestibular lesions, e.g. Meniere's disease Impaired central coordination, e.g. cerebrovascular disease Unstable support base, e.g. turning quickly, walking downstairs or arising from a chair

If balance is already impaired, falls are precipitated by: • Acute illness, e.g. chest infection, worsening of heart failure • Drugs, e.g. tranquillizers • Occult ill health, e.g. anaemia, hyponatraemia

Reflex mediated (neurovascular instability) Vasovagal Carotid sinus hypersensitivity Orthostatic hypotension Situational syncope (cough, micturition, etc) Cardiac Arrhythmias Obstruction (aortic stenosis, pericardial effusion etc) Neurological Vertebrobasilar insufficiency Subclavian steel syndrome

Rare

Points to note in the history are: • Circumstances of the fall; • If the fall occurred soon after standing up (raising the possibility of orthostatic hypotension) • Loss of consciousness (can the patient remember hitting the floor?). There are only two common causes syncope (Table 7.6) and epilepsy; • Syncope accounts for up to 6% of medical admissions and 20% of elderly patients presenting to A & E with unexplained falls, such as drop attacks. Patients will sometimes deny loss of consciousness, despite unequivocal evidence that it occurred; • Vasovagal syncope may be preceded by the classic symptoms of lightheadedness, sweating and nausea, but in the 'malignant' variety there is no warning, the patient falls unexpectedly, the attack is prolonged with slow recovery and injury, and convulsions and incontinence are common; • Palpitations before the fall, a sense of dizziness or faintness and dimming of vision are important pointers to syncope; • Loss of consciousness, dizziness and faintness are not features of transient ischaemic attacks. These depend for their diagnosis on focal neurological signs (e.g. motor or sensory loss, dysphasia); • The patient's drugs will need to be checked. Sedatives or hypnotics frequently slow the patient down and may precipitate a fall. B-Blockers, certain calcium channel blockers and diuretics may cause orthostatic hypotension or vasovagal syncope; • Acute or chronic medical problems

1

182

Fig. 7.6

SUMMARY 3 Typical features in patients with recurrent falls • • • • •

Have several risk factors, especially lower limb muscle weakness Significantly impaired gait and balance Difficulty in accounting for how they fell Show fear of falling Generally have multiple defects both in the sensory systems concerned with balance control (vision, proprioceptors and the vestibular system) and in central coordination centres

• Mental state should be assessed if there is a suspicion of dementia or depression; • A history of tinnitus, deafness or vertigo should be sought. If present, this may indicate a vestibular lesion, either peripheral (e.g. Meniere's disease) or central (vascular disease in the brainstem or cerebellum). • A sudden onset of severe vertigo suggests a posterior circulation stroke. Episodic vertigo lasting less than 1 minute and provoked by rapid positional change is probably benign positional vertigo, which is confirmed by a positive Hallpike test (for description see p. 183); In the general examination: • The lying and standing blood pressure should be measured (a drop in systolic pressure of more than 20mmHg indicates postural hypotension). • Carefully examine the heart. • The range of neck movements should be assessed. • Watch the patient rise from a chair, walk several paces and return. • Normal old people should not have a positive Romberg test (i.e. closing the eyes when standing should not markedly impair balance). • Check for impaired righting reflexes by tapping the

RECENT ADVANCES IN THE PREVENTION OF FALLS 1. Intervention studies have demonstrated significant reductions in falls. Because falls' are multifactorial broad-based interventions are best. Programmes such as the following reduce the risk of falling by 30%: • Review and adjust drugs • Balance and gait training • Muscle strengthening exercises • Practise transfer skills from bed/chair/toilet • Make home safer. 2. Assessment and appropriate treatment and referral of patients attending an A & E department lowers the risk of recurrent falls, reduces fracture rate by 50% and decreases the odds of hospital admission. 3. The Frailty and Injuries: Cooperative Studies of Intervention Techniques (FICSIT) programme demonstrated that exercise alone could produce a 25% reduction in falls. In particular, Tai Chi appeared beneficial and led to a 47% reduction in falls incidence in elderly women. A home visit by a physiotherapist and the prescription of 30 minutes of strength and balance retraining exercises and an outdoor walk three times a week reduces fall rate and remains effective for at least 2 years. 4. Hip protector pads reduce the risk of hip fracture. They are indicated for frail at-risk patients who are sufficiently well motivated to wear them. 5. Patients with parkinsonism can be taught how to manoeuvre more safely in the home and to walk with a normal stride length using markers on the floor or attentional strategies.

patient lightly on the sternum or giving the shoulders a tug from behind. Be ready to catch them if they fall. • In severe cases there will be manifest anxiety and fear of falling, with the patient reluctant to move without clutching on to furniture or onlookers for support. • Check muscle strength (especially quadriceps), lower limb joints, vision, neurological function (especially lower limb peripheral nerves). In addition to routine investigations: • A 24-hour ambulatory ECG should be obtained for patients suspected of having episodes of cardiac syncope due to an arrhythmia. • Patients with a normal 24-hour tape, but who have symptoms suggesting vasovagal syncope or carotid sinus syncope, require head-up tilt testing and carotid sinus massage (a positive response produces asystole exceeding 3 seconds, a decrease in systolic blood pressure exceeding 50mmHg, or a combination of the two). 1 • An EEG is occasionally helpful, although the diagnosis of epilepsy is essentially clinical (see Ch. 24 p. 1321).

Early morning falls in patients taking a long-acting hypoglycaemic drug (e.g. chlorpropamide) raise the possibility of hypoglycaemia. Patients suspected of having a vestibular lesion can have this accurately localized only by specialist examinations, which include electronystagmography and caloric tests. The Hallpike manoeuvre can be carried out in the clinic and tests for the presence of positional vertigo. The nystagmus of benign positional vertigo occurs after a latent period of 2-20 seconds when the head is reclined and turned to the affected side. To carry out the test the patient is seated at the top end of a flat examination couch and warned that they will experience vertigo. The examiner holds the patient's head firmly and turned 45° to the left or the right; the patient is then carried rapidly backwards until the head is dependent. The patient is asked to keep his eyes open all the time and look at the examiner's nose. The nystagmus of benign positional vertigo is rotatory (torsional) and is directed towards the affected ear when it is undermost (i.e. when the left ear is affected the nystagmus is to the left when the head is hanging to the left.) The nystagmus lasts for up to a minute and coincides with a sense of vertigo, which may be severe. When the patient sits up the nystagmus may reappear beating to the opposite side. With repeat testing the symptoms and signs adapt and fatigue. Central types of positional nystagmus may also be recognized by this test. In contrast to benign positional vertigo the central type of nystagmus appears after no latent period, it persists for longer than a minute, it does not fatigue, vertigo is usually absent, and the direction is variable. The patient's vision, both with and without spectacles, should be noted (depth perception, low contrast, etc.). Low-contrast visual acuity and contrast sensitivity (the detection of large visual stimuli under low-contrast conditions) are better predictors of falls than impaired high-contrast visual acuity.

a

MANAGEMENT Many patients with recurrent falls have multiple postural defects and their balance is precarious. All require a multidisciplinary assessment. Sometimes a minor illness such as a chest infection or a newly prescribed sedative drug can simply prove too much for a frail patient. Identification of precipitating factors enables the patient to be appropriately advised. Culprit drugs should be withdrawn in patients with syncope. Vasovagal syncope may be treated with B-blockers, SSRIs or pacing. Cardioinhibitory carotid sinus syndrome usually needs a permanent pacemaker. Cervical spondylosis should be treated with neck exercises, not a cervical collar, which often makes the patient feel more unsteady. Faulty spectacles should be replaced and everything possible done to improve the patient's vision, including better illumination in the home.

183

CASE STUDY 7.1

FALLS AND 'FY T

An 83-year-old woman, who looks after her 90-year-old husband, gives a 2-year history of increasing difficulty with walking. When standing or walking she feels unsteady, as if she might fall, but there is no sense of vertigo. She goes out for a walk every day with her daughter, who lives nearby, but lacks confidence and does not go out of doors on her own. She has had several spontaneous falls, sometimes going over backwards. She says that her walking has become difficult and that her legs feel 'as if they are in concrete', but they are not painful. Sometimes when she starts walking her legs will not move - 'they seem to be nailed to the floor' - but after a few seconds she is able to get going. She finds a similar problem when she turns: her legs lag behind her upper body, with the feet seemingly stuck to the floor, and she has fallen over twice as a result. She also describes 'funny turns'. These occur about once a week without warning. She has an unpleasant sick feeling in her stomach that rises rapidly to her head. Her daughter says that during these episodes her mother looks vacant. Her eyes are open, but she does not respond to questioning and sometimes makes a funny grunting noise. The episodes last just a minute or two, but she often feels unwell for some hours afterwards. The daughter has also noticed that her mother's

memory has deteriorated. On direct questioning the patient admits to urinary urge incontinence and daytime frequency, sometimes having to pass urine every hour. At night she gets up two or three times. There is no dysuria.

Questions 1, What gait abnormality has the patient described? 2. What is the cause of her 'funny turns'? 3, What is the likeliest explanation for her urinary incontinence?

The patient's description of her feet sticking to the ground when she tries to walk or turn is known as freezing. It is a feature (in order of frequency) of progressive supranuclear palsy, arteriosclerotic parkinsonism, normal pressure hydrocephalus and idiopathic Parkinson's disease. It is rare in multisystem atrophy and very rare in drug-induced parkinsonism. The commonest type of freezing is start hesitation (sometimes called gait ignition failure), but it can also be observed in speech, the eyelids, in handwriting and in tasks such as shaving. Her 'funny turns' are typical of complex partial fits (elderly patients

Peripheral vestibular lesions may be improved with cinnarizine (15 mg t.d.s.) or betahistine (8mg t.d.s.), but these drugs may have troublesome sedative effects. Central vestibular lesions are rarely helped by drugs and these should therefore be avoided if this diagnosis is definitely made. Phenothiazines should not be prescribed for vague complaints of dizziness, because of the risk of drug induced parkinsonism. Benign positional vertigo can be treated by a physiotherapist with the Epley manoeuvre or Cooksey1

184

Case 7.2

0 Figs 7.8-7.9

0 Fig. 7.7

do not have petit mal). There is a steep rise in the incidence of fits in old age and the commonest cause is cerebrovascular disease. She has described urge incontinence and frequency, and the likeliest explanation for this is detrusor instability. Examination of the patient The patient scored 24/30 on the minimental state examination, confirming mild cognitive impairment. She was unable to stand unsupported with her feet together, even with her eyes open. When asked to walk there was start hesitation before she got into her stride. She walked with a broadbased, short-paced gait. Her posture was upright and she swung both arms normally. There was no tremor and tone in her arms was normal. In her legs tone was increased and there was also bradykinesia, shown by marked slowness and frequent hesitations when asked to rapidly tap her heel on the ground. Reflexes were brisk in her legs, but plantars were flexor. The rest of the examination, including PV and PR, was normal. Is this idiopathic Parkinson's disease? Probably not. Despite having three of the four cardinal signs (rigidity, bradykinesia and gait disturbance) the signs are all confined to the legs and this strongly suggests arteriosclerotic parkinsonism

Cawthorne exercises. The Epley manoeuvre is based on the premise that debris moving in the endolymph of the posterior semicircular canal stimulates the hair cells and causes vertigo. The manoeuvre aims to direct the debris out of the canal into the utricle. About 80% of patients experience immediate relief of vertigo and nystagmus after a single session. Cooksey-Cawthorne exercises are suitable for any patient with chronic dizziness. They are performed twice a day and help the patient to develop tolerance to the vertigo and increase confidence. The patient's chair should be at the right height (the seat level with the top of the knee) so that getting out of it is not difficult. A walking frame may initially help both mobility and confidence, but should be removed once the

7

CASE STUDY 7.1 CONTINUED (sometimes known as lower-half parkinsonism). Further support for this diagnosis and against idiopathic Parkinson's disease is the symmetry of the findings, the initial presentation with a gait abnormality, normal arm swing and upright posture, the early appearance of cognitive impairment and the absence of tremor. Management Patients with arteriosclerotic parkinsonism (unlike idiopathic Parkinson's disease) only rarely improve with levodopa. Treatment was started with co-careldopa 12.5/50 one tablet b.d., and gradually increased until she was taking the equivalent of 400 mg levodopa a day. The drug made her feel sick and

shaky and there was no improvement in her walking, and so it was stopped. Gait, mobility and confidence improved with physiotherapy. After an MSU was checked to exclude a urinary tract infection she was started on bladder retraining; after 6 weeks she was no longer incontinent and was managing to hold for 2-3 hours between voids during the day. A CT brain scan confirmed small vessel disease. (Case Fig. 7.1.1) She was checked for vascular risk factors and started on 75 mg aspirin daily. Although hypertension is associated with small vessel disease there is no evidence that lowering blood pressure or taking aspirin slows the rate of progression of the disease.

patient's walking is better. Balance and muscle strengthening exercises and measures to improve confidence and wellbeing are of proven benefit. If the falls have been such as to warrant hospital admission, then follow-up for a few weeks in a day hospital is helpful. In case of another fall, the patient should be taught how to get up off the floor 3 and advised of the various alarm systems that can be installed in the home. An occupational therapist should also visit the home and correct obvious environmental hazards and teach the patient safe transfers. Preventing fractures is important. Patients should be assessed for osteoporosis and treated accordingly (see p. 175). FURTHER READING ON BALANCE AND FALLS AGS/BGS/AAOS Panel on Falls Prevention 2001 Guidelines for the prevention of falls in older patients. J Am Geriatr Soc 49:664-672. Campbell A J, Robertson M C, Gardner M M 1999 Falls prevention over 2 years: a randomised controlled trial in women 80 years and older. Age Ageing 28:513-518. Close J, Ellis M, Hooper R et al 1999 Prevention of falls in the elderly trial (PROFET): a randomised controlled trial. Lancet 353:93-97. Davies A J, Kenny R A 1999 Syncope in older patients. Rev Clin Gerontol 9:117-126. Lempert T, Gresty M A, Bronstein A M 1995 Benign positional vertigo: recognition and treatment. BMJ 311:489-491. Maki B E, Mcllroy W E 1996 Postural control in the older adult. Clin Geriatr Med 12:635-658. Nutt J G, Marden C D, Thompson P D 1993 Human walking and higher level gait disorders, particularly in the elderly. Neurology 43:268-279.

CASE FIG. 7.1.1 CT of the head showing leukaraiosis. This is a radiological diagnosis indicating periventricular white matter hypodensity. It is commonly caused by small vessel disease and is associated with gait disturbance, falls and dementia it may also be seen in normal elderly people.

Province M, Hadley E, Hornbrook M et al 1995 For the FICSIT Group. The effects of exercise on falls in elderly patients. A preplanned meta analysis of the FICSIT trials. J Am Med Assoc 273:1341-1347

URINARY INCONTINENCE Although this is more common in the elderly, the causes and management are similar to those in the young (see Ch. 20). The major difference is that elderly patients are more likely to suffer in silence or even to deny the problem. Doctors must be proactive and should routinely ask at-risk patients whether they have 'any bladder problems'. After a pertinent general assessment (diuretics, mental state, mobility, etc.), examination to exclude prolapse, pelvic mass and prostatic carcinoma and urine tests for infection, blood, glucose and protein, the patient is referred to the continence nurse specialist for initial management. Age has little effect on prognosis and the majority of patients can expect to become dry following treatment.

DETRUSOR INSTABILITY The majority of patients are incontinent because of idiopathic detrusor instability. The cortical centre for this willed control over the hindbrain-sacral reflex lies in the frontal premotor area. In old age these tracts are vulnerable to cerebrovascular disease and Alzheimer's disease. An early sign of detrusor instability in old age is nocturia,

185

TABLE 7,7 Principles of bladder retraining 1. 2. 3. 4. 5. 6.

Explanation of condition Establish baseline micturition pattern using chart Select appropriate time for patient to wait between urinations, e.g. 1-2 hours Provide patient with a suitable pad to wear in case of incontinence Gradually extend interval as patient improves Concomitant relaxation therapy for stressed or anxious patients

which may progress to overactive symptoms of urgency, urge incontinence and daytime frequency. Stress incontinence is usually due to urethral sphincter weakness, but similar stress leakage may be seen in patients with detrusor instability and is due to cough or sneeze raising intraabdominal pressure and triggering an unstable contraction. A cystometrogram is needed to distinguish between the two causes, and patients with genuine stress incontinence can expect good results from pelvic floor exercises and surgery. Whether the detrusor instability is idiopathic or due to cortical damage (e.g. from a stroke), the response to bladder retraining is good provided that the patient can comprehend the instructions and is well motivated. About 80% of patients will be dry after 6 weeks' treatment. Bladder retraining (see Table 7.7) depends on asking the patient to urinate only after a certain fixed time, the underlying assumption being that 'holding' in this way strengthens cortical inhibition over the sacral reflex. If patients are struggling with retraining they may benefit from the addition of tolterodine m/r 2mg o.d. or oxybutyrin m/r 5-30 mg o.d. The modified release formulation is less likely to cause dryness of the mouth. If despite these measures patients continue to wet the bed or have very troublesome nocturnal polyuria, they can be helped by desmopressin tablets 0.1-0.2 mg at bedtime. This reduces urinary output in patients with a high nocturnal diuresis (>0.9mL/min) and is ideal for occasional use, such as a stay in a hotel. Up to 3 weeks treatment is safe; over longer periods blood pressure and serum sodium must be monitored. 12

VOIDING DIFFICULTIES These increase with age and also occur in women. Typical symptoms, such as hesitancy, poor stream, straining to void and a feeling of incomplete bladder emptying, do not reliably distinguish bladder outlet obstruction from detrusor hypocontractility, which may be idiopathic or sec-

1

186

Case 7.3

2

ondary to, say, a cauda equina or peripheral nerve lesion. Neurological and rectal examination and pressure-flow studies are required for an accurate diagnosis. Hypocontractility causing a large residual urine volume carries the risk of recurrent urinary tract infections, and is managed initially by advising the patient how to empty the bladder completely and, if necessary, with prophylactic antibiotics. Long-term management is with intermittent self-catheterization. Patients with benign prostatic obstruction have a choice of treatments: watchful waiting if symptoms are causing little trouble, drugs if symptoms are troublesome and surgery is declined (a-blocker or a 5-a-reductase inhibitor), TURP, or alternatives such as laser prostatectomy or thermotherapy.

POSTOPERATIVE URINARY RETENTION This may happen to any elderly man following surgery. It is commonly assumed to be due to prostatic outflow obstruction, but is much more likely to result from a combination of postoperative pain, preoperative opiates, anticholinergic anaesthetic agents, a bladder overdistended with intravenous fluids, and lying immobilized in bed. If the patient does not respond to an oc-blocker, such as alfuzosin 2.5mg b.d. (beware hypotension and give the first dose at bedtime), then the bladder should be emptied with intermittent catheterization until normal detrusor activity returns.

CATHETERS A permanent indwelling catheter is the last resort for urinary incontinence, but is not necessarily a bad solution. Some patients are very relieved to be clean, dry and comfortable for the first time in years. The gauge should be 14 or 16 Ch and the retaining balloon should contain no more than 5 mL of water to reduce the risk of provoking unstable contractions, which will cause urine to leak out around the catheter. If leakage persists tolterodine or oxybutyrin b.d. should be tried; if this is unsuccessful the best solution is to change to a suprapubic catheter. Catheters always become infected within 2 weeks of insertion. This is rarely a problem if drainage is satisfactory and fluid intake is l-1.5L/day. Catheter specimens of urine should only be sent for culture if there is an unexplained deterioration in the patient's condition or symptoms of system infection. Bladder washouts and prophylactic antibiotics are ineffective (see Table 7.8).

FURTHER READING ON URINARY INCONTINENCE Fig. 7.10

Incontinence. Causes, management and provision of services. London: Royal College of Physicians, 1995.

TABLE 7.8 Good practice guidelines: Urinary incontinence

FAECAL LOADING

Summary of recommendations from Good Practice in Continence Services (Dept. of Health 2000) and US Department of Health and Human Services: Clinical Practice Guidelines: Urinary Incontinence in Adults (1996). The strength of evidence supporting each recommendation is based on the following criteria: A Scientific evidence from properly designed and implemented controlled trials providing statistical results that consistently support the guideline statement; B Supported by scientific evidence from properly designed and implemented clinical series; C Supported by expert opinion.

This is the commonest cause of faecal soiling. Rectal sensation is impaired, probably aggravated by chronic rectal distension, and the patient often leaks before experiencing a call to stool. Problems result not only from a large hard stool in the rectum, but also from a mass of soft stool, which is not readily recognized. The rectum and lower colon should be cleared either with repeated enemas, which are uncomfortable and time-consuming, or a kinder alternative such as oral polyethylene glycol (Movicol). To clear faecal impaction, eight sachets in a litre of water are taken over at least 6 hours on 3 consecutive days. Bran must be used with caution, as it may make the stool consistency too soft and can actually cause faecal incontinence.

In primary and secondary care • All patients require initial assessment, to include a review of symptoms, examination of abdomen and perineum (including pelvic floor contraction) to identify prolapse and excoriation, and rectal examination to exclude faecal impaction and urinalysis (grade B). • Detrusor instability should be treated with bladder training (grade A).and, if necessary, anticholinergic drugs (grade A). Symptoms of stress incontinence are reduced by pelvic floor muscle exercises (grade A). • There is no evidence that oestrogen supplementation improves incontinence in postmenopausal women (grade B). • Colposuspension and sling procedure are more effective than anterior colporrhaphy or needle suspension (grade B). • Appropriate continence aids such as pads need to be provided (grade C). • Existing medications (e.g. diuretics) need to be reviewed (grade C). • Refer immediately to a urologist patients with acute retention of urine, renal impairment, carcinoma of the prostate, haematuria or recurrent infection (grade C). • Refer immediately to a gynaecologist patients with a pelvic mass, vaginal bleeding or a history of previous gynaecological surgery (grade C). • If, after initial assessment and 6 weeks of bladder retraining or pelvic floor exercises patients are not improving, they should be referred for specialist review (grade C).

SLEEP AND INSOMNIA Insomnia is a common complaint in the elderly and there is great pressure on doctors to prescribe hypnotics. The elderly receive more hypnotics than any other age group. It is often assumed that hypnotics are both harmless and effective, but for the elderly neither assumption is true. Elderly patients taking hypnotics regularly rate the quality of their sleep as worse than those not on hypnotics, and more than one in 10 persons aged 70 or over taking nitrazepam (10 mg) at night have troublesome daytime sedation, with confusion unsteadiness and an increased risk of falling. Any patient complaining of insomnia - but particularly an elderly one - needs careful assessment and not just a prescription for a hypnotic.

TABLE 7.9 Causes of faecal incontinence

NORMAL SLEEP

• Secondary to colorectal disease, e.g. infective diarrhoea, carcinoma of the rectum • Idiopathic weakness of the anal sphincter and pelvic floor muscles • Faecal loading • Neurological causes, e.g. dementia, impaired consciousness and rectal instability

A person falling asleep 'descends' rapidly through progressively deeper stages of sleep. Slow-wave sleep - which occupies about 20% of the night in the young - is reduced to only 5% by 70 years of age, and stage four is almost completely absent (Fig. 7.11). The elderly wake more frequently and take longer to fall asleep, so that even for the normal old person sleep becomes increasingly fragmented. Rapid sleep onset is promoted by dilatation of the blood vessels of the hands and feet, which increases distal heat loss. A hot water bottle at the feet rapidly induces vasodilatation and the resulting heat loss is most effective when the ambient temperature is cool. Difficulty falling asleep in old age may reflect an inability to vasodilate owing to impaired autonomic responses. Thus, the doctor needs to decide whether an elderly patient's complaint of insomnia is an unrealistic expectation of what constitutes a good night's sleep. Less physical activity and daytime naps will further reduce the ability to sleep well at night.

FAECAL INCONTINENCE Faecal incontinence is distressing for both patient and carer and is a major reason for care breaking down in the home. The prevalence in the community is less than 1%, rising to 10% in residential homes and 25-30% in nursing homes or on long-stay wards. The causes are given in Table 7.9.

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187

TABLE 7.10 Advice to patients with insomnia • • • • • •

Avoid daytime naps. Avoid caffeine or alcohol at bedtime (a hot milky drink is better). Ensure that the bed is warm and comfortable. Only go to bed when tired. Do not read or watch television in bed. If not asleep in 20 minutes get out of bed and sit in another room until feeling tired again. • Get up at the same time every morning.

A similar effect can be seen after hypnotics are withdrawn, when the patient complains of anxiety, tension and insomnia. If these withdrawal effects are not understood by the doctor and patient then a hypnotic may be needlessly represcribed.

CHOOSING A HYPNOTIC

FIG. 7.11 Typical hypnograms for young adults and elderly people The elderly wake more frequently and have less deep sleep.

SUMMARY 4 Causes of insomnia • • • • • •

Age-related changes in sleep pattern Nocturia (probably due to detrusor instability) Pain Anxiety and depression Drug induced, e.g. alcohol, withdrawal from hypnotics Specific problems, e.g. sleep apnoea, myoclonus

CAUSES OF INSOMNIA

188

Insomnia may be age related, as discussed above. Nocturia is another common reason for an old person waking up; the condition may be caused by heart failure, renal failure or diabetes, but is most likely due to detrusor instability (especially if associated with some urgency). Pain is also an important cause of insomnia, and the akinetic parkinsonian patient who cannot turn over in bed will find that sleep is disturbed. Anxiety and depression commonly cause sleep disturbances, and are best managed by psychiatric treatment directed at the primary condition. Insomnia may be drug induced. The most familiar example is alcohol which, if taken in the evening, will quickly induce sleep but because of its rapid metabolism results in rebound insomnia with awakening later the same night.

Hypnotics should only be used when insomnia is impairing the patient's daytime performance, and after advice on non-pharmacological measures (see Table 7.10). There should be a clear indication, such as a recent bereavement or impending major surgery, and the prescription should be limited to 7 or 10 days wherever possible. The drug should have a rapid onset of action, particularly if the patient's main complaint is difficulty in falling asleep. There should be no daytime sedation, although this may occur because of the accumulation of long-acting hypnotics and their active metabolites, or because of an age-related alteration in sensitivity to the drug.

Benzodiazepines Diazepam has a half-life in hours approximately equivalent to the person's age, but the constant clearance rate means that its average steady-state plasma level is unaffected by ageing. However, the half-life of its major active metabolite, desmethyldiazepam, is prolonged as a result of reduced plasma clearance. The dose necessary to produce sedation is therefore inversely correlated with age, owing partly to an increased sensitivity to the drug in old age and also to accumulation of the active metabolite. Diazepam (2 mg or 5 mg) may be a suitable hypnotic for anxious old people where a daytime anxiolytic effect is required. Daytime drowsiness, confusion and falls, however, may be a problem. Nitrazepam also produces more sedation in the elderly, probably as a result of increased receptor sensitivity (as the pharmacokinetics remain unaltered). The unwanted daytime sedation is largely dose dependent (Fig. 7.12); 2.5 mg is the maximum dose that should be given to an old person.

Morgan K 2001 Mental health factors in late life insomnia. Rev Clin Gerontol 11:71-81.

7

SEXUAL FUNCTION

FIG. 7.12 Relationship of daily dose (5.0-9.9mg/day and 10.0 or more mg/day) to the frequency of unwanted daytime CNS depression attributed to nitrazepam, with the population stratified according to age

Temazepam has a half-life of only 5-10 hours in young people but may be as long as 30 hours in the elderly. Accumulation therefore occurs and, after a week of continuous dosing at 20mg each night subjects show a significant slowing of reaction times. The effect is likely to be dose related; 10 mg at night rarely causes serious problems. Lormetazepam has a good pharmacokinetic profile for use in the elderly. Although the elimination half-life is prolonged to about 14 hours in elderly subjects, accumulation does not occur and there is no impairment of daytime performance with a nightly dose of either 0.5 mg or 1.0 mg.

Other hypnotics Zopiclone, a cyclopyrrolone, has a half-life of about 8 hours in the elderly; it does not accumulate over 7 days' treatment and psychomotor performance is unimpaired. Treatment should start with 3.75mg. Clomethiazole (chlormethiazole) is valuable in the elderly. Its pharmaco-kinetics are unaltered by age and its short plasma half-life of 3-4 hours prevents accumulation. It is metabolized by the liver, and should be used with caution in patients with cirrhosis of the liver or in alcoholics. One capsule (192mg of chlormethiazole base) may be sufficient but two capsules is still safe. Restless and confused patients are often best sedated with haloperidol (0.5-3mg nocte). Long-term use carries a risk of extrapyramidal side-effects and should be avoided in parkinsonian patients.

In western society sexuality among adolescents and young adults is openly studied and discussed. No such liberal attitude exists towards sex in old age and, unfortunately, the stereotype of the sexless old persists. Although sexual activity does decline with advancing age, much of this is due to ill health or the death of the marriage partner. Old age itself causes very little impairment of sexual enjoyment: 81% of married men and women aged 70-79 are sexually active and find it enjoyable. Overall, it would appear that continued sexual activity in old age depends on the frequency and enjoyment it afforded in middle age, the availability of a suitable partner and (particularly in men) continuing good health. The main physical changes in women result from a lack of oestrogen, which may cause vaginal and clitoral soreness, with reduced lubrication and painful intercourse. Length of orgasm may be reduced but many postmenopausal women report increased desire and arousability. Male fertility is usually maintained into extreme old age, although the volume of prostatic secretions reduces, it takes longer to achieve an erection, orgasm is briefer and the following refractory period is longer. Many doctors are reluctant to discuss sexual practice with their elderly patients and thereby lose the opportunity for helpful counselling. Vaginitis due to oestrogen deficiency responds to topical oestrogen cream and lack of lubrication is helped by over-the-counter products such as K-Y jelly or Senselle. Complaints of impotence in the male should prompt a thorough physical examination, including a blood sugar estimation. Sildenafil is generally safe and effective, but is contraindicated in patients taking nitrates. Many drugs interfere with sexual function and the elderly should be warned about this when they are prescribed. Propranolol and thiazide diuretics may produce impotence. All of the phenothiazines may cause impotence; thioridazine may also cause lack of ejaculation. Haloperidol is free of these problems. Sexuality - or the lack of it - in old age should not be seen in isolation. The need for affection, tenderness and caressing may be more important than intercourse, and counselling as to what is normal and appropriate may dispel fears of inadequacy or embarrassment.

ALTERED REACTIONS TO DISEASE FURTHER READING ON SLEEP AND INSOMNIA Espie C A 1993 Practical management of insomnia: behavioural and cognitive techniques. Br Med J 306:509-511.

In the elderly acute illness frequently presents in a non-specific way, such as with confusion, falls and incontinence.

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TABLE 7.11 Differential diagnosis of confusion and dementia Differential diagnosis Acute confusional state

Dementia

Onset Clouding of consciousness

Abrupt Yes

Course

Fluctuates, lucid intervals during day. Worse at night Yes (may be intermittent)

Gradual, months or years No (but there may be drowsiness due to sedation) Stable over course of day

Disorientation and cognitive impairment Alertness Hallucinations Duration

Increased or impaired Yes (common) Hours or days

After treatment of any underlying cause, management of the confused patient relies mainly on the correct environment, and sedation should be kept to a minimum. The patient is best looked after in a side-ward so as to avoid disturbing other patients. A relative or nurse should stay with the patient at all times to reassure, comfort and explain what is happening. The light should be kept on in the room at night. Sedation is best avoided but may be needed if the patient is very restless, e.g. haloperidol 1-3 mg q.d.s. by mouth, or 2.5-5mg i.m. (NB the oral and i.m. doses are not equivalent).

Yes

Usually normal Yes (uncommon) Steadily progressive

N.B, None of the clinical features of the acute confusional state is reliable and a confident diagnosis depends on the history.

CONFUSIONAL STATES A toxic confusional state is the ageing brain's response to a number of insults: the stress of a physical illness, a variety of powerful drugs, and alterations in the old person's familiar environment. It tends to occur more commonly in those whose mental state is already impaired, for example by Alzheimer's disease, or who have communication difficulties because of defective hearing and vision. Typically, the onset is abrupt over hours or days. This and the clouding of consciousness are the main points of differentiation from dementia (see Table 7.11). Typically, the acutely confused patient is drowsy; it is difficult to get their attention and there are fluctuations in the level of consciousness. The patient's agitation and confusion are usually worse at night. About 15% of elderly patients admitted to acute medical wards are delirious. One-third die within a month; of the survivors, 80% will have recovered mentally within a month.

Investigations

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Management

Proper assessment and diagnosis are essential, and require a careful history from a reliable witness. Physical illness, coexisting dementia, recent emotional stress, alcohol abuse, drugs (especially benzodiazepines, antidepressants, antiparkinsonian drugs, analgesics, NSAIDs and steroids), or head injury are important precipitating factors. In hospital, surgery is an important cause of confusional states. Physical examination should concentrate on identifying possible causes. The commonest are cardiac failure, Gram-negative septicaemia and pneumonia.

ABSENCE OF PAIN For reasons not clearly understood, pain due to illness or trauma, which would be expected in a younger individual, is often minimal or absent in the elderly. Thus, myocardial infarction is commonly pain free and the patient presents instead with dyspnoea or non-specific illness. Similarly, abdominal pathology such as gastric ulcers or mesenteric thrombosis may be silent; however, acute appendicitis often has a fulminating course in older patients, with the rapid development of gangrene and peritonitis. Even a fracture of the neck of femur may cause the patient only slight discomfort, evidenced by a disinclination to walk.

MULTIPLE PATHOLOGICAL PROCESSES The explanation of all symptoms, signs and abnormal investigations by one diagnosis is seldom possible in older patients, the usual pattern being one of multiple disorders. Thus, a momentary cardiac arrhythmia which may produce only a slight feeling of dizziness or palpitations in a young person may cause loss of consciousness or even a stroke with hemiplegia in an old patient. Similarly, a chest infection may precipitate heart failure because the cardiac reserve is already impaired by ischaemic heart disease. Common conditions such as obesity, osteoarthritis, diverticular disease, hypertension, diabetes, dementia and presbyacusis may all be present in a single individual, and the aim then is to decide which are causing important functional disability.

UNREPORTED ILLNESS The early identification of disease or disordered function allows treatment to be initiated or social support organized before things have gone too far. Studies in general practice show that an elderly person has, on average, at least three disabilities, and for every one known to the GP there is another that is not. Typically, cardiac, chest and neurological disabilities are known to the GP, but incontinence,

difficulty in walking, painful feet, dementia and depression often go unreported.

FURTHER READING ON ALTERED REACTION TO DISEASE Treloar A 1998 Delirium: prevalence, prognosis and management. Rev Clin Gerontol 8:241-249.

CLINICAL APPROACH When assessing an elderly patient it is generally more useful to think in terms of functional ability than to emphasize the underlying pathology. For example, the distinction between rheumatoid and osteoarthritis in a patient with arthritis of the knees may be largely academic: the fact that the patient has poor mobility is much more important. Emphasis is placed on physiotherapy, walking exercises and possibly surgery to improve mobility and independence.

HISTORY A full history remains the primary investigation. In a confused patient it is necessary to obtain additional information from a relative, community nurse, or someone who knows the patient well. The tempo with which the symptoms have developed is particularly important. Forget fulness gradually increasing over 2 or 3 years suggests Alzheimer's disease (AD), whereas a sudden onset of confusion over a day or two indicates a toxic confusional state and requires a search for underlying physical problems, such as an infection or myocardial infarct. A sudden onset of headaches or a recent change in bowel habit is never normal in old age, whereas gradually failing hearing and vision may be. The history must include a full list of the patient's medications, including details of dose and frequency; details of their functional ability (shopping, cooking, cleaning and personal toilet); and social circumstances. The main carer at home should be identified, as well as additional support that might be provided by family, neighbours and social services.

ASSESSMENT The chances of successfully discharging an elderly, frail person, if his or her homelessness, anxiety and impaired psychological state are ignored, are remote. Seeing the patient as a whole is thus not only good for the patient, it

is essential if limited health service resources are to be used effectively. Recent legislation and guidance place a responsibility on local authorities, health authorities and health providers to work together to assess, plan and meet the needs of people leaving hospital. An overall view of the patient includes assessment of medical, functional, social and psychological status, and usually brings together the professional views from several disciplines. The doctor attends to the physical and mental diagnosis and appropriate treatments. The nurse notes to what extent the patient can wash and feed him or herself or use the lavatory, and also particular problems such as incontinence, pressure sores or nocturnal confusion. The physiotherapist is concerned with whether the patient can get in and out of bed, rise from a chair, balance and walk; and as the patient improves, the occupational therapist assesses how well they can dress, bathe, cook and care for themselves. Discharge planning begins as soon as possible after admission. The social worker or discharge liaison nurse enquires into the patient's social background to find out what circumstances are like at home - whether they are already receiving support from relatives, neighbours, community nurse or social services, and whether this support will be continued or need to be increased once the patient returns home. Whether the patient's needs are simple or complex the social worker, together with the rest of the multidisciplinary team, draws up a care plan before discharge and later reviews this plan as an essential part of the care management process. The aim is to ensure that patients are speedily and effectively treated and returned to their own home in a planned and thoughtful manner, so that the gains resulting from treatment are likely to be maintained. A similar process of assessment can be initiated by family doctors using community staff, for patients living at home.

7

PHYSICAL EXAMINATION An extensive and detailed examination of every system can exhaust a frail patient. However, with practice, the

SUMMARY 5 Assessment of an elderly patient • Main stress is on functional disability, rather than underlying pathology. • Overall view essential: Medical status - manner of onset of symptoms is important. Full drug history required. Functional ability - washing, cooking, shopping etc. Psychological status - depression, anxiety, confusion etc. Social circumstances - support available at home from family and friends. • Involves a multidisciplinary team of doctors, nurses, occupational and physiotherapists and social workers.

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examination can be thorough, informative and quick if the doctor concentrates on identifying disabilities and assessing loss of function.

General appearance The examination should begin with an observation of the patient's general appearance and clothes, noting any signs of self-neglect. Facial pallor is frequently present and so is a poor indicator of anaemia. Pupil size is often small, with reduced response, and upward gaze is often limited. Angular stomatitis - if not due to ill-fitting dentures - suggests multivitamin deficiency or iron deficiency anaemia, but a black hairy tongue or sublingual varicosities are of no significance.

Skin changes Loose, dry, scaly skin is a common finding, as is senile purpura owing to increased capillary fragility on the dorsum of the hands and extensor surface of the arms. Sunexposed skin should be searched for basal cell carcinomas or actinic keratoses, which are potentially malignant. The incidence of both conditions increases with years of exposure to the sun, and both are common in the elderly. Intertrigo - sore, inflamed patches of skin under the breasts or in the abdominal folds of obese patients - is often the result of poor personal hygiene. A keratinized transverse crease across the abdomen is the consequence of long-standing kyphosis, following osteoporotic spinal wedging. The breasts should be examined for lumps.

of unwanted drug effects (see p. 199). Systolic murmurs usually of the ejection type and present at the left sternal edge and aortic area - are found in up to 60% of the elderly. They are commonly associated with significant disease such as cardiac failure, ischaemic heart disease, arrhythmias and hypertension, and should not therefore be regarded as always benign.

Feet

Bowels and bladder

The ankles and feet should be inspected for signs of peripheral vascular disease (especially in diabetics), oedema and the need for chiropody. 1

A rectal examination is essential: carcinoma of the rectum or prostate is common in the elderly, and there may be loading of the rectum with faeces - a common cause of faecal incontinence. The presence of urinary incontinence should be noted and, particularly in bedridden patients, the pressure areas inspected for sores.

Cardiovascular Abnormalities of cardiac rhythm are frequently present: occasional ectopic beats occur in about one-sixth of elderly persons, but any other arrhythmia should be regarded as abnormal and investigated by electrocardiography. Systolic and diastolic blood pressure increases with age, although there is little change over the age of 65; values up to 160/90 can be regarded as normal. Overviews confirm that treating systolic or diastolic levels above this reduces total mortality as well as coronary and stroke mortality and morbidity in persons up to the age of 85 years (Fig. 7.13), but the value of treatment needs to be set against the risk

FIG. 7.13 Distribution by age of deaths from stroke in England and Wales The single most important risk factor for stroke is hypertension. Lowering the diastolic pressure at any level by 7mmHg halves the relative risk of stroke.

Eyesight and hearing The patient should be asked whether their vision is satisfactory; if it is not, it should be tested with eye charts (Fig. 7.14). Hearing is probably adequate if the patient can hear a normal conversational voice. Examination of the eardrums for wax should be routine, particularly where a hearing aid is worn, as the earpiece may compress wax into a hard, impenetrable lump.

Neurological changes 1

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Fig. 7.11

Ankle jerks are absent in about 10% of elderly patients. Superficial abdominal reflexes are also often absent, but the presence of extensor-plantar responses is always pathological.

ing the benefits and risks of investigation and treatment. For example, a patient may be having repeated falls associated with loss of consciousness which do not bother them unduly but cause the relatives great stress and anxiety, because they dare not leave them alone in the house. Tilt table testing could be used to detect whether the falls are due to cardioinhibitory carotid sinus hypersensitivity. If they are, then a pacemaker can be safely inserted - even in the very elderly - with the potential for a considerable improvement in quality of life.

7

FIG. 7.14 Causes of visual impairment and blindness in the elderly

Vibration sense in the lower limbs is reduced, and may be absent at the ankles, in up to a half of patients over 75. However, joint position sense is usually normal. Appreciation of pain, temperature and light touch is very variable, but at least one of these sensations is impaired in about a quarter of the elderly. Both the glabellar tap, and primitive reflexes such as the pout reflex (tap the upper lip and the lips pout), grasp reflex and palmomental reflex (the palm is scratched and the chin wrinkles on the same side), can often be elicited in the elderly, particularly in those who have dementia.

Gait and balance Healthy old people show very little change in gait. There may be slight slowing, but a speed greater than 1m per second is still maintained. Nearly a fifth of the very elderly have a normal gait. A variety of pathologies, especially cerebrovascular disease, produce the senile (or cautious) gait typified by a normal to mildly widened base, shortened stride, slowing of walking and en bloc turns. There is mild disequilibrium in response to a light tap on the chest or a flick on the shoulders from behind, and difficulty in balancing on one foot (see section on falls).

WILL THE INVESTIGATION INFLUENCE MANAGEMENT? Before ordering an investigation it is necessary to consider whether the result is likely to usefully influence management. For example, a severely demented patient with an abdominal mass and positive faecal occult bloods could have the presumptive diagnosis of carcinoma of the colon confirmed by a barium enema. However, if surgery is not being considered (because of the patient's poor general condition and inability to cope with a colostomy), there is little point in the barium enema. On the other hand, if the same patient is found to be unable to walk following a fall, the hips should certainly be X-rayed. Repair of a fractured neck of femur will not only relieve the patient's pain: it is also much easier to nurse an ambulant patient than one who is bedridden.

WILL THE DIAGNOSIS AFFECT PROGNOSIS? It is important to consider whether the investigation will establish a diagnosis which significantly affects prognosis. A very frail patient with severe dyspepsia can be treated easily with an H2 antagonist. But if symptoms persist it may be important for the patient and relatives to know if the diagnosis is peptic ulceration or carcinoma of the stomach.

INVESTIGATION IN THE ELDERLY Potentially remediable conditions cannot be ignored simply because the patient is elderly, but it is not good medicine to order invasive, uncomfortable and possibly expensive tests when the potential benefit to the patient is minimal.

OVERALL STATE OF HEALTH Does the patient have the physical and mental capacity to benefit from a proposed treatment? If surgery is an option, would the patient be fit for operation? If the patient is debilitated and being looked after by family at home, then the views of these relatives must be included when assess-

ROUTINE SCREENING Most patients seen in clinic or admitted to hospital will have a full blood count, ESR (or viscosity), urea and electrolytes, glucose and TSH. Urine should be analysed for protein, glucose and blood. All of these tests can usefully detect treatable disease where the clinical diagnosis is unsuspected or doubtful. This is particularly true of thyroid disease, which is found on screening in about 4% of elderly inpatients in whom the classic symptoms and signs of hypoor hyperthyroidism may be absent. The interpretation of thyroid function tests can be difficult in the elderly because of the effects of severe systemic illness, which cause a reduction in circulating T3 often accompanied by a rise in reverse T3. As the illness becomes more severe T4 levels

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fall, partly due to interference with binding to plasma proteins. TSH immunoradiometric assays can accurately measure the subnormal range and are now widely used as the single first line test of thyroid function. Although TSH measurements are usually reliable, in very severe illness this may not be true with subnormal levels being seen during the acute stage and sometimes a rebound to slightly above the normal range during recovery. A number of drugs can interfere with thyroid function, both lithium and amiodarone commonly cause goitre and either hypothyroidism or hyperthyroidism. In the case of amiodarone the total and free T4 levels are raised and cannot be used to diagnose thyrotoxicosis. A routine chest X-ray is usually taken, as about 5% of patients over 65 admitted to hospital are found to have an unexpected lesion on chest X-ray (such as a tumour, cardiomegaly or TB). It is particularly valuable in patients presenting with falls, immobility, incontinence or deteriorating mental function; nearly a quarter of these have cardiopulmonary disease without classic features. An electrocardiogram is not routine, but is required for patients with cardiopulmonary disease, strokes (quite commonly associated with a myocardial infarct) and falls (which might be caused by a cardiac arrhythmia).

In addition to the routine blood tests, the patient should have the serum B12 level checked and a VDRL test to exclude syphilis. Although it cannot positively diagnose dementia or Alzheimer's disease, a CT scan is a valuable screening test as it can identify multiple infarctions, spaceoccupying lesions and hydrocephalus. However, only 2% of all demented patients could expect an improvement in their mental state from treatment following a CT scan. Thus, CT is only indicated in patients with mild to moderate dementia (i.e. a mini mental state examination score of 10-26/30) of less than 1 year who are fit enough for surgery if a remediable lesion is found. 1

INVESTIGATION OF DEMENTIA

INVESTIGATION OF GASTROINTESTINAL LESIONS

The main concern in the investigation of dementia is not to miss a cause for which there is specific treatment. Although rare among elderly patients referred to a geriatrician or general physician, such reversible dementias are

In the investigation of upper gastrointestinal lesions, both barium meal and endoscopy give accurate results. However, endoscopy has the advantage of providing a tissue diagnosis where a tumour is suspected, and tends to be

relatively common among referrals to specialist neurological centres. Conditions which may respond to treatment include: • • • • • • • •

depression and other psychiatric disorders normal pressure (communicating) hydrocephalus resectable tumours subdural haematoma toxic drug effects thyroid disease pernicious anaemia syphilis.

RECENT ADVANCES IN THE CARE OF THE ELDERLY 1. Comprehensive geriatric assessment with immediate and ongoing specialist multidisciplinary interventions improves functional status and reduces the length of the initial hospital stay and the likelihood of subsequent readmissions. It also reduces the rate of immediate nursing home admissions and delays permanent nursing home placement. 2. Older adults who adopt or maintain a lifestyle with increased moderate daily physical activity derive considerable health benefits. The range of activities of daily living is increased, walking speed and balance improve, and there is a reduced risk of morbidity, institutionalization and mortality. Even social and productive activities involving little or no physical exertion improve survival.

1

194

MCQ 7.4

2

Fig. 7.12

3. The benefit of thrombolysis following myocardial infarction increases with age and is most cost effective in patients 75 years and older. The development of left ventricular failure is a more important determinant of outlook than age. 4. A daily supplement of 200 mg of vitamin E improves T-cell-mediated immune response in healthy elderly people. Vitamin E may also delay the progress of Alzheimer's disease and reduce cardiovascular events. Randomized controlled trials on the use of vitamin E have given conflicting results and its use as a regular dietary supplement is not currently recommended. 5. Hypertension as a risk factor for coronary artery disease, stroke and heart failure has a greater impact on elderly than on middle-aged patients.

RECENT ADVANCES IN THE CARE OF THE ELDERLY (CONTINUED) Lowering blood pressure, particularly systolic pressure, has a marked effect on reducing the incidence of stroke. Isolated systolic pressure greater than 140 mmHg or a diastolic greater than 85 mmHg should be treated, in patients up to the age of 80. No trial has looked specifically at those aged 80 and over, although the Hypertension in the Very Elderly Trial is underway. A meta-analysis of other trials which included very elderly subjects suggests that antihypertensive treatment reduces stroke, cardiovascular events and heart failure, but does not reduce mortality or major coronary events. At present no firm clinical guidelines can be given, but patients over the age of 80 should stay on existing treatment. Treatment decisions in newly diagnosed patients should be based on biological rather than chronological age. Treatment should begin with a low-dose thiazide, calcium antagonist or ACE inhibitor. 6. Non-rheumatic atrial fibrillation is associated with a fivefold increase in the risk of stroke or transient ischaemic attacks. Its prevalence increases with age to 11% in those aged over 75. The absolute annual risk of stroke in patients with atrial fibrillation is about 5% and this is increased in the presence of other stroke risk factors (see below). For primary prevention warfarin prevents 31 strokes for every 1000 patients treated per year, but at a cost of three haemorrhages. In secondary prevention warfarin prevents 80 strokes for every 1000 patients treated per year but at a cost of 21 major haemorrhages. Aspirin is less effective than warfarin in the secondary prevention of strokes in patients with atrial fibrillation, and prevents 40 strokes per 1000 patients treated each year at a cost of seven haemorrhages. Patients with non-rheumatic atrial fibrillation should be considered for warfarin if they are aged 65-75 and have one stroke risk factor, and over the age of 75 if they have two risk factors. Patients with no risk factors should be given aspirin. Paroxysmal atrial fibrillation carries the same risk of stroke as continuous atrial fibrillation, and patients should be considered for warfarin if they have one or more risk factors present. For patients on warfarin the INR should be kept around 2.0 to minimize the risk of bleeding. Aspirin or

better tolerated by a frail elderly patient. It is the investigation of choice but may need to be preceded by a barium swallow (to check if a pharyngeal pouch is present) when investigating dysphagia. For lower bowel disorders the first steps are usually rectal examination, sigmoidoscopy, stool culture, examination of the stool for occult blood and, finally, barium enema and possibly colonoscopy. Colonoscopy is the investigation

7

warfarin is best begun within a few days of the stroke, provided that a CT scan has excluded haemorrhage. If the cerebral infarct is very large there is a risk of haemorrhagic transformation and warfarin should not be started for 14 days. Contraindications to warfarin include cerebral haemorrhage, active peptic ulceration, uncontrolled hypertension, falls, moderate to severe cerebral periventricular small vessel disease and concerns over compliance. It is particularly important for elderly patients taking these drugs to have annual review to reassess the risk-benefit ratio. Treatment with aspirin is simpler and safer than warfarin and should always be considered for patients in atrial fibrillation when warfarin is difficult to control or is contraindicated.

Stroke risk factors • Previous stroke, transient ischaemic attack, myocardial infarct or peripheral arterial thromboembolism • Hypertension • Ischaemic heart disease • Recent heart failure • Diabetes mellitus • Thyrotoxicosis • Echocardiographic abnormalities, e.g. impaired left ventricular function, enlarged left atrium, enlarged left ventricle, intracavity thrombus. 7. Advances in surgical techniques have meant that major cardiac and vascular surgery is now routinely carried out on elderly patients. Thrombolysis and angioplasty allow successful treatment of peripheral ischaemia, and carotid endarterectomy should now be considered for a patient of any age who has a stenosis of greater than 70% and is either having transient ischaemic attacks or has made a good recovery from a cerebral infarct. Patients over the age of 70 years undergoing aortic valve replacement have a survival rate of 95% at 1 year and 75% at 5 years, which is no different from age- and sex-matched controls from the general population. Even in octogenarians undergoing aortic valve replacement the 5-year survival is 65%. By comparison aortic balloon valvuloplasty results are poor. 0

of choice for colonic adenoma, carcinoma or angiodysplasia, as it is more sensitive than barium enema and often better tolerated. Treatment of non-metastatic colonic malignancies gives a good prognosis; vigorous investigation of fit and active elderly patients is therefore justified. In the frailer patient, however, more caution is necessary before ordering a barium enema. Both the preparation (laxatives and sodium citrate enema) and the barium

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enema itself are uncomfortable and difficult procedures for elderly patients to undergo. Ultrasound scans have the advantages of being non-invasive, quick and relatively cheap, and are particularly useful for investigating jaundice, abdominal masses, pancreatic tumours and possible liver metastasis. In some centres CT scanning of the colon is now established as an alternative to barium enema in frail patients. Investigation of faecal incontinence is described on page 187.

INVESTIGATION OF BACTERIURIA

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A routine midstream urine (MSU) test in elderly patients admitted to hospital will show significant bacteriuria (bacterial count of more than 100000 organisms per mL) in 20-30% of men and women. Provided the patient is asymptomatic this bacteriuria is best ignored, as it is not associated with excess morbidity or mortality. A better guide to infection is pyuria, and in the presence of lower urinary tract symptoms even a sterile pyuria may be relevant. This is most conveniently detected by the finding of leukocytes on urine dipstick (e.g. Multistix 8 SG), with an MSU being sent for culture and sensitivity if dipstick testing is positive. The cardinal feature of a urinary tract infection is dysuria, but there is increasing recognition that some patients with urinary incontinence have no dysuria yet have a low-grade infection indicated by pyuria, and when this is treated with antibiotics the symptoms improve. Similarly, some patients complain of suprapubic or perineal pain during bladder filling, which may not be attributed to infection if the MSU fails to show a significant bacteriuria (i.e. more than 105 organisms per mL). However, it is possible that this criterion is inappropriate in these patients and bacterial counts of 102 per mL may be relevant. Urine should also be cultured for Chlamydia trachomatis, Trichomonas vaginalis and yeast. In summary, patients with a significant pyuria (positive urine dipstick or more than 10 leukocytes per highpowered film) who have lower urinary tract symptoms should be given a course of an appropriate antibiotic, such as trimethoprim or nitrofurantoin. Some patients require several weeks' treatment before the urine is clear. Patients with recurrent urinary tract infections associated with lower urinary tract symptoms should be considered for continuous low-dose antibiotic prophylaxis. A number of different regimens have been used, but all appear equally effective. Patients with recurrent urinary tract infections should have their postmicturition residual urine checked. If this is increased it is usually the result of detrusor hypocontractility or bladder outflow obstruction, and patients need to be advised on the importance of emptying the bladder completely as a chronic residual urine increases the risk of further infection. Surgery or intermittent self-catheterization may be needed. A group of patients often difficult to manage are those with recurrent episodes of suprapubic or perineal pain

during bladder filling, which is relieved by emptying and associated with frequency and urgency, but no actual urinary incontinence. Repeat urine testing is always unremarkable and antibiotics do not relieve symptoms. These patients usually have idiopathic detrusor hypersensitivity and some improve with bladder retraining. Patients with severe pain or with red cells in their urine should undergo cystoscopy to exclude interstitial cystitis or bladder cancer.

FURTHER READING ON INVESTIGATIONS IN THE ELDERLY Kafetz K 1998 Blood tests in elderly people and their interpretation. Rev Clin Gerontol. 8:305-318.

ASSESSMENT OF FITNESS FOR OPERATION Advanced age is no longer a contraindication to surgery as over the last 40 years the surgical mortality rate for patients over 80 has fallen from 25% to about 5%. In those over 90 mortality is around 10%. This compares with less than 2% for younger patients. This increased risk is only justified if surgery offers a reasonable prospect for improving the quality of the patient's life, or preventing loss of function. Average life expectancy for a 70-year-old male is 11 years and for a female 14 years, and many patients feel that this potential outweighs high surgical risks. Surgery for the relief of severe pain or complete bowel obstruction would probably be indicated even in the most severely disabled patient. However, a patient would need to be relatively fit and active before removal of a non-obstructive malignant bowel tumour, repair of an aortic aneurysm or a coronary artery bypass would be considered. Ageism should not be allowed to cloud the issue and each patient requires careful individual assessment. This is especially true of cancer in old age, which is less extensively investigated and receives less treatment than in younger patients, a difference not wholly explained by appropriate adjustment for comorbidity or frailty. Patients should always have a specialist opinion, as chemotherapy and radiotherapy protocols can be modified in less fit patients. The 1999 report of the National Confidential Enquiry into Perioperative Deaths highlighted the need for senior surgeons, anaesthetists and physicians to be closely involved in the care of elderly patients who have poor physical status and a high operative risk. Patients needing an urgent operation should be given a high surgical priority. The increased surgical mortality in the elderly is due to several factors, which are shown in Table 7.12. The mortality risk must be weighed against the likely final outcome of surgery. Total hip replacement has trans-

TABLE 7.12 Selecting patients for surgery or intensive care Chronological age alone is a poor indicator of outcome: • Good results in the elderly reflect good selection criteria • Consider the patient's previous health, level of physical independence, exercise tolerance and mental state • Patients' and families' views must be considered; they may be much less enthusiastic than the doctor about major surgery Increased mortality is associated with: • The presence of unsuspected heart disease • Reduced pulmonary and cardiac reserve (making a postoperative chest infection or myocardial infarct more likely) • Greater susceptibility to anaesthetic drugs • Greater risk of developing pressure sores postoperatively

is practicable). Many patients will have a minor ECG abnormality which provides a useful baseline measurement for comparing postoperative changes. Preoperative ECG abnormalities do not reliably predict postoperative cardiovascular complications, which can be expected in about one-fifth of elderly patients and consist mainly of heart failure with some cases of myocardial infarction. Cardiovascular disease is the major cause of increased mortality following general surgery in the elderly. Impaired mental function and poor motivation are also barriers to postoperative rehabilitation. If concentration and short-term memory are poor the patient may be unable to grasp the physiotherapist's instructions; episodes of mental confusion and agitation may also occur.

7

FURTHER READING ON SURGERY formed the lives of many old people and is now a routine operation. However, if chronic lung disease or an old stroke has reduced the patient's exercise tolerance to a few yards, the operation is unlikely to be worthwhile unless for the relief of severe pain. Before surgery, heart failure and diabetes should be controlled, dehydration and electrolyte disturbance corrected, and severe anaemia remedied by blood transfusion. A routine preoperative ECG is worthwhile. Its major use is in detecting a recent myocardial infarct, which would mean postponement of surgery for 6 months (if this

Seymour D G 1999 The ageing surgical patient - an update. Rev Clin Gerontol 9:221-233.

PRESCRIBING FOR THE ELDERLY A general rule when prescribing drugs for the elderly is 'not too many and not too much'. Although the elderly make up only 18% of the total population, they receive almost half of all prescriptions issued.

CASE STUDY 7.2 SURGERY IN OLDER PATIENTS A 90-year-old woman was admitted to hospital for rehabilitation following an accidental fall at home. She had a past history of left ventricular failure due to ischaemic heart disease, which was well controlled with drugs. She also suffered chronic osteoarthritis of her hips and 2 years previously she underwent an elective total hip replacement on the left. She lived alone in a house with downstairs bed and toilet. She was fairly independent and mobile around the house with the help of a walking frame. She had home care visits five times a week. She was taking furosemide (frusemide) 40mg o.d., captopril 25 mg b.d., diclofenac 50mg t.d.s., aspirin 75 mg o.d. and co-codamol 2 tablets q.d.s. She weighed 47.6kg.

A few days after admission she had an episode of haematemesis and melaena. Although frail she was alert and haemodynamically stable. Pulse 90 per minute, BP 140/100. Abdominal examination was normal, haemoglobin 8.8g, serum albumin 27 g. The rest of her blood results, chest X-ray and ECG were normal.

Question

1. How would you manage this patient?

She needs a blood transfusion (2 units were given) and an urgent oesophagogastroduodenoscopy (OGD). This showed a duodenal ulcer with a deformed pylorus. CLO

test was negative. The aspirin and diclofenac were stopped and she was given omeprazole 20 mg daily. Over the next few days she made good progress and was eating and drinking well, but she then had a second episode of haematemesis and melaena. Haemoglobin was 10.4 g. The omeprazole was increased to 40 mg daily. Three days later the nurses reported faecal vomiting. The abdomen was distended and tender, but bowel sounds were normal and the rectum was empty. Plain abdominal X-rays showed only gaseous distension with no signs of obstruction. She was treated with intravenous fluids, given nil by mouth, and had a phosphate enema. The nausea and vomiting persisted intermittently for the next few days. 197

CASE STUDY 7.2 CONTINUED A barium enema showed only diverticular disease of the colon. She was referred to the surgeons, who recommended the continuation of conservative management as she was considered unfit for surgical intervention.

Question 2. Do you think that this was the right decision?

The view of the physicians at the time was that this patient should have had surgery. Prior to admission she had been in relatively good health. Her heart failure was well controlled and she had successfully undergone a total hip replacement. All of these factors would point to a relatively good prognosis. The 1999 report of the National Confidential Enquiry into Perioperative Deaths stressed the importance of a team of senior surgeons, anaesthetists and physicians being closely involved in the care of elderly patients who have poor physical status and high operative risk. Furthermore, the experience of the surgeon and anaesthetist need to be matched to the physical status of the elderly patients as well as to the technical demands of the procedure. Following the decision not to operate the patient continued to have

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nausea and vomiting and steadily deteriorated. Four weeks after the second episode of haematemesis her haemoglobin had dropped to 8.6g and her weight was now 38kg. She declined a repeat OGD and a barium meal showed complete pyloric obstruction. Again she was referred to the surgeons, who remained very reluctant to operate. The opinion of the anaesthetist was sought and he felt that surgery might be considered under epidural anaesthesia. Despite her general frailty the patient was fully alert, and after the available options and surgical risks were explained to her she opted for surgery. She was transferred to the intensive therapy unit where total parenteral nutrition was given for 3 days; by this stage her weight was 32 kg. She then underwent gastrojejunostomy under epidural anaesthesia, which was successful. She had an uneventful postoperative recovery. Three days later nasogastric tube feeding was started and 2 days after that she was swallowing liquids. After another 10 days she was able to start rehabilitation, and 2 months following surgery, by which time she weighed 38 kg, she successfully returned home. Discussion This patient had haematemesis and melaena as a result of peptic ulcer disease, presumably secondary to her intake of non-steroidal anti-

About 75% of those over the age of 65 and living at home are taking some kind of medication, with 15% receiving four drugs or more. However, multiple prescriptions increase the risk of drug interactions and adverse effects, and compliance is likely to be poor. Over 90% of people in residential and nursing homes receive prescribed medicines: many of these are unnecessary. Adverse reactions are two or three times more common in the elderly than in those under the age of 60. This is due primarily to slower rates of inactivation and excretion but also, with some drugs, to increased sensitivity

inflammatory drugs. She developed gastric outlet obstruction due to a deformed pylorus. Conservative management was initially adopted, but without success. Despite the high surgical risk this patient survived, but with hindsight it is apparent that the surgical risk would have been considerably less had the operation been carried out electively 2 or even 3 weeks previously. Emergency surgery for whatever reason in older people increases the surgical risk. Mortality in patients over the age of 70 undergoing emergency surgery is 20%, compared to 1.9% in patients undergoing elective operations. Postoperative complications and morbidity are also higher. Over the last few years surgery has become much safer owing to improvements in anaesthesia and surgical expertise. Age is generally a poor predictor of surgical morbidity or mortality, and certainly a much poorer predictor of outcome than severity of illness. Careful preoperative assessment of a patient's co-morbidities is more important than age in determining risk. This patient's major preoperative risk was associated with her poor nutritional status: weight loss of more than 20% or a serum albumin less than 35 g/L increases mortality. Giving preoperative total parenteral nutrition for severely malnourished patients probably reduces morbidity and mortality, although the evidence is inconclusive.

of the target organ. Thus, many drugs need to be given in lower dosage.

ALTERED PHARMACOKINETICS Drug absorption Changes in gastrointestinal function with increasing age include a rise in gastric pH, decreased gastric emptying time, decreased splanchnic blood flow, and loss of small

bowel mucosal surface area. Although these changes are theoretically rate-limiting for drug absorption, none appears to be important for passively absorbed drugs.

young patients. The drug plasma concentration may have to be measured.

Distribution

ALTERED PHARMACODYNAMICS

There are a number of theoretically important changes that affect drug distribution in the elderly: • A decrease in lean body mass and total body water reduces the distribution of water-soluble drugs. • Increase in body fat results in an increased volume of distribution of lipid-soluble drugs such as lidocaine (lignocaine), chlordiazepoxide and diazepam. • The small decrease in plasma albumin that occurs in the elderly will reduce drug binding and may thus result in an increased distribution of the drug. As it is the unbound fraction that is clinically active, there may be an increased pharmacological effect. This may be important in sick or malnourished patients, who have a greater reduction in plasma albumin concentration. • Conversely, if the drug binds predominantly to a1-acid glycoprotein (e.g. lidocaine (lignocaine) and disopyramide) then protein binding is likely to be normal, or even slightly increased, in the elderly.

Metabolism There is a reduced rate of hepatic metabolism with increasing age. This reduces presystemic metabolism and causes a marked increase in the bioavailability of drugs metabolized by the liver, such as propranolol, labetalol, lidocaine (lignocaine), clomethiazole (chlormethiazole) and verapamil. In the case of propranolol the age differences in plasma concentrations are large, with the mean concentration in the elderly being about twice that found in the young. However, because of reduced sensitivity, the dosage need not be lowered. Age-related effects on drug metabolism are variable, so that even some extensively metabolized drugs, e.g. warfarin or diazepam, may show no change in clearance.

Excretion Advancing age is accompanied by a reduction in both glomerular filtration rate and tubular function. At 60 years of age renal function is about half that at age 30, and will be further impaired by dehydration, cardiac failure and urinary retention, as well as by diseases such as diabetic nephropathy. Normal elderly people may have significant reductions in glomerular filtration rate and tubular function yet have a normal blood urea and serum creatinine. For drugs excreted by glomerular filtration the rate of excretion correlates with glomerular filtration rate. Some of these drugs, e.g. digoxin, gentamicin, lithium, cimetidine and chlorpropamide, have a low therapeutic index and their dosage therefore needs to be carefully chosen in the elderly. In general, a lower dose will be needed than in

7

The most clinically important result of altered pharmacodynamics occurs with drugs acting on the central nervous system. Sedatives and tranquillizers are more likely to produce drowsiness and hangover effects in the elderly. Although nitrazepam and diazepam have similar plasma concentrations in both young and old, psychological testing shows that the elderly make more mistakes and have longer reaction times for 36 hours after a single dose. They also show increased sensitivity to anaesthetic agents such as halothane. A reduced sensitivity to adrenergic agonists is seen in the elderly heart. Sensitivity to propranolol also decreases, so that despite the higher plasma propranolol concentrations seen in elderly subjects the degree of B-blockade is reduced. The dose of warfarin needed to produce anticoagulation in the elderly is reduced, but this is not due to an agerelated rise in plasma warfarin concentration. Warfarin acts by inhibiting the synthesis of vitamin K-dependent clotting factors, and this inhibitory effect is greater in the elderly, resulting in an increased sensitivity.

ADVERSE REACTIONS Whenever a reduction in drug elimination or increase in receptor sensitivity occurs, there is the likelihood of an excessive drug effect and hence an adverse reaction. The risk of these adverse reactions increases with age (Fig. 7.15A). About 3% of all admissions to geriatric units in the UK are due solely to unwanted drug effects; in a further 8% of cases an adverse reaction is a contributory cause. Two-thirds of all reactions are caused by two groups of drugs: • Cardiovascular drugs: diuretics, digoxin and hypotensive drugs • Drugs acting on the central nervous system: antiparkinsonian drugs, antidepressants, hypnotics and tranquilizers. Although more than 70% of patients taking cardiovascular drugs make a full recovery from the adverse reaction, only 46% recover from the ill effects of antiparkinsonian drugs. The risk of an adverse reaction increases with the number of drugs taken (Fig. 7.15B). Elderly people are more likely to have multiple diseases than the young, and the likelihood of polypharmacy is therefore high. Not only is the patient apt to be muddled by a large number of drugs and inadvertently take the wrong dose, but drug

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FIG. 7.15 Adverse drug reactions A The increase in adverse drug reactions with age; B Prevalence of adverse reactions related to number of prescribed drugs. The risk in a patient taking only one drug is about 11%, but is 27% if six drugs are taken.

interactions lead directly to an increased adverse reaction rate. This is particularly likely to occur when drugs with a low therapeutic index, e.g. anticoagulants, antidepressants, anticonvulsants and antihypertensives, are used in combination. There are a number of important causes of adverse drug reaction in the elderly other than altered pharmacokinetics and pharmacodynamics. Inadequate clinical assessment is perhaps the most common. Dependent leg oedema, for example, is more often due to immobility than to congestive cardiac failure, and a diuretic is thus not an appropriate treatment. Similarly, old people who complain of dizziness are often expressing a sensation of unsteadiness and fear of falling, rather than true vertigo. Prochlorperazine - an effective vestibular sedative - is frequently prescribed in this situation but is quite useless and also carries a serious risk of parkinsonian side-effects. Loneliness and social problems often present as minor aches and pains, unhappiness and insomnia. Although both difficult and time-consuming, it is far better to deal with the underlying problems than simply to issue a number of drug prescriptions.

COMPLIANCE There is no evidence that the elderly are less compliant than the young, but they do make more medication errors. These occur in up to three-quarters of old people taking

1

200

MCQ 7.5

2

Fig. 7.13

drugs, but only about a quarter are potentially serious, usually because of underdosage. Medication errors are more commonly made by patients over the age of 75 who are living alone and are confused. Poor visual acuity often prevents an old person from reading the instructions correctly, and impaired manual dexterity may make it difficult or even impossible to unscrew the cap on the bottle (particularly if it is one of the child-resistant types). Compliance can be improved, and errors in medication reduced, by careful counselling and an explanation of when and how to take the drug. After a single lesson in inhaler technique up to 30% of elderly patients are still unable to use a metered dose inhaler. Further instruction may be needed, or patients can be given a breath-activated device or a large-volume spacer, which they find easier to use and thus prefer. Written instructions or a calendar pack can be helpful. Dosette boxes (devices which organize a week's supply of tablets) can be useful for patients who are motivated to take their drugs but are absentminded. They can be prepared by the pharmacy or by a carer. 1

CHOLESTEROL LOWERING IN STROKE Total and low-density lipoprotein (LDL) peak at around age 65 in males and 75 in females, and thereafter decline. There is probably also a decline in high-density lipoprotein (HDL) after age 65. Thus cholesterol levels measured in old age do not necessarily reflect lifetime levels. There is an inverse relationship between serum cholesterol and haemorrhagic stroke, and a direct relationship with ischaemic stroke. In general the association between cholesterol and stroke is considerably weaker than those reported for blood pressure, diabetes and atrial fibrillation. Systematic reviews indicate that for people with known CHD and cholesterol levels in the mid to elevated range statins significantly reduce stroke risk by approximately 32%. This is probably greater than the relative stroke risk reduction achieved with aspirin therapy (approximately 25%) and compares with the 40% resulting from antihypertensive treatment. The number needed to treat to prevent one stroke over 5 years using statins in patients with CHD is approximately 80-150, compared with 40-70 for treating elderly hypertensives. The best advice at present is that patients up to the age of 75 years with known CHD and total cholesterol >5 mmol/L will benefit from a statin to reduce the risk of a first stroke, and also to reduce the risk of further CHD events. Patients up to the age of 70 with cholesterol >5 mmol/L and no history of CHD, but at high cardiovascular risk, benefit from a statin because of reduced CHD risk. The cardiovascular risk can be assessed using various tables

RECENT ADVANCES IN STROKE REHABILITATION

RECENT ADVANCES IN DYSPHAGIA AFTER STROKE

• The accuracy and completeness of clinical notetaking is improved by using a clerking proforma. Although there is no reliable evidence it is likely that improved assessment leads to improved outcome. Certainly audit is facilitated and, where the process being audited is of proven effectiveness (e.g. the use of aspirin as secondary prevention of ischaemic stroke), it is reasonable to assume that improved performance (i.e. ensuring that all ischaemic stroke patients leave hospital taking aspirin) will lead to improved outcome. • An overview of controlled trials confirms that stroke units reduce early mortality by 28%, disability (measured as an 'activities of daily living' score) is significantly reduced and there is a substantial reduction in the odds of being dead or requiring institutional care 1 year after a stroke. 2 • The characteristics of a stroke unit are: coordinated multidisciplinary rehabilitation with involvement of carers; a specialist interest in stroke disease and rehabilitation; and training and education programmes for both staff and carers. • There is early evidence to suggest that, after discharge from hospital, stroke patients have better outcomes if physiotherapy is continued in their own homes rather than at geriatric day hospitals.

Patients should be routinely tested by asking them to sip some water and observing any tendency to choke, make a gargling sound when asked to say 'aah' or have a 'wet voice'. The gag reflex is unreliable. Patients with dysphagia should take nothing by mouth, be given intravenous fluid, and be assessed by a speech and language therapist. After 48 hours many clinicians start tube feeding, but there is no evidence that early feeding increases the proportion of patients surviving without severe disability, or indeed whether a nasogastric tube or percutaneous endoscopic/gastrostomy (PEG) is preferable. There is an indication from a small trial that a PEG is better tolerated and produces a greater improvement in nutritional state, but the evidence is not strong and there is considerable uncertainty regarding when tube feeding should begin, which is the best method, and, for patients who are able to swallow, whether nutritional supplements by mouth improve stroke outcome. A large international trial (FOOD) is under way to try to resolve these issues.

(e.g. Sheffield table or the New Zealand guidelines) that predict risk based as the ratio of total: HDL cholesterol, age, sex and the presence of hypertension, smoking and diabetes. • Patients who have had a non-haemorrhagic stroke or TIA are at high risk of a myocardial infarction, and a statin is justifiable for the secondary prevention of CHD if total cholesterol is >5mmol/L up to the age of 75.

REHABILITATION The aim of the rehabilitation team is to help restore maximum capability within the limits of the elderly patient's needs and disability.

PRINCIPLES OF REHABILITATION When setting a realistic rehabilitation goal it is important to consider the patient's needs. For a very elderly and frail

amputee wheelchair independence may be perfectly satisfactory, but this would not be acceptable for a fit 65-yearold amputee who is a keen golfer. Although rehabilitation is a core activity of geriatricians it has suffered in recent years as services have had to focus on the increasing number of acute admissions. As a result, rehabilitation goals are often set merely at achieving independence in activities of daily living (ADL), so that patients can be discharged from hospital as quickly as possible, but goals directed towards quality of life, such as driving the car or using public transport, may be just as important to the patient. Rehabilitation does not stop once the patient leaves hospital, and there is increasing interest in the role of rehabilitation as a means to prevent hospital readmission. Programmes of chronic disease management agreed between primary care and the relevant specialist teams improve outcomes and are cost effective. Hospital admissions can be reduced for patients with chronic obstructive pulmonary disease by comprehensive pulmonary rehabilitation (coordinating medical treatment, nutrition and exercise) and for heart failure by nurse-led monitoring and advice. For patients with Parkinson's disease home-based rehabilitation can be particularly effective. Patients can be taught to break up long movement sequences into separate steps and do only one movement in the sequence at a time. They can be advised to avoid doing two things at once, such as carrying a tray of drinks when walking, and to consciously think about each movement before starting to do it. Movement around the home can be improved by the occupational therapist providing visual cues, which are par-

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ticularly useful in overcoming freezing episodes. Cue cards can be placed around the house with instructions such as 'go' or 'step', and strips of adhesive tape on the floor, particularly in confined spaces such as bathrooms or kitchens, can encourage more normal walking patterns. For patients who have had falls it might seem obvious that a home visit by an occupational therapist should concentrate on removing environmental hazards. However, apart from correcting obvious dangers (such as a broken light bulb at the top of the stairs) most studies on environmental manipulation have shown little benefit in the form of reduced rate of falls. However, what the occupational therapist can do is to teach the patient how to cope safely with various everyday activities and to help them regain their confidence. There is some evidence that this type of intervention reduces the risk of falling not only in the home, but outside it as well. The principles of rehabilitation in the elderly are essentially the same as for young patients, but some special features of old age should be noted. Multiple pathology is likely to be present, so that the speed with which a stroke patient can be mobilized is often hampered by shortness of breath due to chronic lung or heart disease. The mental barriers to recovery may also be greater, whether due to dementia or to the increased feelings of passivity and dependence sometimes shown by older people. There may be difficult social problems owing to lack of family support or poor housing. Rehabilitation is concerned with helping the patient to learn to do things for him or herself, and there may be times when it is better to let a stroke patient struggle to feed himself rather than to always rely on feeding by a carer. Patients enjoy exercising their painfully regained skills and it is essential to regain independence before leaving hospital and returning home.

THE MULTIDISCIPLINARY TEAM

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The most effective approach to rehabilitation is through a multidisciplinary team, with each member contributing their special skills and working together with the patient and family towards an agreed goal. The team meets regularly to discuss the patient's progress and review future plans. With a good team the patient is undergoing rehabilitation all the time and not just during the half an hour a day spent with the physiotherapist or occupational therapist. Although elderly patients can be successfully rehabilitated on a busy general medical ward, there are definite advantages to grouping them together in one ward: the nurses develop greater expertise, the pace of treatment can be better geared to the patients' needs, and it is easier to create an atmosphere of 24-hour-a-day rehabilitation. Correct positioning of a stroke patient is something all nurses and doctors should be aware of (Fig. 7.16). Before discharge, the occupational therapist will take

FIG. 7.16 Positioning the stroke patient A Incorrect; B Correct. The forearm on the affected side should be supported and should point straight forwards with wrist and fingers extended and thumb abducted. The arm must not be allowed to hang from the shoulder in internal rotation. Choosing a suitable chair - with unrestricted view and with arm rests - is important3, C Transferring the stroke patient to a chair. Note the support given to the affected arm.

the patient on a home visit to see how well they cope in familiar surroundings. This also allows assessment of the need for a specific aid, e.g. a grab handle on the wall next to the lavatory, and the opportunity to have it fitted before the patient arrives home. The social worker not only organizes the care package at home or arranges funding for patients going into residential or nursing homes, but also plays a valuable role in providing support and advice. Increasing disability and loss of independence can cause considerable distress to both patient and family, which can be helped by skilled counselling.

FURTHER READING ON REHABILITATION Department of Health 2001 National Service Framework for Older People. Standard 5: Stroke, www.doh.gov.uk/nsf/olderpeople.htm Young J, Brown A, Forster A, Clare J 1999 An overview of rehabilitation for older people. Rev Clin Gerontol 9:183-196.

COMMUNITY CARE AND LONG-STAY CARE The demand for community and long-stay care rises rapidly with age. Of those aged 65-74 only 1 % are living in institutional care and only 6% are receiving visits from a home help. For those aged 85 and over the figures rise to 26% and 36%. In the UK the principal demographic change in recent years has been a one-third rise in the number of those aged 85 and over. The escalating cost of caring for this frail and dependent section of the population (Fig. 7.17) has caused governments of all industrialized countries to think hard about how this need might be met. In the UK the NHS and Community Care Act of

7

FIG. 7.17 Resources required to keep pace with demographic change Demographic change has the most marked effect on spending on long-term care C 1991 = £8 billion: this includes nursing and residential homes as well as NHS long-stay beds. A Hospital and community health services expenditure 1991 = £16 billion B General practitioners and prescription medicine expenditure 1991 =£5.5 billion.

1990 (implemented 1993) coordinates domiciliary, day care and respite services so that the old person can live in their own home for as long as possible; when this becomes no longer feasible they are cared for in private residential or nursing homes. The cost of this is borne by the individual until capital has dwindled to a threshold level (currently £18500), when the bill is then picked up by the local authority. Local social services departments and health authorities have to agree joint policies for providing both residential and nursing home care and arrangements for discharge from hospital to the community. An old person living at home in need of support has a care worker who identifies his or her needs and plans a package of care. This may involve home carers, district nurse, bathing attendant and 'meals on wheels'. Respite care to give the carers a break may be arranged in either a residential or nursing home or the local community hospital. Day care is available at local authority centres, where the needs are mainly social, or at the geriatric day hospital if the needs are medical. Patients in hospital may not be sent home until there is an agreed discharge plan based on a multidisciplinary assessment. If this assessment, whether carried out in hospital or in the community, determines that the patient is no longer able to cope at home then a decision will be made whether to admit them to a residential or nursing home (paid for as outlined above). Patients with complex conditions or multiple problems who need continuing weekly assessments by the geriatric medical team are cared for free of charge in an NHS long-stay hospital bed. These patients now make up only a tiny minority and the

FIG. 7.18 Vicious circle

NHS withdrawal from the long-stay sector has raised important issues about standards of medical care in private institutions. The Community Care Act has brought improvements in the form of a better coordinated, patient-orientated service, but the time patients spend in hospital waiting for transfer to institutional care has increased because of funding difficulties, and there are continuing uncertainties about the eligibility criteria for an NHS long-stay bed. Increasing acute hospital admissions and a declining number of available beds are putting unprecedented pressure on acute medical services. An important response has been to try to find ways of preventing inappropriate admissions of elderly patients to district general hospitals and to speed up the discharge of those whose investigations and treatment is completed. Initiatives include improved community rehabilitation services; hospital at home; rapid response teams to provide short-term support for patients sent home from A & E departments; and increasing use of community hospitals. This range of services is now described as intermediate care. Despite these developments, community services have not been expanded sufficiently to cope with the increased demand resulting from hospital bed closures. Elderly people are being discharged from hospital 'quicker and sicker', and this has two predictable results. The increased demand on social services departments from a few people with a high level of personal care needs means that very many people who require less intense service packages receive no service at all. Secondly, the pressure for earlier hospital discharge results in

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insufficient rehabilitation, creating a vicious circle (Fig. 7.18). This will only by broken by joint working between the NHS and social service departments to develop better services. It should not be forgotten that in the UK, as in other countries, the unpaid support provided by relatives, friends and neighbours easily outweighs that provided by statutory services. Advising and helping these carers is an important part of the doctor's role. It is also important to remember that the quality of care in long-stay institutions, private or NHS, is crucially dependent on the visiting doctor's vigilance and enthusiasm. This applies not only to ensuring that high-quality nursing standards are maintained, but that the environment for the patients is made homely, pleasant and comfortable. The emphasis should be on educating patients to do as much for themselves as possible, and physiotherapy and occupa-

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tional therapy may be entirely appropriate for certain patients.

FURTHER READING ON COMMUNITY CARE AND LONG-STAY CARE Black D, Bowman C 1997 Community institutional care for frail elderly people - time to structure professional responsibility. Br Med J 315:441-442. Department of Health 2001 National Service Framework for Older People. Standard 3: Intermediate care. www.doh.gov.uk/nsf/olderpeople.htm Nikolaus T, Specht-Leible N, Bach M et al 1999 A randomised trial of comprehensive geriatric assessment and home intervention in the care of hospitalised patients. Age Ageing 28:543-550. The Coming of Age - improving care services for older people. London: Audit Commission, 1997.

8

Psychological Medicine Jeremy Holmes

Classification and overview 205

Hysteria 235

The causes of psychiatric illness 210

Histrionic personality and related conditions 238

The psychiatric examination 211

Eating disorders 239

Treatments in psychological medicine 212 Anxiety 212

Drug dependence 243 Alcoholism 247

Loss, grief and bereavement 217

Mental handicap or learning difficulties 252

Depression 218

Psychiatry and the law 253

Suicide and parasuicide 223

Mental health legislation 253

Mania and hypomania 226

Medicine and the emotions 255

Schizophrenia 228

Sex and medicine 256

Paranoid states 231

Death and dying 257

psychiatry are psychology and psychoanalysis, child development and sociology. Neurochemistry and neuroimaging, and the new genetics and neo-Darwinism, are making increasingly important contributions to the subject. The central meeting ground for medicine and psychiatry is the doctor-patient relationship. All patients, whatever their illness, have feelings and fears that the doctor needs to understand and know how to handle. The meaning to the patient of a particular symptom - chest pain, for example, whether due to angina or to anxiety in a 40-yearold man whose father died suddenly of a heart attack in middle age - needs to be understood, in order to appreciate its impact on the patient, as well as diagnosed and investigated. Psychiatry is concerned with meaning as well as explanation, and with methods of communication with the patient, as well as the technology of treatment. Despite the inseparability of psyche and soma, many doctors find psychiatry difficult and confusing. This is partly because the subject is inherently complex and multifaceted, but also because psychiatry involves the doctor's own feelings and attitudes in a way that can often be avoided in other branches of medicine. In approaching psychiatry, doctors have to learn to deal not just with the patient, but also with themselves.

CLASSIFICATION AND OVERVIEW A simple classification of psychiatric illness is summarized in Table 8.1. Some aspects of psychiatry of old age are also considered in Chapter 7.

Somatoform disorders 233

MINDS AND BRAINS

Psychiatric disease constitutes a large proportion of disability and illness in society (Fig. 8.1 and Summary 1). The World Health Organization has identified depression as the main cause of disability throughout the world; suicide is one of the commonest cause of death in young people, especially males, in developed countries. Somatization disorders are among the most frequent cause of consultation in general practice. Throughout the western world, most of the large mental hospitals have now closed and acute psychiatric illness is treated in general hospital units and the community, alongside the other medical disciplines. The boundary between general medicine and psychiatry is much less rigid: patients and their illnesses are no longer seen by physicians purely as scientific puzzles to be solved: psychological aspects of physical illness are, through liaison psychiatry, now recognized to be of great importance. Medical science is, in turn, making an increasingly important impact on psychiatric knowledge and practice. The basic disciplines underlying

An eminent neurologist once stated that 'psychiatry is neurology without physical signs'. This would be true if psychiatry were simply concerned with the brain and its disorders; the problem of psychiatric diagnosis and classification would then be no different from that of any other system of the body. A significant part of psychiatry is indeed concerned with diseases of the brain - the organic psychoses, such as confusional states, for example, or the affective symptoms (i.e. disorder of mood) caused by adrenal disorders. The 19th century discovery that the psychosis known as general paralysis of the insane (GPI) was caused by syphilis stimulated one of the founding fathers of psychiatry, Emil Kraepelin, to search for other physical causes of insanity, with the expectation that all mental illness would soon be found to be caused by diseases of the brain. Psychiatry continues, rightly, to try to understand the structural and biochemical correlates of psychiatric disorders, but the Kraeplinian project can never be fully realized, partly because brain research is difficult and at a rather primitive stage, but also because psychiatry is concerned with minds as well as brains.

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TABLE 8.1 Classification of psychiatric disorders Organic syndromes Delirium Dementia Intoxication and withdrawal syndromes Functional psychoses Schizophrenia Manic-depressive psychosis Paranoid states Neuroses Anxiety Phobias Depression Obsessive-compulsive neurosis Somatoform disorders Conversion Somatization Hypochondriasis

Others Addictions Alcohol Drugs Eating disorders Sexual dysfunction and deviation Personality disorders (Axis II in DSM) (see p. 180) A. Paranoid Schizoid B. Antisocial (psychopathic) Histrionic Borderline C. Avoidant Dependent Obsessive-compulsive

Prevalence Prevalence of psychiatric ill health in the community Prevalence of psychiatric disorder in general practice Prevalence of psychiatric disorder among schoolchildren Psychiatric referral rate from general practice Psychiatric beds as a proportion of all NHS beds Major disorders Severe depression Suicide attempts Suicide Chronic mental illness Severe mental handicap

SUMMARY 1 The prevalence of psychiatric morbidity among adults aged 16-64, living in private households, in Great Britain • 14% of adults have a neurotic health problem. Women are far more likely to suffer this type of problem than men. • The most common neurotic symptoms are fatigue (27%), sleep problems (25%), irritability (22%), and worry (20%). • The most prevalent neurotic disorder is mixed anxiety and depressive disorder (7.7%), followed by generalized anxiety disorder (3.1%). The prevalence of all neurotic disorders is higher among women than men. • Functional psychosis has a prevalence of 0.4%. • The overall rates of alcohol and drug dependence are 4.7% and 2.2%, respectively. Men are three times more likely than women to have alcohol dependence and twice as likely to be drug dependent. Alcohol and drug dependence are most prevalent among young adults, particularly young men aged 16-24.

Mind has three main properties: • The ability to experience emotions • Intentionality (i.e. having desires and goals) • Self-awareness.

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Although psychiatric diagnosis approaches the mind as if it were an organ, this is often merely an analogy. When we speak of psychiatric illness we may be speaking about a brain disease, e.g. GPI, Alzheimer's disease or (possibly) some forms of schizophrenia, in the same way we speak of pneumonia as a disease of the lungs. On the other hand, although conditions such as personality disorders or agoraphobia are in some ways like illnesses, they also differ in many important respects because they affect the mind. They are best seen as disorders, rather than diseases. This important distinction between mind and brain may

Neurotic disorders Social pathology Chronic alcoholism (identified cases) Chronic alcohol ism (unidentified cases) Juvenile delinquency Problem families One-parent families with children under 15 FIG. 8.1 Epidemiology of psychiatric disorders A Prevalence of, and provision for, psychiatric ill health in the community. B Cases per annum of various psychiatric disorders in a typical British general practice population of 2500.

help to explain the discomfort some feel when confronted with the essentially rather simple issue of psychiatric diagnosis. The categories of mental illness are few and not difficult to memorize. The main problem is philosophical, rather than one of classification. A number of other difficulties may also be encountered on first approaching psychiatry. First, psychiatric diagnoses tend to be at a rather general level. They are symptomatic/syndromic rather than pathological/specific. The diagnosis of anxiety neurosis or schizophrenia is analogous to that of 'heart failure' rather than 'mitral stenosis'. Secondly, with the exception of the organic psychoses, the underlying pathology of psychiatric disorders is usually complex and multifactorial. This follows from the nature of mental phenomena. Just as there is usually no simple reason why an individual chooses medicine as a career, so

there is rarely a single 'cause' of depression. There may be many explanations for a particular symptom or problem. A third difficulty encountered in psychiatric diagnosis is that of deciding what is normal or abnormal, which is sometimes more a political or ethical question than a technical one. The doctor's own standards and feelings are involved in assessing a psychiatric patient. This also leads to two errors commonly made by newcomers to psychiatry: either the student identifies the patient with himself, and so decides there is nothing much wrong, or he identifies himself with the patient and worries that he must be psychiatrically ill! (Note that throughout this chapter 'he' is used to mean 'he or she'.) Two systems of classification are widely used in psychiatry: ICD (International Classification of Diseases), which is favoured in Europe, and DSM (Diagnostic and Statistical Manual), which has been developed in the USA by the American Psychiatric Association. The latter is interesting in that it is a multiaxial classification: Axis I diagnoses classify the psychiatric disorder; Axis II classifies any personality disorder that may or may not accompany the psychiatric illness; and Axis III allows for the diagnosis of any concomitant physical disorder.

FURTHER READING ON MINDS AND BRAINS Fulford K W 1989 Moral theory and medical practice. Cambridge University Press, Cambridge Kendell R 1975 The concept of disease and its implications for psychiatry. Br J Psychiatry 127: 305-315

PSYCHOSIS AND NEUROSIS The distinction between psychosis and neurosis has been and remains fundamental to psychiatric thinking, although neither is easily defined on its own, and some classifications have attempted to do away with the rather vague and blanket term neurosis. The difference turns on four main issues: • • • •

Relationship to reality Severity Relationship to normality Insight.

Relationship to reality The essence of psychosis is that the patient loses contact with everyday reality. This may happen as a result of either hallucinations or delusions, or both. Delusions and hallucinations are not a feature of neurosis. The neurotic's feelings and beliefs about himself may be distorted, but perception and understanding of the external world remains intact.

SUMMARY 2 The distinction between psychosis and neurosis Feature Relationship to reality

Psychosis Loss of contact with reality Delusions and/or hallucinations

Neurosis Perception of external reality intact Problem is with the self

Severity

More severe, more global disturbance

Areas of normal function remain

Relationship to normality

Clear distinction between normal and psychotic experience

Represents extremes of normal difficulties

Insight

Usually lacking

Present

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Hallucinations A hallucination is a false perception. The patient undergoes a sensory experience in the absence of an external stimulus, for example hearing a voice when there is nobody there. For this to be diagnostic of psychosis it should be clear-cut; hearing an 'inner voice', which the person recognizes as really part of himself, is not a hallucination. An illusion should be distinguished from a hallucination in that it is an elaboration of a real percept, e.g. 'seeing faces in the fire', and is of less, if any, pathological significance. In hallucination, any of the five senses may be involved in the patient's altered perception of reality. Hearing Auditory hallucinations are probably the commonest type of hallucination, found especially in paranoid states, in schizophrenia, and occasionally in psychotic depression. Sight Contrary to popular belief, schizophrenic patients rarely 'see things': visual hallucinations occur most commonly in drug and alcohol withdrawal states, temporal lobe epilepsy and hysterical psychosis. Smell and taste Olfactory hallucinations are usually a sign of organic disease, e.g. temporal lobe seizures. Touch Tactile hallucinations are rare, but can occur in schizophrenia and drug withdrawal. Hallucinations are not always a sign of pathology. After bereavement, visual or auditory hallucinations of the lost loved one are common. Delusions A delusion is a fixed and firmly held false belief. The patient's perceptions are unaltered, but his interpretation of them is, and is at variance with common experience. The patient sees people chatting at a bus-stop and is convinced

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they are talking about him, saying he is homosexual or a spy, for example. These beliefs may be well concealed and not evident in superficial conversation. We normally assume that our thoughts are private, that individuals are autonomous, that the non-human world is indifferent to our existence, that we are not in any special danger, and that we are not of any particular importance or interest to strangers. The deluded patient (e.g. in schizophrenia) has experiences that conflict with these everyday beliefs. The patient may feel that his thoughts can be interfered with from outside, or that his movements can be controlled by others; he may believe there is some special significance in the number plate of a passing car, that he is in great danger from hostile forces, or that television programmes or public events are caused by, or directed at, himself.

SUMMARY 3 Classification of psychosis Organic Acute (delirium) Chronic (dementia)

Functional Manic-depressive psychosis Schizophrenia

oneself and one's emotions and motives without denial or self-deception. Although insight in this second sense may be desirable, it bears no relationship to the presence or absence of illness. It is possible to be perfectly healthy and yet to lack self-knowledge, or to be profoundly insightful yet mentally ill.

THE PSYCHOSES Severity In general, psychotic disorders are more severe, more disabling and produce greater overall disturbance of mental functioning than neuroses. There are exceptions to this. An obsessional neurosis, for example one in which the individual may spend many hours a day engaged in complicated washing or dressing rituals, can be incapacitating.

Relationship to normality In psychosis there is a clear departure from normality. In contrast, minor neurotic symptoms, e.g. depression, anxiety, obsessional symptoms and hysteria, are common in normal people. The neurotic population is best seen as an extreme end of a normal distribution curve in which quantitative, but not qualitative, change has taken place.

Insight

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It is commonly stated that the difference between neurosis and psychosis is that the psychotic 'lacks insight'. The psychotic patient attributes his symptoms to reality rather than illness, and cannot be persuaded out of these delusions or hallucinations; the neurotic, on the other hand, can usually see that his view of the world might be mistaken. However, although it is undoubtedly true that the psychotic lacks insight, there are several reasons for giving less prominence to insight than is customary. First, if the psychotic is identified on the basis of a loss of touch with reality, then he will, by definition, lack insight. If the patient knew that his delusions or hallucinations were false, he would not be deluded or hallucinating. Secondly, the patient often tacitly accepts that he is ill by coming for help, despite the apparent illogicality of complaining to a doctor about a delusion. Thirdly, the word 'insight' has two distinct meanings in psychiatry: one, given above, refers to the patient's relationship to reality and his illness; another more literal meaning refers to the ability to look into

Psychoses may be divided by their features and causes into two main groups: organic and functional (or, more accurately, 'of unknown origin'). In organic psychosis there is established biochemical, infective or structural brain disease. In functional psychosis no such disease process can be demonstrated. Organic psychoses can be divided into acute organic psychoses (also known.as acute confusional states, delirium or 'acute brain syndrome') and chronic organic psychoses (also known as dementia and 'chronic brain syndrome') (see also Ch. 24).

Functional psychosis vs. acute organic psychosis It is essential to be able to distinguish functional psychoses from acute confusional states, as the former require psychiatric, the latter medical, treatment. The key difference is the state of consciousness. In functional psychosis consciousness is clear and the patient fully orientated: it is possible to complete a complicated crossword puzzle while suffering from paranoid schizophrenia. In organic psychosis, however, there is almost always some disturbance of consciousness; this is usually variable ('fluctuating level of consciousness') and is often worse at night. Some causes of acute organic psychosis are given in Table 8.2.

Functional psychosis One hundred years ago, Kraepelin divided the functional psychoses into two main groups: manic-depressive psychosis, and schizophrenia (or, as he called it, 'dementia praecox'). Manic-depressive psychosis is primarily a disorder of mood. The patient becomes psychotically depressed or elated ('unipolar manic depression') or experiences episodes of both ('bipolar manic depression'). There are usually periods of normality between episodes of illness. Schizophrenia is primarily a disorder of thinking, and on the whole it produces, a more severe and more general disturbance of mental functioning. The prognosis is less good than for manic depression.

TABLE 8.2 Some causes of acute organic psychosis Cause

Examples

Systemic infection Metabolic disturbance Vitamin deficiency

Malaria, HIV, pneumonia (especially in the elderly) Electrolyte imbalance, renal failure, liver failure Thiamine deficiency (Wernicke-Korsakoff syndrome in alcoholics, and beriberi) Hypoglycaemia, hypothyroidism, steroid administration Anticonvulsants, hypnotics, antidepressants, LSD, amphetamines CVA, subarachnoid haemorrhage, tumour, cerebral abscess DTs, benzodiazepine withdrawal

Endocrine Drug intoxication Intracerebral Withdrawal syndrome

cal health than those who are mentally untroubled. Childhood adversity, for example, is strongly associated with poor physical health in adult life. This link was orginally conceptualized by Freud in terms of 'hysterical conversion disorders' - i.e. the 'conversion' of mental distress into bodily symptoms. The basic themes of hysteria were denial, dissociation, displacement and dependency. The patient denies a painful conflict and thus avoids anxiety or depression, but at a price: she (many hysterical patients are female) dissociates herself from her feelings and displaces the latter into her body instead. Psychic pain is thereby converted into physical symptomatology, and the patient becomes dependent on doctors and others. Although the possibly perjorative and aetiologically loaded term 'hysteria' has been replaced with the more neutral 'somatization' the underlying themes remain.

THE NEUROSES

Obsessive-compulsive neurosis

Unlike psychosis, in neurosis the patient experiences no alteration of external reality. Instead, he is troubled by, and tries to avoid, some unacceptable aspect of himself or of his internal reality. There are four main patterns of neurosis:

Here the patient deals with anxiety - often aroused by fear of his own feelings of aggression, sexuality or wish for power or independence - by an attempt at control. A ritual action or a repetitive thought is repeated over and over again in the magical hope that this will keep some imagined danger at bay. The patient knows it is absurd (thus has insight and is not psychotic), tries to resist, but still has, say, to wash in a particular way every morning in order to feel safe to start the day.

• • • •

Anxiety neurosis and phobia Depressive neurosis Hysteria and somatization Obsessive-compulsive neurosis.

Anxiety neurosis and phobia Anxiety is an almost universal feature of all psychiatric illness. It is the psychic equivalent of pain. Anxiety is normally a response to external threat or unpredictability in the environment. In anxiety neurosis, rather than being alerted and mobilized into action by anxiety, the patient is paralysed or overwhelmed by it. Where anxiety is experienced only in specific situations, the patient is said to suffer from a phobia. In phobic disorders the patient attempts to master anxiety by avoidance (e.g. an agoraphobic patient avoids public places).

Depressive neurosis If anxiety is the psychic equivalent of pain, depression is the equivalent of disability (although anxiety can also of course be disabling, and depression intensely painful). In depression, the patient has lost not a limb or a function but a relationship. It is usually a person who is lost, but the 'lost object' can also be a job or a house, or the patient's own self-esteem. Depression can be seen as an attempt to avoid painful reality by withdrawal.

Hysteria Body and mind are inseparable. There is good evidence that patients with psychiatric disorders have worse physi-

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PERSONALITY DISORDER Individuals are recognizable not just by their appearance but by their personality which, despite ageing and change, remains relatively constant through time. Personalities can be classified dimensionally or categorically. A dimensional approach is exemplified by Hans Eysenk who, following his intellectual opponent Jung, devised a method for assessing personalities along the dimensions of extrovert (outgoing, gregarious, stimulusseeking) and introvert (inner-directed, shy, stimulusavoiding). The problem of differentiating between normal and abnormal personality is even more difficult than in neurosis. There are undoubtedly individuals whose personalities are very unusual, at least in the statistical sense, but they are not necessarily abnormal. An alternative approach to the classification of personality uses psychiatric categories to describe different types of individual. Someone suffering from schizoid personality, for example, is withdrawn and aloof, preoccupied with material objects or intellectual pursuits rather than people, lacking in close emotional contact, and is defensive and easily hurt. These features may only be a personality trait, and may even be advantageous: many creative people have schizoid tendencies. However, when taken to extremes they become a personality disorder. Here, the individual is so handicapped by

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SUMMARY 4 Classification of personality Dimensional approaches e.g. extrovert/introvert DSM categorization A. Paranoid Schizoid

B. Antisocial (psychopathic) Borderline Histrionic

C. Avoidant Dependent Obsessive-compulsive

his personality that he seeks, or is brought for, help, e.g. someone with a schizoid personality who suffers from severe social isolation. Unlike psychosis and neurosis, a personality disorder is not an illness. Its features date back to childhood or adolescence, and so there is no premorbid period of normality. However, personality disorder often coexists with, and may predispose to, psychiatric illness (this is an example of 'comorbidity'). Personality disorders are conveniently grouped into three main types. Group A have some of the features of schizophrenia and paranoia, but without any overt signs of psychosis. They may, however, predispose to a psychotic illness, and eventually develop into one. Thus someone with a paranoid personality may, in later life, develop pamphrenia. In group B, sometimes described as 'dramatic', patients experience social difficulties that often bring them into conflict with authority. Many of the patients who present to casualty departments after episodes of deliberate self-harm (see below) suffer from borderline personality disorder, characterized by unstable relationships, substance abuse, chronic feelings of emptiness, and difficulty in regulating emotions. For histrionic personality disorder, see page 238, and for antisocial personality disorder, page 253. Group C are neurotic personalities typified by anxiety, avoidance of threat or challenge, and dependent relationships. An example is that of obsessional personality disorder. Here the individual is meticulous, controlled, orderly and rigid, and may find the sloppiness of others unbearable. Such characteristics may be advantageous in certain circumstances, e.g. the armed forces or the operating theatre, but may also bring the individual into conflict with others when flexibility is needed, e.g. under stress and in intimate relationships.

THE CAUSES OF PSYCHIATRIC ILLNESS

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The complexity of the interactions underlying psychiatric illness can be confusing. A causal model of the type 'one pathogen-one disease' rarely applies in psychiatry. There are three main types of causal factor in psychiatric illness: genetic/biochemical, developmental, and social. All play at least some role in most psychiatric disturbances, and part of the art of psychiatry lies in assigning the appropriate weight to each factor and identifying which may be

FIG. 8.2 The origins of psychiatric disorder

the most important (Fig. 8.2). Most psychiatric illnesses are genuinely 'multifactorial' in origin. This is not surprising, considering the complexity of brain development and the numerous branching pathways that development can take. The eventual outcome in terms of mental health will depend on genetic inheritance, childhood environment, resistance or vulnerability factors, adverse and healthpromoting experiences, and accidental factors such as loss and trauma. Eliciting this personal narrative or life story is central to psychiatric history taking and provides an essential backdrop to understanding current psychiatric disorder.

Genetic/biochemical ('organic') Occasionally a single genetic defect can determine a psychiatric illness, e.g. the psychiatric manifestations of Huntington's chorea. However, although genetic inheritance may, as in schizophrenia, be a necessary organic cause of illness, it is rarely sufficient. Biochemical, viral, immunological and nutritional factors may well be important in a number of psychiatric illnesses, although few have so far been convincingly demonstrated as a unique cause.

Developmental ('infrapsychic') Each individual is a product of, and in a sense contains and continues, his past. Psychological development, especially that shaped by early childhood experience and family relationships, plays a crucial part in determining personality and ways of reacting to stress in later life.

Social ('interpersonal') Many psychiatric illnesses are triggered by recent social events, such as bereavement, divorce or unemployment. The patient's social and family situation can play a major role in both initiating his illness and helping or hindering his capacity to recover. The quality of family relationships is itself influenced by the personality, which is in turn a product of both genetic and developmental factors.

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THE PSYCHIATRIC EXAMINATION The psychiatric examination, although similar to the medical examination insofar as it is a systematic gathering and ordering of facts and observations, is unique in a number of important ways. First, it consists of a detailed account of a person's biography and current circumstances. Second, in gathering the history the interviewer uses a much more open style than is usual in the closed-question 'checklist' approach of conventional history-taking. The 'facts' of psychiatry are often feelings, and these are often most effectively elicited by open questions such as 'How do you feel about...?' or 'What was the worst moment .. .?' Third, the interviewer's own reactions and thoughts, rather than being put aside, should be recognized as relevant data to be noted and recorded. The interviewer should maintain a non-judgemental, balanced, compassionate but neutral position. The interviewer should also be gentle but firm and should not avoid eliciting material (e.g. sexual or traumatic) that may be painful for the patient simply because of his own scruples or anxiety. The psychiatric history, which may have to be supplemented by interviewing close friends or relations, should include the following: • Reason for referral. Did the patient ask for help, was he encouraged to seek it, and if so by whom, or was he brought unwittingly or unwillingly to the doctor? Why now? • History of present complaint. A detailed account, as far as possible in the patient's own words, of what he experiences as 'wrong', unusual or bizarre, or would like to change in his life. • Previous psychiatric and medical history.

SUMMARY 5 Psychiatric history and examination History • Reason for referral • History of present complaint • Previous psychiatric history • Previous medical history • Drugs and alcohol • Family history - genogram • Personal history • Personality Examination • General appearance and behaviour • Speech - form and content • Mood • Abnormal beliefs • Abnormal experiences • Cognitive state • Insight • Interviewer's responses

FIG. 8.3 A genogram

Drug and alcohol history. Family history. A detailed description of the patient's 'family of origin' and 'family of procreation' (if they have one) can conveniently be recorded in the form of a family tree or 'genogram' (Fig. 8.3). Personal history. Detailed biography, starting at birth, recording all significant memories and events, including early separations, family atmosphere, school experiences and achievements, work history, psychosexual and marital history. Personality. A person's likes and dislikes, interests, attitudes and aptitudes should be recorded to establish a premorbid stage against which to evaluate the present condition.

MENTAL STATE EXAMINATION This is a systematic compilation of the abnormal phenomena observed and elicited by the interviewer or complained about by the patient. • General appearance and behaviour. How is the patient dressed? How does the patient relate to the interviewer - is he relaxed and friendly, or suspicious and taciturn? Does the patient sit immobile in the chair, or is he fidgety and restless?

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• Speech. Is the speech normal in form and content, slowed down, or accelerated? Does it follow a logical progression or does it jump from idea to idea ('flight of ideas'); or is there evidence of a disorder of the logical progression of thoughts ('thought disorder')? • Mood. Is the mood normal, depressed or elated? Is the person troubled by feelings of guilt and unworthiness and suicidal thoughts, or is the patient grandiose and overexcited? Is the patient anxious or agitated? • Abnormal beliefs (delusions). Does the patient feel he is being spied on, talked about or got at? Are his thoughts or actions being interfered with? • Abnormal experiences (hallucinations). Has the patient had any bizarre or unusual sensations? Is he hearing noises or voices when no-one is around? • Cognitive assessment (for mini-mental state examination, see p. 1288). What is the general level of intelligence? Is there evidence of impairment of consciousness, immediate memory or recall? Is the patient fully oriented in time, place and person? • Insight. What is the patient's self-appraisal and theory about what is happening to him? • Response of the interviewer. How does the patient make the interviewer feel? Sympathetic? Angry? Irritated? Bored?

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The examination should be concluded by a formulation containing the salient points of the history and mental state, with a differential diagnosis and some ideas about possible aetiological and precipitating factors. Risk assessment should be considered in each case, with a specific discussion about suicidality ('How suicidal do you feel at the moment', or 'How would you rate your suicidality on a scale of 0-10?'), and consideration of risk to others, based on past history of violence, if any. Example of a psychiatric formulation: 'Mr A is a 22-yearold unemployed man currently living in a bedsit. For the past few months he has become increasingly withdrawn and self-neglectful, and caused worry to his landlord, whom he has accused of spying on him. He has been smoking cannabis on a daily basis since leaving school at the age of 16. He has few friends, and has only held down casual jobs for short periods. In his background his maternal uncle suffered from schizophrenia; his parents split up when he was 8, he has lost contact with his father and does not get on with his stepfather, whom his mother married 2 years ago. On mental state examination he appears mildly depressed and shows evidence of paranoid delusions of being watched, and occasionally hears a voice warning him that he is in danger. There may be some suicide risk, but there is no history of any violence to others. The differential diagnosis includes schizophrenia, cannabis psychosis, depressive disorder, and insidious organic brain disease. A degree of maternal neglect (his delusion could reflect a psychotic expression of his feeling of being unnoticed), lack of a positive male role-model, low self-esteem and underachievement may all contribute to the underlying dynamic of his developing illness'.

FURTHER READING ON THE PSYCHIATRIC EXAMINATION Leff J, Isaacs A 1990 Psychiatric examination in clinical practice. Blackwell, Oxford Sims A 1995 Symptoms in the mind, 2nd edn. WB Saunders, London

TREATMENTS IN PSYCHOLOGICAL MEDICINE Psychiatric treatments are of three types: • physical - psychotropic drugs - ECT • social - housing - day centres • psychological - see Table 8.3

ANXIETY Anxiety, like pain, is an unpleasant necessity. A person unable to feel anxious would be severely incapacitated. Arousal, which may be experienced subjectively as anxiety, leads to an adaptive response to threat: fight or flight.

AROUSAL AND ANXIETY There are three main components of the arousal response: • Psychophysiological • Psychological • Interpersonal.

The psychophysiological component This is mediated by the autonomic nervous system and is accompanied by increased adrenaline (epinephrine),nora-

SUMMARY 6 Manifestations of anxiety Physical Tachycardia Tightness/pain in chest Difficulty in breathing Headache Paraesthesia Muscular pains Muscular weakness Dizziness Difficulty in swallowing Abdominal discomfort Diarrhoea Frequency of micturition

Psychological Irritability Inability to memorize Inability to concentrate Fear of impending death Fear of madness (depersonalization and derealization)

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TABLE 8.3 Choosing a psychological therapy Principal recommendations

Evidence

• Psychological therapy should be routinely considered as an option when assessing mental health problems (B)

Psychological therapy shows benefits over no treatment for a wide range of mental health difficulties.

• Patients who are adjusting to life events, illnesses, disabilities or losses may benefit from brief therapies such as counselling. (B)

There is evidence of counselling effectiveness in mixed anxiety/depression, most effective when used with specified client groups, e.g. postnatal mothers, bereaved groups.

• Post-traumatic stress symptoms may be helped by psychological therapy, with most evidence for cognitive behavioural methods. Routine debriefing following traumatic events is not recommended. (A)

CBT has been found helpful. Some evidence of efficacy has been shown for other forms of psychological therapy. Single session debriefing appears to be unhelpful in preventing later disorders.

• Depression may be treated effectively with cognitive behavioural therapy (CBT) or interpersonal therapy (IPT). A number of other brief structured therapies for depression may be of benefit, such as psychodynamic therapy. (A)

CBT & IPT effectively reduce symptoms of depression. Benefit has also been found for other forms of psychological therapy.

• Anxiety disorders with marked symptomatic anxiety (panic disorder, agoraphobia, social phobia, obsessive-compulsive disorders, generalized anxiety disorders) are likely to benefit from cognitive behaviour therapy. (A)

CBT effectively reduces symptoms of panic and anxiety. Behaviour therapy and cognitive therapy both appear effective in treatment of obsessional problems.

• Psychological intervention should be considered for somatic complaints with a psychological component with most evidence for CBT in the treatment of chronic pain and chronic fatigue. (C)

Psychological therapies have benefit in range of somatic complaints including gastrointestional and gynaecological problems. CBT found more effective than control in improving functioning in chronic fatigue and chronic pain.

• Eating disorders can be treated with psychological therapy. Best evidence in bulimia nervosa is for CBT, IPT and family therapy for teenagers. Treatment usually includes psychoeducational methods. There is little strong evidence on the best therapy type for anorexia. (B)

Efficacy of CBT and IPT in bulimia has been established. Individual therapies have shown some benefit in anorexia, with little to distinguish treatment types. Early onset of anorexia may indicate family therapy, and later onset, broadly based individual therapy.

• Structured psychological therapies delivered by skilled practitioners can contribute to the longer-term treatment of personality disorders, (C)

Meta-analysis found a number of therapy approaches, both individual, group and milieu show some success, including dialectical behaviour therapy, psychoanalytic day hospital programme and therapeutic communities.

The recommendations are weighted as follows: A. Based on a consistent finding in a majority of studies in high quality systematic reviews or evidence from high quality studies. B. Based on at least one high quality trial, a weak or inconsistent finding in high quality reviews or a consistent finding in reviews that 'high quality'. C. Based on evidence from individual studies that do not meet all the criteria of 'high quality'. D. Based on evidence from structured expert consensus.

drenaline (norepinephrine) and corticosteroid secretion. These result in tachycardia, piloerection, sweating and pupillary dilatation; and subjective manifestations of autonomic activity, including paraesthesiae, giddiness, 'butterflies in the stomach', breathing difficulties, a sensation of painful pressure in the chest, and muscular tension, especially around the head and neck. These symptoms may be mistakenly attributed by both patients and doctors to organic illness.

The psychological component There is a continuum of arousal responses to threat, from alertness and readiness, through mild fear to severe anxiety and incapacitating panic. Effective action depends on an optimal state of arousal: little can be achieved when an individual is either barely aroused or in a state of panic. Examination nerves, if not too great, improve results. During a panic attack the patient experiences a sense of threat, or even of impending death. Chronic anxiety states

not meet all the criteria of

SUMMARY 7 Aetiology of anxiety syndromes Past Genetic factors (predisposition) Faulty learning (as a child) Early childhood relationships (Attachment theory)

Present External threat Relationships to attachment figures Internal conflict

may produce irritability, lack of concentration and a subjective sense of failing memory. Anxious patients fail to habituate to stimuli and so remain chronically overaroused; this can result in extreme sensitivity to sudden noises or movements. In extreme anxiety a state of detachment may supervene in which anxiety suddenly disappears, to be replaced by a feeling of being outside of oneself (depersonalization) and cut off from one's surroundings, which appear unreal and distant (derealizatiori). These

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TABLE 8.4 Classification of anxiety syndromes Primary anxiety Generalized Situational Agoraphobia Social phobia Hypochondriasis Specific (e.g. spiders) Panic attacks (hyperventilation syndrome)

Secondary anxiety Psychiatric illness, e.g. depression Organic illness, e.g. thyrotoxicosis Alcohol-related withdrawal symptoms Benzodiazepine-related withdrawal symptoms

experiences may be misinterpreted by the patient as signs of 'going mad'.

The interpersonal component A frightened individual 'regresses' (see p. 217) and, childlike, clings to those he loves and on whom he depends. This is part of 'attachment behaviour' and, like anxiety, is adaptive: species survival depends on secure bonding. The dependency and excessive demands on others that so often accompany anxiety states (and which can be trying to both relatives and doctors) can be understood as part of the attachment response to threat.

anxiety syndromes because in a phobia the patient avoids the feared situation and is thus restricted by the underlying anxiety. Situational anxiety syndromes include: • Specific phobias, e.g. snake or spider phobia, or fear of heights. These have a good prognosis, are found in otherwise healthy individuals, and respond well to behavioural treatment (p. 215). • Agoraphobia is named after the Greek agora, or meeting place. In agoraphobia the patient is frightened to leave home unaccompanied, avoids public places such as supermarkets and department stores, and cannot travel on public transport, especially underground railways and aeroplanes (claustrophobia is usually part of agoraphobia). The patient is usually female and may be very dependent on her mother, daughter or husband. The prognosis is less good than with specific phobias, but behavioural therapy is usually helpful. Agoraphobic symptoms may develop as part of a depressive illness (p. 218). • Social phobia, i.e. fear of meeting people in social situations, e.g. parties, canteens. This affects mainly young people and is an extreme form of normal 'shyness'. Patients can be helped by social skills training in groups with fellow sufferers in which they 'role-play' the feared situations. • Hypochondriasis, a morbid fear of illness, leading to a frequent need for reassurance by family, friends and doctors.

ANXIETY SYNDROMES Anxiety may be a primary diagnosis, or secondary to another psychiatric or physical illness. It is a non-specific symptom which occurs in a wide range of psychiatric syndromes, including benzodiazepine withdrawal, depression, alcoholism and schizophrenia. It can also be an important manifestation of organic illness, particularly thyrotoxicosis, paroxysmal tachycardia, carcinoid syndrome, hypoglycaemic attacks, phaeochromocytoma and temporal lobe seizures.

CLASSIFICATION Primary anxiety syndromes may be classified as shown in Table 8.4.

Generalized anxiety Individuals who experience anxiety symptoms, either chronically or intermittently, without a clear stimulus or an obvious focus of fear, suffer so-called 'free-floating' anxiety.

Situational anxiety 214

In situational anxiety there is an identifiable precipitant to which the anxiety is related. Phobias are closely related to

Panic attacks (hyperventilation syndrome) These may be part of a specific syndrome, e.g. agoraphobia, or may occur on their own. They frequently present to physicians as medical emergencies and are usually selflimiting. The patient presents in a state of terror, overbreathing, complaining of chest pain, and often feeling he is dying. The diagnosis can be established by provoking these symptoms with voluntary overbreathing, which are then relieved by rebreathing from a paper bag. Tetany may be a feature. Organic causes (e.g. hyperthyroidism) must be eliminated and a positive psychiatric history should be established (i.e. a history of recent stress/conflict, or a background of chronic difficulty).

Aetiology There is no single cause of anxiety syndrome. Individuals vary in their tendency to become over-aroused: genetic factors may play a part in this. Anxiety may also arise from faulty learning. A child who senses his mother's tension in social situations may become socially phobic himself. Repeated avoidance of a feared stimulus then exaggerates the threat associated with it, as there is no opportunity for mastery through repeated exposure. Attachment theory explains how early childhood relationships may predispose to anxiety in later life. In order

to survive, a developing child must bond to an attachment figure (usually the mother). If the mother is consistently present, reliable in her handling and 'good enough' in her emotional responsiveness, then a bond of secure attachment, or 'secure base', will develop. This enables the child to engage in exploratory behaviour, to deal with new situations without becoming overanxious, and so gradually to separate, safe in the knowledge that the mother is available if necessary. The child builds up an internal image of a good parent, which provides a sense of security. If, on the other hand, the early relationship with the parent is disrupted - by separation or by inconsistent handling, for example - the child may develop a bond of anxious attachment. Rather than being able to explore and become autonomous, the child clings to the mother, at first physically and later emotionally, showing signs of distress when separation is threatened. This childhood experience then acts as a template for separations in later life. Faced with threat, the anxious individual clings to attachment figures • spouse, parent, child or doctor. The following factors should be considered in cases of anxiety: • The nature of the current external threat. This may be obvious, such as major illness in the patient or a close relative. The 'threat' may, on the other hand, appear as trivial and 'normal' as an adolescent leaving home, or a family holiday. For an anxiously attached individual these can be major hurdles. • The relationship to attachment figures, past and present. A pattern of anxious attachment in childhood now repeated in relationship to spouse or children is often found. • 'Internal threat'. Anxious patients often experience an inner conflict between their need for dependency and their feelings about those on whom they depend. The patient is threatened not so much by external circumstances as by himself. A patient who feels angry, for example with an unfaithful spouse, but is unable to express this because of fear of separation and loss, may develop anxiety symptoms. He fears to bite the hand that feeds. The patient is frightened by his own inner impulses: sexual or aggressive feelings, or the wish for independence and autonomy. Anger in particular often coexists with anxiety; the angry individual is often a frightened one, and vice versa.

SUMMARY 8 Management of anxiety syndromes • Exploratory psychotherapy • Cognitive-behavioural psychotherapy

• Psychotropic drugs

Exploration and resolution of underlying conflict. Non-directive. Aims to change patients' behaviour directly through desensitization, and/or to, challenge their underlying assumptions. Antidepressants, minor tranquillizers, B-blockers.

MANAGEMENT

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Michael Balint, a psychoanalyst who pioneered the use of psychotherapeutic methods in medicine, wrote 'the doctor is a drug: the question is in what dose, and with what frequency it should be prescribed'. The two drugs most commonly prescribed for anxiety are tranquillizers and, via supportive psychotherapy, 'doctor'. Both can be effective in the short term, but can in the long term produce the complication of dependence, and may even exacerbate the symptoms of anxiety.

Exploratory psychotherapy Normal individuals who become anxious are usually relieved of their fears by reassurance, and the ability to reassure is thus an important part of a doctor's skill. Reassurance in neurotic individuals is often ineffective, however, because it deals only with the surface fear and not with the underlying conflict. A man who develops repeated attacks of pain, in which he is convinced that he is about to die of a heart attack, can be reassured that his ECG is normal and that he is a fit man, and be discharged. Yet a few days later he may develop another attack and present again to the doctor. The underlying fear, and the root cause of his anxiety, of which he may be unaware or unconscious, may be that his mother, on whom he is very dependent and who has recently had an illness, will die and that he will be left alone. Only when this fear is exposed and when he has learned to accept the dependent part of his himself, will his panic attacks cease. This kind of exploration is helpful in the evaluation of most cases of anxiety. In some cases it may need to be followed by longer-term psychotherapy. If the patient can learn to resolve his inner conflicts through his relationship with a doctor or therapist, and so move from a position of anxious attachment to one of secure attachment, he will be relieved of the symptoms.

Cognitive-behavioural psychotherapy (CBT) In exploratory psychotherapy the doctor aims to be understanding but is non-directive. In behavioural psychotherapy, on the other hand, the doctor aims to change the patient's behaviour directly. A phobic patient associates the feared stimulus (e.g. a spider or a department store) with unpleasant feelings. The therapy aims to desensitize the patient by gradual exposure to the feared stimulus, often in the reassuring presence of the therapist. An important feature of behavioural treatment for anxiety is relaxation training. Here the patient learns to control anxiety through muscular relaxation and deep breathing, sometimes with the aid of tape-recorded instructions. Physiological measures of arousal - galvanic skin response and pulse rate - may provide objective evidence of anxiety

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TABLE 8.5 Side-effects of benzodiazepines Tolerance Drowsiness Incoodination, ataxia Emotional blunting Anger and irritability Diminished sexual response (women) Withdrawal syndrome: insomnia anxiety depression (may be profound) irritability muscular pains and twitching perceptual distortion fits

reduction. When self-administered, this is known as autogenie training. Behavioural therapy, as its name implies, works directly with how the patient behaves and acts in the world. The focus in cognitive therapy is on the patient's thoughts, which may themselves be as anxiety-provoking as real-life situations. Indeed, one of the basic principles of CBT is Epictetus' dictum: 'Men are troubled not so much by things as by their thoughts about things'. In cognitive therapy the patient's underlying assumptions and view of the world are challenged: for example, someone with fear of flying is asked to consider rationally the probabilities of an aircraft crashing and to compare them with accident rates for road and rail travel. Their tendencies to catastrophize (i.e. fear the worst) and dichotomize (divide the world into black and white, good and bad) are pointed out, and alternative strategies suggested.

Psychotropic drugs When anxiety is a manifestation of depressive illness, the treatment of depression with antidepressants (many of which are sedative) also relieves the anxiety. Short-term (up to 10 days) prescription of minor tranquillizers such as benzodiazepines is occasionally justified for the relief of stress-related anxiety. Longer-term prescription of tranquillizers should be avoided because of the likelihood of habituation and physiological dependence. B-Receptorblocking drugs relieve the peripheral symptoms of anxiety and may also occasionally be useful. Side-effects of benzodiazepines are common (Table 8.5) (see also p. 23).

DEFENCE MECHANISMS

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Life is beset with threats. A variety of social and psychological defence mechanisms exist that keep anxiety within manageable limits. Many of these can be observed on

SUMMARY 9 Defence mechanisms against anxiety Denial Dissociation or conversion Splitting Projection

Idealization Regression Obsessional defence Intellectualization

hospital wards, where both patients and staff face the daily threat of illness and death and yet usually manage to remain cheerful and efficient.

Denial 'Everything's wonderful'. One way of dealing with fear or pain is simply to pretend it does not exist. Men are particularly prone to this in everyday life, but false cheerfulness (sometimes known as manic denial) may conceal unvoiced fears or sadness.

Dissociation or conversion 'I'm not worried about anything, doctor, it's just that I keep getting this pain ...'. Akin to denial is dissociation, in which a fear is displaced or converted into a bodily symptom. Patients who have inexplicable and elusive pains, in addition to established physical disease, may well be harbouring unspoken fears and conflicts.

Splitting 'You're wonderful, doctor, not like those terrible doctors at the other hospital.' As Trojans should fear Greeks bearing gifts, so doctors should beware the patient who heaps excessive praise (as opposed to expressing genuine gratitude). The patient may be dealing with anxiety by splitting his world into good and bad, and clinging to the good in the vain hope of absolute security. As with the Trojans, the tables may suddenly turn and we may be seen as bad, and they good. Patients can sometimes split ward staff in this way; physicians and nurses must learn to take both praise and condemnation with equanimity.

Projection 'It's the psychiatrists who are mad, not me'. Closely linked to splitting is projection, in which unwanted feelings are attributed instead to a convenient other.

Idealization 'The doctors here are the best in the world'. The defence of idealization is closely linked to splitting and projection. It is probably best seen as an example of

positive transference, in which past childhood feelings towards one's parents are, under the threat of illness, transferred on to current medical attendants.

Regression

SUMMARY 10 Mourning responses • • • •

Denial Numbness Searching Guilt

8 • Anger • Detachment • Acceptance

'Nurse ... nurse ...'. The sick, like children, are tucked up in bed, fed, pampered and waited on. This sometimes helps the physiology of recovery, but can also lead to helpless behaviour on the part of the patient, who may deal with the fear associated with illness by becoming more and more childlike, regressed and demanding.

Obsessional defences 'I always have my bowels open at such-and-such o'clock, doctor.'

MOURNING The mourning response is divided for convenience into a number of stages, which can be summarized as denial, despair and detachment, but emotional reality does not conform to any such neat sequence. Grief is characterized by surges and cycles of often confused feelings, rather than an orderly progression of recognizable stages.

Denial

The 'malade-d-petit-papief - the patient who presents with a written list of symptoms - is a familiar figure in medical folklore. The obsessional defence is an attempt to deal with fear by control. This may produce feelings of irritation and discomfort in the doctor that mirror the patient's feelings. This is an example of how the doctor's subjective response to the patient (technically known as countertransference} can be a useful guide to what the patient is feeling.

The initial reaction, especially to sudden bereavement, may be denial: 'Oh no .. .'. This attempt to resist the reality of death may persist long after the bereaved have consciously and rationally accepted their loss; they find themselves talking to their lost loved one, or may 'hear' or 'see' them in one of the hallucinatory experiences that not uncommonly occur after bereavement.

Intellectualization

Another early response to bereavement is a complete absence of feeling. The bereaved person may appear to be coping very well because of this emotional shutdown which, like the analgesia of a soldier injured in battle, enables him to get through the initial phase of loss. When this is prolonged, however, it produces chronic impoverishment of emotional life.

'Just a few more tests should clinch the diagnosis.' This defence applies more to doctors than to their patients. Incurable illness and death are inescapable reminders of the limitations of medicine. The feelings of inadequacy and sadness that this creates may be defended against by a preoccupation with diagnostic precision and excessive investigation and treatment.

FURTHER READING ON ANXIETY Holmes J 1993 John Bowlby and attachment theory. Routledge, London Marks I 1987 Fears and phobias. Oxford University Press, Oxford

LOSS, GRIEF AND BEREAVEMENT

Numbness

Searching Part of the 'work' of grief involves a mental combingthrough of the events that led up to the loss of the loved one. This phase is often accompanied by intense anxiety and restlessness. Searching, a form of separation anxiety, may lead to apparently aimless wandering, or visits to familiar spots associated with the lost one. The bereaved person appears to be struggling to negate the reality of the loss, or to rewrite history with a different, happy ending. Acceptance of loss only occurs when this impossible task has been attempted countless times.

Guilt Man is not an island, and human beings are inevitably vulnerable to loss. The mourning response - a patterned sequence of psychophysiological reactions to the loss of a loved one - is as deeply embedded in our psyche as are the phases of inflammation in our pathophysiology. Common to both are the experience of pain, immobility and gradual recovery.

Pangs of guilt or self-blame are a very common feature of bereavement. Survivors blame themselves, often quite irrationally, for the loss of their beloved. 'If only', they say, T had phoned the doctor earlier/not gone on holiday/been kinder...'. This response can be seen as an example of omnipotence, a relic of childish thinking which attempts to deny human vulnerability to fate and fortune.

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Anger Anger and guilt go together in bereavement. Outbursts of anger towards medical staff or close relatives often occur after a death, and should be met by acknowledgement of the underlying pain rather than with retaliation.

Detachment As mourning proceeds, so the grieving individual begins to separate himself from the loss and develop new interests and attachments. Pangs of grief recur, particularly at times of stress and on special dates such as birthdays, Christmas, and anniversaries of loss.

one. Feelings of guilt (associated perhaps with past fantasy wishes that the person would die) are more intense in such cases. 'Symbiotic' relationships, such as those involving unmarried daughters living with their mothers, are also often difficult to recover from when they are severed. Personality of the survivor. Dependent, insecure or depression-prone individuals are more vulnerable to prolonged grief, as are those with difficulty in expressing feelings. The latter may in part account for the greater vulnerability of men to lasting problems after bereavement. Social circumstances of the survivor. A lack of close family, friends, religious beliefs or employment all make recovery from loss more difficult.

Acceptance When mourning is 'successful' and circumstances favourable, the bereaved individual may come to accept that death and loss are part of life and may sometimes even be enriched by the experience. More usually, scars remain, and many bereaved people continue to struggle with feelings of meaninglessness and diminished vitality for many years.

Physiological changes Psychological reactions to loss are accompanied by physiological changes, including disturbance of corticosteroid metabolism and depression of T-lymphocyte response. Death from 'a broken heart' is a reality: mortality rates, mainly from coronary artery disease, are higher in widowers and widows than in their non-bereaved counterparts.

DELAYED OR PATHOLOGICAL MOURNING Return to near-normality after a major loss generally takes from 1 to 3 years. However, chronic states of depression, numbness, anger, anxiety and hopelessness can continue for much longer following a bereavement. The patient becomes stuck in one of the phases of mourning and is unable to progress towards detachment and acceptance. The likelihood of pathological grief depends on four main factors: • Type of death. A sudden, untimely (of a child, for example) or horrifying death is especially hard to accept (see Recent Advances in Post-traumatic Stress Disorder). • Nature of the relationship. An ambivalent relationship (one in which love and hate coexist) is more likely to lead to pathological mourning than a straightforward

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MCQ 8.1

MANAGEMENT About one-third of bereaved persons may be in need of professional support or intervention. Support groups, such as those for widows (in the UK, CRUSE) or for parents whose children have died (the Compassionate Friends), can be very helpful. Psychotherapy may be necessary in order to recapture and work through buried feelings associated with the loss. Sometimes this is systematized as guided mourning, in which the sufferer is encouraged to think about the lost one, talk about the details of his or her death, look at photographs of him or her, visit the grave, and so face and accept loss with diminished denial.

FURTHER READING ON LOSS, GRIEF AND BEREAVEMENT Garland C (ed) 1999 Understanding trauma: a psychoanalytical approach. Butterworths, London Parkes C M 1988 Bereavement: studies of grief in adult life, 2nd edn. Penguin, London

DEPRESSION The complaint of 'depression' can refer to a number of different feelings and reactions - anger, boredom, frustration,

SUMMARY 11 Features of depressive illness (as opposed to unhappiness) • • • • •

Sustained lowering of mood Severe Definite onset Low self-esteem Physiological changes: disturbance of sleep, appetite, weight, libido • Sometimes atypical features brought to the surface by depressive illness: pain, obsessional thoughts, violence

RECENT ADVANCES IN POST-TRAUMATIC STRESS DISORDER (PTSD) The word trauma comes from the Greek 'to pierce'. It is now known that trauma, whether individual or in mass disasters, pierces not just the body but also the psyche of those affected, either directly, or as witnesses or relatives. Also, the recognition that as many as 60% of psychiatric inpatients, whatever their diagnosis, may have been sexually abused in childhood suggests that many psychiatric disorders have PTSD as at least a component of their aetiology. These people, after diagnosed as 'personality disordered', are sometimes referred to as suffering from 'complex PTSN'. In the USA the lifetime prevalence of traumatic events - accidents, suicide, homicide or sexual assault is estimated to be around 70%. Of those so exposed, 20-40% will develop post-traumatic stress disorder. Diagnostic criteria include feelings of intense fear, horror and hopelessness at the time of the traumatic event; intrusive imagery ('flashbacks') in waking consciousness and dreams; avoidance behaviour, e.g. being unable to pass the spot where an accident occurred, or to read accounts of similar events; hyperarousal phenomena, such as disturbed sleep, increased reactivity to noise, muscular tension, poor concentration; and significant interference with normal coping behaviour; all of these lasting for more than one month after the event.

Risk factors include the nature of the trauma itself: the more horrific and violent, the greater the likelihood of PTSD; denial of emotional difficulty on the part of the sufferer; a previous history of trauma, especially in childhood; and dismissal of the severity of the symptoms by significant others such as family and doctors. Comorbidity (i.e. the coexistence of other diagnoses) is common, especially affective disorder. Neurobiology of PTSD. It is now known that prolonged exposure to high cortisol levels (as occurs in clinical stress) produces shrinkage of the hippocampus and that PTSD is associated with neuro-anatomical changes, especially in the non-dominant hemisphere. Management includes: (a) 'debriefing' - a detailed 'action replay' of the traumatic event and the sufferer's reactions, although there is some evidence to suggest that this may have a reinforcing effect and so should be used judiciously; (b) cognitive-behavioural treatment directed at intervening in the intrusive thought-avoidance cycle: the subject is systematically asked to recall the painful events until they can look squarely at them without undue anxiety; and (c) long-term psychotherapy if the trauma has reawakened previous childhood trauma such as sexual abuse; (d) in some cases antidepressant medication can be helpful.

anxiety, hopelessness and helplessness - as well as the specific psychophysiological state that psychiatry recognizes as 'depressive illness' and which is sometimes colloquially referred to as 'clinical depression'.

table, and takes no pleasure in anything. He feels he has no future and that it is pointless or impossible to make plans. Thoughts of suicide almost invariably present, although the patient may try to resist these by saying I would not have the courage'. • Low self-esteem. The patient feels worthless, inadequate, unwanted and useless. He feels intense guilt and plagues himself with thoughts of past failures and mistakes. He can only see himself in a negative light and emphasizes his weaknesses and faults. • Physiological changes. The most important of these is sleep disturbance. Anorexia, weight loss, loss of libido, constipation, retardation (slowing of thought and movement) or occasional agitation are also all important features, especially in severe or psychotic depression. • 'Atypical' features. Sometimes a depressed patient may present atypically, with physical symptoms such as unexplained pain, obsessional thoughts, agoraphobia, criminal behaviour (such as shoplifting) or episodes of anger and violence. These may have been brought to the surface by a depressive illness. In a so-called 'smiling' or 'masked' depression, the patient conceals severe depressive feelings behind a cheerful facade.

DEPRESSIVE ILLNESS Clinical features Clinical depression can be distinguished from both 'ordinary' depression or sadness (transient depressive moods) and depressive personality by three main features: • Depressive illness is a sustained depression of mood lasting for weeks or months. • The seventy of the depression is great enough to interfere with normal functioning. • The depression has a definite onset, with a distinct change from normal to depressive thinking. Depressive illness involves an alteration of many different aspects of mind, body and behaviour. It is nearly twice as common in women as in men. The features of depression may be summarized under four main headings: • Depressed mood. The patient feels weepy and miserable, 'low in spirits', anxious, lacking in concentration and irri-

Although the presentation of depressive illness can vary greatly, there are two common clinical pictures (Table 8.6). 1

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TABLE 8.6 Clinical features of neurotic and psychotic depression Clinical features

Psychotic

Neurotic

Severity of depression Delusions/hallucinations Sleep disturbance

More severe Yes Early morning wakening Yes, prominent

Less severe No Difficulty in getting off to sleep Yes/No

Worse on wakening and a.m. Yes Yes

No, or worse p.m.

Yes No

Sometimes

No

Yes

Yes

Yes

No

'Vegetative features', e.g. weight loss, constipation Diurnal mood variation 'Reactive', i.e. precipitated by loss Genetic factors, e.g. family history of manic-depressive psychosis Dexamethasone suppression test abnormal Response to tricyclic antidepressants Response to ECT

Neurotic depression Here the patient, despite depressive feelings, remains in contact with reality: 'I know it is stupid, but I feel as though I have let everybody down'. The patient might be a woman in her 30s with several small children, living in poor housing and with a husband who drinks and who is having an affair which she has just discovered. She is tearful, has lost weight and cannot fall asleep at night. She feels she is not coping with her job or housework, and no longer enjoys company or television.

Psychotic depression

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Depressive psychosis is a part of manic-depressive psychosis, an affective psychosis. The depth of the depression is here much greater than in neurotic depression. The ratio of women to men affected is more equal. The patient becomes immobilized in both thought and action. He wakes very early in the morning and may have diurnal mood variation, feeling at his worst in the morning and improving slightly towards the evening. Depressive delusions develop, the patient becoming convinced that he has, for example, brought ruin on his family, that he is evil or ugly or radioactive. Depressive hallucinations may occur: the patient may hear a voice telling him that he is evil, or he may feel that his insides are rotting and complain that he smells. Endocrine disturbance may occur in psychotic depression, with disruption of the pituitary-adrenal axis. In some cases the normal diurnal variation of cortisol output is abolished, providing the basis of the dexamethasone suppression test, in which dexamethasone is administered but fails to reduce urinary steroid levels.

SUMMARY 12 Factors contributing to depression • Loss • Genetic • Biochemical, e.g. reduced catecholamine levels at postsynaptic nerve endings • Social, e.g. lack of close relationships, unemployment, lack of good childhood experiences to build self-esteem, learned helplessness

DIFFERENTIAL DIAGNOSIS OF DEPRESSION The differential diagnosis of depression includes: • Organic illness, especially hypothyroidism • Drug administration, especially steroids and some antihypertensive drugs • Alcohol-induced depression, where depression is secondary to alcoholism (or drug addiction), and withdrawal of the intoxicant results in lifting of depressive symptoms • Anxiety states, as anxiety is a common feature of depression. When they coexist, treatment of the depression usually (but not always) removes the anxiety • Other psychoses, especially schizophrenia.

THE CAUSES OF DEPRESSION Depression is often divided into: • Reactive depression, whose symptoms correspond with neurotic depression and which is said to be a response to external events; • Endogenous depression, where the symptoms are psychotic in character and where there is no clear environmental precipitant. The distinction is misleading. Psychotic depression is usually also 'reactive' in the sense that it is triggered by a painful event in the patient's life; and neurotic depression can be 'endogenous' in the sense that genetic and personality factors influence the likelihood of an individual developing depression in response to misfortune. Loss Loss plays a central role in the origins of depression and is the link connecting grief with depression. The grieving person is in pain not just because of the loss of an external relationship, but because he has lost a part of himself. His internal world as well as his external world has been impoverished. The similarity between the clinical features of grief and those of depression are striking. In grief, an external loss dominates the picture; in depression, it is an internal feeling of loss. In 70% of depressions there has been a preceding external loss or stress: a bereavement (delayed grief is best seen as a special case of depression),

loss of job, break-up of a relationship, a child leaving home or a theft, for example. It is when this then leads to a feeling of internal loss - of optimism, vitality and (especially) of self-esteem - that a depression occurs. Whether or not a particular individual reacts to loss by developing depression depends on a number of interrelated factors, genetic, social, developmental and psychological.

Genetic/biochemical make-up Twin studies have shown that genetic factors play an important part in manic-depressive psychosis. Changes in neurotransmitter biochemistry in depression are important: current views emphasize a reduction of catecholamine levels at postsynaptic nerve endings. Antidepressant drugs may work by preventing the breakdown of cerebral amines (monoamine oxidase inhibitors), or reducing their reuptake (tricylic drugs) at central nerve endings. Similarly selective serotonin reuptake inhibitors (SSRIs) increase the concentration of serotonergic neurotransmitters in the synaptic cleft.

Current social situation The presence of a close confiding relationship, usually with a spouse, protects individuals from developing depression after the experience of loss. Employment is another protective factor; the unemployed are thus doubly vulnerable to depression, the loss of a job being a precipitant and lack of a job being a vulnerability factor. Women with three or more children under 15 and long-term social and financial difficulties are more vulnerable to depression following loss.

Early childhood experience Women who have lost their mothers before the age of 11 - whether through death, separation (for example, due to illness) or divorce - are especially vulnerable to depression in later life. A reservoir of good experiences in childhood is needed for an individual to develop a lasting sense of self-esteem. This provides a child with a good and secure internal world which can withstand the inevitable separations and losses of later life, and enables them to respond to such situations with appropriate sadness rather than by developing depression.

Psychological factors Recent studies of depression have focused on the vicious circle of depressive thinking and its accompanying negative assumptions about the self and the world. The depressed individual has developed learned helplessness, feeling that nothing he can do will make any difference to the situation. Actions and experiences that might make the individual feel better are avoided, and he continues to view himself in a negative light. His depression thus becomes a self-fulfilling prophecy. Depression produces and may be produced by patterns of dysfunctional thought, such

SUMMARY 13 Management of depression Psychological treatment Exploratory therapy Cognitive-behavioural therapy Family/marital therapy

8

Physical treatment Anti-depressants ECT

as dichotomous thinking (seeing everything as black or white), catastrophization (making a drama out of every crisis - inability to buffer and cope with minor setbacks), and a cascade of negative thoughts about the self that are triggered by everyday events, minor losses or difficulties. These serve to reinforce a basic view of the world characterized by hopelessness about the future, helplessness in the present, and guilt and remorse about the past.

Management Mild depression This is best dealt with by psychotherapy, which may take one of three main forms. Exploratory and psychodynamic psychotherapy Here, the patient is encouraged to express depressive feelings, to vent anger and despair and - through the relationship with the therapist (who may be a GP, social worker, psychotherapist or physician) - to experience the responsive empathy and containment that was lacking in childhood and so to recognize and recapture some of the good experiences the depression has blotted out. As self-esteem improves, so the patient can begin to tackle some of his current difficulties, which in a depressed state seem overwhelming. Cognitive-behavioural therapy (CBT) and interpersonal therapy (IPT) Controlled trials have shown that CBT is as effective as antidepressants in the treatment of mild-to-moderate depression. CBT counteracts learned helplessness and negative depressive thinking by challenging the erroneous assumptions on which they are based (e.g. if I phone my boyfriend and he is out, it does not mean that he does not love me, merely that he is working late), and by considering positive features of the self. The patient is encouraged to set himself small, easily accomplished tasks and to feel pleased if he succeeds. IPT is similarly focused and time limited. It explicitly adopts a medical model, seeing depression as an illness over which the patient has little control. IPT homes in on one of four underlying factors that contribute to depression: 'role transitions', e.g. depression associated with retirement, or becoming a mother, or divorce and so becoming single; grief and bereavement linking depression with unworked-through losses; interpersonal conflict, usually with partners; and social skills deficits: here depression is linked with lack of personal effectiveness and competence, and therapy is specifically designed to improve communication and social flexibility.

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Family and marital therapy Here the aim is to improve the marital relationship, which can then provide a bulwark against depression in response to loss. Partners often unwittingly contribute to the maintenance of a depressed state, perhaps by being overconcerned and 'helpful' and so reinforcing the sufferer's sense of their own helplessness and loss of role. The safe expression of anger can strengthen a relationship and reverse the inward turning of anger that is so common in depression. Moderate depression A combination of antidepressant drugs and psychotherapy can be more effective than either alone in treating moderate depression. Both depressed mood and biological symptoms improve with drugs; low self-esteem and social difficulties improve with psychotherapy. Antidepressants are always indicated when sleeplessness and guilt are prominent features. Tricyclic antidepressants (TCA) such as amitriptyline (75-200 mg/day) take 10-14 days to produce their full effect. Side-effects include parasympathomimetic symptoms of dry mouth and urinary retention, constipation, blurred vision and 'muzziness'; and cardiac arrhythmias can occur. Dosulepin (dothiepin) and lofepramine have fewer side-effects. Imipramine and clomipramine are less sedative. Tricyclics should be avoided in patients with prostatism or a history of heart disease. Mianserin, a tetracyclic, has fewer side-effects but can produce haematological reactions and is possibly also less effective in its antidepressant action. If mianserin is used, a blood count should be carried out every 4 weeks. Selective serotonin re uptake inhibitors (SSRIs) such asfluoxetine,fluvoxamine, sertraline and citralopine have fewer antimuscarinic side-effects and low cardiotoxicity, and are therefore preferable, especially when the suicide risk is strong. They may, however, cause nausea and vomiting. Venlafaxine has mixed SSRI and TCA properties and is another popular antidepressant. Monoamine oxidase inhibitors (MAOIs) such as phenelzine (15-90 mg daily) are still occasionally useful as second-line drugs, especially when phobic symptoms are present, but dietary restrictions (e.g. no cheese or yeast-extract) are needed because of harmful (hypertensive) interactions with tyramine-containing substances. Moclobemide is a newer MAOI that can be taken without any major dietary restrictions. Severe depression Depressed patients who are severely incapacitated, psychotic or actively suicidal require hospital admission. Antidepressants, which may have to be given in large doses (up to 250mg of amitriptyline or equivalent daily), are the first line of treatment.

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ECT Despite debate about its mode of action and efficacy, and despite popular prejudice, controlled trials of electroconvulsive therapy (ECT) have shown it to be an effective and rapid treatment for depressive delusions and hallucinations (Fig. 8.4); it is also free from side-effects, apart

FIG. 8.4 Effect of ECT on severity of depression

from the dangers of the anaesthetic and some short-term memory impairment. ECT is a first-line treatment in depressive stupor or where the patient is refusing food and drink. When the patient refuses consent, in the UK it can only be given after Section 3 of the 1983 Mental Health Act has been applied and a second, independent, psychiatric opinion obtained, although in a life-threatening situation one application of ECT may be given pending the second opinion. ECT produces a rapid improvement in severe depression and is especially effective in elderly patients, in whom tricyclics may produce confusion and cardiac arrhythmias. The basis of ECT is the delivery of a convulsion or fit, and its effectiveness depends on an adequate fit of around 25 seconds. A 'course' of ECT, given twice or thrice weekly, should deliver a total of around 250 seconds of fit if relapse is to be avoided. ECT can be given to both hemispheres (bilateral) or to the non-dominant one (unilateral), depending on the position of the electrodes. Unilateral ECT produces less memory impairment but may also be less effective. ECT is very effective in the short run but, unless supported by psychological and pharmacological therapies, relapse is also common. Chronic or recurrent depression Most depressive illness has a tendency to remit, but relapse is common. Prolonged treatment with tricyclics has a prophylactic effect, as does 'maintenance' psychotherapy. Relapse of depressive psychosis may in some cases be prevented by prophylactic lithium carbonate. Chronic depressive states are rare but disabling, and prolonged attendance at a supportive day hospital may be required.

FURTHER READING ON DEPRESSION Brown G, Harris T 1978 The social origins of depression. Tavistock, London

TABLE 8.7 Clinical profiles of suicide and parasiticide Suicide

Parasuicide

Central theme

Despair, depression

Anger, frustration

Epidemiology

Increase in men aged 15-25, 1985-1999

Increase in all groups 1985-1999

8

Commoner in women aged Age, sex, class Commoner in age range 25-34; commoner in men 18-35 and in social than women; no class classes IV and V preference; recent increase in death by suicide in young men Social circumstances

Isolated, e.g. unemployed, retired, divorced, children left home, few friends or religious/social groups

Disturbed but not isolated, e.g. teenager unhappy with parents or boyfriends

Method and build-up

Planned. Usually leaves a note; method often violent, e.g. hanging, shooting, drowning

Impulsive. Commonest method is swallowing pills. Cutting (usually wrists) a more disturbed subgroup

Alcohol

May play a part - 'Dutch courage'

Attempt very commonly associated with alcohol/ drugs, i.e. reduced impulse control

Illness

90% of suicide case are mentally ill, usually with depressive illness. Physical illness also common

Only about 30% are mentally ill. Some have personality disorder. Majority normal or with 'minor affective illness'

Outcome

Not all 'succeed'. Survivors need hospital admission for treatment of mental illness

Not all survive, but most do. About 5% repeat. May benefit from counselling or psychotherapy

FIG. 8.5 Death rates for suicide and undetermined injury in England 1969-91

Lee A 1999 (ed) Affective and non-pychotic disorders. Gaskell, London Scott J 1995 Psychological treatments for depression. Br J Psychiatry 167: 289-292

SUICIDE AND PARASUICIDE Suicide appears to be an integral part of human psychology. There are few individuals lucky and happy enough never to have had even a fleeting thought of suicide at some point in their lives. There has been a worrying increase in suicides in young men (Fig. 8.5). 'Parasuicide', a syndrome of deliberate self-harm, appears to be a relatively recent phenomenon and has reached epidemic proportions over the past 25 years. It is the commonest cause of hospital admission for women under 65, and the second commonest for men. Many cases of deliberate self-harm go unreported; probably only about one-third reach hospital.

Clinical profiles The clinical profiles of suicide and parasuicide are, on the whole, distinct (Table 8.7). A person who commits suicide could be a male with a previous history of depression and alcoholism, recently divorced or made redundant, living alone and with few close friends or relations. He deliberately tells the neighbours and milkman that he is going away for the weekend, and then takes a bottle of aspirin or shoots himself. A parasuicidal person might be a woman in her late teens living with her mother and stepfather, and getting on badly with her boyfriend. After a row with him, in which both have been drinking, she goes home, swallows some of her mother's sleeping tablets, and is then noticed to be drowsy. When challenged about what has happened, she immediately 'confesses' and is rushed to hospital.

The central theme of suicide is despair and depression; in parasuicide it is anger and frustration. Although there are important differences there are also psychological similarities. Both involve a physical attack on self, on the body. In both cases the patient feels a combination of personal inadequacy and anger towards friends and family. This anger is directed inward, but there is often a wish to punish or harm those to whom the patient feels close. This is done indirectly via the suicide or suicide attempt. It is often said that parasuicide cases 'do not really mean it'. This is only partially true, and can sometimes be used by staff as justification for adopting a punitive attitude. It is best to assume that both suicide cases and parasuicide cases want both to die, and not to die. The relative proportion of the two feelings varies greatly, but both feel both. A third point of overlap follows from this. Not all suicide cases succeed and, conversely, it is possible in parasuicide to die by mistake. Patients who have made major suicide attempts may recover and, with the help of drugs, psy-

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FIG. 8.7 Primary diagnosis of suicides (England and Wales Suicide Inquiry cases), 1996-2000 FIG. 8.6 Age and sex profile of general population suicides (England and Wales), 1996-2000

chotherapy and time, regain the will to live. In the majority of parasuicide cases the attempt resolves the difficult social situation that prompted it, and so is not repeated. In a minority - about 5% - the attempts are repeated, and a proportion of these will eventually 'succeed'. Parasuicide repeaters are more likely to have a personality disorder, to be addicted to drugs or alcohol, or to have been in trouble with the law. (See Figs 8.6 and 8.7.) 1

Management of 'failed suicide' The causes of suicide are essentially the causes of depressive illness, and the management of attempted suicide is that of prevention, and particularly the early detection, of depression. About half of successful suicide cases have contacted a helping agency - a counselling organization, a GP, social worker or priest - in the month before they kill themselves. It is important to ask troubled, unhappy or depressed patients about suicidal feelings. Fleeting suicidal thoughts - 'I would like to sleep' or 'I would like to be dead but would never have the courage to do anything' - are less worrying than a definite suicide plan. Talking about suicidal thoughts may in itself be a relief. Suicidal patients with symptoms of depressive illness should be admitted to a psychiatric unit. Patients who are managed as outpatients need to be seen frequently while they are in a suicidal state.

1

224

MCQ 8.2

Antidepressants can be prescribed, but only in small amounts, as hoarding of tablets can be a danger. Although the prevention of suicide remains the ideal, this is difficult to achieve in practice. Counselling organizations such as the Samaritans seem not to have had a major impact on overall suicide rates, but the incidence of suicide in the UK has fallen slightly over the past 30 years compared with the rest of Europe. Suicide is a reminder of the limitations of psychiatric and social care. When a patient who is receiving treatment commits suicide, it is especially stressful for the doctors and nurses involved, as it always is for the patient's family. Feelings of guilt and anger are inevitable. Suicide, like any death, is a reminder that doctors are not omnipotent. In dealing with suicide or the threat of it, it should be remembered that, ultimately, a person determined or ill enough can always find a way to end his life.

DELIBERATE SELF-HARM Causes The causes of attempted suicide cannot be found solely within the individual. Social factors that need to be considered in understanding the increase in parasuicide rates include: • Complex family structures without clear rules or roles, such as unsupported one-parent families; adolescents who want freedom but lack the emotional or financial resources to leave home; families with step-parents; • Drugs being a socially acceptable means of dealing with distress: the commonest tablets taken in parasuicide are mild analgesics and minor tranquillizers;

8

CASE STUDY 8.1 SUICIDE OF A 20-YEAR-OLD ART STUDENT A 20-year old art student was brought by her friends to the psychiatric ward in a highly aroused state. She had not slept for several days, was dishevelled, could not sit still, and was talking 'nineteen to the dozen'. She was convinced that she was a direct descendant of van Gogh and that her paintings were worth several million pounds. She came from a loving family but one in which there was a very high incidence of mental illness. Her mother suffered from alcoholism, her half-sister had committed suicide, and her father, a very successful businessman, had marked mood swings. A diagnosis of hypomania was made. She was treated with haloperidol and started on lithium carbonate. After 2 weeks in hospital she was well enough to return home, but not to resume her studies. She was followed in outpatients and offered fortnightly supportive psychotherapy in addition to her continuing drug therapy. She found the side-effects of the neuroleptic drugs troublesome, and often 'forgot' to take her haloperidol. Her mood continued to be somewhat elated, and she worried her parents by mixing with what they saw as a 'wrong' crowd, many of whom had also suffered psychiatric illnesses or abused drugs. She suffered an episode of depression when an exboyfriend killed himself while drunk, and had once more to be admitted to hospital for a brief period. Two years after her original admission she felt well enough to resume her studies at art college. Things seemed to be progressing well, and she reduced her contact with psychiatric services to a

3-4-monthly outpatient attendance. She wanted to come off all her drugs, and was only persuaded to continue with lithium with some difficulty. Then one weekend, apparently without warning, she was found dead in her flat having taken an overdose of aspirin. On reconstructing the preceding history it appeared that she had taken no lithium for several weeks prior to her tragic death. Lithium levels were supposedly checked by the student health service every 3 months, but she had failed her most recent appointment.

Questions 1. What was the diagnosis? 2. Could her suicide have been prevented?

Discussion She showed many of the features of manic-depressive psychosis, bipolar type. There was a strong family history of mood disorder. She showed features of hypomania on first admission, which responded to neuroleptics and a mood stabilizer. Later she developed depressive symptoms in response to a painful life event. The mortality rate from suicide in manic-depressive illness is around 10%, and there is some evidence that taking a mood stabilizer such as lithium reduces mortality. There was an administrative and ethical conflict between the patient's reasonable desire to lead as normal a life as possible and the fact that she was

An epidemic factor. Deliberate self-harm is often behaviour learned from friends, fellow patients, relatives or television.

Management The medical management (p. 23) of the parasuicide patient takes initial precedence over the social and psychiatric

suffering from a potentially lethal psychiatric illness. Insisting on regular contact with medical/psychiatric services - her GP, community psychiatric nurse or consultant psychiatrist - might well have meant that her deteriorating mental state and poor drug compliance would have been picked up. Even better would have been attendance at a 'lithium clinic' run as part of a mental health service. Ongoing psychotherapy could also have identified the recurrence of her depressive symptoms and her irrational view of herself as useless and a burden to everybody, which was revealed in her suicide note. But all of this is to be wise after the event. She appeared to be doing well, and there is a limit to the extent to which treatment can be imposed on someone who feels and seems to be functioning well. Her case illustrates one of the most poignant dilemmas of psychiatry. Severe mental illness affects young people and has a mortality comparable to that of diseases such as leukaemia. She survived for nearly 5 years after diagnosis, a result which would be considered quite good in physical medicine but can lead to a very pessimistic appraisal of psychiatric treatments. All this had to be discussed in the case review, which occurs whenever there is a suicide among patients known to psychiatric units - open meetings in which staff can express their feelings without fear of censure, and work through the inevitable emotions of guilt, failure, anger and despair that suicide can evoke.

assessment. Medical staff often feel angry with overdose patients compared to those whose illness is not selfinflicted and, like alcoholics and drug addicts, such patients may become scapegoats. Their irresponsibility affronts the overworked nurses and doctors, who are often similar in age and maturity to the patient. In addition, medical staff work in a stressful and hierarchical situation in which they can at times feel angry or frustrated, and these emotions

225

can be displaced into a punitive attitude towards parasuicide patients. This can be avoided if ward procedures give time for discussion of these patients and the feelings they arouse.

History A careful history must be taken from the overdose patient, who should be kept in hospital until alert and cooperative enough for this to be possible. The presence of depressive illness and suicidal rather than parasuicidal features must be identified. The risk of a repeat attempt has to be assessed (Table 8.8). Social isolation, marked sleep disturbance preceding the attempt, strong feelings of guilt or unworthiness, evidence of preplanning, inability to look to the future and previous psychiatric history - especially if there are drug or alcohol problems - all point to serious disturbance and should lead to referral to a psychiatrist. A detailed account of the attempt itself and of events surrounding it should be taken. It is often unhelpful to ask the patient 'why' he harmed himself. If the patient knew, he might not have had to do so. In attempted suicide one often finds an acting-out of feelings, rather than the capacity to contain or verbalize them. The patient will find it much easier to answer questions about 'what happened,

TABLE 8.8 Deliberate self-harm: assessment of severity of disturbance. Ideally, all eases should be referred for psychiatric assessment, Psychiatric referral is essential if any of the following are present Circumstance of the attempt Evidence of preplanning (e.g. suicide note, use of car exhaust) Violent method used (e.g. attempted hanging) Social circumstances of patient Alone Away from home Personal history of patient Recent loss (e.g. bereavement, divorce/separation, unemployment) Physical illness Previous attempts Alcohol or drug addiction History of depressive illness Family history of patient Suicide Depressive illness Mental state examination Sleep disturbance, low mood before attempt Low self-esteem, hopelessness Psychotic features (e.g. 1 deserve to die')

226

Future No relatives or other support Unresolved crisis Continued determined suicidal intent

and how'. This provides an 'action replay' of the attempt, which will contain the clues to the question of 'why'. Most commonly the patient feels angry but is unable to express this directly, usually for fear of rejection by a partner, spouse or parent on whom he feels dependent. As in depression, he dare not bite the hand that feeds, and so attacks himself instead. It can be useful to ask the patient who he thinks would have been most distressed if he had died. Later, it is often helpful to discuss alternative strategies with the patient, to examine what he could have done in the same situation other than attempt suicide. Followup counselling after discharge, either as an individual or in a family, by a social worker, psychiatrist or psychotherapist, may be offered, although less than half of patients accept such help. However, even without follow-up the prognosis of parasuicide, in the absence of depressive illness or personality disorder, is fairly good.

FURTHER READING ON SUICIDE AND PARASUICIDE Hawton K 1987 Assessment of suicidal risk. Br J Psychiatry 150: 145-153. Hawton K, Catalan J 1987 Attempted suicide: a practical guide to its nature and management. Oxford University Press, Oxford Owens et al 1999 Assessment of deliberate self-harm in adults. In: Lee A., ed. Affective and non-psychotic disorders. Gaskell, London.

MANIA AND HYPOMANIA Clinical features In depression, mood is abnormally lowered. In mania, or its milder form hypomania, it is abnormally elevated. In unipolar manic-depressive psychosis the patient may have recurrent depressive or recurrent manic episodes. If both manic and depressive episodes occur, the patient has bipolar manic-depressive psychosis. There are three main groups of symptoms in mania and hypomania: • Psychological symptoms. The patient feels elated, cheerful and expansive, and his thoughts are speeded up. He may develop grandiose delusions of wealth, potency and fame. He is full of optimistic (and unrealistic) plans for the future. • Physical symptoms. The patient is restless, sleeps little, eats voraciously or not at all, often loses weight, has poor concentration, and tries to do several things at once. • Behavioural symptoms. The patient often spends large amounts of money, dresses flamboyantly and may behave in an outrageous, disinhibited and promiscuous manner. Outbursts of irritability and aggression are common. Speech is rapid, may be incoherent, and flits from subject to subject (known as flight of ideas). The patient is often humorous in an irreverent and infectious way.

CASE STUDY 8.2 A 32-YEAR-OLD WOMAN WHO HAS TAKEN AN OVERDOSE A 30-year-old married woman was sent to A&E by the emergency GP service having been found by her husband in a comatose state with a bottle of Prozac beside her and smelling of alcohol. She was admitted to the medical ward, given a fluid diuresis, and made a full physical recovery within 12 hours. The duty psychiatric team was then called to evaluate her. She said that she had been feeling low for several weeks, with poor sleep and reduced appetite. She had had a difficult year, since her mother had been killed in a car accident, and her 9-year-old son had been diagnosed as suffering from hyperactivity attention deficit disorder and excluded from his school. Her husband, a builder, had been unemployed because of a bad back, and on the day of the overdose they had received a final demand for a gas bill which she could not pay. This felt like the final straw - she felt she could not cope, her husband was out at the pub with his friends, and her son would be better off without her. She and her husband had been getting on badly, with lots of rows, she had no libido and they had not had sex for several months. She had a history of puerperal depression after the birth of her son, and had taken a minor overdose in her teens following a row with her boyfriend. She was an only child. Her parents had separated when she was 13. She had stayed with her mother who soon remarried, but the patient had not got on with her stepfather. She saw her father infrequently and felt awkward with him. On examination she was a bedraggled, miserable-looking person, appearing older than her 30 years. She was overweight. History-taking was difficult and she made little eye

contact. Her speech was normal in form but slightly slowed. She was subjectively and objectively depressed. She felt guilty towards her family, feeling she had let them down and that she was in some way responsible for her son's problems. She had no delusions or hallucinations. Cognition was normal and she was of average intelligence. The interviewer felt a mixture of pity and irritation towards the patient. She said that she no longer felt suicidal, but was unable to visualize how things would be different if she returned home. On being offered admission to a psychiatric ward, she refused.

Questions 1. What is the diagnosis? 2. How serious is the risk of further self-harm or suicide? 3. Should she be compulsorily admitted to hospital?

Discussion The diagnosis of depressive illness is fairly clear in this case. She gives a history of low mood, poor appetite, loss of libido and difficulty in sleeping over several weeks, culminating in an overdose of tablets with suicidal intent. She felt guilty, unattractive and useless. This was not a purely situational episode of deliberate selfharm, although there was an impulsive element to it, and there was no evidence of preplanning and she had not written a suicide note. The depression was of moderate severity, but there were no psychotic features. She claimed that her suicidal feelings had resolved, but was unable to give

8

a convincing account of how things could change in her life. Her home support was problematic. There was a definite, but not extreme, continuing suicide risk. Compulsory admission is a grave step, especially in the absence of psychotic features, but to let her go home might be to court disaster. During these deliberations her husband appeared on the ward. He was interviewed and revealed himself to be a reasonable man, desperately worried about his wife and shocked by her suicide attempt. He admitted that he too had felt depressed and had tended to resort to alcohol and avoid his home problems by going to the pub with his friends. He was strongly opposed to compulsory admission and said that he would guarantee to keep a close eye on his wife. Compulsory admission requires the consent of the nearest relative, unless that power is taken away by applying to a local magistrate - an extreme measure. A further attempt to persuade the patient to stay in hospital was made, and she reluctantly agree to stay voluntarily. While on the ward she was started on a more sedative antidepressant, sertraline, joined a self-esteem and assertiveness group, and she and her husband attended marital therapy sessions, in which her anger about the way in which she felt he had abandoned her was clearly expressed. He accepted the legitimacy of this and apologized. She could link this with her feelings about her father, who had abandoned her after her parents' divorce, and began to see that, despite his faults, her husband was a loyal and loving man. Her suicidal feelings lifted, she began to sleep better and was discharged from hospital, although therapy continued.

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Hypomania frequently coexists with depressive symptoms: the patient laughs and cries almost simultaneously. This is known as a mixed affective state. Hypomanic episodes may, like depression, be triggered by a painful rejection or loss. This has led to the concept of manic defence, whereby the patient escapes into mania as a way of avoiding unhappy or sad feelings.

Management A hypomanic patient can cause havoc to both himself and his family. Hospital admission is often indicated but may be hard to achieve voluntarily, as the patient denies illness, often claiming to have never felt better, or to have discovered the secret of life. Immediate management is with tranquillizers such as chlorpromazine (100-600 mg daily) or haloperidol (15-60mg daily). Subsequent relapses may be prevented by prophylactic lithium carbonate (800-1600 mg daily). Lithium also has a mild immediate antimanic effect. Blood levels should be monitored regularly and be in the range 0.8-1.5mmol/L. Lithium may produce hypothyroidism and renal damage, leading to nephrogenic diabetes insipidus, and thyroid and renal function should be monitored. Other side-effects include abdominal pain, fine tremor, subjective memory impairment, thirst and lowered zest for life. Patients should be encouraged to keep up fluid intake in hot weather. Anticonvulsants such as carbamazepine (400-1600 mg daily) can be used as second-line antimanic prophylactics if lithium is ineffective or cannot be tolerated.

SCHIZOPHRENIA Just under 1 % of the population develop schizophrenia at some point in their lives, a statistic that appears to hold true for all cultures and countries. Chronic major mental illness in people under 65 is due mainly to schizophrenia. Until the move towards community care began, about half of all hospital beds in the UK were in mental hospitals and the majority of these (for the under-65s) were occupied by patients with a schizophrenic illness. As the number of hospital beds has fallen, a significant proportion of the vagrants living in large inner-city hostels and prison recidivists are found to be suffering from schizophrenia.

Aetiology Schizophrenia is the core disorder in adult psychiatry. Much debate has raged about the nature of schizophrenia, or even whether it is a valid clinical entity. It is probable

1

228

MCQ 8.3

Chances of developing schizophrenia (%) Relationship Parent: one Parents: both Sibs (neither parent schizophrenic) Sibs (one parent schizophrenic) Children Half sibs Uncles and aunts Nephews and nieces Grandchildren First cousins Fraternal twins Identical twins FIG. 8.8 Lifetime expectation of schizophrenia in relatives of schizophrenics

that schizophrenia is not a single disease but a group of related conditions. Both genetic and environmental factors are important in the aetiology of schizophrenia. It is best seen as a developmental disorder of the brain to which genetic and perinatal factors (birth trauma or maternal viral infection) contribute, but manifesting itself in late adolescence when brain maturation is finally completed. Pathogenic environments contribute to relapse in schizophrenia, but their role in aetiology is uncertain. It is possible that abnormal brain development may result from unstimulating or traumatic environments. • Twin and adoption studies have demonstrated the role of heredity in schizophrenia (Fig. 8.8). The concordance rate for identical twins is about 50%, that for nonidentical twins around 15%. • The efficacy of antipsychotic drugs such as chlorpromazine, with its inevitable parkinsonian side-effects, suggests a disturbance of midbrain dopaminergic pathways in schizophrenia (the 'dopamine' hypothesis). There is convincing evidence of increased D2 activity in patients with positive symptoms of schizophrenia. Dopamine abnormality may be the end result of other metabolic aberrations. It seems likely that serotonin (5HT) is also involved, perhaps by increasing D2 levels. Also glutamate, an excitatory neurotransmitter, may behave abnormally, leading to underactivity of Nmethyl-D-aspartate, which in turn may stimulate abnormal dopamine and 5HT activity. • A subgroup of patients show ventricular abnormalities on CT scan. There is slight ventricular enlargement, a reduction in the normal asymmetry between the cerebral hemispheres and, particularly in males, a reduction in cortical grey matter, especially in the temporal lobes. It has been suggested that structural abnormalities are more common in patients who lack a family history of the illness, suggesting that non-genetic organic factors, perhaps associated with perinatal brain injury, may be important in some cases.

SUMMARY 14 Schneider's first-rank symptoms

TABLE 8.9 Relapse rate for schizophrenia

• Delusional perception • Auditory hallucinations Audible thoughts (thought echo) Voices arguing or discussing ('third person') Voices commenting on the patient's actions • Thought disorder Thought withdrawal Thought insertion Thought broadcasting • Passivity experiences: delusions of control 'Made' feelings (includes somatic hallucinations) 'Made' actions Somatic passivity (body invaded from outside)

A. At 9 months

• Family and social factors have also been shown to be important, although not pathognomonic. In established schizophrenia the relapse rate is high when the patient is living in an over-involved family where there is a negatively charged emotional atmosphere (high 'expressed emotion', or 'EE') (Table 8.9). • Schizophrenic patients have a high state of psychophysiological arousal, possibly related to family stress. This may reflect limbic system dysfunction and lead to a difficulty in processing sensory stimuli.

8

Relapse rate 50% 12%

High EE homes Low EE homes B. In high EE homes Face-to-face contact

Maintenance therapy

Relapse rate

High High Low Low

No Yes No Yes

92% 53% 42% 15%

Delusions In schizophrenia these include the feeling that one's thoughts originate from outside ('thought insertion'), that they are being interfered with, removed ('thought block' and 'thought withdrawal') or transmitted to outsiders as though on a loudspeaker ('thought broadcasting'). 'Passivity feelings' are the feeling that one's thoughts or actions are 'made' from outside.

Delusional perception Clinical features Schizophrenia usually starts in young adulthood (the exception being paraphrenia, a form of paranoid schizophrenia affecting the elderly). There is a slight preponderance of men. The features of the illness can be divided into two parts: the effects on mental processes, and the effects on social functioning.

Mental disturbance There is a general disturbance of mental functioning in schizophrenia. The normal progression of logical thought is disrupted ('thought disorder'). The privacy of the self is breached. Certain patterns of disorganization of thinking are characteristic of schizophrenia, and are known as Schneider's first-rank symptoms.

Hallucinations These are usually auditory. Characteristic of schizophrenia are 'third-person' hallucinations, in which more than one person is heard discussing the patient and referring to him as 'he', 'she' or 'it'. Voices commenting on a person's actions like a 'running commentary' are also characteristic, as are voices that echo the patient's thoughts. Tactile or 'kinaesthetic' hallucinations, for example electric-shock feelings in the limbs, are rare but pathognomonic.

In delusional perception, a neutral stimulus (e.g. a car number plate or a traffic light) suddenly acquires special and often frightening significance for the patient. 1

SUMMARY 15 Management of schizophrenia • First attack: admit to hospital or day hospital for assessment, confirm diagnosis, establish contact and initiate treatment. • Treat symptoms with neuroleptics. Chlorpromazine 100mgt.d.s. by mouth Trifluoperazine 5mg t.d.s. by mouth Risperidone 2-4 mg b.d. by mouth Examples of Olanzapine 5-10 mg b.d. by mouth moderate moderatedoses doses Flupentixol ('Depixol') 40 mg 2-weekly Fluphenazine ('Modecate') 25 mg 2-weekly Treat side-effects as necessary with antiparkinsonian agents, e.g. Kemadrin 5 mg t.d.s. • Assign 'community key worker' as part of community care programme who will offer supportive psychotherapy and coordinate care package. • Assess family situation: offer psychoeducational programme to lower 'EE' if indicated. • Rehabilitation: attend day hospital, day centre, sheltered workshop, live-in hostel, sheltered housing. • Where resistant to medication consider newer neuroleptics: clozapine and risperidone.

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Social deterioration The second main feature of schizophrenia is social deterioration. This is known as a negative feature of the illness, as opposed to the positive features of thought disorder, delusions and hallucinations. The patient may withdraw from social contact, give up his job, shun his friends and family, and spend many hours in isolation.

Differential diagnosis

Antipsychotic drugs These are of two main types: the so-called 'typical' antipsychotics, and the newer 'atypicals', orginally developed in the search for drugs with fewer extrapyrimidal side-effects (EPSs), which are rapidly becoming standard treatments. 'Typicals' can be divided into three main groups. All are potent D2 receptor antagonists.

An important subtype of schizophrenia is paranoid schizophrenia, characterized by paranoid delusions. Here the onset is later (around 30-40 years of age), social deterioration is much less marked, and the personality is relatively well preserved. Schizoaffective disorder has features of both schizophrenia and an affective illness, e.g. first-rank symptoms plus considerable depression. Its diagnosis is intermediate between that of the two 'parent' disorders. Not all madness is schizophrenia. The differential diagnosis includes:

• A group characterized by profound sedative effects and moderate antimuscarinic and extrapyramidal effects, e.g. chlorpromazine (50-1000 mg daily); • Moderate sedative effects, marked antimuscarinic effects, but fewer extrapyramidal effects, e.g. thioridazine (25250 mg daily), often used as a sedative in the elderly; • Fewer sedative and antimuscarinic effects but more pronounced extrapyramidal effects, e.g. trifluoperazine (2-30 mg daily); haloperidol (2-80 mg daily); flupentixol (2-100 mg daily).

• Organic psychosis, such as acute confusional states and drug- and alcohol-related psychosis; • Manic or depressive psychosis (in which auditory hallucinations occur but are more often 'second-person', in which voices speak directly to the patient); • Hysteria; • Stress-induced or 'psychogenic' psychosis; • Severe personality disorder.

Atypical' antipsychotics tend to have strong 5HT2a receptor antagonist activity. They include:

Prognosis The course of schizophrenia is very variable. About 30% of patients have only one episode. A good prognosis is more likely if the psychosis has an acute onset, a clear precipitant, florid symptoms, marked mood change in addition to disturbance of thinking, and good previous social adjustment and personality. At the other end of the scale, about 15% remain severely disabled and will still be in institutional care after a year. In these patients the negative features of schizophrenia (withdrawal and inertia) may predominate. In the middle group, representing the majority of patients, the illness has a fluctuating course but relapse and some residual disability are likely to occur.

Management Acute schizophrenic symptoms respond well to antipsychotic medication. There is some evidence that prompt treatment is associated with a good prognosis. The patient will normally be admitted to a psychiatric unit and treated initially with 100-1000 mg daily of chlorpromazine or its

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equivalent. The longer-term management of schizophrenia is difficult. It involves both prevention of relapse and management of chronic disability.

MCQ 8.4

• Clozapine. This has serotonergic and dopaminergic properties and is effective against positive and negative symptoms of schizophrenia which have failed to respond to typicals. Its main drawback is that it causes agranulocytosis in 3% of subjects, and weekly blood count monitoring is necessary. Excessive salivation and sedation can also be problematic. • Risperidone. Also effective against positive symptoms, but can cause agitation and insomnia. • Olanzapine and quetiapine (an anagram of quiet-apine!, subtly drawing attention to its sedative properties) are also effective drugs and generally well tolerated, although they can cause alarming weight gain. A wide range of side-effects and idiosyncratic reactions may be produced with the antipsychotic drugs (Table 8.10). Perhaps the most serious of these is the rare but potentially fatal neuroleptic malignant syndrome, characterized by hyperthermia, confusion, muscular rigidity and autonomic disequilibrium (tachycardia, labile blood pressure, sweating). The patient should be admitted immediately to a medical unit; all antipsychotics should be discontinued and bromocriptine and dantroline given. Psychosocial interventions Analytical psychotherapy is generally not favoured in schizophrenia, and indeed the emotional arousal it may evoke can cause deterioration. There are, however, a number of 'psychosocial interventions' that significantly improve the wellbeing of patients with this disease. These comprise: • Family intervention. Because high 'EE' is associated with relapse, measures to reduce EE, either in families or in the hostels where some patients with schizophrenia live,

TABLE 8.10 Side-effects and toxic effects of antipsychotic drugs (e.g. chlorpromazine, flupentixol) Type of effect

Examples

Autonomic (antimuscarinic)

Blurred vision Dry mouth Constipation Precipitation of glaucoma Postural hypotension Inhibition of ejaculation Urinary hesitancy Akinesia (Parkinson-like) Acute dystonia Tardive dyskinesia (involuntary repetitive movements) Akathisia (motor restlessness) Weight gain Galactorrhoea and amenorrhoea Gynaecomastia Agranulocytosis Cholestatic jaundice Skin rashes

Extrapyramidal

Endocrine effects

Hypersensitivity reactions

Neuroleptic malignant syndrome Provocation of epileptic fits Hypothermia (especially in the elderly) Skin photosensitivity

will be valuable. A programme of 'psychoeducation' for families teaches them about the nature of the disorder and, via family group therapy or regular therapy sessions with families, works to reduce the emotional tension and foster a more benign atmosphere. Long-term supportive psychotherapy. Therapy in schizophrenia has to be long-term: perceptible change may take 4 years or more. A stable consistent therapeutic relationship with a psychiatrist or community key worker is needed and often bears fruit. Cognitive-behavioural therapy (see Recent Advances box). 1

Management of chronic disability Chronic mentally ill patients are severely handicapped. Their prospects of employment are poor, they may have little or no family support, and their capacity to care for and occupy themselves may be very limited. They are sometimes also shunned or made scapegoats by society, which tends to fear and despise madness. For at least 150 years these problems were dealt with by removing patients from society and locking them away in mental hospitals, thereby reinforcing the helplessness and isolation produced by the illness. Because of this, and also because mental hospitals are expensive to run and often sited on valuable land, government policy in the UK has now shifted away from the mental hospitals and towards community care. Patients are supposed to be cared for within the local community, in a network of hostels, sheltered houses, day hospitals and day centres, and community mental health centres. These are run by a locally based team of professionals, the 'multidisciplinary team' including community psychiatric nurses (CPNs), social workers and general practitioners, as well as psychiatrists. However, although this pattern of care is desirable for many patients, and is already a reality for some, it is not necessarily suitable for all patients, some of whom continue to need highly staffed or secure facilities on an intermittent or continuous basis. The care programme approach aims - through ensuring that every patient has an identified key worker, a definite 'care programme' and regular reviews with all concerned - to prevent patients from drifting away from services and thus to prevent the relapse that is likely to ensue when continuity of care is lost.

8

FURTHER READING ON SCHIZOPHRENIA Drug and Therapeutics Bulletin 1996 Drug treatment of patients with schizophrenia. Drug Ther Bull 33:81-86 Kane J, McGlashan T 1995 Treatment of schizophrenia. Lancet 346:820-825 Lewis S, Buchanan R 1998 Schizophrenia. Health Press, Oxford

PARANOID STATES Long-term maintenance on medication (which in the case of 'typicals' can sometimes be given in the form of a weekly or fortnightly injection because of problems of compliance) prevents relapse in schizophrenia. Phenothiazines can, however, have unpleasant and serious side-effects, especially a feeling of tiredness and extrapyramidal syndromes of stiffness and involuntary movements (Table 8.9). Antiparkinsonian drugs such as orphenadrine (100 mg t.d.s.) or Kemadrin (5 mg t.d.s.) should be given to counteract these. Reducing family tension has also been shown to prevent relapse. This can be achieved by family counselling sessions and by physical separation of the patient from an over-involved family through the provision of hostel accommodation and/or attendance at a day centre.

Paranoia means literally 'to be beside oneself, or 'out of one's mind'. In psychiatry, it refers to a psychosis whose

SUMMARY 16 Conditions resulting in paranoid states • • • • • •

Organic psychosis Manic-depressive psychosis Paranoid schizophrenia Paranoid psychosis Paranoid personality Paranoia in the elderly

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RECENT ADVANCES IN THE PHYSHOSOCIAL MANAGEMENT OF SCHIZOPHRENIA Schizophrenia remains psychiatry's greatest challenge. Although the essential nature of the schizophrenias remains as elusive as ever, the past few years have seen, for the first time for two decades, significant psychotherapeutic advances. There is evidence that the longer the time between the onset of symptoms and beginning treatment, the worse the prognosis. This has led to much current interest in the notion of 'early intervention' in schizophrenia - trying to pick up the prodromal stages of the illness and initiating treatment, both psychosocial and pharmacological, as early as possible.

Psychosocial treatment of schizophrenia Exciting results have recently been claimed for cognitive-behavioural treatment in schizophrenia. Contrary to earlier views, it seems that patients can develop some control and mastery over their symptoms, especially abnormal beliefs and auditory hallucinations. Patients can, for example, distract themselves from voices by concentrating on external tasks, by playing music on 'Walkman' headphones, or even by 'bargaining' with the voices so that they confine 'their' attentions to particular times of the day. With the help of a therapist, or even a self-help 'voices' group, patients can also be encouraged to test the validity of delusions, e.g. 'if I go into that shop I will be killed', and on the basis of the 'results' of these 'tests', modify their beliefs. Early studies of these approaches are encouraging in producing, for some patients at least, reduced symptoms, improved

central theme is a feeling of persecution and fear of being attacked. Paranoid states are common in general medical and hospital settings. A postoperative patient may suddenly rip out an intravenous cannula and attack one of the nurses. A patient may refuse all drugs, convinced that the staff are torturers dressed up as doctors and nurses. The conditions resulting in paranoid states are as follows: • Organic psychosis. This is by far the commonest cause in hospital settings. Paranoid delusions are frequently found in patients with acute confusional states. Any of the causes of organic psychosis (p. 208) may be responsible, with steroid-induced psychosis, alcohol withdrawal syndrome and amphetamine psychosis being particu-

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Case 8.1

social functioning and compliance, and reduced drug dosages.

Compliance therapy A major problem in schizophrenia is drug noncompliance. Borrowing on the techniques of 'motivational interviewing' developed for addiction, researchers have shown that compliance can be dramatically improved if the clinician provides much greater information about the drugs, and attends closely to patients' feelings about side-effects and the stigma associated with taking long-term antipsychotic medication. A simple useful intervention appears to be to compare the schizophrenia sufferer's need for medication with the diabetic's need for insulin. From this perspective schizophrenia becomes a disability to be lived with, rather than a disease which is either denied or devastating. Assertive outreach programmes aim to tackle non-compliance by treating the patient in his or her home environment and by offering intensive therapeutic nursing, family and practical help at a time of maximum stress.

Early intervention The prognosis in schizophrenia is worse the longer the gap between the onset of symptoms and starting therapy. Early intervention programmes aim to identify and treat young schizophrenia sufferers using a combination of destigmatization, drug therapy, combating concomitant substance misuse ('dual diagnosis') and psychosocial intervention.

larly common. Alcoholism may also produce a chronic paranoid state in which auditory hallucinations predominate (p. 251). Manic-depressive psychosis. Feelings of being disliked and shunned are common in depression, and may assume psychotic proportions if the patient feels he is so wicked that he is deservedly in danger of attack. Paranoid ideas can occur in mania, but elation and overactivity are usually more prominent features. Paranoid schizophrenia (see p. 229). Paranoid psychosis. Sometimes the patient develops paranoid delusions and hallucinations without the full range of features of schizophrenia. There is often a sexual content to the psychosis. The patient may, for example, become convinced that his spouse is having an affair (morbid jealousy, or Othello syndrome). The feeling that workmates or strangers are accusing the patient of homosexuality is often a prominent feature of paranoid psychosis. Paranoid personality. People with paranoid personalities have a tendency to mistrust and blame others, and so

frequently become involved in complaints and battles with authority. The patient is often sensitive, isolated, insecure and quick to take offence, and misinterprets the behaviour of others as hostile. When his fragile self-esteem is threatened by illness or rejection, he may develop a paranoid psychosis. • Paranoia in the elderly. Elderly patients may develop a paranoid psychosis (paraphrenid) with schizophrenic features. Deafness, social isolation and previous paranoid personality are important predisposing factors. Common to all the different forms of paranoia are isolation, insecurity, mistrust and misperception. In some cases the defence of projection seems to be operating. Here an inner state of persecution is transferred on to the external world, presumably as a defensive manoeuvre designed to reduce inner mental tension. Thus a cancer patient may develop a paranoid state in which he denies there is anything physically wrong, but refuses to leave hospital on the grounds that he is in danger of being attacked. Here the 'hostility' felt from the cancer within is attributed to the outside world instead. Paranoid states can be treated symptomatically with phenothiazines (see p. 230), but the underlying cause itself should be treated whenever possible.

SOMATOFORM DISORDERS Somatoform disorders are conditions in which (a) physical symptoms are present for which no organic or physiological basis can be found, and (b) where there are demonstrable underlying psychological factors or conflicts, i.e. the physical symptoms are manifestations of underlying psychological distress or disease.

Terminology and definitions There are several terms commonly used to describe physical disorder in which psychological mechanisms may be important. The outmoded but still widely used term psychosomatic illness refers to conditions in which there is definite structural physical illness (e.g. bowel inflammation in ulcerative colitis) but whose precipitant or maintaining factors are thought to be in part psychological. The term functional is sometimes used to describe symptoms produced by changes in organ function in the absence of structural change. Functional illness may or may not be psychological in origin. Functional bowel disease (irritable bowel syndrome, see p. 817), for example, may result from faulty diet or disturbance of the autonomic system (potentially stress related) or both. Controlled trials suggest that chronic intractable irritable bowel syndrome responds well to psychotherapy. The term psycho genie usually implies that the symptoms are entirely psychological in origin. Many of the ill-defined

conditions seen in general practice and medical outpatient clinics could be labelled psychogenic, although this term may obscure the fact that physical factors (e.g. muscular tension) are also important. The concept of hysteria (p. 235) has a long history and has become differentiated from the more non-specific psychogenic symptoms. Hysteria is divided into two types:

8

• Conversion disorders. These are psychogenic illnesses often simulating neurological disorders - based on unconscious mechanisms, in which mental conflict is avoided both by 'converting' anxiety into physical symptoms (hence conversion hysteria) and by dissociation (i.e. a split between the mental self and the physical self). • Somatization disorders. These are polysymptomatic disorders in which the patient experiences multiple unexplained symptoms without physical disease and in the context of a disturbed personality. 1 In psychosomatic illness psychological factors aggravate, prolong or cause relapses in an illness whose basis is physical (just as a poor ward atmosphere has been shown to delay postoperative wound healing). Psychogenic symptoms are often based on circular patterns in which, for example, emotional conflict produces muscular tension, which results in pain, which leads to greater emotional stress, or anxiety (e.g. fear that the pain may be due to cancer), which results in more muscular tension and so on. Chronic fatigue syndrome (CFS, see p. 236) can be thought of as a somatoform disorder; some however would classify it as a psychosomatic illness, in which psychological factors exacerbate an organic illness, albeit one whose pathology is currently unknown.

MIND-BODY MODELS There are two extreme but widely held views on the nature of psychosomatic illness. The first, corresponding to the philosophical position of materialism, holds that all phenomena are physical in origin and denies the existence of the mind. For the materialist there are no psychogenic conditions, only illness whose physical cause has yet to be determined. The second, idealist, view holds that psychosomatic illness is mental in origin. There are problems with both these models. The materialist might point to the numbers of patients labelled as hysterical who have subsequently died of carcinoma or multiple sclerosis; but the existence of mind is undeniable. The idealist, on the other hand, tends to confuse the symbolic meaning of an illness with its cause, claiming, for example, that a man who developed oesophageal cancer did so because he could not swallow his wife's infidelity. A classic error of this type was the pre-1956 theory of Down's syndrome. This held that Down's syndrome was caused by physical or mental trauma in pregnancy, as mothers of Down's syndrome babies regularly reported such traumatic incidents. Only when the chromosomal abnormality

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responsible was found was it realized that the trauma theory was a retrospective rationalization rather than a causal explanation. In reality, the relationship between mind and body is far more complicated than either the pure materialist or the idealist model allows. The interesting questions concern the interactions between the mental and the physical, just as many important problems in genetics involve interactions between heredity and environment. For example, there is good evidence that psychological adversity in childhood - neglect or abuse - is associated with poor physical health in adult life. The mechanisms by which this is mediated remain to be elucidated. To some extent they may result from excessive alcohol and drug abuse, and smoking, which are associated with both psychological stress and poor physical health. The effects of stress via the hormonal system on immune mechanisms may also play a part. Thus the 'Descartian' split between mind and body is beginning to be seriously challenged. It has been cogently argued that we 'think with our bodies': that the body is more than just a metaphor for much emotional experience (we speak of 'gut feelings' and 'emotional pain'), but that we use bodily sensations to help us choose between different equally rational courses of action. Body and mind, reason and emotion are ultimately inseparable.

more likely to develop coronary artery disease than those with more placid temperaments. This is particularly true where aggression plays a large part in the 'type A' makeup. Similarly, the prognosis of breast cancer may depend in part on personality: women who are emotionally inhibited appear to have, on average, a less good prognosis than those more able to express anger and sadness. The intervening variables that link the psychological to the physical are largely unknown. Autonomic and corticosteroid responses to stress play their part, as do changes in the immune system (especially T lymphocytes), but the precise pathways and links remain to be elucidated. Current evidence does not support the view that psychosomatic diseases are primarily psychological in origin, nor that any specific relationship exists between personality type and a particular disease or target organ.

Experimental evidence

Development of the body image

There is evidence that painful events in a person's life can precipitate physical illness. The link between stress and myocardial infarction, for example, is well documented (Fig. 8.9). Bowel disease, such as ulcerative colitis or even appendicitis, may also be triggered by a preceding painful or stressful life event. Personality plays an important part in determining the impact of such events. Individuals with 'type A personality' (competitive, driving) are, other factors being equal,

In adult life mind and body are separate realms. The body is experienced as an object among other objects in the world, but is also, for its 'owner', the source of knowledge and sensation and the means by which contact and communication with others is possible. The mind, though experienced as a separate domain, is indissolubly connected to the body. As Freud pointed out, it only takes a toothache to feel that 'the molar hole contains my soul'. The adult state in which the self comfortably inhabits both mind and body, experiencing each as separate and yet connected, is a complex product of health, maturation and culture. The infant is born in a state of psychosomatic unity: pain for a young child is both mental and physical. In adult life physical illness may produce regression to a childlike state. Childhood experiences may play a crucial part in determining later relationships between mind and body. In early childhood, the parents' love and care for the child and his body sow the seed of healthy self-love in later life. A girl who was 'meant' to be a boy may have to struggle with the effects of her parents' disappointment for years to come. Later, the adolescent has to learn to accept his or her body and sexuality. Self-acceptance is an essential precondition of loving others. When this process is disturbed, some individuals may, when anxious, ask their doctor for an examination, complaining that there is something wrong with their body or even asking for it to be changed by plastic surgery. The patient is looking for the acceptance and care he feels he missed from his parents. If external relationships fail, the patient may turn for interest and gratification to his

FIG. 8.9 Experience of potentially stressful life events by myocardial infarction patients in the 12 weeks before Ml occurred

PSYCHOLOGICAL APPROACHES TO SOMATOFORM DISORDERS Psychiatric understanding of psychosomatic and psychogenie illness can be considered under two headings: the development of the body image, and repression and the unconscious.

own body, and this too can lead to development of, and preoccupation with, psychogenic physical symptoms.

Repression and the unconscious Repression is the active removal from consciousness of painful or disturbing thoughts, feelings or memories. The mind's eye is blinded to problems and conflicts. The difficulties and the feelings they evoke remain, however, even though the patient is unconscious of them. They may then manifest themselves in physical symptoms, by the process of displacement. Thus a 20-year-old student presented with a hysterical hemiplegia and unexplained fits. She described her family life as happy and uneventful. In the course of therapy it emerged that her father had had a disabling stroke when she was 10, and that a fellow student had attempted to rape her a few weeks before her hemiplegia presented. She had 'forgotten' both of these painful events, but the neurological aspect of her presenting symptoms were reminiscent of her father's disability, suggesting that at some level they were still active in her mind, albeit at an unconscious level. The trauma of the rape re-evoked the shock, terror and vulnerability she had experienced when her father became ill.

'MINOR' PSYCHIATRIC ILLNESS Minor psychiatric illnesses are hard to classify and often go undetected, hiding behind and contributing to physical symptoms (Tables 8.11 and 8.12). In these illnesses a somatic 'facade' conceals difficulty in adjustment to social stress ('adjustment disorders'), symptoms of anxiety and/ or depression, or personality difficulties. Once these are explored and the patient reassured, the physical symptoms may be relieved. In considering patients with somatization disorders, a number of psychosocial factors should be explored: • Stress factors, especially recent losses, such as bereavement, unemployment, children leaving home, financial difficulties, divorce and termination of pregnancy; • Social support, relationship with partner (including sexual relationship), parents, children and friends, housing conditions; • Personality: how the person has reacted to stress in the past, previous stressful or painful experiences, especially in childhood, and whether the patient is able to respond with appropriate anger or sadness; • Alcoholism, drug abuse and eating disorders, which frequently present indirectly via physical symptoms.

FURTHER READING ON SOMATOFORM DISORDERS Goldberg D, Huxley P 1980 Mental illness in the community - the pathway to psychiatric care. Tavistock, London Lloyd G 1991 Textbook of general hospital psychiatry. Churchill Livingstone, Edinburgh

TABLE 8.11 Characteristics typical of doctors who frequently detect psychological problems • • • • • • •

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Show empathy Sensitive to emotional cues Use appropriate psychiatric questions and probes Tend to ask for clarification of the patient's complaints Make early eye-contact with the patient Do not bury themselves in notes Good at dealing with interruptions and garrulous patients

TABLE 8.12 Psychiatric illness in general practice: how much goes undetected? Category

All patients

Probability of detection by GP

Physical illness without psychiatric disorder Physical illness and unrelated psychiatric disorder Physical illness with secondary psychiatric disorder

67%

not available

8%

19%

1%

74%

19% 13.5%

47% 33%

5.5%

85%

5%

95%

Somatization Physical illness with symptoms exacerbated or caused by psychiatric disorder Somatized psychiatric illness (no diagnosable physical illness) Psychiatric disorders presenting with psychological symptoms

Smith G 1999 Managing somatoform disorders. In: Lee A (ed) Affective and non-psychotic disorders. Gaskell, London Wilson A, Hickie I, Lloyd P 1994 A treatment of chronic fatigue syndrome: science and speculation. Am J Med 96:544-550

HYSTERIA The essential features of hysteria are: (a) physical symptoms, (b) absence of organic pathology, and (c) psychological conflict.

Classification and clinical features There are three main patterns of hysteria: monosymptomatic, polysymptomatic and epidemic. Monosymptomatic hysteria (conversion disorder) Typically there is gross loss of neurological function. This may involve: • the limbs, e.g. paralysis, anaesthesia or dystonia

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RECENT ADVANCES IN CHRONIC FATIGUE SYNDROME (CFS) Patients suffering from feelings of chronic physical exhaustion frequently present to physicians and sometimes to psychiatrists. Although there may be nothing new in this - such patients were formerly seen as suffering from 'neurasthenia' - much recent effort has been devoted to the clarification of diagnostic criteria, the search for possible causes, and developing structured treatment approaches. The criteria for CFS include disabling physical fatigue which is unexplained by primary physical or psychiatric diagnoses, myalgia, depression and poor concentration, all lasting for more than 6 months. CFS subsumes other diagnostic labels such as Royal Free disease, postviral syndrome and, where there is or has been definite evidence of infection, postinfectious fatigue syndrome. There is no generally accepted theory about causation. Enteroviruses have been implicated, and increased litres of anti-Coxsackie B IgM are reported; muscle fibre damage is found in some cases; some have claimed deficiency of intracellular magnesium. In contrast to the metabolic explanations, psychiatric intervention shows much promise. Fifty per cent of CFS sufferers meet the criteria for major depression. Whether this is cause or

consequence is unclear: one study found that 100% of patients who lacked evidence of infection were depressed, suggesting that 'CFS' represents a number of disorders of differing aetiology. Management includes:

• the higher functions, e.g. hysterical fits, hysterical blindness, fugue states (in which the patient has complete memory loss), or even hysterical psychosis (where the patient develops a short-lived and dramatic psychosis in response to external stress).

with monosymptomatic hysteria, their prognosis is poor and is related to general personality difficulties rather than a specific conflict.

The pattern of dysfunction follows the patient's 'idea' of how the body works, rather than anatomy. Similarly, in hysterical psychosis the patient behaves in the way he thinks a madman ought to behave, rather than demonstrating the specific symptoms of schizophrenia. A neurologist can usually determine the integrity of the nervous system, either by subtle physical examination (extensor activity in apparently paralysed limbs) or by investigation (intact visual evoked potentials in hysterical blindness). The patient may also exhibit the belle indifference described by Janet, i.e. an apparent lack of anxiety in the face of a crippling disorder. Psychophysiological measures of arousal show that hysterical patients are in fact often highly aroused, despite the absence of manifest anxiety.

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Polysymptomatic hysteria (Briquet's syndrome, somatizotion disorder) Patients suffering from polysymptomatic hysteria (usually women in their 30s) develop a wide variety of physical complaints with no organic basis over a number of years. These often involve pain in the abdomen, back and pelvis. Such patients have often been extensively investigated by physicians and frequently admitted to hospital. Their medical notes are thick but inconclusive. Unlike patients

• A sensitive and tactful approach in which the patient is engaged and supported via the adoption of a psychosomatic approach (see main text) which does not attempt to deny the reality of the symptoms or to undermine directly the patient's belief system about his illness; • Psychotherapy directed to helping the patient to adjust to the losses (e.g. of job, mobility, social life) that result from CFS; • Cognitive-behavioural therapy aimed at reattribution of symptoms (e.g. 'I am tired because I am unused to exercise, rather than because my muscles are irremediably damaged'); • Anxiety management to reduce tension and panic; a programme of graded exercise • if depression is a prominent feature; prescription of antidepressants.

Epidemic hysteria This rare and self-limiting condition occurs in schools and other situations where young people are in close proximity. Fainting, nausea and paraesthesia brought on by overbreathing are common presentations. The condition is sometimes wrongly assumed to have an infective cause.

Diagnosis Hysteria is not an easy diagnosis to make. A proportion of patients diagnosed as hysterical turn out to have genuine organic disease: multiple sclerosis or occult cancer, for example. Others may develop another psychiatric condi-

SUMMARY 17 Psychological mechanisms in hysteria • • • • • • •

Dissociation Denial Primary gain - elimination of mental pain Secondary gain - attention, care Identification Illness behaviour Unconscious avoidance of conflict

tion, such as a depressive illness or even schizophrenia. However, it is important to recognize and diagnose hysteria when it does occur, so as to spare the patient unnecessary investigation. Hysteria and organic illness can also, and often do, coexist; establishing one diagnosis should not prevent the search for another.

SUMMARY 18 Management in hysteria • • • • • •

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'Psychosomatic' attitude on part of doctor Exploration of conflict Behavioural approaches (Antidepressants) Abreaction Long-term psychotherapy

Meaning and aetiology The manifestations of hysteria are often dramatic, and therein lies a clue to its nature. Most people, especially as children, have the capacity to act a role. This involves an internal splitting, or dissociation, between the actor and his part. The actor is not really Hamlet, yet becomes Hamlet as he acts the role. The hysteric is not paralysed and yet, psychologically, can become so. According to Freud, the symptoms in hysteria have a meaning which can be understood in terms of the patient's life. Psychological theories of hysteria also highlight several other important aspects of the illness: • Defence. Hysteria is a defence against the anxiety created by conflict. A young man from an academically minded family was facing exams which he feared he would fail; he became paralysed. • Unconscious behaviour. Although a conflict is often obvious to others, the patient is unconscious of it. • Personal gain. There are two kinds of gain for patients in being ill. The primary gain is the fact that they are unaware of their conflict and thus do not experience anxiety. The secondary gain is the care and attention they get from family, friends and relatives. This is only possible if the family to some extent go along with it, or allow the patient to manipulate them. Here they may be meeting their own needs, e.g. the husband who only feels potent when he has a sick wife to look after. 'Manipulation' is a normal process in childhood, and hysteria always has childlike aspects. The child who does not want to go to school develops a tummy-ache; his mother lets him stay at home with her. A similar process is at work in hysteria. The child is not consciously making himself ill or malingering (as, for example, is the soldier who deliberately shoots himself in the foot to avoid going to battle): there really is a pain, even if it clears up quickly once the danger of having to go to school has passed. • Identification. A common finding in the histories of hysterical patients is that there has been a close relative who has suffered illness, often serious. The young man who became paralysed because he feared his exams had had a younger brother who had died with cerebral palsy, and on whom his parents had lavished all their care and attention. The patient often has such a model of illness and its accompanying behaviour which influences him. Sociologists speak of 'illness behaviour' to describe the socially sanctioned behaviour that accompanies illness and which is not strictly related to the pathophysiology of the disease. Sick people are allowed to retire tem-

porarily from work and spend time in bed; they receive flowers, cards and gifts from relatives and are treated with special consideration; they are allowed to be childish and demanding. Their medical attendants also adopt a particular role, usually one of reassurance, benevolence and quasi-omniscience. One of the rules of illness behaviour, however, seems to be that the patient should recover, or at least attempt to recover. When this does not happen there may be a sudden switch: the previously privileged patient may be seen as manipulative, attention-seeking and deviant, and be shunned or covertly punished by irate relatives and medical attendants. In hysteria this often results in a worsening of the symptoms.

Management It is tempting to try to argue a hysterical patient out of his illness. Occasionally this can be helpful, but more often it entrenches the patient more deeply in his symptoms and an escalating battle between doctor and patient may then ensue. There is, moreover, a sense in which the patient is right: he is ill, but psychologically, not physically. There is something wrong, namely a psychological conflict, albeit one of which the patient is unconscious. A more helpful approach is therefore to adopt a psychosomatic attitude. This involves explaining to the patient that stress can cause illness, that he may have a psychological conflict, and that there may be a connection between this and the physical problem, both of which are real. The patient who has committed himself to a physical illness should be offered appropriate physical treatments (e.g. physiotherapy, massage) and should not be deprived of it out of spite. When recovery does take place the temptation to say T told you so' should be resisted. Instead, the patient needs a face-saving formula: the paralysed person must be allowed to put his crutch down gradually, inadvertently even, not have it knocked from under him. The psychological principles of treatment are: • Exploration of conflict. With allowance for face-saving, this is perhaps the most helpful strategy. If the conflict is removed (e.g. the time for exams past) the symptoms will usually remit. • Cognitive-behavioural approaches. These are often useful. They (a) aim to avoid reinforcement of the symp-

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toms, e.g. by suggesting to ward staff or relatives that they respond positively to any signs of movement in the paralysed patient, but as far as possible ignore (nonpunitively) helpless behaviour; (b) are directed towards helping the patient overcome his cognitive responses (e.g. of panic and catastrophe) towards the imagined illness. The latter is sometimes known as 'reattribution therapy' - the patient learns how he wrongly attributes normal bodily sensations to illness, and that this may be influenced by emotion, especially anxiety. Drugs. Where hysteria is secondary to a depressive illness antidepressants should be prescribed. In general, however, drug treatment should be avoided in hysteria, as the patient is often very suggestible and tends to develop dramatic reactions and side-effects. Hysterical amnesia can sometimes be approached by abreaction, in which painful experiences are 'relived' with the help of an intravenous injection of a sedative drug such as diazepam. Psychotherapy. Some patients will benefit from longterm psychotherapy.

HISTRIONIC PERSONALITY AND RELATED CONDITIONS There are a number of conditions that are related to hysteria but which take the form of a lifelong personality disorder rather than an illness. These conditions share with hysteria the capacity for dissociation and the use of illness for manipulation of those around them.

HISTRIONIC PERSONALITY A patient with histrionic personality (usually female) finds it difficult to form close attachments, and when she does they are highly dependent. Her emotions are often superficial and rarely satisfying. She may be very alluring and attractive to men, but finds it difficult to enjoy sex herself. She carries with her an atmosphere of drama: her life is often a series of emotional or practical crises. Her feelings

SUMMARY 19 Conditions related to histrionic personality

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Multiple personality

Aspects of the self entirely dissociated from one another, with lives of their own

Factitious illness

Self-inflicted illness

Fictitious illness Patient travels from hospital to hospital (Munchausen's syndrome) with fictitious illnesses. Pseudologia phantastica.

are dramatized and exaggerated; her headaches are always 'migraines', her diarrhoea 'dysentery' and her pains invariably 'excruciating'. She uses her crises to coerce those around her (including doctors and nurses), and sometimes has a husband whom she abuses and yet clings to, and who appears to submit willingly to all her demands. As a child she may have felt emotionally neglected and insignificant, helpless and dependent. The anger and manipulation that manifest themselves in adult life can be seen as a continuation of this, an attempt, through the coercive power of illness, to keep attached to her those whom she feels may otherwise ignore or abandon her. Patients with histrionic personality sometimes develop the physical symptoms of hysteria.

MULTIPLE PERSONALITY The adult personality is made up of a number of elements: • Some come from identifications based on parents ('he has his father's temper and his mother's charm'). • Some represent different aspects of the self: the caring self, the aggressive self, the childish part of the self, and so on. • Some can be defined in terms of relationships: in a marriage a partner may be expected to be a spouse, lover, parent, colleague and friend. Eric Berne has summarized the different aspects of the self as 'parent', 'adult' and 'child', all of whom coexist within one person. In the mature personality there is a blending together of the different aspects into a coherent whole, so that a person is all of a piece, although minor discontinuities and splits in the personality are common. The fascinating but rare clinical condition of multiple personality, in which several quite separate personalities appear to inhabit the same individual (fictionalized in such works as DrJekyll and Mr Hyde and The Three Faces of Eve), is an extreme example of this everyday splitting. In multiple personality the different personalities have lives of their own which are entirely dissociated from one another; the good self is totally unaware of the bad self and would be horrified by its activities. This enables, say, a prudish aspect of the self to live alongside the sexual side without being aware of it, thereby avoiding anxiety or guilt. Patients with multiple personality can occasionally be helped towards integration with psychotherapy.

FACTITIOUS ILLNESS Patients with unexplained symptoms are sometimes found - often after lengthy investigation - to have caused their own illness. A patient with unexplained and extensively investigated 'haemoptysis' was found to be venepuncturing herself, swallowing blood and then spitting into a sputum pot; a person with unexplained intestinal bleeding

may be inserting foreign bodies into the rectum; hypoglycaemic attack can be produced by insulin injections in non-diabetics; dermatitis artefacta (p. 436) is yet another example of such factitious illness. Occasionally such behaviour is due to psychosis, but more often it is a manifestation of a personality disorder. These patients are often very 'nice'; they may be nurses or members of the other caring professions. They are often on good, even intimate, terms with medical staff. They may induce incomprehension, abhorrence and anger once they are discovered. Factitious illness is best seen as an extreme example of histrionic personality disorder. The patient has split off an angry, destructive, defiant part of herself which acts semiautonomously and of which the 'good' self may be partially unaware. The principles of management of hysteria may be applied in these cases. A full history will reveal underlying conflicts, and the patient can then be told, in as gentle and unconfrontational a way as possible, that these conflicts may be responsible for her symptoms and that she may thus be playing a part in causing her own illness. Although the patient may become angry, the results of such an approach are rarely disastrous. The patient will often be relieved and even begin to accept psychological help.

FICTITIOUS ILLNESS: MUNCHAUSEN'S SYNDROME Baron von Munchausen was an 18th-century fictional character who travelled extensively and told fantastic stories. His name is now used to describe a group of patients with characteristic features: • Patients often experience recurrent unexplained symptoms, especially abdominal or chest pain, which are often thought to be due to renal colic, myocardial infarction or intestinal obstruction. The patient may be given opiates and have had several inconclusive laparotomies, which reveal themselves as multiple abdominal scars. • These patients travel from hospital to hospital, usually discharging themselves after a brief admission, and using a variety of assumed names. • They give dramatic accounts of their lives, for example stories of heroic wartime feats or tragic losses, none of which can be corroborated and none of which quite add up. These stories are sometimes labelled pseudologia phantastica, Munchausen patients may be seen as the male counterparts of factitious illness patients. They are hard if not impossible to manage or help, but awareness of the diagnosis will avoid unnecessary or dangerous investigations. Most doctors have had at least one experience of being hoodwinked in this way, and this may be a necessary learning experience. The doctor must be friendly but firm in refusing to treat these patients as though they are ill. The patient usually disappears, but may occasionally accept social help and often become highly dependent on medical services.

SUMMARY 20 Factors contributing to anorexia nervosa • • • •

8

Contradictory social attitudes towards eating and thinness Enmeshed, i.e. mutually overdependent, families Fear of loss of control of eating and of sexuality Fear of separation

EATING DISORDERS Eating is not just about physiology: food has great psychological and sociological significance. Morality starts with the child's discovery of what is good and bad to eat, and a mother's self-evaluation may continue to depend on how well she feels she feeds her family. Birth, the reaching of adulthood, marriage and death are all marked by a meal. In addition, there are two factors, specific to many highly industrialized western societies, that are of especial relevance to eating disorders: the role of the food industry, with its large marketing system; and the emphasis on a slim body image as a mark of vitality and attractiveness. Eating disorders are increasingly common, especially among women (Fig. 8.10). Although the overall incidence of anorexia nervosa is only 1 per 100000 population, 1% of 16-18-year-olds are affected; 2% of women attending a family planning clinic suffer from bulimia nervosa; and the prevalence among dance students is 20%.

ANOREXIA NERVOSA Aetiology and pathogenesis No single cause of anorexia nervosa has been found. A number of factors appear to be involved: • Social pressures towards both eating and thinness, though contradictory, are important.

FIG. 8.10 Epidemiology of anorexia nervosa Social class distribution of anorexic patients (father's occupation) compared with that for general population.

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CASE STUDY 8.3 A 30-YEAR-OLD WOMAN WITH AN EATING DISORDER AND A WEIGHT OF 30 KG A 30-year-old woman was admitted to a psychiatric unit weighing 30 kg. Her body mass index (weight in kilogrammes divided by height in metres, squared) was, at 13, near the lower limit considered to be compatible with life. She was brought in by her husband, who had been increasingly worried about her but up to this point had been unable to persuade her to accept help. She had had eating disorder symptoms since at least the age of 15, when she had left home to live with her boyfriend, who eventually become her husband. She was terrified of excess weight and weighed herself several times a day. She ate little more than a crispbread and a slice of cucumber daily. She had never had regular periods, although, unusually for someone with anorexia nervosa, had managed to get pregnant with the help of ovulationassisted fertility treatment. She was closely involved with her mother, to whom she presented an 'everything is normal' front, while seeing her almost every day. She was very worried about her parents' marriage, which she saw as in great jeopardy. She was treated with a refeeding schedule, with which she was surprisingly compliant, until she weighted 45 kg, and then was discharged from hospital. Her outpatient care consisted of a combination of individual psychotherapy and family therapy. Her individual therapy concentrated on looking at all the ways in which she pretended to herself and others that she was eating when in fact she was avoiding food. It used an 'addiction' model and suggested that she was addicted to not eating in the way that an alcoholic is addicted to alcohol - using it as a refuge whenever she felt stressed or confused. Therapy also looked at her

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image of herself as a woman, and at how frightened she was about becoming 'like' her mother, whom she saw as being trapped in a loveless marriage, constantly at her father's beck and call. The family therapy sessions tried to help extricate her from the parent-child relationship she had established with her husband and to foster a more equal partnership, in which she took charge of her own eating, rather than either deceiving him or relying on him to prompt her to eat. There were no further admissions, but her weight hovered just under 7 stone for many years, and she said that the idea of being 7 stone terrified her. Over the years she made many life changes. She left her husband and formed a new partnership, which was more emotionally open and caring, although not without its problems. Her new partner was more able to help her to eat at times when she was in the grip of her anorexic symptoms. Her parents' marriage also broke up, and she become much less involved with her mother.

Questions

1. Could intervention have started earlier? 2. What is the long-term prognosis of anorexia nervosa?

Discussion It is notoriously difficult to engage people suffering from anorexia nervosa in treatment. Teenage sufferers are often taken unwillingly to the doctor by worried parents. It is always important for the doctor usually a family doctor in the first instance - to interview the patient on her own and to make determined

attempts to establish rapport, a process which may take several interviews. There is a danger that the doctor will be pulled into identification either with the worried and exasperated parents, in which case he may become heavy handed and insensitive, or with the patient, when he may minimize the seriousness of the situation and fail to be appropriately firm and challenging. Anorexia is 'delusional' in the sense that such patients are convinced that they are fat, despite every rational argument to the contrary. There has been much debate about the ethics of admitting people with anorexia compulsorily to hospital. The current consensus is that the thinner the patient the less rational they are, and that in lifethreatening situations the use of the Mental Health Act is justified. On the other hand, it is essential to help the patient move towards taking responsibility for her own illness, and a Section may militate against that. Many patients put on weight while in hospital but immediately revert to dangerous weight loss once they are back home. Anorexia nervosa is a very varied illness, with many different trajectories, making it difficult to generalize about prognosis. In general, the shorter the interval between onset of illness and treatment, the better the prognosis. Most studies suggest a 60-70% recovery rate within 5 years. The longer the period of illness the greater the mortality. Different studies have shown lifetime mortality of between 5 and 10%. Partial recovery is probably the best that can be hoped for in a chronic form of the illness such as that suffered by the patient described, whose symptoms had lasted for more than 15 years.

• The fear of losing control, both of eating and of sexuality, and a feeling of inadequacy and of not being a separate person are characteristic of the anorexic's inner world. Anorexia is an attempt by the individual to remain in complete control by regulating her food intake and her weight, and thereby putting her sexuality into reverse. • Family function in anorexia is often abnormal. The families (where food is frequently a central theme) tend to be 'enmeshed', i.e. mutually overdependent. This causes little difficulty in early childhood, but with the advent of adolescence the family may be threatened by the possibility of autonomy and separation. • Endocrine abnormalities occur in anorexia nervosa. Hypothalamic function is disturbed, with reduced luteinizing hormone (LH) and gonadotrophic hormone output, but this is more probably a consequence rather than a cause of weight loss. Low levels of plasma thyroxine and plasma TSH are also common. There may be alkalosis if there is surreptitious vomiting.

Clinical features

overweight, which may appal the girl, who then begins to pursue thinness. Her thoughts are dominated by food and how to avoid it. She absents herself from family meals, although she may pride herself on providing food for others, while secretly despising and envying those who eat normally or, as she sees it, gluttonously. As long as she is thin she will be happy. To be thin is to be good; to be fat, bad. She may augment her efforts at dieting by taking laxatives, amphetamines or diuretics, and by self-induced vomiting. Battles about food may develop with her parents. Denial of weight loss (p. 216) is an important feature: she may conceal her emaciation within voluminous and floppy clothes. She is physically overactive as part of her secret plan for weight loss. Sometimes, deliberately excessive exercise may be a major factor in the weight loss. She complains of a feeling of 'fullness' in her stomach which prevents her from eating. She will be emotionally and socially, but not intellectually, less mature than her peer-group. Physical examination will reveal thinness, scanty secondary sex characteristics, possibly peripheral cyanosis, a soft downy covering of the face and body (lanugo hair), hypotension and bradycardia.

8

Four features are characteristic of anorexia nervosa.

Differential diagnosis • The most important is phobic avoidance of normal weight. The patient is terrified by the idea of her normal weight. • With this goes a distortion of body image, known as overperception. By asking women to choose a silhouette that they feel represents their shape, it can be shown that it is normal for women aged 15-30 to perceive themselves as up to 50% fatter than they really are. Patients with anorexia nervosa see themselves as at least 100% bigger than they are: an emaciated girl of 35kg may be disgusted by what she perceives as her gross obesity. • The consequence of phobic avoidance and overperception is relentless dieting, especially the renunciation of carbohydrates. • Amenorrhoea is an essential diagnostic feature. In males (10% of all anorexics) there is disturbance of sexual function, usually with loss of libido. Anorexia nervosa usually starts in early or midadolescence. There is frequently an initial period of mild

SUMMARY 21 Features of anorexia nervosa • • • • • • • • • •

Phobic avoidance of normal weight Lanugo hair Hypotension Relentless dieting Denial, concealment Self-induced vomiting, laxatives Overperception of body image Excessive exercise Enmeshed families Amenorrhoea

The clinical picture may be one of two types: • In typical anorexia the only obvious psychological abnormality is the difficulty in eating. Here, the main differential diagnoses are organic causes of weight loss in a young woman, for example malabsorption syndrome, thyrotoxicosis or occult neoplasm. • An atypical picture also occurs. Here the woman is often older (in her 20s) and her anorexic symptoms coexist with other psychiatric features, such as depressive symptoms of misery and withdrawal; obsessional symptoms centring, for example, on cleanliness; and personality difficulties.

Management A patient weighing less than 35 kg should be admitted to hospital. A behavioural regimen in which the patient agrees on a target weight and is rewarded with privileges (watching television, being allowed visitors) in return for weight gain is usually effective in the short term. Occasionally a small dose of a phenothiazine (e.g. chlorpromazine 50 mg b.d.) is helpful. However, the patient will often lose weight again once she is discharged, unless psychotherapy is also started. Psychotherapy is the treatment of choice for outpatients. Mild anorexia can respond to simple counselling. In more severe cases family therapy is the best treatment for those under 17, whereas for older patients (especially if they have left home) individual psychotherapy is the preferred treatment. In each case, the aims of therapy are: • to maintain normal weight (body mass index 18-25) and a regular eating pattern. Some patients use therapy as a diversion from this central task;

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to help both patient and family to move away from the area of food as a focus for all conflicts and difficulties; to help the patient accept herself as she is, in both her body and her feelings, i.e. to cope with the problems in living from which the eating disorder may have been a diversion as well as a cause.

SUMMARY 22 Treatment of bulimia nervosa • Keep a diary of everything eaten and all episodes of vomiting • Re-establish dietary control; eat three meals per day even if bingeing • Identify triggers to bingeing (anger, loneliness) • Challenge erroneous assumptions, e.g. 'If I eat a chocolate bar will become grossly obese and no-one will love me'

Prognosis Twenty-five per cent of anorexic patients recover spontaneously; 25% make a full recovery with medical intervention; about 25% continue to experience some difficulties with eating but can lead a normal life; and 25% remain quite severely handicapped. About 5-10% die of the condition. Poor prognosis is associated with later onset, 'atypical features' (see above), marked body image disturbance and self-induced vomiting. Recovery is accompanied by a reversal of the hormonal abnormalities and the onset of normal menstruation. 1

BULIMIA NERVOSA Bulimia nervosa is a syndrome of 'binge eating' (bulimia: to stuff oneself with food) and self-induced vomiting in the presence of normal weight. There is an overlap here with anorexia nervosa, where binge-vomit cycles can also occur, but in anorexia the patient is always abnormally thin and also amenorrhoeic. The usual age of presentation in bulimia also tends to be older, with patients (usually women) in the 20-30 age range, rather than the teens. The bulimic is frightened of becoming fat, but can accept her normal weight. She is terrified by her greed and tries to avoid its consequences by making herself sick. She normally feels deeply ashamed about this. She lives in a state of dietary chaos, in which she is determined to fast, succeeds for a while, then succumbs to hunger and starts eating. She binges, then feels guilty, makes herself sick and then starves; and so the cycle starts again. The physical consequences of bingeing and vomiting include erosion of dental enamel from exposure to gastric acid, Mallory-Weiss oesophageal tears, and even oesophageal rupture. Repeated vomiting causes hypokalaemia, which may in turn produce tetany, paraesthesiae, ileus, cardiac arrhythmias and epileptic fits. Bulimia is more common than anorexia: the prevalence rate in Europe and North America is 1-2%, compared to 0.5-1% for anorexia; 20% of women attending a family planning clinic admitted to bingeing, and 2% had the full syndrome. Like anorexia, bulimia may exist either on

1

242

MCQ 8.5

2

MCQ 8.6

its own, or as part of a general disturbance of personality, and be associated with alcoholism, deliberate self-harm or shoplifting, all of which make the prognosis less good. Treatment of bulimia nervosa is usually successful and involves helping the woman to re-establish a regular eating pattern, and to feel less guilty. The bulimic often feels a great relief when dietary control is re-established, unlike the anorexic, who feels threatened at the idea of giving up her own control. In addition to a cognitive-behavioural approach, exploration of the conflicts underlying the bulimia (such as marital difficulties or feelings of anger which the patient is unable to express) is also necessary. A proportion of bulimics have experienced sexual abuse in childhood, and this too needs psychotherapeutic exploration.

OBESITY Obesity in itself is not a psychiatric problem, but morbid obesity can be experienced as a severe handicap, comparable to amputation or disfigurement. Respiratory, endocrine and cardiovascular complications are common and serious, and gross obesity should, like anorexia nervosa, be considered a life-threatening condition. Obese people feel ostracized and experience self-disgust. They long to be 'normal' and may become depressed by unsuccessful efforts at dieting. There are often marital and family difficulties which are both a cause and a consequence of their obesity. The prognosis for weight loss, either by dieting or surgery (e.g. intestinal bypass) is not good. Psychotherapy can be a precursor to weight reduction if it helps the patient to accept himself as he is. The patient may then find it easier to diet, being less inclined to resort to the comfort of food whenever an emotional upset occurs.

FURTHER READING ON EATING DISORDERS Fairburn G C, Wilson G (eds) 1992 Binge eating. Guilford, New York. Schmidt U, Treasure J 1992 Getting better bit(e) by bit(e). Laurence Erlbaum, Hove Tiller J, Schmidt U, Treasure J 1993 Treatment of bulimia nervosa. Int Rev Psychiatry 5:75-86.

by doctors) and 'bad' ones (self-administered by addicts). This distinction does not take account of the fact that almost all drugs, even when medically prescribed, have harmful effects and can be misused: analgesics and tranquillizers are the best examples of this. Conversely, opiates can be of great benefit in the treatment of severe pain. Current definitions of drug dependence are based on the interaction between the individual and the drug, leading to a compulsion to take it:

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• In order to experience its psychic effects, and/or • To avoid the unpleasant effects of its withdrawal (abstinence syndrome). There is no single cause of drug addiction. The prevalence of addiction is determined by:

FIG. 8.11 New and former addicts notified to the Home Office

• The availability of the drug. The greater the availability, the greater prevalence of addiction. In Hong Kong, where heroin is widely available, 8-10% of the adult male population is addicted. • The accessibility of the drug. This explains the relative commonness of drug addiction among doctors and nurses, and in inner-city and coastal areas. • The susceptibility of individuals to addiction or misuse. Management of drug addiction is equally multifaceted and involves a combination of physical, psychological and social rehabilitation.

DRUG DEPENDENCE Addiction to illicit drugs, especially opiates, is a source of widespread medical and social concern (Table 8.13) 2. There are several reasons for this. First, there has been an epidemic increase in opiate abuse over the past 50 years. In 1936 there were about 500 known addicts in the UK (of whom one-quarter were doctors); by the mid-1970s this figure had risen to 6000; and in 1988, following the introduction to the UK of cheap heroin, the number of known addicts was estimated to be at least 50000 (Fig. 8.11), of whom 9000 were registered with the Home Office. By the year 2000 this figure had reached 20000. Secondly, the impact of opiate addiction has profound medical and social consequences. Within 5 years of diagnosis 10% of addicts will have died from drug-related causes, including AIDS, hepatitis B and overdose. Thirdly, 'drug addiction' is a microcosm of a much wider social problem. Finally, there is increasing concern about the way that substance abuse complicates and worsens the prognosis of many psychiatric illnesses. For example, schizophrenia may be accompanied by, and sometimes be difficult to distinguish from, cannabis, heroin and/or amfetamine abuse, leading to a so-called 'dual diagnosis'.

Nature and causes of drug dependence In the past, definitions of drug abuse have concentrated on a contrast between the harmful and the beneficial effects of drugs, thus dividing drugs into 'good' ones (prescribed

OPIATE ADDICTION Causes The most important cause of opiate addiction is availability. Susceptible individuals expose themselves to the drug, either because they inhabit a subculture in which drug taking is prevalent, or because they are psychologically vulnerable owing to family difficulties, depression or boredom. The pharmacological features of opiates - tolerance and withdrawal syndrome - ensure the establishment of a habit, and social as well as physiological factors then maintain the addiction and make rehabilitation difficult.

Biochemical factors The discovery in 1977 of the encephalin neurotransmitters was a major advance in the understanding of opiate addiction. Endorphins are naturally occurring, opiate-like substances which mediate pain and other sensations in the midbrain. It is possible that individuals susceptible to addiction may genetically be deficient in endorphins and so 'opiate hungry'. Both opiates and endorphins reduce the amount and effects of other cerebral neurotransmitters, such as acetylcholine. This has led to the 'supersensitivity' theory of withdrawal syndrome, which postulates that addicted individuals have reduced amounts of transmitter reaching postsynaptic receptors. Stopping the drug then

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TABLE 8.13 Addictions: Prevalence data Substance use is one of the major social and health problems facing society Illicit drugs • 23% of those aged 14-15 have taken an illegal drug in last year, 13% in last month, 29% of those aged 16-24 in last year, 14% in last month. • Known heroin addicts have increased from about 5000 in 1980 to about 50000 now, with growth continuing at about 20% per year. • The number of seriously problematic drug misusers in UK is estimated to be between 100000 and 200 000. • Amfetamine seizures have increased from about 3000 in 1987 to about 18000 in 1997. Cocaine use is also increasing rapidly. Alcohol • 41% of men aged 18-24 drink above recommended levels, but recent increase highest among young women (currently 25%). • Alcohol use increasing rapidly among schoolchildren - currently 5-10% 14-15-year-olds drinking more than recommended adult levels. • 51% of rough sleepers are alcohol dependent. • More elderly people are drinking above recommended limits - from 1984 to 1996 increase from 12% to 18% of men, and 3%-7% of women. Smoking • By 13 years, 19% smoking cigarettes daily. 29% of 16-19-year-olds are current smokers, 39% of 20-24-year-olds and 28% of all adults. Mortality • Between 1000 and 3000 drug misusers died as a result of overdose in 1998 in England and Wales (uncertainty relates to problems with current databases). Compared to the general population, mortality rates are higher among addicts (SMR = 7) • Injecting drug users have a mortality 12-22 times greater than their peers. Compared to the general population, suicide rates are high among addicts (SMR for males = 4.4; SMR for females = 11.3). • 25% of road accident fatalities have blood alcohol above 80mg%, 30% of pedestrians sustaining injuries. Illicit drugs are found in blood of 15-20% of drivers involved in fatal road accidents. • 40000 alcohol-related deaths per annum. • 120000 smoking related deaths per year in England and Wales. This accounts for 20% of deaths at all ages, and 25% of deaths between 25 and 35. Psychological and physical morbidity • 62% long-term injectors are positive for hepatitis C, and 52% for hepatitis B. About 80% of those positive for HCV will develop long-term infection, and 5% of those positive for HBV. About 20% of those with chronic infection will develop cirrhosis or liver cancer. Between 152000 and 228000 drug users in the UK are currently infected with HCV. • 10000 individuals seek help for their own or someone else's drinking problems each day. • 30-40% of hospital in-patients drink alcohol excessively. Alcohol is associated with heart disease, liver cirrhosis, cancer, neurological and gastro-intestinal problems. • 30-40% of substance misusers also have a psychiatric diagnosis. 60% of parasuicides are alcohol related. In a health district of 250000, 3000 problem drinkers will also have severe mental health problems. • Alcohol is strongly related to high-risk sexual practice, unwanted pregnancy and sexually transmitted disease. • Domestic violence, accidents and social disharmony: 30% of divorces, 40% of domestic violence, 20% of child abuse cases and 30% of domestic accidents are associated with alcohol misuse. Crime • 32% of proceeds of acquisitive crime is spent on heroin or cocaine. • The costs of drug-related crimes to the criminal justice system is at least £1 billion per year. Approximately 30% of prisoners are problem drinkers. 30-60% prisoners claim to have offended under influence of alcohol. 60% of those arrested test positive for drugs, 20% for opiates. Costs • The costs to industry of excessive alcohol consumption are estimated at £2330 million per year, as a result of unemployment, premature death and sickness absence. • Smoking costs the NHS approximately £1500 million per year. For a typical health authority this means £14 million per year, broken down as GP visits £2.5 m, prescriptions £1.5m, in-patient stays £3.2m, day-care £1.9m and outpatient visits £4.9m. Cost-effective treatments require proper training and specialist support • Many studies have shown that the treatment of opiate users saves much more money than it costs. • In North American studies it is estimated that for every $10000 invested in alcohol treatment, $30000 is saved by the managed care provider. • Smoking cessation interventions cost between $212 and $873 per life year gained, compared with £17000 as the median cost per life year gained of 310 common medical interventions.

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results in a sudden increase in transmitter and stimulation of the already supersensitive receptor.

Psychological factors Drugs can be administered ('dropped') by injection ('fixing'), either subcutaneously ('skin-pop') or intravenously ('mainline'); or by smoking ('chasing the dragon'). All these methods are powerful reinforcers in the pavlovian sense:

TABLE 8.14 History and examination of suspected opiate abuser History Previous contact with a prescribing doctor or clinic History of recent use (doses, frequency, legal, illegal) Assessment of demands or requests Assessment of withdrawal symptoms Current legal problems

• Primary reinforcement from both the pleasure ('buzz') and the removal of withdrawal symptoms; • Secondary reinforcement from the associated rituals of administration, e.g. filling the needle; • Social reinforcement from fellow addicts.

Examination Injection sites: needle marks, tracks, bruises, thrombosed veins, abscesses, skin ulcers Arterial spasm or gangrene (caused by, e.g. dipipanone, cyclizine) Jaundice from hepatitis Emaciation

Psychiatric factors

Investigation Urine for drug assays Liver function tests Hepatitis serology HIV test (with consent)

Opiate addiction is more likely to be a cause than a consequence of psychiatric illness. 'Loners' may well be suffering from anxiety and depressive symptoms which they are trying vainly to treat with opiate drugs. Hospitalized addicts (as opposed to the generality of addicts) tend to be suffering from personality disorder and to have difficulty in forming close relationships. Addicts are caught in a vicious circle in which their primary relationship comes to be with the drug, which is felt to be more accessible, reliable and instantly gratifying than a person. There is some evidence that family discord and alcoholism are more common in the childhood histories of addicts than in controls. The anxiety associated with the early stages of opiate withdrawal may mirror early childhood experiences of separation from desired, but inaccessible, parents.

Social factors There is no particular social class preponderance for opiate addiction.

Presentation Addiction to opium and its derivatives, morphine and heroin (diacetyl morphine), can be considered as a model of drug addiction in general. The physical signs that should arouse suspicion of opiate abuse are listed in Table 8.14. Addicts present to doctors in one of four ways: • With infective complications of self-administered injections, e.g. septic abscess at injection site or septicaemia, infectious hepatitis or manifestations of HIV; • With confusion or unconsciousness due to drug overdose, either deliberate or accidental; • Wanting, or apparently wanting, help with their habit; • With a withdrawal syndrome. This consists of a craving for the drug together with physiological features, which include rhinorrhoea, lacrimation, yawning, perspiration, irritability, gooseflesh, nausea, diarrhoea, cramps,

8

muscle pains, tachycardia, flushing and involuntary movements. It is not life-threatening and the symptoms begin to recede about 72 hours after last taking the drug.

Management Legal requirements In the UK, any doctor attending a patient who is known or suspected to be addicted to opiates is required to inform the Home Office Drug Branch. Only specially licensed doctors are permitted to prescribe morphine and diamorphine (heroin) for the maintenance of addiction. Other opiates, such as methadone, may be prescribed by any doctor for the management of withdrawal syndrome, but this should be done only with great constraint and in an emergency. General management Drug abusers may not be open about their habit, which should be suspected in unexplained cases of psychosis, sepsis, serum hepatitis or HIV infection. Scapegoating should be avoided, and drug users should be treated with the same concern and courtesy as any other patient. At the same time, caution should be exercised: addicts may steal prescription pads and syringes, and exaggerate their drug needs in order to obtain drugs, which are then sold. In an initial interview a urine screen should be carried out to confirm that the patient is a user, and blood should also be tested for hepatitis serology and HIV (the latter normally with the patient's consent). Whenever possible, the patient should then be referred for specialist help. Occasionally

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TABLE 8.15 A typical detoxification schedule for opiate addiction 10-day detoxification (volume kept at 25 ml)

28-day detoxification (volume kept at 25 ml)

Methadone 25 mg/day - 2 days 15mg/day-2days 8 mg/day - 2 days 4 mg/day - 2 days 2 mg/day - 2 days

Methadone 30 mg/day - 4 days 25 mg/day - 3 days 20 mg/day - 4 days 13 mg/day-3 days 10 mg/day-4 days 6 mg/day - 3 days 3 mg/day - 7 days

TABLE 8.16 Characteristics of methadone linctus which justify its use as a treatment • • • • •

Non-injectable Not attractive to users looking for buzz Low street retail value Controlled drug - able to be prescribed on daily collection Long half-life for established users, hence reliable urine testing and stabilizes drug-taking experience • If it does 'leak' from the drug service to the streets it is likely only to be used by established users for whom it is a safer preparation. Some of these will use purchased methadone for detoxification • As a linctus', consumption can be supervised if necessary

(e.g. in a casualty department at a weekend) withdrawal symptoms have to be treated and a dose of methadone given equivalent to the average daily intake which the doctor calculates is being used. The usual dose is between 20 and 70 mg of methadone. Typical detoxification schedules are given in Table 8.15. Where heroin intake is low, diphenoxylate and clomethiazole (chlormethiazole) can be used. Prescriptions should be on a daily basis for not more than 2 days. A clear management policy should be instituted and explained to the patient. Treatment of medical complications of addiction The main medical complications of addiction are septicaemia (p. 273), hepatitis (p. 846), endocarditis (p. 574) and HIV infection (Ch. 11).

Rehabilitation In the UK, all regions have drug clinics to which the addict should be referred. Here, the patient may be offered an oral methadone maintenance programme (Table 8.16) in the hope - not always realized - of reducing the use of illicit drugs. An attempt is made to form a rapport with the user. After establishing a baseline habit, some addicts will be gradually withdrawn from the drug over a 10-week period, either as an outpatient or, more rapidly, as an inpatient. Others will be stabilized on a maintenance methadone programme as a way of facilitating a period of stability in their life which reduces the need for crime and enables them to form a relationship with the drug clinic team. Withdrawal is an essential, but by no means sufficient, aspect of treatment. Addicts exposed to enforced abstinence, e.g. in prison, almost always relapse when released. Psychotherapeutic and social help is also needed if the addict is to remain drug-free.

FIG. 8.12 Changing patterns of consumption of non-opiate drugs in the UK A Prescriptions for sedatives/tranquillizers and hypnotics, 1974-1985. B Current benzodiazepine use and dependence in the UK. In one year, (A) 9-10 million people use benzodiazepines. (B) Of these, 3.2-3.5 million use them for more than 4 months and are at risk of dependence. (C) Of these, 0.64-1 million are likely to suffer withdrawal problems.

Benzodiazepines ADDICTION TO NON-OPIATES

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Dependence on non-opiate drugs has become a major health problem in recent years. The changing pattern of dependence is shown in Figure 8.12.

Benzodiazepines have now replaced barbiturates both in popularity and as a cause for widespread addiction. Although the three million annual prescriptions cause less mortality than barbiturates (as they do not produce respiratory depression), they are an important source of mor-

TABLE 8.1? Symptoms of benzodiazepine withdrawal • • • • • • • •

Insomnia Anxiety Depression Outbursts of anger Muscular pains Tremor Headache Nausea, weight loss, anorexia

• Sweating • Tiredness • Perceptual abnormalities Visual disturbance Depersonalization Vertigo • Fits • Psychosis

bidity (see p. 216). There is an increased incidence of road traffic accidents in benzodiazepine takers. A withdrawal syndrome occurs in patients who have taken more than 20 mg daily over 6 weeks (Table 8.17). The symptoms of minor affective disorder (often self-limited), for which benzodiazepines are initially prescribed, may also then become part of a withdrawal syndrome, which can be mistaken for the original illness and lead to further prescriptions. Like barbiturates, benzodiazepines are best withdrawn in a slowly reducing dosage over several weeks. Antidepressants or even ECT (see earlier) may be needed to treat the depression associated with withdrawal.

Barbiturates Barbiturate addicts now comprise a small number of older patients (mostly women) who are relics of the barbiturate era, and a number of young multiple-drug users for whom barbiturates are one of a number of drugs in their repertoire. The effects of barbiturates are similar to those of alcohol, i.e. intoxication, ataxia and depression of consciousness. Respiratory depression due to overdose is a frequent cause of death. A withdrawal syndrome occurs in which convulsions are common. This should be controlled by pentobarbital (short-acting) 4-6-hourly. Withdrawal should be carried out slowly over several weeks.

Stimulants Amfetamines do not appear to cause physiological dependence, but produce a psychosis which is clinically very similar to paranoid schizophrenia. Symptoms abate within 2 weeks of withdrawal. Diagnosis is by urine screening. Treatment is by neuroleptics such as phenothiazines. Withdrawal from amphetamines often leads to a severe state of depression. Ecstasy, a synthetic amfetamine derivative, is widely used, especially at 'rave parties'. Fits, hyperpyrexia, renal failure and death may follow. Tactile hallucinations ('formication') are a feature of cocaine intoxication, which otherwise produces effects similar to amfetamines.

Removing the hydrochloride molecule from cocaine produces 'crack', which can be smoked rather than snorted. Crack is said to be the most powerful stimulant of all and produces profound depression and anxiety, and concomitant craving, following withdrawal.

8

Hallucinogens Hallucinogenic drugs such as LSD (lysergic acid diethylamide) and 'magic mushrooms' produce a toxic psychosis characterized by vivid hallucinations and delusions. Prolonged psychosis may be precipitated by LSD in susceptible individuals. 'Flashbacks' may occur for several months after an LSD 'trip'.

Cannabis Cannabis, like alcohol, appears to have few harmful effects if taken in moderation. Ten per cent of all young people have tried cannabis at some time, and 25% of students use it at least once a week. In some cultures and subcultures (e.g. Rastafarians) regular cannabis use, especially among males, is the rule. The active principle is tetrahydrocannabinol (THC), which is sometimes used as an antiemetic in terminal care. As with LSD, excessive use (or occasional use in susceptible subjects) produces a psychosis, and a withdrawal syndrome may occur. It has been suggested that regular use of cannabis may produce a state of apathy or amotivational syndrome.

Solvent abuse Inhalation of solvents such as toluene and acetone (used as vehicles for glue and other agents) produces a temporary state of euphoria. Glue-sniffing is common in certain youth subcultures. It is dangerous: an appreciable mortality has been recorded from direct cerebral damage, as well as asphyxia from the use of polythene bags to concentrate the vapour. Morbidity includes hepatitis, renal damage, cardiac arrhythmias, polyneuropathy and aplastic anaemia.

Drug screening Urine can be analysed for benzodiazepines, cannabis, amfetamines and opiates (but not LSD), and this is a useful test in cases of psychosis where drug abuse may be a possible cause.

ALCOHOLISM Alcohol is a major cause of medical and psychiatric morbidity in the UK (Table 8.18; see Table 8.13) and worldwide. In the UK, a 200% increase in alcohol consumption since 1950 (Fig. 8.13) has been accompanied by a 25-fold increase in admissions for alcoholism to psychi-

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TABLE 8.18 Alcohol consumption and alcoholism in the United Kingdom (population 55 million) Alcohol consumption

Estimated numbers

Regular drinkers Heavy drinkers Problem drinkers Addicted drinkers

36m 2m 700000 200000

TABLE 8.19 Criteria of alcohol dependence • • • • •

More than 80 g of alcohol consumed daily Tolerance: blood alcohol levels greater than 150mg/100mL Withdrawal symptoms Continued drinking in spite of psychological, social, and physical problems Abnormal blood tests, e.g. macrocytic anaemia and raised y-GT

Definitions Some criteria for alcohol dependence are given in Table 8.19. Two important patterns of alcoholism require definition: problem drinking and alcohol dependence. Problem drinking The WHO defines alcoholism as drinking that causes emotional, social or physical damage to the individual. Problem drinkers may suffer from all three, e.g. anxiety or depression related to alcohol; divorce, unemployment or financial difficulties; and gastritis or physical trauma associated with drinking. Alcohol dependence The essential feature of alcohol dependence is the development of a withdrawal syndrome when the drug is removed. The dependent alcoholic will drink, usually early in the day, in order to stave off withdrawal symptoms such as nausea, tremor, sweating or agitation. Other features of alcohol dependence include: • Narrowing of the drinking repertoire. The ordinary drinker's consumption varies from day to day. The dependent alcoholic has a daily drinking routine that must be followed. • Predominance of drinking over other activities. For the alcoholic, drink, even if it is clearly damaging their life, comes first. • Tolerance. The capacity of the dependent individual to drink large quantities of alcohol is an expression of physiological tolerance.

FIG. 8.13 Trends in alcohol consumption and expenditure in the United Kingdom A Alcohol consumption 1910-1990. 00 Consumer expenditure on alcohol, 1965-1990.

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atric hospitals. About 20% of admissions to medical wards are due to alcohol or alcohol-related diseases. Forty per cent of male attenders at hospital casualty departments have drink-related problems (p. 861). In 2000 40% of UK students drank above safe limits and 25% of the general population drank above safe limits.

Presentation: the hidden alcoholic Alcoholics have to be very ill or very brave to complain of their condition directly. Only about 10% of alcoholics in the community are in contact with psychiatric services, and about half are known to other agencies such as GPs, social services or parish priests. The remainder are unknown and untreated. Doctors need a high index of suspicion if they are to diagnose these hidden alcoholics correctly. The following factors should alert the examining doctor: • Unexplained gastrointestinal complaints • Complaints of anxiety and depression or panic attacks without obvious external precipitants

SUMMARY 23 Some presentations of undeclared alcohol abuse (should raise Index of suspicion') Psychological Memory lapses Depression Anxiety Outbursts of unprovoked anger Suicide attempts Morbid jealousy Paranoia Acute confusional state (DTs) Unpredictability

Physical Gastrointestinal symptoms Dyspepsia Pain Nausea Haematemesis Neurological symptoms Tremor Paraesthesia Muscular weakness Unexplained fits

Social Marital difficulties Problems at work Accidents at home or on the roads Delinquency, crime Violence

TABLE 8.20 The CAGE questions* • • • •

Have you ever felt you ought to Cut down on your drinking? Have people Annoyed you by criticizing your drinking? Have you ever felt bad or Guilty about your drinking? Have you ever had a drink first thing in the morning to steady your nerves or get rid of a hangover (Eye-opener)?

'Positive answers to two or more of these suggests a drinking problem.

Table 8.21 Factors associated with risk of alcoholism Factor

Examples of occupations affected

Availability of alcohol

Workers in the drink trade, caterers, business executives Coal miners, seamen, medical students, journalists Company directors, lawyers, GPs Commercial travellers, seamen, oil-rig workers, service personnel Coal miners, doctors, military personnel, actors Doctors, the unemployed Doctors, workers in the drink trade

Social pressure to drink

• • • • • •

Social difficulties, e.g. marital disruption, absenteeism Unexplained accidents Smelling of alcohol at unexpected times Single males over 40, socially isolated females Certain occupations, e.g. publicans, journalists, doctors Unexplained macrocytosis, or elevated liver enzyme values.

Where alcoholism is suspected, a detailed alcohol history should be taken. Vague questions such as 'How much do you drink?' are unlikely to be informative, but positive answers to two or more of the CAGE questions (Table 8.20) suggest a drinking problem. A detailed account of a typical 'drinking day' is required. Alcohol intake is measured in units. One unit equals half-a-pint of beer, a quarter-of-a-pint of strong lager, one 'short' or one glass of wine. Regular intake of six units or more per day puts men at risk of alcohol dependence. Women need half as much (i.e. three units per day) for half as long (e.g. as little as 2 years) for dependency to occur. The patient should be asked when he last had a day without a drink; about the longest period without a drink in the preceding 5 years; about withdrawal symptoms; and about blackouts. A 'drink diary', in which the patient records his drinking behaviour for a week, can be a useful aid to history taking. Raised serum y-glutamyl transpeptidase (y-GT) and increased mean corpuscular volume (MCV) are useful supportive evidence of abnormal drinking and are also helpful in monitoring progress. A blood alcohol concentration may confirm suspicions of recent excessive intake.

Aetiology Mutually interacting genetic, psychological and cultural factors underlie alcoholism. Adoption studies show that adopted children of alcoholics are four times as likely to develop alcoholism as are adopted children of nonalcoholics. The biochemical mediator of an inherited

8

Freedom from supervision Separation from normal social or sexual relationships Strains, stresses, and hazards High or low income Collusion by colleagues

tendency to alcoholism is unknown; however, active alcohol dehydrogenase leading to higher (and unpleasant) acetaldehyde levels has been postulated as protective against alcoholism. Psychological factors operate in two ways in alcoholism: • Imitation learning. An individual's tendency to drink follows that of his subculture, parents and peer group (Table 8.21). • Alleviation of unpleasant feelings. Alcohol reduces unpleasant feelings such as social anxiety and guilt. Each time an individual drinks, the experience of reduction of unpleasant mood ('drowning your sorrows') is reinforced. Family disruption is a common experience in the history of alcoholics. The true aetiology should be distinguished from the reasons for drinking offered by the patient, as the alcoholic's explanation of why he drinks is often a rationalization. The alcohol addict drinks because of his physiological state of addiction.

Physical complications The physical complications of alcoholism (see Chs 12,16, 24) include liver disease (Ch. 16), neurological syndromes (Ch. 24) (including peripheral neuropathy, cerebellar

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CASE STUDY 8.4 A 50-YEAR-OLD FARMER WITH CONFUSION A 50-year-old separated farmer was brought to A&E by his neighbour because he had been acting strangely for 2 days and was saying things that did not make sense. He was unable to give a clear history, but it seemed that he had separated from his wife 6 months previously and had been living on the farm on his own, although she continued to visit by day to help with the farm work. He had a new girlfriend but she lived in a different part of the county and he felt he could not afford the petrol to visit her. He had no previous psychiatric history and denied illicit drug taking, but was a smoker and admitted to heavy drinking over the past few months. He had been eating poorly. His farm had been in the family since the 14th century, but times had been hard recently and he had had to diversify into holiday letting, and had sold his milk quota. On examination he was a well-built man with obvious signs of weight loss. He was dishevelled and confused. His speech was normal in form but rambling. He did not appear depressed. He believed that he was being spied on by some unknown power, and that his thoughts could be extracted from his brain. His level of attention and orientation seemed to fluctuate, but on systematic examination he was generally orientated although he got the date wrong. Physical examination was essentially normal, apart from the evidence of weight loss and slight generalized tremor and sweatiness. He was admitted to the psychiatric ward for further observation but almost at once appeared to fall and injured the back of his head, with extensive bleeding. He remained unconscious for several minutes. The emergency crash team was called, but his vital signs were normal and consciousness returned. He was very confused, complained of headache,

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and on examination, although his pupils reacted equally to light there was weakness of elevation of the eyes, which was hard to evaluate as his cooperation with examination was poor. He became more lucid as the day went on, and was able to explain that he had been drinking a bottle or more of vodka a day for several months, but that he had decided to stop drinking some 5 days before admission, and confirmed that he had eaten little for several weeks. Later he had a grand mat fit.

Questions 1. What is differential diagnosis in this man's case? 2. What further investigations are needed? 3. What treatment, if any, should be instituted?

Discussion There are several diagnostic possibilities here. 1. The combination of delusional ideas with fluctuating consciousness makes this likely to be a confusional state ('acute brain syndrome') rather than a functional psychosis such as late-onset schizophrenia ('paraphrenia'), although at this stage no possibilities should be ruled out. 2. A first presentation of a psychotic illness in a 50-yearold man, accompanied by weight loss with a history of smoking, who then develops fits, should arouse the suspicion of organic pathology, such as a cerebral secondary tumour from a bronchial primary, or possibly cerebral non-metastatic manifestations of lung cancer.

3. The head injury was confusing: was his confusional state the result of the head injury and a possible subdural haematoma, or was some intracerebral pathology causing fits? 4. The history of heavy drinking, poor diet, sudden cessation of alcohol intake and possible eye muscle dysfunction makes alcohol withdrawal syndrome ('DTs') or even Wernicke's encephalopathy a distinct possibility - alcohol problems are common and 'common things commonly occur'. An emergency CT scan could help decide whether there was any intracerebral pathology - a haematoma or a tumour - although this investigation is difficult in such a restless and confused subject. Chest X-ray would eliminate the possibility of a lung primary. Liver function tests and haematology would help clarify whether there was any evidence of alcohol-related damage. Interviewing informants such as his ex-wife or girlfriend would help confirm and clarify the history - a good history is worth a thousand investigations in psychiatry. In the absence of any positive evidence of intracerebral pathology a presumptive diagnosis of DTs with possible Wernicke's encephalopathy was made. His confusional state coming on 5 days after stopping drinking, 'rum fits', and eye movement disorder were consistent with this diagnosis. He was given injections of parenterovite and started on a 'detox regimen' of reducing doses of carbamazepine, starting with 400 mg q.d.s. and reducing to 200 mg daily over a 5-day period. He made a good recovery and returned to his farm, determined to decide between his wife and girlfriend, to employ a neighbour to provide him with regular meals, and to abstain from alcohol.

degeneration, myopathy and convulsions), cardiomyopathy, pulmonary tuberculosis, anaemia, hypoglycaemia and pancreatitis. Children of alcoholic mothers may be born with a syndrome of low birthweight and developmental retardation known as the fetal alcohol syndrome.

Psychiatric complications There are three levels of severity at which psychiatric complications of alcoholism occur. In the initial stages the patient may present with minor psychiatric symptoms of panic attacks, anxiety, depressions or sexual difficulties. If withdrawn suddenly from the drug, the alcoholic addict is at risk for delirium tremens and sometimes alcoholic hallucinosis. Prolonged and severe alcohol addiction leads to alcohol-related dementia, including Korsakoff's psychosis (Ch. 24). Delirium tremens (DTs) is discussed on page 1438. Alcoholic hallucinosis Alcoholics may experience auditory hallucinations, usually derogatory or persecutory, in the presence of clear consciousness (consciousness is always clouded in DTs). These usually stop when drinking ceases but occasionally persist, suggesting coexisting schizophrenia. Morbid jealousy Alcohol is a frequent cause of a syndrome of morbid jealousy, in which an individual (usually male) becomes convinced that his spouse is unfaithful. Wernicke-Korsakoff syndrome (q.v.) and alcoholic brain damage are discussed in Chapter 24.

Management The outcome of treatment for alcoholism (Table 8.22) depends less on the nature of the treatment than on the social situation and personality of the patient. Addicts with a stable family and employment and a good personality do best. The impulsive or psychopathic drinker lacking home, family or job has a very poor prognosis for sobriety. The aim of treatment should almost always be abstinence. Any doctor who attempts to help alcoholics must be prepared for disappointment, as relapses ('slips') are common. A combination of limit-setting and acceptance is needed in all of the following treatment approaches.

TABLE 8.22 Outcome of treatment for alcoholism Outcome

1 year (%)

2 year (%)

Improved Still drinking Dead Lost to follow-up

35 45 1

25

19

21

51 3

Psychotherapy A supportive relationship, with either a spouse, a peer (e.g. through Alcoholics Anonymous) or a professional helper, is probably essential. Formal psychotherapy or social help should be conditional on sobriety, on the principle that whatever an alcoholic's problems (and they will be many), drink makes them worse. Wherever possible, the spouse and family should be included in any psychotherapy programme.

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Inpatient treatment Brief admission for 'drying-out', or longer admission to a therapeutic community with group therapy, can help maintenance of sobriety. Patients who need admission are by definition more disturbed, and the long-term prognosis is therefore often poor. Drug treatment Disulfiram (Antabuse) reacts with alcohol to produce acetaldehyde, producing unpleasant feelings of flushing and nausea. Some patients find it helpful to have this internal 'chemical fence' to discourage drinking. Alcoholics anonymous Alcoholics Anonymous (AA), started in the 1930s by an alcoholic doctor ('Bob'), is a worldwide self-help organization for alcoholics run by ex-alcoholics. It offers a structured personal and group psychotherapy programme aimed at sobriety. An important feature of AA is that it provides a social life that is not based on pubs or drinking. A parallel organization, Al-Anon, offers support to the families of alcoholics. 'Shop-front'/'dry house' programmes The 'skid-row' alcoholic has usually lost everything - job, home, family, possessions, friends - through drinking, and special facilities are needed for this group of patients (about 10% of alcoholics). These include non-threatening 'drop-in' day centres, after-care hostels and long-term medical and social support.

Prevention There is a direct relationship between per capita consumption and the price and availability of alcohol. As the real cost of alcohol has fallen steadily in the UK over the past decade, so per capita consumption and hence alcoholism rates have risen accordingly (Fig. 8.11). Internationally, there is a direct correlation between the price of alcohol and the incidence of cirrhosis and other indices of severe alcoholism. Governments, through pricing policies and licensing laws, can have a direct effect on alcoholism rates. Well-funded education programmes are also needed to alert the public to the dangers of alcohol.

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FURTHER READING ON ALCOHOLISM AND DRUG ABUSE Chick J 2000 Treatment of alcohol dependence. In: Gelder M, Lopez-Ibor J, Andreason N (eds) New Oxford textbook of psychiatry. Oxford University Press, Oxford Ghodse A 1997 Drugs and addictive behaviour. Blackwell, Oxford Heather N, Robertson I 1997 Problem drinking. Oxford University Press, Oxford Royal College of Psychiatrists and Royal College of Physicians 2000 Drugs: dilemmas and choices. Gaskell, London

MENTAL HANDICAP OR LEARNING DIFFICULTIES Mental handicap can be defined as the arrested or incomplete development of the cognitive (i.e. intellectual) part of the mind. Such a broad definition covers a wide range of individuals: • Severely mentally handicapped, who lack speech, are unable to learn, cannot dress or feed themselves, may be incontinent, and may have stereotyped movements such as rocking or thumb-sucking. The majority are looked after in institutions. • Moderately mentally handicapped, who have a considerable handicap (e.g. very restricted speech) but are able to live in sheltered accommodation in the community. • Mildly mentally handicapped, who have the capacity to learn and to live normal, if somewhat restricted, lives. Their primary problems are social and educational rather than medical. Most can live independently in the community.

MENTAL ILLNESS AND MENTAL HANDICAP It is only recently that mental illness and mental handicap have been properly distinguished. It is now understood that the majority of mentally handicapped people are not psychiatrically ill, and that they should be cared for by the social, rather than medical, services. Nevertheless, the mentally handicapped are particularly vulnerable to mental illness because of both their physical handicap and their emotional and social immaturity. They can develop the full range of mental illnesses, including schizophrenia, manic depression, anxiety states and hysteria. Distress is likely to be expressed behaviourally, for example through withdrawal, temper tantrums, compulsive masturbation or lawbreaking (e.g. shoplifting or self-exposure), rather than verbally.

• A single gene disorder, e.g. untreated phenylketonuria, tuberous sclerosis, mucopolysaccharidoses, untreated galactosaemia and Tay-Sachs disease; • Chromosomal, e.g. Down's syndrome, fragile-X mental retardation, deletion and duplication syndromes; • Traumatic, e.g. birth injury or anoxia. Here, the mental handicap is usually associated with spasticity; • Infective, e.g. maternal toxoplasmosis, cytomegalovirus and rubella; bacterial and viral meningitis. All may cause severe mental handicap; • Other causes include rhesus incompatibility, lead poisoning, and maternal drugs such as anticonvulsants or alcohol. Mild mental handicap usually lacks a specific inherited or environmental cause. It is thought to be a result of polygenie inheritance, often coupled with an impoverished environment.

AUTISM AND ASPERGER'S SYNDROME Autism is one of the most serious of the development disorders. It is characterized by 'autistic aloneness', in which the child is unable to make warm relationships; speech and language disorder, in which conversation as opposed to monologue may be deficient; an obsessive desire for sameness; and bizarre mannerisms. IQ is usually impaired, although the child often has artistic or musical abilities. The aetiology is unknown but is thought to be genetic, and possibly also due to perinatal minor brain injury. There is no known treatment that alters the condition, although individual psychotherapy has been claimed to have achieved remarkable results in some cases. The management usually consists of support for the family and special educational arrangements for the child. As in autism, in Asperger's syndrome there are marked impairments in social interaction, but the development of language and curiosity about the environment is normal. Sufferers usually show intense circumscribed interests or restricted repetitive stereotyped patterns of behaviour. The abnormalities persist into adult life, and most Asperger sufferers are 'loners', who are able to work but rarely able to sustain intimate relationships.

Management The principles of management of adult mental handicap are shown in Table 8.23.

Prevention CAUSES OF MENTAL HANDICAP 252

Moderate and severe mental handicap usually has a distinct cause. This may be:

Primary prevention is exemplified by rubella inoculation and the provision of lead-free paint. Secondary prevention is made possible by genetic counselling and by prenatal diagnosis and screening (see Ch. 3, p. 74).

TABLE 8.23 Principles of management of adult mental handicap • Accurate diagnosis • Treatment of coexisting mental and physical illness • Provision of training facilities, day centres, sheltered workshops and social clubs • Residential provision, e.g. hostels for those whose relatives cannot cope or are not available • Provision of emotional support for carers who, for example, worry about what will happen when they are no longer able to care for their mentally handicapped dependant

FURTHER READING ON MENTAL HANDICAP OR LEARNING DIFFICULTIES Bouras N 1994 Mental health in mental retardation. Cambridge University Press, Cambridge Matson J, Mulick J (eds) 1991 Handbook of retardation. Pergamon, Oxford

PSYCHIATRY AND THE LAW Mental illness may be associated with crime in one of three ways: • Psychosis. The most famous example of a crime being the result of a psychosis is the 19th century McNaughten case, in which a man who had tried to shoot the American President was acquitted 'by reason of insanity'. • Neurotic disorder. Depression, for example, may make a criminal act such as shoplifting more likely ('diminished responsibility'). • Psychopathic personality.

ANTISOCIAL PERSONALITY DISORDER People with an antisocial personality disorder may be described as those with persistent social difficulties (often, but not always, involving law-breaking) in the absence of a psychosis or neurosis. Their crimes, if they do occur, may be as trivial as repeatedly breaking shop windows, or they may be serious, such as murder. In the 19th century these individuals were classified as 'morally insane'; they were not deluded or hallucinated, but they appeared not to know right from wrong, or to be aware of the consequences of their actions. The term antisocial personality disorder is now used in order to avoid the derogatory connotations of 'psychopath'. The concept implies: • A persistent abnormality of interpersonal functioning, extending backwards to a childhood which was often disrupted and poor ('depraved because deprived');

• A major problem of social adjustment; • The absence of another psychiatric disorder.

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An antisocial individual has trouble not just in relation to himself or to immediate family (although this usually does happen), but also to institutions such as the law, school, the armed services, employment and marriage. He is both dependent on institutions and unable to coexist peaceably with them. There is often associated alcohol and/or drug abuse. The dividing line between normal and abnormal is harder to draw in this than any other psychiatric category and it is not a diagnosis that should be applied lightly. It is also important not to make such patients scapegoats. Antisocial individuals sometimes benefit from psychotherapy (providing firm limits are set), and from help with the social consequences of their disorder, such as homelessness and unemployment.

Dangerousness and risk assessment Psychiatrists are often called upon to assess the dangerousness of an individual so that decisions can be made about whether he should be allowed to live freely in the community. Assessment of dangerousness, which cannot be an exact science and will always to some extent be dependent on clinical judgement, rests on two main criteria: • Past behaviour. Violent or law-breaking behaviour in the past is the most reliable predictor of future trouble. A very careful history, taken in an atmosphere of trust, is essential if this is to be reliably assessed. • Psychological understanding of the causes of specific episodes of violence. Unless caused by organic factors such as epilepsy, violence rarely, if ever, emerges out of the blue. There are always antecedents and triggers that can be identified and which constitute a psychological explanation for the violent episode. These can best be elucidated by reconstructing a detailed 'action replay' of the events leading up to the episode. Thus many people resort to violence when they feel cornered, threatened, or are made to feel inadequate. Substance abuse often plays a major part in lowering thresholds to violence. Risk can be reduced if these factors are known, and steps can be taken to avoid them; conversely, situations likely to increase the likelihood of violence can be identified.

MENTAL HEALTH LEGISLATION Psychotic patients lack insight and may occasionally be dangerous, either to themselves or to others. In the UK, until the 1930s nearly all psychiatric inpatients were legally detained in hospital. Today, less than 10% of patients are detained on a 'Section'. Although compulsory admission is sometimes necessary for the protection of the patient and the public, this power is open to misuse or even abuse. The

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CASE STUDY 8.5 APPLICATION OF THE MENTAL HEALTH ACT TO A 45-YEAR-OLD MAN WITH HYPOMANIA A 45-year-old man was brought by his son to the accident and emergency department at 11.30 at night. The history was that since losing his job recently he had not slept for several days, had run up huge debts on his credit cards, and had become irritable and aggressive, so much so that his wife had temporarily moved out of the family home. He was complaining of a headache and his son, who was at his wits' end, had persuaded him to come to the hospital to have it investigated. On assessment there was no previous history of formal psychiatric disorder, although he had been prone to mild episodes of depression and withdrawal. Physical examination revealed no abnormality. He was restless, spoke rapidly without sticking to the subject, and was hard to interrupt. He appeared to have no insight into his situation and repeatedly demanded to leave. The provisional diagnosis was hypomania. The junior psychiatrist was worried about him, and felt that he needed further psychiatric assessment. Not surprisingly, he refused the offer of informal admission to hospital. Arrangements were therefore made for him to have a formal mental health assessment. This involved assembling a consultant psychiatrist (who was approved under Section 12 of the 1983 Mental Health Act), a mental health-approved social worker and his GP. During this time the patient was insisting on leaving, but with the help of psychiatric nurses he was distracted enough to stay. Eventually the assessment team arrived, he was duly put on a Section

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for assessment and admitted, with much protest, to the psychiatric ward, with a diagnosis of hypomanic disorder.

Questions 1. Under what powers can patients be held in hospital against their will? 2. What safeguards are there for both patient and doctor in this situation? The law requires that a strict procedure be followed if someone is to be deprived of their liberty under the Mental Health Act. There is often a period prior to bringing that procedure into play in which the patient may need to be restrained. The legal safeguard here is 'common law', i.e. the right (and duty) of a citizen to protect an individual from causing harm either to others or to himself. In this instance the patient was clearly in danger of harming others or himself. His aggression had resulted in his wife having been physically hurt; equally, he was likely to provoke others to hurt him; his financial profligacy (a typical symptom in hypomania) was also self-injurious. His headache was unexplained, and he needed investigation and overall assessment as well as restraint. Following the mental health assessment he could be given appropriate treatment - in this case tranquillizing drugs such as haloperidol - and if he refused to take them forcible administration was

United Kingdom Mental Health Act of 1983 (currently under review) aimed to provide safeguards against such abuse, and the Sections of the Act of particular relevance to general physicians are described below. In all cases it is a duty of the hospital administration to inform the patient of his Section, and a statutory right of the patient to appeal against compulsory detention.

permissible (although this is rarely necessary). The assessment procedure could begin in a safe environment. The 'Sectioning' procedure involves a clear reading to the patient of his 'rights' including the right of appeal against the Section, to be heard by independent experts in as short a time as possible. In this case the full mental health assessment team had to be brought together. However, had the patient already been formally admitted to hospital the junior psychiatrist would have had the right to impose a 'Section 5.2' on the patient, giving the staff the powers to hold him against his will for up to 72 hours, until a formal assessment could be mounted. Thus the combination of the 'common law' provision, with rights of appeal, gives both doctor and patient some safeguards. The Section 2 imposed on the patient was in fact lifted some 2 weeks later as his clinical condition improved, his insight returned, and he could begin to see that he needed help. Had this not happened, the Section 2 would have expired by the end of 28 days, and were he to have needed further restraint a 'Section 3' treatment order would have been needed. The rules of appeal apply equally to this procedure. The Mental Health Act is currently under review in the UK. It is likely that any decisions about detention for longer than 28 days will be taken out of the immediate hands of clinicians altogether, and referred to a mental health panel comprising an independent psychiatrist, a lawyer and a lay member.

Admission for assessment (Section 2) The patient may be detained for up to 28 days if (a) he is suffering from mental disorder which warrants assessment; or (b) he is a danger to himself or others. The application for such assessment must be made by a social worker or the patient's nearest relative. There has also to be a medical

recommendation from two medical practitioners. One of these must be a doctor officially approved as having special psychiatric experience ('Section 12' doctor, often a consultant psychiatrist); the other should, if possible, have known the patient previously (and is thus usually the patient's GP). In an emergency the patient may be detained for up to 72 hours (Section 4) on the basis of only one medical recommendation, which need not necessarily be by a psychiatrist.

detained patients can still be treated without their consent (e.g. given ECT or phenothiazine drugs), but a second opinion must first be obtained from a doctor appointed by the Mental Health Commission. Patients may not undergo psychosurgery (a brain operation occasionally undertaken in cases of depression or phobic anxiety) if they do not consent to it. Even if they do, a doctor and two nonmedical appointees of the Mental Health Commission must scrutinize the case to ensure that consent has been validly given.

8

Admission for treatment (Section 3) The patient may be detained for up to 6 months. The conditions of the application and recommendation are therefore more stringent, and the rights of appeal greater than under Section 2. The patient must have a defined mental disorder, be thought likely to improve, and be unable to be cared for within the community. Section 3 can be extended for a further 6 months, with the approval of an independent tribunal.

Emergency detention of patients already in hospital (Section 5) An informal patient may be held in hospital for up to 72 hours on the recommendation of the doctor in charge of his treatment without a Section 2 or 3 being instituted. Under Section 5(4), a psychiatric nurse can detain an informal patient already being treated for mental illness for up to 6 hours. Under Section 5(2) a patient in a general hospital who is being treated by a non-psychiatrist can be detained, under the report of the doctor in charge of the case (the 'responsible medical officer' RMO), for up to 72 hours. A psychiatrist should see the patient as soon as possible to decide whether further detention is needed. Section 5(2) cannot be renewed.

Powers of the courts (Sections 36, 37, 38) Under these Sections, mentally ill offenders can be compulsorily admitted to psychiatric units for assessment and treatment, rather than going to prison.

Place of Safety Order (Section 136) Police officers have the power to remove to a place of safety any person whom they find in a public place who appears to be suffering from mental disorder and who is in immediate need of care and control for his own sake or that of others. Once removed, the patient must be medically examined and assessed. The place of safety is often a police station, but may also be a hospital A&E department.

Consent to treatment (Sections 57, 58) An important feature of the Act is a tightening of the procedure surrounding consent to treatment. Compulsorily

FURTHER READING ON MENTAL HEALTH LEGISLATION Faulk M 1994 Basic forensic psychiatry, 2nd edn. Blackwell, Oxford Gunn J, Taylor P 1993 Forensic psychiatry: clinical, ethical and legal issues. Butterworth-Heinemann, Oxford

MEDICINE AND THE EMOTIONS There are two basic types of mental activity. One is pictorial, non-rational and emotional, and concerns the biological fundamentals of birth, attachment, sex, separation and death, as well as art and creativity; the second is rational, verbal and logical and concerns the achievement of specific goals and the solving of particular problems. Freud called these the primary and secondary processes. Non-rational thinking is primary because it precedes rational thinking developmentally: infants and young children think in feelings and pictures. The secondary processes are only gradually acquired. In healthy adult life both coexist. Much of waking life is dominated by secondary processes, but in dreams, daydreams and instinctual activity the primary processes take over. In mental illness the balance of primary and secondary processes may be disturbed: the psychotic, for example, is dominated by primary processes, whereas the patient with obsessional neurosis is trying to apply the false logic of secondary processes to his emotions. Modern medicine is based on scientific rationality. This means that at times doctors may find it difficult to comprehend the emotional reactions of the patient to illness, death or sexuality. For the doctor, the patient who needs a routine hernia operation presents a technical problem to be solved; the patient, however, may at some level be wondering whether he will survive the operation and, if so, whether his sex life will continue. Medical training is predominantly a training in rationality, in learning to set feelings aside. In order to understand the 'irrational' anxieties that trouble patients the doctor has to remain in touch with and respect the primary processes. The following sections on sex, and on death and dying, highlight some of these issues.

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SEX AND MEDICINE Sex matters for three main reasons: identity, attachment and continuity. Sexual abuse in childhood threatens all three and is an important underlying cause of psychiatric disturbance.

Identity Gender is fundamental. When a baby is born the mother asks 'Is it alright?', then 'Is it a girl or a boy?'. Gender is integral to a sense of identity, and this can be threatened by illness at any of the stages of development. Hypospadism, hirsutism, hernia, delayed puberty, amenorrhoea, infertility, hysterectomy, prostatectomy, diabetes-related impotence are just a few of the many medical conditions that may threaten the sense of identity that is rooted in gender and sexual functioning.

Attachment Human attachment occurs through the body. Even when communication is at a distance, hands are, needed to write a letter, a voice to speak on the telephone. Sexual bonding is a powerful and rewarding form of attachment. The adolescent worries whether his or her body is 'good', 'big' or attractive enough to find a partner. Where sexuality is threatened by illness and disability, the patient fears that the basis of his or her attachment may be undermined: 'Who will want me i f . . . I have a colostomy ... a mastectomy ... am impotent... ?' Psychogenic symptoms such as lower abdominal discomfort, pruritus or back pain may both arise from and lead to sexual difficulties. Such symptoms may draw attention to an underlying sexual anxiety, and at the same time provide the patient with the care and attention that he fears may be lost through sexual failure. Occasionally, guilt about masturbation may be based on the misconception that it is 'wrong' or harmful, and this too may lead to psychogenic symptoms.

Continuity Psychologically, sex and reproduction may serve as an insurance against the fear of extinction. The idea of personal death is more acceptable if there is family continuity, or if an individual feels he has contributed something: that children, memories, ideas or objects will live on in the next generation. Threat to this sense of continuity can lead to feelings of anxiety or depression.

1

256

MCQ 8.7

TABLE 8.24 Common anxieties about sex Adolescence Masturbation Homosexuality Genital inadequacy Young adults Impotence Anorgasmia Infertility Lack of libido

Middle-aged Extramarital affairs Sex and illness Any age Incest Fetishism Non-consummation of marriage

Taking a sexual history Sex, at least in theory, is no longer a taboo subject, but in practice both doctor and patient are likely to feel anxious about some aspects of their sexuality. It is important that the doctor feels reasonably comfortable when asking about a patient's sexual life. All human beings have a sexual life - in the sense of thoughts, fantasies and feelings about sex - regardless of whether or not they are celibate. The doctor needs to be sensitive to the common anxieties about sex and to be aware of those that may apply to a particular patient's age and situation (Table 8.24).

SEXUAL AND MARITAL DIFFICULTIES Divorce and family disruption are becoming increasingly common. More than one in three marriages in the UK now ends in divorce; in the USA the figure is one in two. There is good evidence that in general marital disharmony and divorce are psychologically damaging for children, who are more likely to have emotional disorders in adult life and to underachieve academically than their counterparts from stable families. Nevertheless, single mothers and even same-sex parents are capable of providing a loving and nurturing environment for their children. Partly in response to this, there is now great interest in marital and family therapy. The commonly encountered sexual difficulties are impotence, premature ejaculation and delayed ejaculation for men, and vaginismus and lack of sexual enjoyment (including anorgasmia) for women. Both sexes may suffer diminished libido. Transient difficulties are common; it is only when they are persistent and cause distress that they constitute a problem. Sexual problems may be primary, i.e. present from the onset of sexual life, or secondary, i.e. developing after a period of satisfactory sexual functioning.

Erectile dysfunction This can be defined as the inability to achieve an erection sufficient for satisfactory sexual intercourse.

Aetiology Contrary to popular belief, as many as 50% of cases of impotence are organic in origin. Where impotence is psychologically based, it arises out of anxiety. This may be in the context of an episode of anxiety/depression, or as a manifestation of personality disorder. Organic causes include: • Endocrine causes, such as hypopituitarism and hypogonadism • Diabetes. At least 30% of diabetic men experience impotence by the age of 50 • Vascular disease, such as Buerger's disease • Alcoholism • Drug induced, e.g. diuretics, p-blockers and neuroleptics.

•

•

•

Treatment • If psychogenic, the Masters and Johnson approach outlined below is normally effective. • The underlying cause should be treated whenever possible. • Symptomatic treatment: - Intracavernosal injections of papaverine, papaverine plus an a-blocker such as phentolamine, or alprostadil (prostaglandin E2) can be self-administered and are effective in up to 70% of cases. The main danger is priapism, and erections lasting more than 4 hours should be treated as an emergency, with venous aspiration together with a vasoconstrictor. The drug Viagra is a significant advance over these cumbersome measures. In the presence of sexual desire and stimulation it produces good erections that have a more 'natural' quality. - Mechanical aids such as a vacuum condom are also useful in some cases. The Masters and Johnson approach Current thinking about sexual dysfunction has been greatly influenced by the work of Masters and Johnson, who studied the physiology of sexual response and introduced a new classification and treatment for sexual difficulties. General principles of the Masters and Johnson approach include the following: • Treatment is in couples. Sexual difficulties are often complementary (e.g. premature ejaculation and an-

SUMMARY 24 The Masters and Johnson approach • • • • • •

Treatment in couples Physical examination/history-taking (to reassure they are 'normal') Instruction in sexual arousal Instruction initially not to make love (to dispel anxiety) Graded exercises based on 'sensate focus' Psychotherapy if necessary

•

•

orgasmia), even though one member may present as the person with the problem. The non-presenting partner is given the role of co-therapist. Physical examination and careful history-taking of both partners are required both to rule out organic causes of sexual dysfunction and to reassure the patients that they are 'normal'. There is more to sex than penetration. Sexual arousal, especially in women, depends on a series of steps, arid a man may need to learn that foreplay cannot usually be omitted if his partner is to be fully aroused. Anxiety is seen as a central element in sexual dysfunction. Anxiety is antagonistic to sexual arousal, and a vicious circle can arise in which the patient fears they will fail (for example to maintain erection, not to ejaculate prematurely, or to have an orgasm), which makes them 'try' harder, which makes them less able to relax and respond to sexual stimuli and thus more, rather than less, likely to 'fail'. The aim of treatment is to break this circle. Paradoxically, the couple are initially instructed not to make love, in order to prevent performance anxiety. They are given a series of graded exercises based on sensate focus or stroking, in which they learn to give and receive pleasure. Initially this is non-genital, but later moves on to 'genital sensate focus', i.e. mutual masturbation. It is ironic that whereas masturbation was viewed (wrongly) by 19th century psychiatry as a major cause of insanity, it is now considered important that both sexes are able to masturbate without guilt. Psychological factors in sexual dysfunction may also need treatment, through either individual or marital therapy. Unexpressed anger is a common cause of sexual disharmony: a couple who cannot row may also not be able to make love. Fear of loss of control, ignorance or guilt may also affect sexual pleasure.

8

The results of the Masters and Johnson approach are generally good, with 60-70% improvement rates reported in well-motivated couples. 1

FURTHER READING ON SEX AND MEDICINE Hawton K 1985 Sex therapy: a practical guide. Oxford University Press, Oxford Hawton K 1995 Treatment of sexual dysfunction by sex therapy and other approaches. Br J Psychiatry 167:307-314

DEATH AND DYING Death is an integral part of medicine, but doctors and other medical staff often feel confused by the psychological and ethical questions it poses. Should a terminally ill patient be kept alive as long as possible, or allowed to die in peace? Should every patient with a fatal illness be told of his diagnosis, and if so how should they be told? Can a dying

257

patient be helped to come to terms with death, and how can this happen? What are the psychological reactions in the relatives of dying patients, and what support do they need? These questions are problematic not only because of a lack of training and technique, but also because death is an intrinsically difficult subject which all but the exceptionally compassionate find hard to face. Patients and doctors alike deny the reality of death in order to carry on with life.

REACTIONS IN THE PATIENT The response of the patient to the knowledge that he has a terminal illness can be compared to a bereavement reaction. The patient enters a state of grief for the loss of his own life. The initial reaction is usually one of numbness and shock, a struggle between denial and acceptance. The patient attempts to fight off what is happening and cannot believe it is true, that it is happening to him. This is often followed by a period of severe anxiety, in which the patient becomes dependent on visitors, family and medical staff, and finds it very hard to be alone. A period of sadness and weeping is inevitable. Anger is also a normal feature of this phase, and the patient may become difficult, complaining, ungrateful and demanding. With time, however, the patient gradually becomes calmer, and during this phase the opportunity to talk may be very helpful. This series of reactions may be compressed into a few hours or spread over months, and, as with bereavement, does not follow a neat, orderly course.

TALKING TO DYING PATIENTS Breaking bad news and talking to dying patients is an art that can be learned through watching others, and through discussion of the feelings and difficulties it arouses. The patient can often be helped if staff and family recognize the subsequent reactions for what they are and then let the patient talk about his anger, panic and sadness. When this has happened the patient may feel better.

258

SUMMARY 25 Emotional reactions in terminally

ill patients • • • • • •

Numbness and shock Struggle between denial and acceptance Severe anxiety Sadness and weeping Anger Eventual calmness

The issue of 'to tell or not' is a false alternative. Some patients want to know their diagnosis in great detail; others would rather not know. It is unnecessary and inappropriate to confront all patients with the stark reality of their illness. On the other hand, far more patients than are officially 'told' want to know their diagnosis or know it already. The patient needs space and time in which to discuss his feelings and ask questions. Gentle probing may be needed to help the patient make use of this opportunity.

REACTIONS IN THE FAMILY Like the patient, families also go through an anticipatory grief reaction when a loved one is dying. The death of a child or adolescent is especially painful and unsupportable. Spouses of dying patients are particularly vulnerable. They may, for example, feel angry with their husband or wife for being ill, and feel very guilty about having such unvoiced thoughts. The stress of death may lead to tense and angry outbursts, either within the family or outside it at medical staff. Doctors and nurses should be prepared for this. Family counselling can help with these grief reactions and help to make death and bereavement, when they come, more bearable.

FURTHER READING ON DEATH AND DYING Holland J, Rowland J (eds) 1990 Handbook of psycho-oncology. Oxford University Press, Oxford

9 Infectious, Tropical

and

Parasitic Disease Mark H Wansbrough-Jones and Stephen G Wright

The relationship between humans and microorganisms 259 Principles of diagnosis and management 261 Antimicrobial agents 262 Infection in the immunocompromised patient 269

Rickettsia 305 BACTERIAL INFECTIONS 307 Gram-positive cocci 308 Gram-negative cocci 310 Gram-positive bacilli 311 Gram-negative bacilli 315

Control of infection 271

Mycobacteria 325

Syndromes of infection 273

Spirochaetes 329

VIRUS INFECTIONS 283

Actinomycoses 330

Enveloped double-stranded DNA viruses 283

Madura foot 331

Enveloped single-stranded DNA viruses 289 Non-enveloped double-stranded DNA viruses 290 Enveloped single-stranded RNA viruses 290 Non-enveloped single-stranded RNA viruses 302 Non-enveloped double-stranded RNA viruses 303 CHLAMYDIAL, MYCOPLASMA AND RICKETTSIAL INFECTIONS 303

Nocardioses 331 SYSTEMIC MYCOSES 332 PROTOZOAL INFECTIONS 335 Protozoal infection of the gut 335 Genital tract protozoa 342 Free-living protozoa causing human disease 342 Non-pathogenic gut protozoa 343

the upper hand, particularly over children. Worldwide, infectious gastroenteritis is the most common cause of death in children under the age of 1 year. The causative organisms are similar in underdeveloped and western countries, but in the former there is more frequent exposure from water supplies, methods of food preparation and poor standards of hygiene, including sewage disposal. The outcome is worse because of the severity of dehydration. Table 9.1 shows how the frequency of some infections varies in different areas of the world. The figures illustrate differences attributable to climate (malaria), standards of hygiene (typhoid) and immunization (poliomyelitis, measles and diphtheria). The mortality associated with these diseases is also higher in underdeveloped countries because of a poor nutritional state at the onset of illness and limited access to medical facilities. The pattern of infections is constantly changing. Infectious diseases become less important as a cause of death as the standard of living improves. England in 1860 was much the same as parts of Africa and southeast Asia today with respect to some infectious diseases (Table 9.2). Improvements in standard of living and immunization account for the change in many of these diseases, but sometimes the pathogen itself changes in virulence. Scarlet fever (scarlatina) is no longer the feared disease it was 50 years ago because erythrogenic toxin-producing streptococci have become less virulent. Changes in microorganisms may produce little change in the clinical disease but are of no less significance. The type of meningococcus most commonly incriminated in bacterial meningitis in the UK has for many years been group B, but recently there has been a resurgence of group C infections. Meningococcal vaccine will protect against group A or C infection, but group B meningococci are poor immunogens. Similar antigenic variation occurs repeatedly in influenza virus. Most of the changes in the pattern of infections are gradual. New infections are extremely rare but can have an enormous impact; an example is human immunodeficiency virus (HIV), the cause of the acquired immune deficiency syndrome (AIDS). All of the infections encountered in temperate and developed areas of the world will be found in tropical regions. Certain infections are exclusive to the tropics because of climate, and the presence of animal reservoirs and insect vectors.

Tissue and blood protozoa 343 HELMINTH INFECTIONS 358 Nematodes 359

Chlamydia 303

Trematodes 370

Mycoplasmas 305

Cestodes 375

The relationship between humans and microorganisms is usually one of balanced conflict. In the first months of life encounters with microorganisms are both a threat and a stimulus to the development of complex immune responses. In many parts of the world microorganisms appear to have

THE RELATIONSHIP BETWEEN HUMANS AND MICROORGANISMS Microorganisms that can cause disease in humans are widely distributed in nature, and humans are colonized by vast numbers of organisms. Whether a particular organism causes disease is determined by its natural distribution, its pathogenicity, and the state of the host defence systems. With common pathogens it is likely that immunity will develop early. The age at which this occurs can influence the outcome of infection. At extremes of age the immune

259

TABLE 9.1 Cases of infection reported to WHO from different geographical regions and countries Region or country Americas (all) USA* Europe

Malaria (1993) 984000 1217

50000

Poliomyelitis (1995)

Measles (1994/5)

Typhoid (1980/1)

Diphtheria (1994/5)

0

22988

42160

0 202

286

324

73729 23594

75203

245379

28418

1420 3791

7810

708

0 49483

312

Africa

2590000

643 411

S.E. Asia

3077000

2269

106773

329980

674000

226

110776

145

614

0

7763

265

13

E. Mediterranean

W. Pacific England and Wales

292000

1992

(Data supplied by Communicable Diseases Surveillance Centre, Colindale.) All figures are to nearest 100. *AII figures for USA are for 1995. AII figures for England and Wales are 1995 (except malaria - 1993)

TABLE 9.2 Deaths from infection in England in 1800 fall age groups) Cause

Number

Measles Scarlatina (scarlet fever) Smallpox Diphtheria Typhus Whooping cough Cholera Tuberculosis

9557 9 681 2749 5212 13012 8553 327 58564

system is either immature or in decline, and the patient is highly vulnerable. Paradoxically, during childhood many viral infections are silent or mild, but the same infection in an adult may be severe and complicated. This may reflect a difference in the vigour with which inflammatory responses are generated.

PATHOGENICITY

260

Microbial pathogenicity - that is, the potential of a microorganism to cause disease - is determined by its ability to enter the host and colonise, to penetrate tissues, to evade host defences and to damage tissues. The virulence of an organism is its degree of pathogenicity. An organism is described as highly virulent if a small number of microbes can cause severe disease. Skin is an effective barrier to most organisms and they usually enter either through a breach or via more delicate mucosal surfaces, such as those of the oropharynx and respiratory tract. Attachment to the cell membrane is essential for viruses, and bacterial colonization is also often facilitated by a specific attachment mechanism. Examples are Vibrio cholerae or Escherichia coll in the intestine, and

E. coli in the urinary tract. In each case a determinant on the bacterial surface interacts with a specific receptor on epithelial cells. Some pathogenic organisms cause disease at the site of colonization by producing toxins (V. cholerae),but most traverse the epithelium and their further success depends on their ability to avoid host defences. In the first encounter between human and organism innate immunity is the only defence. In the case of bacteria this centres on phagocytosis, and some bacteria are equipped with capsules that confer resistance to phagocytosis. Interferons play a major part in first-line resistance to viruses, but viruses differ both in their ability to stimulate interferon production and in their susceptibility to its effects. The mechanisms of disease provoked by bacteria are complex, but a distinction can be made between effects caused by exotoxins (tetanus or diphtheria toxins, for example) and those resulting from release of bacterial components such as endotoxins.

SUSCEPTIBILITY TO INFECTION

The effects of even virulent microbes are curtailed by an immune response. Infections therefore typically result from a small number of identifiable situations: • First encounter with a virulent organism, in sufficient numbers, entering by an appropriate route; • Breach of normal anatomical barriers, e.g. by surgery, injury or indwelling lines; • Impairment of innate immune responses; • Impairment of adaptive immune responses. When anatomical barriers are breached by surgery, tissues that are usually sterile are exposed to normal microbial flora at the adjacent site. Similarly, accidental injury often results in exposure to environmental organisms, such as Clostridium tetani present in the soil. Impairment of immune responses leads to susceptibility to infection by organisms of low pathogenicity as well as

9

FIG. 9.1 Incubation periods and periods of communicability of common infectious diseases

to virulent organisms. Infection by organisms of low pathogenicity is called opportunistic. Patients with impaired immunity may therefore present with frequent infections, infection caused by opportunist microorganisms, unusually severe disease caused by infection, or repeated infection by the same organism.

• Incubation period: time from contact with microorganisms to onset of symptoms (Fig. 9.1) • Prodromal illness: minor symptoms preceding the definitive illness • Overt disease • Resolution (convalescence).

This approach will often lead to a simple management plan. It may also be necessary to establish the source in the community. In some cases the doctor has a legal obligation to notify the disease (see Control of infection, p. 271).

This pattern is often influenced by the immune state of the patient and may be altered by drug therapy. Some symptoms, such as sore throat and fever, are more commonly associated with infection than with other disease processes. The pattern of fever may be helpful, but patients may say that they have had a fever when they have not measured their temperature. They may mean aching in the limbs, sweatiness feeling hot or cold, shivery, or true rigors. Of these, a rigor is a good indicator. This is a sensation of coldness accompanied by shivering (associated with a rise in temperature) followed by a hot sensation and marked sweating. Although no one symptom is specifically associated with infection there are many symptom complexes that are highly suggestive of an infective aetiology. For example, although headache has many causes, the combination of headaches with fever, photophobia and vomiting strongly suggests infection of the meninges (meningitis).

Is the disease caused by infection and, if so, where is the site of infection?

Examination The findings on examination may be helpful in three ways:

A careful history and examination will provide important indicators that the patient is suffering from infection.

• Some infections are associated with signs that are specific or which suggest only a short list of differential diagnoses. Examples are the rash of chickenpox or measles, neck stiffness caused by acute meningitis, or the characteristic cough of whooping cough. • More commonly a combination of signs is highly suggestive of an infection. For example, exudative tonsillitis, generalized lymphadenopathy and splenomegaly together suggest infectious mononucleosis; fever, relative bradycardia, splenomegaly and rose spots suggest typhoid. • Physical signs may indicate the site of infection. Consolidation in the lungs suggests pneumonia; loin tenderness is associated with pyelonephritis; inflammation,

PRINCIPLES OF DIAGNOSIS AND MANAGEMENT The principles guiding the clinician in the diagnosis and treatment of an infective illness can be considered by asking some simple questions: • Is the disease caused by infection and, if so, where is the site of infection? • What is the microorganism responsible? • Which drugs can eliminate the organism, and will treatment benefit the patient?

History Three aspects of the history are likely to be helpful: • Pattern of the illness • History of contact with patients with a similar illness, or types of behaviour that confer a risk of infection • History of travel to places where particular infections are known to be common. Illnesses caused by infection tend to have a form that is reproduced in most individuals and which is characterized by the following features:

261

volume of fluid permits. The yield will be higher and a Gram stain can be performed. • Think of culture before allowing a tissue specimen to be immersed in fixative such as formalin. • Ensure that specimens for culture are transported to the laboratory without delay. Microorganisms must be nurtured, and all too often they die waiting for transport, or are overgrown by contaminant organisms. Specimens for viral or fungal culture often require special collection techniques and the laboratory should be consulted before obtaining the specimen.

Which drugs can eliminate the organism from the infected site, and wifl treatment benefit the patient?

FIG. 9.2 111ln white cell scan in a paracolic abscess At 24 hours after the intravenous injection the activity is localised, indicating the accumulation represents an enclosed abscess rather than inflamed bowel. (Reproduced by kind permission of Dr Seth Saverymuttu.)

swelling and fluctuance beneath the skin suggest an abscess.

What is the microorganism responsible? A careful history and examination may point to a diagnosis of infection and can be specific for a particular infection. More frequently, infection is strongly suspected but the site and the organism responsible are unknown. Imaging techniques are often helpful in finding the site of infection, e.g. ultrasound or CT scanning can demonstrate an abscess in soft tissues. Gallium or technetium (99mTc) leukocyte scans frequently demonstrate a soft tissue abscess. In the latter technique the patient's leukocytes are labelled with 99mTc and reinjected (Fig. 9.2). Labelled leukocytes enter sites of acute inflammation, such as an abscess, surgical wounds and the bowel wall of patients with inflammatory bowel disease. Before appropriate treatment can be started the right samples must be collected and sent to the laboratory. The laboratory can give most help if the correct samples are taken and are accompanied by a brief summary of the patient's illness. The drug history is particularly important, as antibiotic in the sample may inhibit the growth of bacteria in vitro. There are simple rules for the collection of samples:

262

• Avoid contamination of the sample with irrelevant organisms by careful cleansing, e.g. cleanse skin with antiseptic before taking blood for culture, and wear gloves during venepuncture. • When infected fluid is to be cultured (e.g. pus) send a fluid sample in a sterile bottle rather than a swab, if the

Some guidelines for the choice of antimicrobial drugs are given on page 263. Whether treatment is to be started immediately or after the results of laboratory tests are available depends on the severity of the disease and the likely consequences of delay. There is virtue in waiting until the precise diagnosis is known if the clinical situation permits, and this applies particularly when antibiotics have been given before admission to hospital. Acute meningitis and septicaemia are obvious exceptions because the patient may die before a final result is available, but even then it is desirable that the correct specimens are obtained before treatment is started. Valuable preliminary information can be obtained by Gram staining and microscopy of specimens such as sputum or pus. Direct testing for microbial antigens may increase in importance for disease caused by a limited range of organisms, such as acute meningitis. Treatment is not always beneficial to the patient, even when an antimicrobial drug with appropriate activity can be delivered to the site of infection in adequate concentration. Faecal excretion of salmonellae may be prolonged by treatment with some antibiotics.

ANTIMICROBIAL AGENTS The choice of antimicrobial drugs is central to the management of infection. General measures should not be neglected: these include use of analgesics, attention to nutrition and hydration, and cleaning, debridement or drainage of infected areas. The term 'antimicrobial agent' can be applied to any substance that is active against microorganisms. Strictly, an antibiotic is a substance produced by a microorganism which inhibits the growth of another. In this chapter 'antibiotic' will be used (inaccurately) to refer to antibacterial drugs, whether synthetic or naturally produced. In this section the dose of antimicrobial is not normally given, as this often depends on the nature of the particular infection being treated, and the reader should refer to sections on the management of specific diseases. Only the more severe side-effects are noted here.

edge of antibiotics, including the known sensitivity of particular organisms to them. The latter are not constant, and so treatment is often started on the basis of an intelligent guess and modified later according to laboratory results. Bacterial sensitivity is tested using discs impregnated with antibiotic and measuring the size of the ring of inhibition on culture plates. Other factors are also important in the choice of antibiotic, such as absorption and penetration to the site of infection. Whenever possible the antibiotic chosen should have a spectrum of antibacterial activity limited to a few organisms, as the broader the spectrum the greater the chance of side-effects owing to disturbance of the normal microbial flora. The choice between a bactericidal and a bacteriostatic drug is not usually critical but it may be important when the organisms are fairly inaccessible, as in infective endocarditis, or when host defences are impaired (see Table 9.6). Combinations of antibiotics are used for one of three purposes:

Choice of appropriate drugs The selection of a suitable antimicrobial agent is fairly straightforward when the microorganism responsible is known (Table 9.3), but often this is not the case and a sensible guess has to be made as to the organisms responsible. In the case of a urinary tract infection in a previously healthy young woman, for example, faecal organisms such as E. coli would be the most likely pathogens, and this would guide initial therapy. The information required to make an appropriate choice can be summarized as follows: • • • • •

Probable organism(s) Probable antimicrobial sensitivities of the organisms Ability of the chosen drugs to reach the site of infection History of allergy to drugs Interaction of these drugs with any other drugs the patient is taking • Side-effects of the chosen drug • Cost of the drug.

• To obtain a spectrum of antibacterial activity that could not be achieved with a single agent (e.g. treatment of septicaemia when the causative organism is not known); • To take advantage of synergy between drugs (e.g. during the initial treatment of infective endocarditis); • To prevent the emergence of resistant organisms (e.g. treatment of tuberculosis).

An example of the process of decision is shown in Figure 9.3. This logical sequence assumes a considerable knowl-

TABLE 9.3 Common sensitivities of some bacteria to antibiotics Bacteria

1st choice

2nd choice

Streptococci (except anaerobic) Staphylococci Neisseria meningitidis Neisseria gonorrhoeae Gram-positive bacilli Escherichia coli (urinary tract) Pseudomonas aeruginosa

Penicillin

Erythromycin

Flucloxacillin Penicillin Azithromycin Penicillin Trimethoprim

Erythromycin Cefotaxime Penicillin

H. influenzae (respiratory infection) Gram-negative (septicaemia)

Route of administration The ideal drug would give adequate serum levels after oral administration, whatever the state of the patient. However, an ill patient often cannot swallow tablets and absorption from the gut may be unreliable. The choice between intravenous (i.v.) and intramuscular (i.m.) administration is determined by the form in which the drug is available and its pharmacokinetics, the discomfort of intramuscular administration, and practical issues such as accessibility of veins and other drugs being administered. Topical antibiotic treatment is sometimes useful in the eye (p. 304), on the skin (Ch. 10) or in the respiratory tract (e.g. in cystic fibrosis, see p. 651), but the development of resistance is a problem.

Amoxicillin

Piperacillin and gentamicin (usually requires a combination) Co-amoxiclav

Ceftazidime and gentamicin

Cefotaxime

Ciprofloxacin Piperacillin and gentamicin

Erythromycin

Duration of treatment The aim of treatment with antibiotics is to eliminate infec-

Antibiotic

Probability of sensitivity

Penicillin

>95%

+ +When meninges inflamed (iv administration)

Allergy

Low

Cefotaxime

>95%

+ + (iv administration only)

Allergy in 10% of penicillin-allergic subjects

High

1st choice in Western world if penicillin allergy

Chloramphenicol

>95%

+ + +(Oral or iv administration)

Very rare marrow aplasia

Low

1st choice in Third World country

Penetration

9

Toxic effects

FIG. 9.3 Choice of antibiotic in a patient with acute pneumococcal meningitis

Cost

Decision 1st choice if no allergy

263

tion, when this is achievable, or to reduce the number of organisms to a point at which host immunity can do the rest. Surprisingly little is known about the duration of treatment needed to achieve these aims in most infections, and there is considerable unsupported dogma regarding the importance of completing a prescribed course of antibiotics. The usual argument for finishing a course of treatment is that early discontinuation encourages the emergence of resistance. However, resistance rarely arises during treatment except when the bacterial population already contains resistant mutants, as in streptomycin therapy for tuberculosis. It is most likely to occur in chronic and heavy infections (e.g. Pseudomonas aeruginosa infection in cystic fibrosis), and with particular antibioticbacterial groupings, such as quinolones or fucidic acid in staphylococcal infections, cephalosporins in some Gram-negative infections, and rifampicin in infections by many bacterial species. There is good evidence about the duration necessary for treatment of tuberculosis, urinary tract infection, gonorrhoea and infective endocarditis, but virtually none about upper and lower respiratory tract infections, which account for 75% of community prescriptions. Opinions vary considerably about the appropriate time to treat in most other infections, and often the only advice available is to be guided by the clinical response.

MECHANISM OF ACTION OF ANTIBIOTICS

TABLE 9.4 Examples of major pathogens which have developed new resistance patterns

Antibiotics act in one of the following ways:

Organism

Resistance to

• Inhibition of bacterial cell wall synthesis (penicillins and cephalosporins); • Inhibition of particular aspects of bacterial cell function: protein synthesis (aminoglycosides, chloramphenicol, tetracyclines, macrolides, clindamycin); DNA replication (rifampicin, quinalones); microbial enzymes (sulphonamides, trimethoprim, isoniazid).

Enterococcus Strep, pneumonias N. gonorrhoeas Staph. aureus

Ampicillin/gentamicin Penicillin Penicillin Methicillin (flucloxacillin)

Resistance to antibiotics There are two major ways in which resistance occurs: • The bacterium produces an enzyme which inactivates the antibiotic. The best-known example is B-lactamase, which alters the B-lactam ring of penicillins and cephalosporins (Fig. 9.4). Aminoglycosides and chloramphenicol are other drugs broken down by bacterial enzymes. • The bacterium may alter such that the antibiotic is rendered ineffective. This occurs either by a change in the permeability of the bacterial cell wall or by an alteration at the target site of the antibiotic.

264

FIG. 9.4 Structure of B-lactam ring

Resistance tends to emerge by natural selection in a population of bacteria exposed to antibiotic. This may be acquired by mutation (leading to a single base alteration), but more often it is the result of incorporation of new

genetic material into the bacterial nucleus or the transfer of genetic material from other organisms in the form of extrachromosomal DNA as plasmids (episomes) and transposons. There is an increasing problem with emergence of resistance among bacteria (Table 9.4) which is largely related to the use of antibiotics acting as a selection pressure. In hospitals methicillin-resistant Staphylococcus aureus (MRSA) colonize the skin of patients admitted with other problems and can be difficult to clear. For the majority of patients these organisms are harmless, but they can cause deep infection in certain, groups, such as orthopaedic and cardiac surgery patients, and there is controversy about whether hospitals should isolate all colonized patients and attempt to clear their skin of infection, or just take steps to protect high-risk groups. On a wider scale, antibiotics introduced in poor communities for the treatment of common conditions become useless after a few years because resistance develops.

This has happened when trimethoprim was given for the treatment of dysentery in the past, and it is an emerging problem with antibiotics used to treat gonorrhoea and Strep. pneumoniae infections. It is most likely to happen when antibiotics are given in inadequate doses in a random manner, which happens when they are available over the counter. Antibiotic policies have been devised to avoid the problem but they are most easily applied in hospitals, and even there they are not wholly successful. So far pharmaceutical companies have been able to produce new compounds to keep ahead of the problem, but it is important that we learn more about the ways in which resistance emerges if it is to be controlled.

ANTIBIOTICS IN COMMON USE B-Lactams

These are the most commonly used antibiotics and have in common the B-lactam ring (Fig. 9.4). There are two major groups, the penicillins and cephalosporins. Penicillins Benzyl penicillin or penicillin G is a highly potent bactericidal natural penicillin which was the forerunner of all the other penicillins. Long-acting forms, procaine and benzathine penicillins, allow longer intervals between doses. Its disadvantages are that it can only be given parenterally, it has little activity against Gram-negative organisms, and many staphylococci are resistant to it. Semisynthetic and synthetic penicillins have been developed to circumvent these problems. Doses are now usually expressed in mg (600mg = 106 units = 1 megaunit). Standard adult dose: 300 mg 6-hourly; high dose 600 mg 4-hourly. Phenoxymethyl penicillin is a natural penicillin which is acid resistant and can therefore be taken by mouth for the treatment of minor infections with streptococci which are highly sensitive. Absorption is variable, and so it should not be used for more serious infections. Standard adult dose: 500 mg qds. Broad-spectrum penicillins, such as ampicillin and amoxicillin, have useful activity against Gram-negative organisms, excluding Pseudomonas species. They are well absorbed from the intestine. Standard adult doses: amoxicillin 250 mg tds; ampicillin 0.25-lgqds. B-Lactamase-resistant penicillins, such as flucloxacillin and methicillin, are used mainly to treat penicillinaseproducing staphylococci. Standard adult dose: flucloxacillin 250 mg qds. Co-amoxiclav is a combination of amoxicillin and the B-lactamase inhibitor clavulanic acid, which makes the amoxicillin active against resistant strains of Staph. aureus, H. influenzae, E. coli and many Bacteroides and Klebsiella species. Standard adult dose: 375 mg (containing amoxicillin 250 mg) tds. Antipseudomonal penicillins: the ureidopenicillins (azlocillin and piperacillin) are distinguished by their activity against Pseudomonas species and have a broader

spectrum of activity against Gram-negative organisms. Standard adult doses: azlocillin 2 g 8-hourly; piperacillin 150mg/kg/day in divided doses, up to 16g daily in severe infections. Toxicity. The most common problem is hypersensitivity causing rash and anaphylaxis (see p. 96). This is an allergic reaction which develops 10-14 days after first exposure, but much sooner on re-exposure. Its severity varies from mild to fatal according to the reactivity of the patient, the dose of drug and the route of administration. There is crossreactivity between penicillins, and to some extent with cephalosporins. Ampicillin is particularly likely to cause rash in patients with infectious mononucleosis.

9

Cephalosporins Cephalosporins have a similar structure and mode of action to penicillins but modifications to their structure have produced a range of drugs with a broader spectrum of activity. Examples are cefaclor, which has a broad spectrum of activity, including some against staphylococci, and can be taken orally (standard adult dose: 250 mg tds); cefotaxime, a parenteral drug with a very broad spectrum excluding Pseudomonas (standard adult dose: 1g 12hourly, or up to 4 g 8-hourly); and ceftazidime, similar to cefotaxime but including Pseudomonas activity (standard adult dose: 1 g 8-hourly, or up to 2g 8-hourly). Ceftriaxone has a similar spectrum of activity to cefotaxime but is unusual in that it is given only once a day (standard adult dose: 1 g daily, or up to 4g daily; doses above 1 g given in several sites). These drugs are expensive and their use should be part of a defined antibiotic policy. Their sideeffects are similar to those of penicillins. Other B-lactams Imipenem is a carbapenem which differs from other (3lactams in its remarkable spectrum of antibacterial activity and resistance to hydrolysis by most B-lactamases and other enzymes. It is administered in combination with cilastatin, which inhibits its renal metabolism by inhibiting a kidney enzyme (standard adult dose: 500mg 12-hourly, up to 750mg 12-hourly). CNS side-effects such as convulsions and confusion limit its usefulness, and meropenem is less likely to cause such toxicity (standard adult dose: 500mg 8-hourly, up to 1 g 8-hourly). These are reserve drugs, only prescribed when conventional drugs have failed. Aztreonam is a monolactam with a spectrum of activity limited to some aerobic Gram-negative bacteria (standard adult dose: 2g 12-hourly). Macrolides Erythromycin is an extremely useful drug with a macrolide structure. It can often be used as an alternative to penicillin when the patient is allergic. In addition it is active against Haemophilus influenzae, Mycoplasma, Legionella, Bordetella pertussis and Campylobacter (standard adult dose: 250mgqds). Newer macrolides such as clarithro-

265

mycin and azithromycin are less likely to cause gastrointestinal side-effects and can be given in shorter courses than erythromycin (standard adult doses: clarithromycin 250 mg bd; azithromycin 500 mg daily for 3 days, or as a single 1g dose treatment for genital chlamydial infection). Chloramphenicol Chloramphenicol is a cheap drug, well absorbed and distributed, with useful activity against Gram-positive and negative cocci and H. influenzae. Its major drawback is the very rare but usually fatal induction of marrow aplasia. It is also difficult to use safely in babies. Standard adult dose 50mg/kg/day in four doses. Tetracyclines Tetracyclines were widely used to treat exacerbations of chronic bronchitis until resistance became common. Now their main use is for the treatment of chlamydial infection, but they are also active against Mycoplasma, Brucella, rickettsiae, Coxiella and Borrelia. They should not be used in pregnant women and children under 9 years old because they cause staining of teeth and sometimes dental hypoplasia. Doxycycline is less prone to cause diarrhoea than other tetracyclines but occasionally causes oesophageal ulceration. Standard adult dose: 200mg on day 1, then l00mg daily. Aminoglycosides Aminoglycosides such as gentamicin, amikacin and tobramycin are used in serious Gram-negative infections. They are ototoxic and nephrotoxic. Blood levels have to be monitored carefully, especially when there is renal impairment, as they are excreted purely by the kidneys. Peak blood levels are measured 15 minutes after intravenous or 1 hour after intramuscular administration, and trough levels immediately before the next dose. Standard adult doses: gentamicin 2-5mg/kg/day in two doses; amikacin 15mg/kg/day in two doses; tobramycin 3 mg/kg/day in three doses. Sulphonamides and trimethoprim Sulphonamides were the first synthetic antimicrobial drugs, but their use is now limited by the development of resistance and by the frequency of troublesome sideeffects such as nausea, rash (Stevens-Johnson syndrome at worst) and bone marrow toxicity. Sulfamethoxazole is still widely used in combination with trimethoprim (cotrimoxazole; standard adult dose 960mg bd, but see p. 344 for treatment of Pneumocystis carinii infection) because they were thought to be synergistic, but it now seems that trimethoprim alone is just as effective in the treatment of

1

266

MCQ 9.1

Gram-negative urinary infection. Trimethoprim can cause thrombocytopenia and megaloblastic anaemia. Standard adult dose 200mgbd. Clindamycin Clindamycin is a lincosamide with activity against Grampositive organisms, including resistant staphylococci, but also against anaerobic organisms. It achieves good penetration into bone and can be used to treat osteomyelitis. Common side-effects include rash and diarrhoea, rarely with pseudomembranous colitis. Standard adult dose 300mgqds. Metroindazole Metronidazole is an excellent drug for the treatment of anaerobic infection. It is cheap when administered orally or rectally, and the more expensive intravenous preparation is rarely indicated. It is also the first choice in treatment of Giardia lamblia, amoebic disease and Trichomonas vaginalis. Serious side-effects are rare, but nausea and abdominal pain are common. Standard adult dose 400mgtds. Sodium fusidate Sodium fusidate is highly bactericidal against staphylococci, including penicillin-resistant ones, but resistance develops during treatment unless another drug is given concurrently. It is reserved for treatment of serious infections such as septicaemia and osteomyelitis. It is necessary to monitor for hepatotoxicity. Standard adult dose 500 mg tds. Vancomycin Vancomycin is reserved for serious penicillin-resistant staphylococcal infection or for the treatment of pseudomembranous colitis. Serum levels must be monitored, as it is ototoxic and nephrotoxic. Standard adult dose 1g infused over 100 minutes 12-hourly, or 125mgqds orally for pseudomembranous colitis. Teicoplanin is a similar drug which is slightly less toxic. Standard adult dose 400 mg 12-hourly for three doses, then reduce to 200400 mg daily. Quinolones Nalidixic acid has been used exclusively in the treatment of urinary infection by Gram-negative organisms, as adequate levels are only found in the urine. Standard adult dose 1 g qds. Resistance to this group of drugs is rare, as they are not susceptible to plasmid-mediated resistance. The newer generation. of 4-fluoroquinolones includes ciprofloxacin, which is well absorbed from the intestine and widely distributed. Standard adult dose 500 mg bd. This group contains the only orally administered drugs active against Pseudomonas, and they have become increasingly important in the management of gut infections and severe systemic infections, including typhoid. Major toxicity is uncommon.

Rifampicin Rifampicin, a synthetic derivative of rifamycin, is central to the treatment of tuberculosis but is also very active against staphylococci, streptococci and E. coli. Its major toxicity is to the liver. Standard adult dose 300 mg bd, but see p. 645 for the treatment of tuberculosis. Quinuprastin/dalfoprastin Quinuprastin/dalfoprastin is a new streptogramin recently licensed in the UK and the USA which is active only against Gram-positive bacteria, including methicillinresistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium (but not E. faecalis) and penicillin/ macrolide-resistant pneumococci, and its use should be restricted to treatment of such infections. Administration is recommended through a central venous catheter, as peripheral lines tend to develop complications. Linezolid Linezolid, a new oxazolidinone antibiotic is active against Gram-positive bacteria which are resistant to other antibiotics. It can be given orally or intravenously (600 mg every 12 hours by either route). 1

ANTIFUNGAL DRUGS Most fungal infections of the skin are treated with topical preparations, but cuticular infection requires prolonged systemic therapy. Visceral infections also require systemic therapy. Amphotericin B and nystatin Amphotericin B and nystatin are polyene antibiotics produced by Streptomyces species. They exert a fungistatic effect by binding to sterols in the fungal cell membrane, causing leakage of cell components. Amphotericin B acts synergistically with the unrelated compound flucytosine, probably by increasing permeability to flucytosine. Amphotericin B can be administered intravenously, after which there is wide tissue distribution but poor penetration to brain and meninges. The plasma half-life is 24 hours and it is excreted very slowly in the urine, 40% of the infused dose appearing in the urine during the following week. Amphotericin B has a broad spectrum of activity and is used against the agents of candidiasis, aspergillosis, histoplasmosis, blastomycosis, coccidioidomycosis, cryptococcosis and some organisms causing mucormycosis. Minor symptoms following infusion are common, and a wide variety of symptoms may be unpleasant enough to require suppression with analgesics, antiemetics etc. More serious side-effects occur when there is impairment of renal function, which is exacerbated by the resultant rise in plasma drug levels. Renal and haematopoietic toxicity are the main problems. Therapy has to be interrupted to allow a fall in plasma level. It is given in a dose of 0.25 mg/kg body weight

intravenously over 6 hours, increasing to 0.8 mg/kg according to tolerance. Treatment is withdrawn intermittently as required to maintain the plasma level at l-1.5mg/L. A less toxic liposomal form of amphotericin B is expensive and its use is limited to febrile neutropenic patients and to those unable to tolerate the native form. Standard adult dose of liposomal amphotericin: Img over 10 minutes test dose, then 3 mg/kg/day in one dose. Neither amphotericin B nor nystatin is absorbed from the intestine but they are useful as topical or mucosal preparations, particularly for treatment of Candida infections. Nystatin is available as a suspension or pastilles for oral infection, cream and pessaries for vaginal infection, and cream or ointment for skin infections.

9

Flucytosine Flucytosine is a synthetic fluorinated pyrimidine which enters fungal cells and inhibits metabolism by interfering with DNA and RNA synthesis. It can be given in combination with amphotericin B for treatment of systemic fungal infections, but is rarely used now. Standard adult dose 200 mg/kg/day in four doses, each infusion over 20-40 minutes. Imidazoles Ketoconazole, miconazole and clotrimazole are imidazole drugs. Most are available only topically and have activity against dermatophytes and Candida. Imidazoles have no place in the treatment of systemic fungal infections. The mode of action is not fully understood, but imidazoles interfere with synthesis of sterols and other fungal membrane lipids, resulting in defective cell wall synthesis. In vitro they enhance killing of Candida by leukocytes. Ketoconazole is an oral preparation which is useful for treatment of severe mucosal infections, such as oesophageal candidiasis which is not responsive to topical treatment. The major toxicity is drug-induced hepatitis, which can progress to irreversible hepatic failure. Standard adult dose 200 mg daily. Triazoles Triazoles are a new group of antifungal agents, including fluconazole and itraconazole, which are useful as oral agents for treating systemic mycoses. Both are effective in treating oesophageal candidiasis using very short courses, e.g. a single dose of fluconazole 150 mg. Prolonged treatment in patients with immunodeficiency often results in emergence of resistant strains of Candida, but at present cross-resistance between itraconazole and fluconazole is uncommon. Fluconazole (but not itraconazole) penetrates into the CSF and is useful for treatment of cryptococcal meningitis (dose 400mg, then 200mg i.v. daily). Sideeffects are rare but there is a small risk of hepatotoxicity. Standard adult dose of itraconazole: 100 mg daily. Griseofulvin and terbinafine Griseofulvin, produced by Penicillium griseofulvum, is

267

absorbed from the gastrointestinal tract and deposited in keratin, where it inhibits the growth of dermatophytes. It is relatively non-toxic and can be used in extensive dermatophyte infections which are unresponsive to topical treatment. It is particularly useful for nail and scalp infections (p. 389), but has to be given for weeks or months. Serious side-effects, such as bone marrow and neurological disorders, have been reported occasionally after griseofulvin use. Standard adult dose: 500mg daily. Terbinafine, an allylamine, can also be used for these infections and may be effective after shorter courses. Standard adult dose: 250 mg daily. 1

ANTIVIRAL TREATMENT Considerable progress has been made in synthesizing agents which specifically inhibit an essential step in virus replication without causing host toxicity. This has been achieved: • By using an agent which is activated by the virus, thus localizing its action within infected cells; • By using an agent which inhibits virus metabolism specifically. Usually this is achieved when the agent inhibits a viral enzyme. Drugs have been developed which are active against herpes viruses, human immunodeficiency virus, hepatitis B and C, influenza viruses, enteroviruses, respiratory syncytial virus, and some viruses which cause viral haemorrhagic fever.

Drugs active against herpes group viruses Aciclovir, the most widely used agent currently available, produces its specific effects using both of these mechanisms. It is inactive until phosphorylated to a triphosphate by viral thymidine kinase in infected cells. In this form it produces its main antiviral action by inhibiting viral DNA polymerase, essential for synthesis of viral DNA. Aciclovir triphosphate is a more powerful inhibitor of viral than of host DNA polymerases. Aciclovir seems to be a safe drug but is expensive. Its use is restricted to situations in which it is clearly beneficial (Table 9.5). Newer drugs such as famciclovir and valaciclovir are similar in their spectrum of activity and toxicity but differ in absorption, so that famciclovir can be given less often than aciclovir, and valaciclovir achieves a higher serum concentration than aciclovir after oral administration. During acute viral infections much of the inflammation is caused by the host response in the later part of the illness, 1

268

MCQ 9.2

TABLE 9.5 Treatment of herpes virus infections with aciclovir Virus

Infection

Route

Herpes simplex virus

Encephalitis Neonatal infection Primary genital infection Keratoconjunctivitis Prophylaxis: bone marrow transplantation Shingles in immuncompromised patients Chickenpox in immunocompromised children Chickenpox in neonates Chickenpox in adults Possible Chickenpox pneumonia

IV IV 0 T 0 IV IV IV IV 10

Varicella zoster

IV = intravenous; 0 = oral; T = topical

and antiviral treatment must be started early to be effective. Antiviral treatment does not affect virus integrated into the host genome, and treatment of the primary herpes simplex infection does not influence subsequent viral reactivation. Ganciclovir, an antiviral drug licensed for treatment of cytomegalovirus (CMV) infection, is activated by phosphorylation in a similar way to aciclovir, but depends on human cellular enzymes for this process (Fig. 9.5). Because phosphorylation occurs in infected and normal cells, toxicity is greater than that of aciclovir and it causes bone marrow suppression. Foscarnet, a phosphonate, also inhibits CMV DNA polymerase and has a different toxicity from ganciclovir.

Antiretroviral drugs There are three main classes of antiretroviral drugs: nucleoside and non-nucleoside inhibitors of HIV reverse transcriptase, and a third class that inhibit HIV protease. At least three drugs are used in combination to limit the development of resistance and, once started, treatment is normally maintained for life (see Ch. 11).

Ribavirin (tribavirin) Ribavirin is another nucleoside analogue that is active against a wide spectrum of DNA and RNA viruses, but its clinical use is confined to treatment of severe respiratory syncytial virus infection causing bronchiolitis, some of the viral haemorrhagic fevers such as Lassa fever, and hepatitis C virus infection in combination with interferon-a. For RSV infection it is given by inhalation.

Interferons Interferon-a, which is produced by T lymphocytes, has been shown to inhibit replication of hepatitis B and hepatitis C viruses, possibly by inhibiting virus assembly. It has many side-effects, including flu-like syndrome early in

9

FIG. 9.5 Mechanisms of action of ganciclovir Virus replication in host cells induces the enzymes (guanosine kinase and phosphorylase). Because the same enzymes are involved in phosphorylation of ganciclovir, infected cells have higher concentrations of ganciclovir triphosphate. This is the activated form, which blocks viral replication,

therapy, lethargy throughout treatment, bone marrow toxicity and depression, and is only effective in a small proportion of patients, but it is the only substance known to have any influence on these infections at present.

FURTHER READING ON ANTIMICROBIAL AGENTS

TABLE 9.6 Some microorganisms causing infection in immunocompromised patients Type

Microorganism

Remarks

Deficiency

Bacteria

Gram-positive, e.g. Pneumococcus Gram-negative, e.g. H. influenzae Mycobacteria, e.g. avium intracellulare

Encapsulated

Ab/Neut/S

Encapsulated

CMI

Both tuberculous and non-tuberculous Reactivation

CMI

Encephalitis Virulent Septicaemia/ pneumonia Mucosal Systemic Meningitis Pneumonia Cerebral Gut Gut Systemic Systemic

Ab Ab/CMI Ab/Neut

Lambert H P, O'Grady F, Finch R, Greenwood D 1996 Antibiotic and chemotherapy, 7th edn. Edinburgh: Churchill Livingstone.

INFECTION IN THE IMMUNOCOMPROMISED PATIENT An immunocompromised patient is defined as one in whom any part of the innate or adaptive immune response is defective. Defects of the immune system are physiological (neonates and the aged), and either primary or secondary. Primary immune deficiency diseases are rare and an account is given in Chapter 4. Secondary immune deficiency is more common and of increasing importance. Causes of secondary immune deficiency are: • Malignant disease and its treatment; • Drug-induced chronic immune suppression, e.g. in organ transplantation or chronic inflammatory diseases, such as systemic lupus erythematosus (SLE); • Infection: the most severe infection is HIV (Ch. 11), but many other viruses cause a milder deficiency of cellmediated immunity (CMI); • Splenectomy; • Chronic diseases, e.g. chronic renal failure, malnutrition, protein deficiency, diabetes mellitus. These conditions cause varying combinations of neutropenia and impairment of humoral and cellular immunity. Deficiencies of antibody or neutrophils are associated with infection by encapsulated bacteria, yeasts and fungi. Defi-

Viruses

Yeasts Fungi Protozoa

Helminths

Herpes, e.g. herpes simplex virus, varicella zoster virus, cytomegalovirus Echo Live vaccines, e.g. measles Candida Aspergilius Cryptococcus Pneumocystis Toxoplasma Cryptosporidium Giardia lamblia Malaria Strongyloides

CMI

CMI CMI CMI CMI/Ab CMI CMI CMI/Ab Ab/S CMI

Ab = antibody; Neut = neutrophil; CMI = cell-mediated immunity; S = post-splenectomy

cient CMI causes infection by a wider range of pathogens, including Gram-positive and -negative bacteria, viruses, yeasts, fungi, protozoans and helminths (Table 9.6). In all these situations immunization with live viral vaccines is dangerous, as the attenuated organism may behave as a pathogen. The pattern of infection in immunocompromised

269

SUMMARY 1 Management of the neutropenic patient with fever

TABLE 9.7 Organisms causing pneumonia in immunocompromised patients

• Take samples for culture: blood, urine, stool, i.v. line tip, etc. as appropriate • Start treatment after taking samples, guided by any previous culture results • Examples of empirical treatment regimens: - gentamicin plus piperacillin or ceftazidime - If no response within 48 hours, switch to - vancomycin If no response, or recurrence, particularly if previous antibiotic courses given - amphotericin B or fluconazole for Candida septicaemia • If chest X-ray shows pulmonary infiltrates, add erythromycin initially for atypical pneumonia. Consider a wide range of organisms (including M. tuberculosis) and viruses (e.g. CMV) if there is no response to antibiotics

Bacteria Gram-positive, e.g. Strep. pneumoniae Gram-negative, e.g. H. influenzae, Klebsiella pneumoniae Viruses Cytomegalovirus, herpes simplex, varicella zoster Measles (giant cell pneumonia) Protozoa Pneumocystis carinii Fungi/yeasts Candida Aspergillus

NOSOCOMIAL INFECTION patients is unusual in several respects. Bacterial infections in splenectomized patients are sudden in onset and rapidly progressive, fulminant pneumococcal septicaemia being the most common. Cellular immune deficiency causes viral infection to be more severe, prolonged and widely disseminated than is usual. Fever in the neutropenic patient (see Summary 1) During periods of neutropenia the onset of fever should be taken to indicate serious infection unless there is an obvious alternative explanation. 'Blind' treatment with antibiotics is started immediately after the collection of specimens, including blood cultures. Blood cultures are negative in over half of such fever episodes, but the choice of antibiotics is guided by positive results in which Gram-negative bacteria, including Pseudomonas species, predominate, and a combination of a broad-spectrum penicillin with activity against Pseudomonas (e.g. piperacillin) and gentamicin is often used (p. 265). New pulmonary infiltrates on chest radiograph New pulmonary infiltrates may be due to infection with a wide range of possible pathogens (Table 9.7). Sputum induction, bronchoscopy and lavage, and transbronchial biopsy may provide diagnostic information. Invasive procedures have a risk in neutropenic and thrombocytopenic patients.

270

Reactivation of herpes viruses Patients with impaired CMI may suffer severe herpes virus infection. Shingles (varicella zoster) in patients with Hodgkin's disease tends to involve more than one dermatome, and there may be dissemination of virus causing widespread chickenpox lesions on the skin and occasionally in viscera. Within affected dermatomes lesions are dense and heal slowly. Reactivation of herpes simplex virus (HSV) may cause extensive perioral ulceration and occasionally visceral dissemination. CMV reactivation causes pneumonia in renal transplant recipients.

Hospital patients may be particularly susceptible to infection and hospital bacteria are often resistant to common antibiotics. Susceptibility is increased in postoperative patients, patients with bums, patients on ventilators, in malnourished patients, and in disease states that compromise immunity specifically. Hospital-acquired infections are known as nosocomial and are a particular problem on intensive treatment units. Nosocomial infection is an increasing problem and the resistance pattern of bacteria is constantly changing. The most important factors influencing the likelihood of cross-infection are the use of handwashing, the ratio of nurses to patients, the number of visits from doctors and the space between patients. The bacteria associated with particular situations can sometimes be predicted, e.g. staphylococci and streptococci are common causes of surgical wound infections, and Pseudomonas frequently infects burns. In ventilated patients difficulties arise in deciding whether bacteria such as Pseudomonas are merely colonizing the respiratory mucosa or whether they are pathogenic. Antibiotic treatment of colonising organisms is undesirable since the local flora then change to more resistant organisms. With increasing use of antibiotics there has been a resurgence of outbreaks of nosocomial infection with methicillin (and flucloxacillin)-resistant Staphylococcus aureus (MRSA). MRSA colonize the skin and nose of normal or diseased subjects, but they are particularly persistent in patients with any form of skin lesion. In most cases MRSA do not cause disease, but occasionally vulnerable patients can develop septicaemia or local suppuration which necessitates the use of vancomycin. Because MRSA spreads rapidly from person to person it is important to isolate infected patients from other vulnerable patients, and to screen staff for carriage. Colonized subjects are treated with topical antiseptic preparations and, in the case of staff, removed from work until repeated swabs are clear. Vancomycin-resistant staphylococci have been isolated and the increasing use of this antibiotic has led to a problem with resistant enterococci. There is some evidence

that antibiotic cycling in intensive care units - that is, changing the first-choice antibiotics every few months limits the rate of increase in resistance among common nosocomial bacteria. For example, resistance to gentamicin in enterobacteriaceae such as Klebsiella pneumoniae and Serratia marcescens increases when gentamicin is used, but decreases when amikacin is substituted. However, there is no consensus on the best policy at present. The use of antibiotics must be controlled both in hospitals and in the community. Most hospitals have antibiotic control policies which recommend the antibiotic to be used in a particular situation and restrict the administration of some drugs to special situations. Policies for antibiotic prophylaxis before surgery need to be reviewed regularly to keep ahead of the development of bacterial resistance.

CONTROL OF INFECTION Containment of outbreaks of infection is required when susceptible subjects may develop a serious illness if they become infected. It is not always desirable to contain infection. Chickenpox, a mild disease in normal children, is usually severe in adults and so outbreaks among schoolchildren should not be controlled. In a hospital where non-immune patients are liable to develop severe manifestations, however, it is important to prevent crossinfection to non-immune individuals (about 10% of the adult population). Isolation of patients in single rooms greatly facilitates control of infection. Other measures are determined by the mode of transmission and the degree of infectivity of the organism. Transmission is by: • Respiratory secretions (e.g. measles, pulmonary tuberculosis) • Excretions and secretions (e.g. gastroenteritis, hepatitis A, typhoid) • Skin contact and fomites (e.g. MRSA). Respiratory transmission can be prevented by having the patient and/or the attendants wear appropriate masks. Organisms transmitted in respiratory secretions usually infect others through the upper or lower respiratory tract, and gowning and handwashing are of minor importance. When excretions and secretions are infectious the most important containment measure is handwashing. When close contact is necessary with a highly infectious patient, such as a patient excreting Shigella in the faeces, gowns and gloves are worn. Special arrangements are needed for the disposal of excreta, contaminated dressings and contaminated clothing and bedding. When microorganisms are found in significant number on the skin, in fomites and in dust around the patient, as when MRSA colonize patients in hospital, additional precautions must be taken, including the use of overshoes together with gowns and gloves.

TABLE 9.8 Notifiable diseases under the Public Health (Infectious Disease) Regulations 1988 (UK, October 1988) Acute encephalitis Acute poliomyelitis Anthrax Cholera Diphtheria Dysentery (amoebic or bacillary) Food poisoning Leptospirosis Malaria Measles Meningitis meningococcal pneumococcal Haemophilus influenzae viral other specified unspecified Meningococcal septicaemia (without meningitis) Mumps

9

Ophthalmia neonatorum Paratyphoid fever Plague Rabies Relapsing fever Rubella Scarlet fever Smallpox Tetanus Tuberculosis Typhoid fever Typhus fever Viral haemorrhagic fever Viral hepatitis Hepatitis A Hepatitis B Hepatitis C other Whooping cough Yellow fever

AIDS is not a statutorily notifiable disease but doctors are urged to participate in a voluntary confidential reporting scheme Source: PHS Communicable Disease Surveillance Centre

In many countries some infections are notifiable (Table 9.8), that is, the medical attendant is obliged by law to report the case to the authority that controls the area in which the patient lives so that steps can be taken to trace contacts. Notification also allows surveillance of the incidence of these infections. Most patients have ceased to be an infectious risk by the time they are discharged from hospital, but intestinal pathogens often remain in the stools for several weeks. Carriers of such pathogens are advised to avoid handling food for others, to wash hands regularly and to avoid towel sharing. Following notification, stool samples will be checked by the local authority until they are pathogen free.

IMMUNIZATION Active immunization Active immunization is the administration of antigen to induce a protective immune response in the host. Antigens used include crude preparations of killed organisms, extracellular products of organisms, and live attenuated organisms. The aim is to induce an optimal response at the site where infection normally occurs, but it has proved difficult to achieve this at mucosal surfaces. Currently, oral poliomyelitis vaccine is the most successful intestinal vaccine because the attenuated virus induces a prolonged and renewable response in the gut. Oral vaccines have been developed against typhoid and shigel-

271

Contraindications to immunization

TABLE 9.9 UK immunization schedule (2001) Age

Immunization

Type of vaccine

Route

2 months

Diphtheria Tetanus Pertussis Polio H. influenzae type b Meningococcus type C As above Measles, mumps, Rubella (MMR)* Diphtheria Tetanus Polio MMR BCG Tetanus Polio Diphtheria Rubella

Toxoid Toxoid Killed Live attenuated Capsular antigens Conjugate vaccine As above Live attenuated

IM or SC IM or SC IM or SC 0 IM or SC IM As above IM

As above

As above

Live attenuated

ID

As above

As above

3 and 4 months 12-18 months 5 years

10-14 years School-leaving Adults

Diphtheria Polio Tetanus Hepatitis B Influenza

For seronegative women For non-immunized " Selected groups

IM

*MMR introduced into UK in October 1988 Detained in UK until MMR established IM = intramuscular; SC - subcutaneous; 0 = oral; ID = intradermal

losis but they are less effective. Oral cholera vaccine has been developed using the adjuvant properties of cholera toxin B subunit, and tests in Bangladesh have yielded promising results. In contrast, the cholera vaccines available using heat-killed organisms are ineffective. A similar local immune system operates in the respiratory tract and further studies may help to develop local vaccines against respiratory pathogens. The immunization schedule in the UK in 2001 is shown in Table 9.9. Mumps vaccine was introduced as part of the routine childhood immunization schedule in 1988. The policy of immunizing only females against rubella has also been changed, as there is still a notable incidence of congenital rubella. BCG (bacille Calmette-Guerin) immunization for protection against tuberculosis is more important in children of racial groups with a high incidence of the disease, and it may be given to neonates who are at risk of developing meningitis. In North America the incidence of tuberculosis was not high enough to justify its routine use. In contrast, BCG vaccination of neonates is a common practice in the tropics.

1

272

MCQ 9.3

• Live vaccines should not be given to anyone with untreated malignant disease or with any form of immunodeficiency, including those receiving immunosuppressive therapy, or to pregnant women. • Live vaccines should not be given within 3 weeks of another injected live vaccine. • Coincidental severe febrile illness may limit the response to immunization. Immunization should therefore be postponed, but not forgotten. • Significant documented allergy to any component of the vaccine may be a contraindication to its use. • Rubella vaccine should not be given in pregnancy, and pregnancy should be avoided for 1 month after immunization against rubella. 1

Passive immunization Passive immunization is the administration of antibody preparations to prevent or ameliorate infection. Pooled human immunoglobulin is the crudest form, and was commonly used to protect travellers against hepatitis A virus infection. More defined preparations of hyperimmune globulin contain high levels of antibodies to particular organisms, usually viruses, which are not present in sufficient concentration in pooled human immunoglobulin to provide protection. Examples are hepatitis B immunoglobulin given following needle-stick injuries, varicella zoster immunoglobulin used in neonates born to mothers who have recently developed chickenpox (p. 284), and tetanus immunoglobulin used for patients at risk of developing tetanus. Most current antibody preparations are derived from human serum. Passively administered antibody has a short half-life, giving protection for only a few weeks. Treatment has to be given soon after exposure to be effective.

PREVENTIVE MEASURES FOR OVERSEAS TRAVEL OR RESIDENCE The question that is most commonly asked prior to overseas travel to or residence in the tropics or subtropics is 'what vaccines are needed?' In fact, the main disease threats do not come from vaccine-preventable conditions, but from trauma, alcohol-related illness, sun exposure, unprotected sexual contacts and infectious diarrhoeal disease. Malaria is the main threat that is amenable to preventive measures.

Protection of skin The skin must be protected against biting insects. This is important not only for the prevention of malaria, but also for protection against viral, rickettsial, protozoal and filarial diseases transmitted by insect vectors. Exposure to ticks occurs mainly in rural bush areas and

so appropriate clothing and footwear is needed to prevent ticks getting on to the skin. Evening and night hours are times for maximum frequency of biting by many insects, and at these times the skin should be covered as much as possible wearing shirts with long sleeves and long trousers or skirts. Insect repellent (diethyltoluamide (DEET)containing compounds with formulations designed to have a long retention time on the skin) is applied to exposed areas, including the forearms, lower legs, ankles and feet, and face and neck. Elasticated wrist and ankle bands can be impregnated with DEET and worn for the same purpose. Mosquito nets should be used in malarial areas if doors and windows are not screened. Impregnation of bed nets and curtains with permethrin enhances protection through its residual insecticidal action. It is also useful to spray bedrooms with insecticide last thing at night. Schistosomiasis is acquired by contact between skin and slow-flowing or still water containing cercariae. Swimming and paddling in fresh water are best avoided in endemic areas.

Protection against malaria Measures to prevent mosquito bites (see above) and chemoprophylaxis against malaria are the sole means of preventing malaria in the traveller. The traveller must be told that there is no vaccine against malaria and that none of the vaccines received prior to travel is of any benefit in this regard. Details of chemoprophylaxis against malaria are given in Table 9.36, p. 352.

Immunization for travellers or overseas residents A range of vaccines is available and the commonly used ones are listed in Table 9.10. Poliomyelitis is still common in many areas of the world, and so adequate vaccination should be assured in all travellers. Meningococcal vaccine is most often recommended for backpackers in subSaharan Africa. It is occasionally a requirement for travel to specified countries, e.g. Saudi Arabia for the Hajj pilgrimage. Yellow fever vaccination is essential for those visiting tropical Africa, the Caribbean and South America. Oral poliomyelitis and yellow fever vaccines should be given either together or separated by an interval of 3 weeks. Active hepatitis A vaccination is available and is usually used in preference to passive immunization, although it is more expensive. Hepatitis B vaccination is particularly recommended for those at particular risk, i.e. healthcare and hospital laboratory workers, although increasingly backpacking travellers are having this vaccine. Pre-exposure rabies vaccination is needed by those who may have any contact with animals, but again increasing numbers of tourists undertaking overland travels are having pre-exposure vaccination. The intradermal route allows more economical use of the vaccine. Tetanus vaccination is needed for any who may be at particular risk of trauma, e.g. military personnel, construction workers etc.

TABLE 9.10 Immunization for travellers to the tropics

9

Isolated visit to main tourist areas Typhoid Polio Hepatitis A Yellow fever (for some locations) Extensive travel (backpacking, trekking, gap-year students) Typhoid

Polio Hepatitis A & B Rabies Meningococcal disease A & C (sub-Saharan Africa) Yellow fever (West Africa, Central & South America, Trinidad) Frequent visitor (business or holiday) or resident Typhoid Hepatitis A & B Rabies Yellow fever (West Africa, Central & South America, Trinidad) Meningococcal disease A & C Note: these groupings of vaccines are guidelines only and need modification for individuals in relation to their potential exposure during proposed travels. Although on a risk/cost analysis some of these recommendations may seem excessive, they give the traveller coverage for vaccine-preventable conditions endemic in many areas. All travellers should be up to date with childhood vaccines.

Typhoid vaccination is a sensible precaution for many areas, but those vaccinated should be told that having the vaccine does not mean that they are 100% protected and can be careless about sources of water and food. Although the whole-cell killed vaccine has the greatest efficacy it also has the greatest incidence of side-effects and is not now obtainable. The choice lies between two vaccines: (a) the Ty21a oral vaccine containing the epimerase-deficient strain of S. typhi, which has the appeal of stimulating an immune response at the site of entry of the natural pathogen, and (b) the vaccine based on the Vi antigen of S. typhi. Cholera vaccination is not effective.

Protection of the gut Gastrointestinal infection is the most common affliction faced by the traveller. Boiled water used to make tea and coffee or left to cool in a covered, clean container is safe to drink. Bottled drinks are safe. Water from the tap or water used to make ice cubes may not be safe. Tincture of iodine (2%) can be used to sterilize water, adding 0.5mL per litre and allowing it to stand for 30 minutes. Iodine is more potent than chlorine-based sterilizing tablets.

SYNDROMES OF INFECTION SEPTICAEMIA Septicaemia is uncontrolled bacterial infection in the blood. Unlike septicaemia, transient bacteraemia is fairly common

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in normal subjects. Septicaemia is a much more serious condition which is likely to lead to death if untreated.

Aetiology A wide range of bacteria can cause septicaemia, but they can be divided into those that do so as part of a primary infection by a single organism acquired in the community, and those that cause septicaemia as a complication of another process, such as abdominal sepsis following surgery, when there is often a mixed infection. Community-acquired infections are usually recognized as part of a specific illness, as when Strep, pneumoniae septicaemia complicates pneumonia, meningococcaemia with meningitis, or E. coli septicaemia with pyelonephritis. The other kind of septicaemia is usually seen in hospitals, often in a debilitated patient, and the likely bacteria can often be predicted from the clinical situation.

Pathogenesis Whole bacteria and substances released by bacterial lysis trigger a complex series of events. A major component is endotoxin, the lipopolysaccharide component of Gramnegative bacterial cell walls, of which lipid A is thought to be responsible for most of the toxic effects. Lipid A can activate complement and Hageman factor and can cause the release of cytokines, including tumour necrosis factor. Important pathological consequences ensuing from activation of the potent inflammatory pathways are hypotension, increased vascular permeability and consumptive coagulopathy. Less attention has been paid to the effects of Grampositive organisms, but activation of inflammatory processes can certainly be triggered by cell membrane components of these organisms. An example is alternate pathway complement activation (Fig. 4.1, p. 80) by teichoic acid found in Staph. aureus membranes.

negative septicaemia, but also occurs with Gram-positive septicaemia. For this reason the general term septicaemic shock is usually used. Prolonged hypotension leads to acute renal failure, and disseminated intravascular coagulation causes bleeding. Acute respiratory distress syndrome (p. 697) frequently complicates hospital-acquired septicaemia. The diagnosis is based on clinical assessment, but blood cultures, urine cultures, wound swab and any aspirate from an infected site should be obtained at the time the patient is seen, so that antibiotic treatment can be started without undue delay. The antibiotic regimen can be changed if necessary when culture results are available and the response to treatment has been assessed. Blood cultures should be taken whether the patient is febrile or not.

Management Treatment is urgent because of the high mortality. Antibiotics and circulatory support are the mainstays of management. The use of plasma expanders and selective vasoactive drugs is discussed on page 731.

Antibiotics The initial choice of antibiotics is based on a logical guess at the bacteria responsible (p. 263). As few antibiotics as possible are given to achieve the necessary cover. At present a common choice is a combination of a broadspectrum penicillin, such as ampicillin, with an aminoglycoside such as gentamicin. One problem is that many patients are in incipient renal failure, which enhances the toxicity of gentamicin. Newer drugs, such as cefotaxime and piperacillin, are active against Gram-positive and Gramnegative bacteria and lack the toxicity of gentamicin, but they are more expensive. If anaerobic septicaemia is suspected metronidazole is often used, and for hospitalacquired staphylococcal infection a B-lactamase-resistant penicillin, such as flucloxacillin, is added. Pseudomonas infections are treated with a combination of drugs, e.g. azlocillin and gentamicin. 1

Clinical features and diagnosis The manifestations depend on the age of the patient, the illness being more featureless and more lethal at extremes of age. Signs are usually non-specific, but there are signs in the skin suggestive of the diagnosis, such as purpuric lesions associated with meningococcaemia and pustular lesions in staphylococcal septicaemia. Usually there is a rapid deterioration in the patient's condition, including a change in mental state. Fever is often present, with tachycardia and a bounding pulse, but as the condition progresses the patient becomes hypothermic with a rapid thready pulse and peripheral vasoconstriction. The latter situation is often considered to be typical of Gram1 274

MCQ 9.4

PYREXIA OF UNKNOWN ORIGIN When a patient has an elevated body temperature for a period of longer than 3 weeks without a cause being found the diagnostic problem is called pyrexia (or fever) of unknown origin (PUO). A febrile patient may lose the normal diurnal variation in body temperature or may sometimes have an exaggerated diurnal pattern, with a rise during the night causing drenching night sweats (common in tuberculosis and lymphoma) followed by a rapid fall. Many patterns of fever are described but they are rarely helpful in diagnosis.

Causes of PUO The most common causes of PUO vary according to the

age of the patient, and published incidences vary with the type of institution at which the problem is studied. Infection is usually the most common cause in children, whereas infection and neoplastic disease are equally important in adults. Connective tissue disease can present with fever at any age: Still's disease and SLE are commoner causes in children and young adults, and polymyalgia and giant cell arteritis more frequent in the elderly. Infection Most bacterial infections cause an illness which is clinically manifest within 3 weeks, but there are some exceptions. Bacterial endocarditis can cause low-grade illness, particularly in the elderly. Most cases can be diagnosed by blood culture, but occasionally blood cultures are repeatedly negative. Infection in the biliary tract may be associated with only minor clinical signs and little abnormality of liver function tests. Intracellular bacteria, such as Brucella and some Salmonella species, can cause recurrent septicaemia, but this can usually be diagnosed by blood culture. Deep-seated abscess is a possible cause of PUO, and modern imaging techniques are helpful in locating the collection (p. 262). Tuberculosis is still a major cause of PUO in developing countries and in some temperate countries such as the UK. Often the granulomatous lesions of tuberculosis are too small to cause pulmonary radiological abnormalities, and the site of infection is often outside the lungs. In recent years tuberculosis has become a common feature of HIV infection. Viral infections rarely cause PUO (within the definition), with the important exception of HIV. The history should therefore enquire into sexual practices, intravenous drug abuse and transfusions. Fungal infections rarely cause PUO without a predisposing cause, but they may do so as a complication of immunosuppressive disease or therapy. An exception is histoplasmosis.

Neoplasia Lymphomas frequently produce a prolonged period of fever before any other manifestation emerges. Leukaemias can also cause PUO, but this is sometimes caused by a complicating infection. Many occult solid tumours can present as PUO, among them hypernephroma, pancreatic carcinoma, intestinal tumours, bronchial carcinoma, ovarian tumours and sarcomas. Fever is particularly likely when there are hepatic metastases. Atrial myxoma is a rare benign tumour (p. 582) which occasionally produces an illness similar to bacterial endocarditis. Connective tissue (autoimmune) disease Most diseases in the category of connective tissue disease can present with PUO before the characteristic disease pattern emerges. SLE, rheumatoid arthritis and Still's disease (including the adult form), polyarteritis nodosa, temporal arteritis and polymyalgia rheumatica should be considered depending on the clinical setting.

Miscellaneous Granulomatous conditions. Granulomatous conditions include sarcoidosis, granulomatous hepatitis and Wegener's granulomatosis. Sarcoidosis often lacks overt signs in the early phase of the disease and should be considered, particularly in ethnic groups with a high prevalence, such as West Indians. Factitious. One of the most odd forms of human behaviour is the habitual feigning, or the deliberate inducement, of illness. Factitious fever is caused in two ways:

9

• In the first the fever disappears when the temperature is measured by someone other than the patient, with the patient under continuous observation. The patient is either saying that fever exists when it does not, or is manipulating the thermometer. • In the other, more serious form the patient induces true fever by self-injury or self-infection. The methods used are diverse, but faeces are the usual source of organisms and infection is induced by rubbing or injecting organisms into the skin or blood. Suspicion is aroused when mixed and varying organisms which could be faecal are found in an unexpected site, or when infection persists despite treatment that would normally be effective. The condition is more common in young females than in males, and the deceit may be helped by some medical knowledge. There are sometimes personal problems, which suggest that this behaviour is a plea for attention or help. When suspicion grows that fever is factitious it is wise to avoid directly confronting the patient with the possibility. Usually it will be denied, and sometimes confrontation can precipitate a psychiatric crisis, even resulting in suicide. It is preferable to attempt to solve the associated problems if they can be identified and to create a situation in which it is difficult for the patient to continue to provoke sepsis, e.g. by removing intravenous catheters or covering inflamed sites. The patient should be made to realize that the manoeuvres are understood, if possible without a direct accusation. The best efforts to resolve factitious fever often fail, and patients either return intermittently or present themselves to another medical team. Bowel disease. Inflammatory bowel disease is usually associated with incriminating symptoms such as weight loss and diarrhoea, but these may be slow to emerge. Whipple's disease, caused by the periodic acid-Schiff-positive Grampositive bacterium now known as Tropheryma whippelii, usually presents with polyarthralgia and diarrhoea in middle-aged men, but initially there may be only PUO and abdominal pain (see p. 792). Intestinal lymphoma may also present with the latter symptoms. Drug reaction. Once thought of, drug reaction is a straightforward cause of PUO. The possibility that the fever is caused by a drug is tested by withdrawal. Multiple pulmonary emboli. When frequent small embolic events occur, pyrexia may be the sole manifestion before the pulmonary circulation is greatly compromised.

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SUMMARY 2 Causes of pyrexia of unknown origin in UK Frequency is given in parentheses • • • • •

Infection (30%) Neoplasia (25%) Connective tissue (autoimmune) disease (20%) Miscellaneous (12%) Undiagnosed (13%)

Other causes. Other occasional causes of PUO are alcoholic hepatitis, familial Mediterranean fever and occult haematoma. There are some young women whose normal evening temperature runs above the normal range by up to 0.5°C. This usually comes to light after an infection with slow recovery. Once it is established that there is no underlying pathology the patient can be reassured. Tropical causes are discussed below.

Diagnosis A careful history and examination of the patient is essential, and it is important to return to the patient repeatedly to go over parts of the history and to look for emergent physical signs. Simple screening tests which may need to be repeated at intervals include full blood count, ESR and CRP, routine biochemistry of blood and urine, cultures of blood, urine and other relevant samples, and chest radiograph. Additional investigations are guided by the clinical findings. There are two approaches. One is to perform tests which are more or less specific for particular diseases, e.g. exclude autoantibodies in autoimmunity or antibodies to particular pathogens. The other is to investigate a particular site which seems to be generating symptoms or signs. The latter is more often helpful, and it is in this area that advances in imaging techniques change the methods for diagnosing PUO. Ultrasound is particularly useful for abdominal examination, both in the detection of solid tissue abnormalities, such as tumours of the kidney or pancreas, lymph node enlargement or infiltration of the liver, and in locating collections of pus (subphrenic, perinephric, intrahepatic etc.). CT scanning supplements, and is in some situations superior to, ultrasound, for example when intestinal gas limits the views on abdominal ultrasound. MR scanning is often more sensitive than CT and is clearly superior for detecting lesions in soft tissue and bone. CT scanning and ultrasound are used to guide the needle during tissue biopsy. The use of 99mTc-labelled leukocytes is described on page 262.

MCQ 9.5

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Even if no localized lesion has been found by imaging techniques, certain biopsy procedures are sometimes rewarding. If the liver enzyme tests are abnormal percutaneous liver biopsy should be considered, as diffuse granulomatous or infiltrative diseases such as sarcoidosis or lymphoma may be detected. Marrow aspiration and biopsy may reveal cryptic tuberculosis, or lymphomatous or carcinomatous infiltration. The marrow and liver biopsy should be cultured for Mycobacterium tuberculosis, bacteria including Brucella fungi and, where relevant, leishmania. Patience and persistence are essential in managing PUO. Neoplasia is the major cause of death among PUO patients, and so the exclusion of treatable neoplastic disease such as lymphoma is a priority. In some cases there is evidence to support a diagnosis of bacterial infection although the infection cannot be defined, and it may be justified to give blind antibiotic treatment. This should be aimed at the type of infection suspected. For example, a Staph. aureus osteomyelitis would require two antibiotics, such as flucloxacillin and fucidic acid, whereas an appendix abscess could be treated with ampicillin, gentamicin and metronidazole to cover E. coli, enterocci and anaerobic bacteria. In other circumstances a therapeutic trial of treatment for M. tuberculosis may be required. In most studies about one-fifth of cases remain unsolved despite the best efforts. 1

The approach to the patient with fever from or in the tropics Febrile illness is common in the tropics, or after travel to the tropics. The causes encompass infectious and noninfectious causes. Infections include those peculiar to tropical regions and those common worldwide (such as urinary tract infection, pneumonia) (Table 9.11). Clinical features A detailed history is essential. This should include accurate recording of the dates of travel, duration of stay and countries visited, with information on the places involved (cities, rural areas, beach resorts etc.) and the reasons for travel. Information about sexual contact during travel is also important. The history should also include details of vaccination prior to travel and malaria prophylaxis,

TABLE 9.11 Leading causes of imported fever (Hospital for Tropical Diseases) Malaria P. fdlciparum P. vivax P. ovale Viral (presumed) Dengue (proven) Bacterial gut infections

42% 57% 9% 4% 25% 6% 5%

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TABLE 9.12 Incubation periods for some tropical diseases Type of organism

Short (less than 2 weeks)

Intermediate (2-6 weeks)

Long (more than 6 weeks)

Viruses

Arbovirus infections (e.g. Dengue) Marburg virus disease

Poliomyelitis Hepatitis A virus Arenavirus infection Ebola virus infection Lassa fever virus infection Haemorrhagic fever with renal syndrome

Hepatitis B Non-A, non-B hepalitis Rabies HIV

Q fever

Rickettsia Bacteria

Typhoid

Typhoid Brucellosis Leptospirosis Relapsing fever Lymphogranuloma venereum

Protozoa

Trypanosoma cruzi infection

Malaria Toxoplasmosis Trypanosoma rhodesiense infection

Helminths

with some assessment of the regularity of taking prophylaxis. The chronology of events should be recorded, particularly noting the interval between the end of the patient's travels and the onset of illness where this has occurred after leaving the tropics. This gives an idea of the incubation period of the disease (Table 9.12). Physical examination should pay attention to the presence of skin lesions, oral lesions, jaundice, adenopathy, hepatosplenomegaly, and involvement of the nervous system. After initial assessment it is vital to reassess the patient at frequent intervals, looking for the appearance of diagnostic symptoms and signs. Antimalarial chemoprophylaxis should be discontinued while investigation is proceeding as it may suppress parasitaemia and prevent diagnosis of malaria.

Visceral leishmaniasis Trypanosoma gambiense infection

Schistosomiasis (Katayama syndrome)

SUMMARY 3 Causes of imported fever Malaria Dengue Other arboviral infections Tuberculosis AIDS related infections Typhoid Rickettsial infections Amoebic liver abscess Visceral leishmaniasis Viral haemorrhagic fevers* * While numbers of cases of VHF are very low it is essential to consider this group of conditions in any patient who has visited an endemic area, is febrile and has a low platelet count. See risk assessment, p. 298.

Investigations The investigations performed will depend on the clinical diagnosis or the differential diagnosis. • Blood films should be examined daily for malaria parasites in any febrile patient who has been to a malarial area until either a diagnosis is made or the fever resolves. Blood films may also be examined for trypanosomes in a patient who has been in rural east or west Africa. A full blood count is useful for looking for leukocytosis (suggesting bacterial infections), leukopenia (typhoid, viral infections), pancytopenia (visceral leishmaniasis) or eosinophilia (helminthiasis: schistosomiasis, fascioliasis, visceral larva migrans, clonorchiasis, Bancroftian filariasis). • A Mantoux test should be done early on. • Blood cultures should be taken and, if brucellosis is a possibility, kept under observation for up to 6 weeks, as the organism grows slowly.

• Serological tests that may be useful include those for syphilis, leptospirosis, rickettsial diseases, brucellosis, amoebiasis, leishmaniasis, trypanosomiasis, toxoplasmosis, filariasis and schistosomiasis. They should be used selectively in relation to the clinical presentation and the exposure. A serum sample should be taken on admission and saved, and a second sample taken 10 days later. This pair of sera can then be used to look for a change (usually a rise) in titre. • Imaging procedures should include a chest X-ray and the scanning procedures mentioned under PUO are used as clinically indicated. • Liver and marrow biopsy (see PUO above) are also performed where there is a clinical indication, with samples cultured for routine organisms, brucella, fungi and parasites, in addition to histological examination of sections and microscopy of smears for tubercle bacilli and leish-

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mania. Bone marrow culture may yield S. typhi in a patient who has previously taken antibiotics.

Management Ideally treatment will follow from the specific microbiological diagnosis of the cause of fever. Occasionally it is necessary to treat the patient for a disease suspected clinically but not proven by available laboratory tests. This may be treatment for malaria, or typhoid or rickettsial infection, or tuberculosis in fevers of longer duration. 1 12

GASTROENTERITIS Gastroenteritis is defined as an acute disease with diarrhoea and/or vomiting and a variable degree of systemic illness. 'Food poisoning' is a term used to describe a selflimiting form of gastroenteritis caused by eating contaminated food.

Aetiology A large variety of microorganisms can cause gastroenteritis (Table 9.13) but in over half of all cases the causative organism cannot be identified. Salmonellae and Campylobacter species are among the most frequent causes. In children the spectrum of organisms is slightly different and rotavirus is the most frequently recognized agent.

Epidemiology Gastroenteritis is a common infection in all parts of the world, occurring sporadically or in epidemics. Epidemics occur when a common source of food or drink is contaminated with micro-organisms and when infection spreads from person to person by the faecal-oral route. For example, Salmonella enteritidis frequently colonize the gut of chickens bred in battery conditions and may infect the oviduct and eggs of hens in batteries. During evisceration in the factory the meat is contaminated and the salmonellae survive freezing and thawing. If such chickens are not thoroughly cooked, salmonellae are ingested and colonize the intestine. During the last few years there have been outbreaks of diarrhoea due to E. coli O:157, which in patients of all ages can go on to cause a haemolytic uraemic syndrome with a significant mortality. This has occurred in retail food outlets where both cooked and uncooked meats are on sale, with the opportunity to contaminate cooked meats with E. coli O:157 from uncooked meat. Some forms of gastroenteritis show striking seasonal variations in frequency but these are usually significant only in temperate areas. Rotavirus is the most common

1

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Case 9.1

2

MCQ 9.6

TABLE 9.13 Common causes of gastroenteritis Cause

Clinical presentation

Invasive bacteria Shigella species Salmonella species Campylobacter jejuni

Dysentery Diarrhoea, vomiting Diarrhoea predominantly

Toxin-producing bacteria Enteroxin E.coli(ETEC) Vibrio cholerae

Secretory diarrhoea Secretory diarrhoea

Neurotoxin Staphylococcus Bacillus cereus Clostridium botulinum

Vomiting (short incubation) Vomiting (short incubation) Vomiting, diarrhoea, neurological

Cytotoxin Clostridium difficile

Bloody diarrhoea, haemolytic uraemic syndrome Watery diarrhoea

Tissue-damaging viruses Rotavirus Norwalk virus Adenovirus Enterovirus

Infantile diarrhoea Winter vomiting Diarrhoea, vomiting Diarrhoea, vomiting

Protozoa Cryptosporidium Entamoeba histolytica Giardia lamblia Cyclospora cayetanensis

Diarrhoea Dysentery Chronic diarrhoea Diarrhoea

E. coli 0:157

cause of infantile diarrhoea worldwide. In Britain and the USA its peak incidence is in 2 or 3 months during the winter, but in tropical climates there is little seasonal variation. Outbreaks of food poisoning caused by Salmonella, Campylobacter or toxin-producing Staph. aureus are more common in summer.

Pathogenesis Organisms must evade the host defences and colonize the intestine before they can cause disease. Gastric acid is an important defence, and patients with a partial gastrectomy are susceptible to intestinal infection. Some bacteria have on their surface determinants that bind to epithelial receptors. Examples are Vibrio cholerae and some strains of E. coli. The known mechanisms by which microorganisms cause diarrhoea can be divided into two groups: toxin secretion and mucosal damage. These are not mutually exclusive, and for many organisms the precise mechanism is unknown. Toxin secretion Three different mechanisms are recognized by which toxins can cause intestinal pathology. Cholera is a good example of small intestinal toxin-mediated secretory diarrhoea (see

9

CASE STUDY 9.1 ACUTE INFECTIVE DIARRHOEA A 21-year-old female student was travelling in rural Nepal staying in guest houses. Overnight she developed fever, chills and generalized body aches and pains. The next day she was anorexic and developed acute watery diarrhoea, but after 12 hours started to get severe griping abdominal pains which were particularly severe in the left lower quadrant. The character of the diarrhoea changed to the passage of frequent small volume stools, with exacerbation of pain. After 12 hours the stools became uniformly bloodstained. She also described the sensation of wanting to empty the rectum with extreme pain in the anus and relatively little blood-stained material coming out (tenesmus). She was wakened from sleep numerous times in the first 24 hours of the illness and sought medical attention at a local hospital. On examination she looked unwell. Pulse 110 regular, BP 90/60, temperature 38.4°C. There

Questions 1. What is the differential diagnosis? 2. What investigations should be performed? 3. What are the main points of management?

was tenderness over the left lower quadrant of the abdomen. She passed a small amount of blood stained watery stool shortly after admission. Comment This history is suggestive of acute invasive bacterial infection of the gut. It is typical of shigellosis, with the initial fever, followed by acute watery diarrhoea and then dysenteric diarrhoea, passing small volumes of stool with pain and tenesmus. However, the distinction between shigellosis, Campylobacter infection and salmonellosis is clinically unreliable. The marked systemic upset initially would be against giardiasis, cyclospora (first described as a cause of diarrhoea in Asia among western travellers in Nepal), cryptosporidium, toxigenic E. coli and cholera. Amoebic dysentery begins more insidiously and is gradually progressive. Investigations must include examination of the stool for amoebic trophozoites, and culture for Shigella and Salmonella. The finding of amoebic cysts in her stool is irrelevant, as motile trophozoites with ingested red cells would be evident in faecal smears in invasive amoebiasis. Microscopy of the stool would have shown large number of pus cells, which do support a diagnosis of invasive bacterial infection.

p. 322), and enterotoxigenic strains of E. coli secrete a heatlabile enterotoxin which acts in a similar way. In staphylococcal food poisoning neurotoxin-secreting staphylococci multiply in food, and the toxin causes vomiting and diarrhoea within hours of ingestion. Staphylococci are not detected in the stools of patients with this type of food poisoning. Bacillus cereus, which contaminates reheated rice, causes vomiting by a similar mechanism. Cytotoxins, such as verotoxin produced by E. coli O:157 and toxin B of Clostridium difficile, cause tissue damage. Mucosal damage Shigellae invade the colonic mucosa and cause local inflammation, and so the faeces contain blood and inflammatory cells. Impairment of water absorption from the colon and exudation of protein-rich fluid through the

Since amoebic cysts were seen in a faecal smear, she was treated with metronidazole as well as norfloxacin for shigellosis. She was also given intravenous fluids as she could not initially tolerate ORS, but within 36 hours of starting treatment the fever regressed and the diarrhoea started to improve, though after finishing 7 days' treatment with both drugs bowel actions remained abnormal both in frequency and the consistency of the stools. No more blood was seen for the remainder of her stay in Nepal or after her return to the UK. The management was appropriate, though one could argue that there were sufficient clues to suggest that norfloxacin alone would have been enough. With marked systemic upset and dysenteric stools there are clear indications to give antibiotics. Rehydration by the oral route was first attempted, with recourse to intravenous fluids when that failed. The persisting abnormalities of bowel habit after effective treatment are an indication of postinfective intestinal irritability, but it is essential to ensure that there is no persisting infection, such as giardiasis, and that there is no possibility of non-specific inflammatory bowel disease which, some reports indicate, may be precipitated by acute gastrointestinal infection.

inflamed and ulcerated mucosa are the cause of fluid stools. Salmonellae, Campylobacter and rotavirus are also invasive and cause tissue damage, but the precise mechanisms are not understood. Damage to the brush border of the enterocytes causes temporary disaccharidase deficiency, which may prolong the diarrhoea even after the pathogen has been eliminated.

Clinical features Most episodes of gastroenteritis are mild and self-limiting. The incubation period is usually short, ranging from a few hours with staphylococcal food poisoning up to 5 days with Campylobacter infection. Vomiting, diarrhoea and cramping abdominal pains are typical features. Large volume stools suggest a small bowel diarrhoea. The stools are fluid

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without blood or pus in toxin-mediated disease (e.g. cholera), but when invasion and mucosal damage occur in Salmonella, Shigella and Campylobacter infections blood and mucus may be seen in the stool. The appearance of the stools is an unreliable guide to the type of organism. The major consequence of gastroenteritis is dehydration with electrolyte imbalance. Babies are more vulnerable and can rapidly become severely dehydrated. It is essential that the clinician can make a reasonably accurate assessment of the degree of dehydration and Table 9.14 gives some guidelines. Fever and signs of systemic illness suggest invasive pathogens. Some invasive organisms can cause septicaemia (e.g. Salmonella typhimurium), and some shigellae produce neurotoxins which enter the circulation in the absence of septicaemia and, on reaching the central nervous system (CNS), cause headache and meningism. The illness is usually over within 7 days, but symptoms are liable to persist for longer with shigellae and Campylobacter. Persistent diarrhoea suggests Giardia infection, especially if steatorrhoea is present. Although amoebiasis is commonly thought of as a cause of acute watery diarrhoea in the tropics it is in fact relatively uncommon, causing only 6% of cases in a large study from Bangladesh. Usually the diarrhoea has an insidious onset and gets worse gradually, though all ranges of severity are possible, from the passage of a little bloodstained mucus with stools to a severe illness every bit as bad as ulcerative colitis.

Diagnosis The diagnosis is usually clear, but problems arise when there is vomiting in the absence of diarrhoea; when abdominal pains are accompanied by localized tenderness, suggesting pelvic inflammatory disease or appendicitis; and when blood in the stools is taken to indicate inflammatory bowel disease. A positive diagnosis is established by identification of the organism in stools by microscopy, antigen assay (for rotavirus) or culture.

Management The management of diarrhoea is concerned mainly with the management of dehydration. After an assessment of the degree of dehydration using the criteria set out in Table 9.14, a plan of management is determined. Where there is no dehydration (<5% body weight lost) oral fluids are given freely and normal feeding is encouraged. When there is some dehydration (5-10% body weight lost) the deficit should be replaced using oral dehydration solution (ORS; Table 9.15) 80ml/kg over 4 hours. In addition to ORS, water and other non-electrolyte fluids should be 1

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MCQ 9.7

TABLE 9.14 Assessment of dehydration A No dehydration

B Some dehydration

C Severe dehydration

Condition

Alert

Eyes

Normal

Restless*/ irritable* Sunken

Tears Mouth and tongue Thirst Drinks Skin turgor

Present Moist

Absent Dry

Lethargic*, unconscious* Very sunken and dry Absent Very dry

None Normally Normal

Thirsty* Eagerly* Reduced*

Drinks poorly* Not able to drink* Markedly reduced*

Features in bold with * are key signs. If 2 signs from column C including 1 key sign are present then severe dehydration is present; if 2 signs from column B including 1 key sign are present, there is some dehydration. (After A Manual for the Treatment of Diarrhoea, World Health Organisation 1990.)

TABLE 9.15 Composition of oral rehydration solution (WHO formulation) Sodium chloride Trisodium citrate, dihydrate Potassium chloride Sucrose Made up to 1 litre with clean water

3.5 g/L 2.9 g/L 1.5 g/L 40 g/L

given to provide water for insensible losses. After each bowel action an additional 400 mL of ORS should be given to replace continuing losses. Oral rehydration solution very effectively replaces lost fluid despite the presence of an enterotoxin-mediated secretory process in the gut, but it does nothing to reduce the volume of diarrhoeal stools produced. The use of rice flour as the source of glucose in cereal-based ORS solutions not only replaces lost fluid but also reduces the volume of faecal effluent. It has the further advantage of being widely available in areas of the world where infectious diarrhoeal diseases are common, but preparing cereal-based ORS requires heating the solution to make a palatable gruel. When there is severe dehydration (>10% body weight lost) intravenous access should be established immediately and Ringer's lactate (or normal saline if that is not available) infused at 30mL/kg over 30 minutes, and then 70mL/kg over 2 hours. Thereafter, continuing losses should be replaced orally if the patient is able to drink, or intravenously if not. In all patients with diarrhoea it is essential that their progress is assessed every hour, so that if symptoms and signs are deteriorating on an ORS regimen they can be

switched to intravenous fluids. Vomiting may prevent successful ORS therapy, but first the administration of frequent small volumes of fluid by mouth should be tried. When initial rehydration has been achieved, continuing faecal losses should be replaced by ORS, 400 mL after each bowel action, and feeding begun as soon as the patient wants to eat. Bowel sedatives have little place in the management of intestinal infections and they may be harmful, precipitating toxic dilatation in elderly and young patients in infections with the invasive bacterial pathogens. Antibiotics are normally not required, but they are needed when there is profuse watery diarrhoea, marked systemic upset and obviously dysenteric (bloodstained) diarrhoea. Empirical treatment with ciprofloxacin 500 mg twice daily for 5 days is usually given. In addition, the following situations merit antibiotic treatment: • • • • • • • •

Septicaemic Salmonella infection (ciprofloxacin) Severe shigellosis (ciprofloxacin) Severe Campylobacter infection (erythromycin) Yersinia (doxycycline) V. cholerae (doxycycline) Entamoeba histolytica (tinidazole, metronidazole) Giardia lamblia (tinidazole, metronidazole) Cyclospora cayetanensis (co-trimoxazole).

Problems associated with use of antibiotics are exacerbation of diarrhoea, prolonged carriage of some organisms (e.g. salmonellae) and development of resistance to multiple antibiotics (e.g. shigellae). There is evidence to suggest that antibiotic treatment in E.coli O:157 infection may increase the risk of renal complications by promoting toxin release. 1

FURTHER READING ON GASTROENTERITIS A manual for the treatment of diarrhoea 1990. Geneva: World Health Organization Programme for the Control of Diarrhoeal Diseases.

ACUTE UPPER RESPIRATORY INFECTION

TABLE 9.16 Causes of upper respiratory infection Disease

Causative organism

Common cold and pharyngitis

Rhinovirus Coronavirus Influenza virus Parainfluenza virus Respiratory syncytial virus Adenovirus Unknown

Pharyngitis/tonsillitis

As above, plus: Epstein-Barr virus B-haemolytic streptococcus group A Mycoplasma pneumoniae Mixed anaerobes and spirochaetes* Corynebacterium diphtheriae* Neisseria gonorrhoeae*

Stomatitis

Candida albicans Herpes simplex virus Coxsackie A and other enteroviruses Mixed anaerobic bacteria

9

*Less common

treatment of choice for streptococcal pharyngitis, with erythromycin for penicillin-allergic subjects. Ampicillin and related drugs should be avoided, as they often cause a rash in patients with infectious mononucleosis. Upper respiratory infections are frequently complicated by otitis media in children and, less often, by sinusitis in adults or children. These are usually caused by secondary bacterial infection, and it is therefore important to recognize them and treat with antibiotics. Common bacterial causes of otitis media include Strep. pneumoniae, H. influenzae (mainly untypable), group A B-haemolytic streptococci and Branhamella catarrhalis. Many H. influenzae are now resistant to amoxicillin, and co-amoxyclav can be used instead. The bacteria that cause acute sinusitis are similar to those incriminated in otitis media, but anaerobes, Gramnegatives and Staph. aureus should also be considered. Upper respiratory anaerobic bacteria are usually penicillin sensitive, in contrast to those found in the large bowel.

Common cold and pharyngitis The common cold has an incidence of 1-4 episodes per person per year. Large gaps remain in our knowledge of pathogenesis, although it is clear that many viruses can cause the same clinical entity. There is considerable overlap between organisms causing colds and those causing pharyngitis (Table 9.16). Pharyngitis is more important, as it is often part of a more systemic illness. The majority of episodes of pharyngitis are caused by viruses. Antibiotic treatment should be reserved for culture-proven cases of streptococcal pharyngitis. In the developed world, group A streptococcal pharyngitis is now rarely complicated by rheumatic fever or glomerulonephritis. Penicillin, as a single i.m. dose or orally for a minimum of 10 days, is the

Acute stomatitis In contrast to pharyngitis, the microbial cause of acute stomatitis can often be diagnosed from the appearance of lesions in and around the mouth. Candida is a common pathogen, particularly in debilitated patients, patients receiving broad-spectrum antibiotics and patients with HIV infection. White plaques occur on an erythematous background. The distribution is wide, including the buccal mucosa. Ulcers are usually superficial and not easily confused with primary herpes simplex infection. The latter is often associated with perioral clusters of vesicles. Severely painful ulceration of the mouth and lips in a young immunocompetent patient is usually due either to

281

Stevens-Johnson syndrome or to primary herpes simplex infection. Coxsackie virus infection may cause small, scattered vesicles and ulcers, but they are more sparse than those of herpes simplex and less painful. Noninfective causes of ulcers must also be considered, such as aphthous ulcers and, rarely, Behget's disease (p. 1153). Infections in the subcutaneous tissue spaces of the

CASE STUDY 9.2

CHRONIC FATIGUE

A 34-year-old female nursery school teacher in a stable relationship complained of recurrent episodes of sore throat, the most recent of which was 2 months ago. She had had difficulty throwing off 'flu and other infections for 3 years and felt tired all the time. She had pains in the neck and the 'glands' in her neck were going up and down. Her muscles ached during and after exertion and she became fatigued sooner than she would have expected. She denied depression and had no problems at work. There were no abnormalities on examination and, in particular, no lymphadenopathy but minimal tenderness in the anterior cervical region. Muscle power was normal and there was no convincing muscle tenderness. Her affect was normal but she was clearly tired of her symptoms, sometimes sighing while describing them, and she was anxious about an underlying persistent disease of a 'weak immune system'. Questions

1. What is the differential diagnosis? 2. What further investigations would you perform? 3. What would be your approach to management? Discussion

The GP had checked her full blood count repeatedly so we know that she did not have neutropenia or lymphopenia. Examination of the pharynx showed normal tonsils but it would be helpful to see her during an episode of sore throat to exclude 282

face and neck often originate from periodontal infection. Ludwig's angina is an anaerobic bacterial infection of the submandibular and sublingual spaces which causes firm swelling of the tissues below the chin. These may press inwards and compromise the airway. There is accompanying fever and tachycardia and the patient requires urgent antibiotic treatment, usually with penicillin and metronidazole.

recurrent tonsillitis. Persistent pharyngeal infection with group A Phaemolytic streptococcus may cause recurrent sore throat but it does not cause tiredness between episodes. One of her episodes of sore throat could have been infectious mononucleosis caused by EBV infection (or, less commonly, CMV or toxoplasma infection); this usually causes one continuous episode of illness and recurrence is rare beyond 12 months after the initial episode but it can cause tiredness persisting for up to 6 months. Many patients are anxious that recurrent upper respiratory infections indicate a disorder of the immune system. This is not so in the absence of recurrent candidiasis and it is not necessary to undertake immunological investigations to prove it but reassurance is often helpful. Simple causes of tiredness such as anaemia and hyper- or hypothyroidism can be excluded by examination and confirmed by appropriate tests. Rather than requesting a wide range of investigations, it is advisable to target them at excluding diseases which have been a particular cause of anxiety to the patient if the anxiety can not be allayed by reasonable discussion. Assessment by a sympathetic psychiatrist can be helpful and should be regarded as a part of the overall investigation of patients with very prolonged symptoms. Chronic fatigue syndrome is diagnosed when the combination of symptoms illustrated by the above patient is present with negative investigations for organic disease. Many patients have the

somatic symptoms of depression but deny the state of depression or attribute it to the presence of physical symptoms. Sometimes anxiety seems to be a more important factor. The term myalgic encephalomyelitis (ME) should be avoided since none of these patients has encephalomyelitis. The patient was reassured by a wide range of normal investigations (including FBC, ESR, CRP, U&E, LFTs, thyroid function, auto-antibody screen, CXR, negative IgM antibodies to EBV, CMV and toxoplasma and negative throat swab). She was seen by a psychiatrist who found no evidence of depression but she discussed some family stress at Christmas and uncertainty about her career; when she was on holiday at Christmas, there was a family row in which she acted as mediator between her brothers and her mother which she found very stressful. Later she was able to resolve this but she missed her holiday because of the stress and her illness (flu). At work she had been considering whether she should go part-time because of her symptoms or aim for promotion to a deputy school headship. Her symptoms had been improving slowly and she now felt optimistic with the summer holidays looming. She was offered counselling which she attended and found useful. She also undertook a graded exercise programme and at review sessions she was encouraged to work through her fatigue. By end of the year, she was working full-time in the same job and coping despite some persistent tiredness.

SEXUALLY TRANSMITTED DISEASES Sexually transmitted diseases (STDs) are infections commonly transferred through sexual contact. They are discussed in detail in Chapter 11.

CHRONIC FATIGUE SYNDROME (POSTVIRAL SYNDROME, MYALGIC ENCEPHALOMYELITIS) This syndrome is seen most often in young adults. There is a prolonged period of lethargy, often with muscle pains and fatiguability, usually after an episode reminiscent of a viral illness but sometimes in the absence of an evident acute illness. The problem causes great distress to patient and relatives because an explanation is lacking and there is prolonged inability to work or play at expected levels, often coupled with an unreasonable need for sleep. Doctors are frustrated by their inability to establish a positive diagnosis or to give any specific treatment, and the patient often turns to alternative medicine.

Aetiology The syndrome is heterogeneous and no single explanation will fit all patients. The term 'myalgic encephalomyelitis' is misleading as there is no evidence of encephalomyelitis and myalgia may not be present. A number of infections have been associated with this syndrome and they are not all viral. Infectious mononucleosis is the best known and studied, but CMV infection and toxoplasmosis have been suspected, and it is likely that many other organisms can act as triggers in susceptible individuals. Enteroviruses, particularly of the Coxsackie group, have also been suspected but

evidence is inconclusive. Often the only evidence for infection at the onset is a history of febrile illness, perhaps with pharyngitis or lymphadenopathy, and a full blood count may have revealed some atypical mononuclear cells. The relationship of postviral syndrome to depression is complex. There is no doubt that some patients develop the symptoms and signs of depression and benefit from antidepressant treatment. More commonly the patient becomes depressed as a result of the illness but lacks many of the features of primary depression. In this situation antidepressant therapy is unlikely to be beneficial.

9

Clinical features The central symptoms are profound lethargy and easy fatiguability. Often these are accompanied by muscular pains, headaches and symptoms suggestive of fever, such as sweating. This is usually mild, and when the temperature is recorded it is normal or only minimally elevated in the evenings. Exertion exacerbates tiredness, and the patient often goes to bed early and wakes late still feeling tired.

Management Patients benefit greatly from having their illness taken seriously, and if a precipitating infection can be positively identified this also helps. Sometimes the greatest problem is anxiety about the outcome or about whether there is an underlying disease that has not been diagnosed, so reassurance is important. When patients have restricted their activity it is worth trying to rehabilitate them by a programme of daily exercise, starting with something light such as walking or swimming, and gradually increasing it in a documented way. The patient is assured that exercise is not harmful and advised to sleep as required. Most patients recover spontaneously within weeks rather than months, but a few continue to suffer for over a year.

VIRUS INFECTIONS Viruses are usually classified according to their nucleic acid content and morphology. The classification of viruses used in this section is shown in Tables 9.17A and B. Arboviruses (arthropod-borne) are viruses transmitted by the bite of an insect vector. Most arboviruses are togaviruses, but bunyaviruses and orbiviruses (RNA viruses in the reovirus family) are also included.

ENVELOPED DOUBLE-STRANDED DNA VIRUSES HERPES VIRUSES Six herpes viruses cause disease in humans: • Varicella zoster virus (VZV)

• • • • •

Two herpes simplex viruses (HSV 1 and 2) Epstein-Barr virus (EBV) Cytomegalovirus (CMV) Human herpes virus 6 Herpes virus associated with Kaposi's sarcoma (HHV8).

Morphologically, herpes viruses are very similar and indistinguishable by electron microscopy. They are similar in some aspects of their behaviour, notably their ability to establish latent infection with the potential for reactivation. During latency in dorsal root ganglia VZV shows no demonstrable evidence of viral replication for many years. With HSV there is evidence of a low level of replication, and reactivation is more frequent. EBV infects B lymphocytes, and EBV and CMV replicate at a low level continuously. CMV can often be detected in the urine of asymptomatic carriers, and herpes simplex in saliva. The mechanisms by which virus replication is suppressed are

283

TABLE 9.17A Classification of viruses:DNA

TABLE S.176 Classification of viruses: RNA

Morphology

Virus

Morphology

Virus and disease

Enveloped double-stranded

Herpesviridae Varicella zoster (VZV) Herpes simplex (HSV I, II) Epstein-Barr (EBV) Cytomegalovirus (CMV) Human herpes virus 6 (HHV6) Human herpes virus 8 (HHV8) Poxviridae Vaccinia Variola (smallpox) Orf Parvoviridae Hepadnaviridae

Enveloped single-stranded

Orthomyxoviridae Influenza Paramyxoviridae Parainfluenza Respiratory syncytial disease Mumps Measles Togaviridae Rubella Alpha (equine encephalitis) Flaviviridae Dengue Yellow fever Encephalitis Hepatitis C Bunyaviridae Arenaviridae Lymphocytic choriomeningitis Lassa Filoviridae Marburg Ebola Retmviridae Lentiviruses (HIV 1 and 2) Oncoviruses - type C (HTLV1 and 2) Rhabdoviridae Rabies Vesiculostomatitis Coronaviridae Coronavirus Reoviridae Rotavirus Reovirus Picornaviridae Rhinovirus Enteroviruses Coxsackie A, B Echo Polio Enterovirus 70, 71 Hepatitis A Caliciviridae Norwalk Hepatitis E virus Astroviridae Astroviruses

Enveloped single-stranded

Hepatitis B Hepatitis D

Non-enveloped double-stranded

Adenoviridae Papovaviridae Papilloma Polyoma

incompletely understood, but T cell-mediated immune mechanisms probably have an important role, as all the herpes viruses are liable to reactivate in patients with depression of cell-mediated immunity, such as those with lymphoma or leukaemia.

Varicella zoster virus infection Chicken pox (varicella) This illness is easy to recognize, common and highly infectious. It is a febrile illness with a vesicular rash (Fig. 9.6). During the primary infection there is a viraemic phase when VZV becomes widely disseminated in white cells. In normal subjects it only produces significant lesions in the skin and mucous membranes, but infection of cutaneous sensory nerves leads to infection of dorsal root ganglia, and here the virus enters a latent state. Reactivation later causes herpes zoster (shingles). During primary infection VZV is present in nasopharyngeal secretions and is transmitted readily by coughing and sneezing. It is also in vesicle fluid in chickenpox and shingles, and this can be a source of transmission. The incubation period of chickenpox is 15-18 days and the patient is infectious from a few days before the rash erupts until new lesions cease to appear. The severity of chickenpox is determined by the age and immunological state of the patient. It is most severe in neonates if they have no maternal antibody to VZV, and in patients immunocompromised by disease such as leukaemia or by immunosuppressive therapy. It is usually a mild disease in children, but it becomes increasingly severe after puberty. 284

Clinical features In children chickenpox starts with the appearance of the

Non-enveloped double-stranded Non-enveloped single-stranded

rash, which is often sparse and not accompanied by constitutional symptoms. The most troublesome feature of the illness is itching. In adults there is a notable prodromal illness lasting 2-3 days, during which headache, backache, shivering and fever occur, sometimes with a sore throat and cough. The more severe the prodromal illness, the more profuse is the rash that follows. The rash starts on the trunk and spreads to the face and limbs (Fig. 9.6). Lesions appear in crops which progress rapidly through the sequence macule, papule, vesicle, pustule, scab. Often the first visible lesions are vesicles containing clear fluid with little surrounding erythema, but the pustular stage is reached within 24 hours. Vesicles on the

9

FIG. 9.6 Vesicles and pustules in a patient with chickenpox

palate, tonsils and pharynx rapidly burst, leaving superficial ulcers. Crops of skin lesions erupt over 2 or 3 days, but it takes several more days for them all to heal. Constitutional symptoms, if present, lessen with the onset of the rash and disappear within 2 days. Complications Secondary infection of the skin lesions, including the scalp, occurs because of scratching, but it usually responds to cleaning and bathing and rarely requires antibiotics. Chickenpox pneumonia occurs in one-fifth of adults, and more frequently in immunocompromised patients. It varies in severity from transient dyspnoea to a fulminant pneumonia. Postinfectious encephalitis is extremely rare and has a variable course, but it is often severe or fatal. Its onset is within a week of the rash and cerebellar involvement is characteristic. Bleeding into the skin, nose or intestine, also rare, is due either to steroid-responsive thrombocytopenia or to consumptive coagulopathy, when the prognosis is much worse. Neonatal chickenpox Most women are immune by the time they reach childbearing age, but if a mother develops chickenpox within a few days of having a baby the child is born without the protection of maternal IgG antibodies transferred across the placenta, and it is immediately exposed to the virus. If the child becomes infected during the first 5 days of life disease is severe, with multi-organ involvement. Disease can be prevented or made milder by the administration of varicella immune globulin 250 mgi.m. at birth. Aciclovir l0mg/kg is given intravenously 8-hourly for 7 days if any signs of infection (e.g. fever) appear. This does not seem to prevent the virus becoming latent. Congenital chickenpox Rarely, VZV can cross the placenta during the first 20 weeks of pregnancy, causing fetal damage or death. Diagnosis and management A clinical diagnosis of chickenpox suffices in most cases.

FIG. 9.7 Dermatomal distribution of varicella zoster lesions

Electron microscopy is the quickest way to establish that a herpes virus is present in vesicle fluid, but does not establish its type. The virus can be identified by tissue culture inoculation, and antibodies are detected by a complement fixation test. Treatment with aciclovir (p. 268) is required only in severe cases susceptible to complications such as chickenpox pneumonia, in immunocompromised patients (such as children with malignant disease), and in neonates (Table 9.5, p. 268). Intravenous treatment (l0mg/kgt.d.s in adults; 500mg/m2 for children aged 3 months to 12 years; l0mg/kg for children less than 3 months) is needed in order to achieve adequate serum concentrations. Many patients with chickenpox pneumonia need ventilation (see Ch. 14) and antibiotic treatment for secondary bacterial infection, the most common organism being Staphylococcus aureus. Shingles (zoster) When VZV reactivates within a dorsal root ganglion it migrates down the nerve into the skin and causes a crop of lesions identical to those of chickenpox but confined to the dermatome (Fig. 9.7). Pain within the dermatome may precede the eruption by a few days and is often severe. One or two adjacent dermatomes on the trunk are most commonly affected, but involvement of the ophthalmic division of the fifth cranial nerve is important because the eye can be damaged by the virus or by secondary bacterial infection.

285

In the elderly it is common for a mild viraemia to occur, causing a few scattered lesions to appear outside the involved dermatome. More serious dissemination with visceral involvement is seen in immunocompromised patients. Patients with Hodgkin's disease are particularly susceptible to shingles, especially during chemotherapy. The skin heals over 2-3 weeks and there is often some residual pain for a few weeks. Rarely, intractable pain continues for years (post-herpetic neuralgia). This is more common following ophthalmic zoster, and after severe infections in immunocompromised patients. 1 Management Most patients do not require admission to hospital and treatment of pain is the main concern. Continuous treatment with simple analgesics such as paracetamol is often effective and should be tried before drugs that have more side-effects. Oral treatment. A small increase in the rate of healing has been demonstrated when oral aciclovir is used in high dose, 800 mg five times daily for 7 days. This benefit may be enhanced with the use of newer alternatives such as valaciclovir, as higher serum levels of aciclovir are achieved. Less frequent administration is needed with famciclovir 250 mg thrice daily. Intravenous treatment. Intravenous aciclovir (l0mg/kg t.d.s for adults) should be given to immunocompromised patients for 1 week. It reduces pain, shortens the healing time and limits dissemination of the virus. Evidence for the benefit of prednisolone in reducing post-herpetic neuralgia is controversial and it is not recommended. Topical treatment • In ophthalmic zoster it is important to combine an antibiotic (e.g. chloramphenicol drops) with aciclovir ointment. • Pruritus treatment, e.g. calamine, is soothing for a few minutes. • Antivirals, e.g. idoxuridine and aciclovir, are impractical and of limited value. 0

Herpes simplex virus infection HSV 1 and 2 cause patterns of disease that differ clinically and epidemiologically but share some characteristics. Both establish permanent, latent infection within sensory nerve ganglia following primary infection, with reactivation causing episodes of disease in the area supplied by the nerve. These viruses are indistinguishable morphologically but can be separated by differences in antigen expression. Infection with HSV 1 is more common. Antibodies are detectable in 80-100% of adults in lower socioeconomic groups, and in 30-50% in higher socioeconomic groups. Both viruses are readily transmitted, mainly in vesicle fluid. HSV 1 is usually acquired during childhood, but HSV 2 infection is mainly transmitted sexually and is most common in sexually promiscuous adults. Clinical expression of infection with these viruses is strongly influenced by age, nutrition and the immunological state of the patient. An immunologically immature neonate is overwhelmed by disseminated HSV infection acquired during parturition. Infection in older children is often asymptomatic or causes localized disease which is most severe in the presence of malnutrition. 0 Primary infection with HSV 1 Acute herpetic gingivostomatitis in children 2-4 years old presents with fever, sore throat, and submental and anterior cervical lymphadenopathy. Clusters of vesicles appear around the lips and in the mouth from gums to pharynx (Fig. 9.8). Inside the mouth lesions rapidly ulcerate, causing pain and dysphagia with consequent drooling of saliva. The child is miserable and may become dehydrated if not encouraged to drink through a straw. The lesions heal over 1-2 weeks. Primary infection can occur anywhere on the skin and, on the finger, a herpetic whitlow can closely mimic a bacterial paronychia. Widespread involvement of the skin can occur in individuals with atopic dermatitis (eczema herpeticum, p. 399) and, particularly in infants, this can be associated

SUMMARY 4 Varicella zoster and herpes simplex infection

286

Primary

Reactivation

VZV HSV 1

Chickenpox Acute or asymptomatic gingivostomatitis Keratoconjunctivitis Encephalitis

Shingles Cold sores Keratoconjunctivitis

HSV 2

Genital

Genital

1

Fig. 9.1

2

MCQ 9.8

4

Fig. 9.3

5

Fig. 9.4

3

Fig. 9.2

FIG. 9.8 Gingivostomatitis caused by primary herpes simplex 1

with systemic symptoms. In the eye keratoconjunctivitis can cause scarring of the cornea and loss of vision. Herpetic encephalitis in adults presents a characteristic clinical picture owing to necrotic lesions in the temporal lobe. This rare manifestation of primary HSV infection is described on page 1422. Primary infection with HSV 2 Although HSV 1 and 2 can cause identical disease, HSV 2 is largely associated with genital infection (see p. 456). 4 Infection of neonates can occur during parturition when the mother has genital herpes, particularly if her infection is primary rather than recurrent. The infant develops scattered clusters of vesicles which recur in the same sites subsequently. Alternatively there may be rapid deterioration as the virus disseminates to all the viscera, causing encephalitis, pneumonia and hepatitis, with a high mortality. Usually this severe illness starts in the first few days after birth, but occasionally onset is delayed several weeks. Reactivation of HSV The mechanisms involved in maintaining latency are not fully understood. Reactivation may occur after exposure to ultraviolet light, an episode of infection or trauma to the sensory nerve. Many episodes have no identifiable precipitant. Reactivation is more common in irnmunocompromised patients, particularly those with leukaemia undergoing treatment. The characteristic lesion of reactivated HSV 1 is a cold sore. Patients often experience minor discomfort in the form of tingling or itching up to 24 hours before a lesion appears. Lesions can occur anywhere on the skin or mucous membranes, but are commonly adjacent to the lips. 5 A macule rapidly progresses to a papule and then to a cluster of vesicles which involute, ulcerate and scab. The whole process takes 1-2 weeks. See Chapter 11 for symptoms of reactivation of genital herpes (p. 456).

underdeveloped countries and in crowded living conditions, but infection is delayed in more prosperous environments. Infection in adolescents and adults usually causes infectious mononucleosis (glandular fever). Other diseases related to EBV infection are nasopharyngeal carcinoma, Burkitt's lymphoma, the very rare syndrome of X-linked recessive progressive combined variable immunodeficiency, and lymphoid interstitial pneumonitis in children with AIDS.

9

Infectious mononucleosis Infectious mononucleosis is an acute febrile illness caused by EBV and characterized by a severe sore throat and generalized lymphadenopathy. Pathology and pathogenesis EBV enters through the pharyngeal epithelium and replicates in B lymphocytes, causing them to proliferate. Fifteen per cent or more of blood mononuclear cells appear 'atypical' during acute infection: these are T lymphocytes reacting to the presence of infected B lymphocytes. EBV does not establish a true latent state but maintains a low level of replication throughout life. During infectious mononucleosis, the spleen and lymph nodes are intensely infiltrated with mononuclear cells and the spleen is unusually friable. Haemorrhage may occur into the subcapsular area, and rarely this leads to intraperitoneal haemorrhage. Clinical features Infectious mononucleosis is most common in adolescents and young adults, but children as young as 5 years old may be affected. The illness is more severe in older patients. The incubation period is uncertain but is probably 1-2 weeks. There is a gradual onset of malaise, general aching and fever. The throat becomes painful and engorged with enlarging lymphoid tissue, so that speech is nasal and swallowing is inhibited by pain. The tonsils are large and coated with thick, white exudate (Fig. 9.9). Petechiae may be seen on the soft palate. There is generalized lymphadenopathy

Management of herpes simplex HSVs are highly sensitive to aciclovir and other DNA polymerase-inhibiting drugs. Only serious primary infections with HSV 1, such as encephalitis in adults, severe eczema herpeticum or disseminated neonatal infection, warrant treatment with systemic antiviral drugs. The usual dose of aciclovir for intravenous treatment of herpes simplex is 5mg/kgt.d.s., but for encephalitis l0mg/kg is needed. Initial attacks of genital herpes are treated with 5 days of aciclovir, with an antibiotic if secondary infection has occurred. For recurrences attention to local hygiene is all that is required and 5% aciclovir ointment may be helpful for local lesions.

Epstein-Barr virus infection Epstein-Barr virus (EBV) is a herpes virus which is transmitted by close oral contact. Infection is frequently acquired asymptomatically during early childhood in

FIG. 9.9 Acute tonsillopharyngitis caused by primary Epstein-Barr virus infection

287

in most patients and splenomegaly is common. Uncommon features (occurring in less than 15% of patients) are rash, jaundice and tender hepatomegaly. Thrombocytopenia or autoimmune haemolytic anaemia occur rarely. The acute stage of the illness lasts 2-3 weeks and most patients are entirely well within a month. A small proportion of patients, particularly when older, make a slower recovery, continuing to feel lethargic for a variable period (see Chronic fatigue syndrome, p. 283). Differential diagnosis Other viral causes of sore throat and lymphadenopathy, such as adenovirus, influenza virus and rhinovirus, must be considered (see Table 9.16). Streptococcal infections can cause an identical appearance in the throat, but the lymphadenopathy is mainly in the anterior cervical region. Streptococci are found on throat swabs in 10% of patients with infectious mononucleosis and their role is unclear. Many virus infections are associated with atypical lymphocytes on the blood film, but these can be distinguished from glandular fever cells by an experienced observer. Atypical lymphocytes are also seen in acute CMV infection and occasionally in toxoplasmosis. Both of these conditions can cause lymphadenopathy but they rarely produce sore throat. Laboratory features Atypical mononuclear cells are usually present in the blood film at some stage of the disease. Tests for heterophil antibodies, i.e. antibodies to heterologous erythrocytes, are the Paul-Bunnell and Monospot tests. Heterophil antibodies are present in 90% of patients by the third week of illness, but in only 30% during the first week. Specific IgM antibody measurements are not reliable. Liver function tests are often abnormal. Management No specific treatment is available. Simple analgesic therapy is used to relieve discomfort in the throat, and frequently the patient can only take fluids in the early stages. Occasionally the degree of congestion is such as to threaten the airways; a short course of prednisolone, starting at 30 mg daily and tailing off over 2 weeks, can produce a rapid reduction in the size of the tonsils. If penicillin therapy is indicated for treatment of concurrent Streptococcal infection, ampicillin and amoxicillin should be avoided as they cause a severe maculopapular rash. X-linked recessive progressive combined variable immunodeficiency (Duncan's disease) This rare inherited disease is now recognized as an abnormal response to EBV infection. Patients either die of overwhelming EBV infection in the acute stage or develop

288

1

MCQ 9.9

4

MCQ 9.10

2

Fig. 9.5

3

Fig. 9.6

a progressive immunodeficiency following infection. Lymphoma may complicate the late stages. 1

Cytomegalovirus (CMV) infection CMV is a herpes virus which rarely causes significant disease in immunologically competent subjects. Infection is usually asymptomatic, but it may be associated with a mild febrile illness during which atypical mononuclear cells appear in the blood; these cells are similar to those seen in infectious mononucleosis. Primary infection in the neonate causes serious disease, and primary infection of pregnant women can cause congenital defects in the fetus. As with other herpes viruses, infection is lifelong. CMV replicates at a low level throughout life, but when immunity is suppressed the rate of replication increases. Patients with kidney or heart transplants are particularly at risk, and CMV sometimes causes severe disease in patients with AIDS (pp. 446-448). Transmission The virus is present in blood during primary infection and can cross the placenta. It can also be transmitted in blood used for transfusion. Infected organs transplanted from seropositive donors can cause primary infection in the recipient, but most CMV disease in renal transplant patients is caused by reactivation. The virus is shed from the cervix during active infection and is also present in semen and urine. Acute infection in normal adults There may be a mild febrile illness which is recognized as viral infection when atypical mononuclear cells are seen in a blood film. Sore throat, generalized lymphadenopathy and splenomegaly occur in less than one-third of patients. Abnormal liver function tests show that there is usually a mild hepatitis, but jaundice is rare. The average age for symptomatic infection is 30 years, about 10 years older than for infectious mononucleosis. Complications are rare in immunocompetent patients, and when they occur they are mild. Pneumonitis, myocarditis, meningoencephalitis, Guillain-Barre syndrome, thrombocytopenia and haemolytic anaemia have all been described. Infection in immunosuppressed patients Both primary infection and reactivation can cause disease in immunosuppressed patients, but in renal transplant recipients the more severe disease is seen during primary infection. Asymptomatic reactivation is common and is shown by culture of virus from urine. Fever, sometimes with atypical mononucleosis, is the most common presentation of disease, followed by interstitial pneumonitis. Interstitial pneumonitis presents with insidious onset of fever, a non-productive cough and dyspnoea. Chest radiography shows bilateral diffuse interstitial changes indistinguishable from those of many other opportunistic

infections. Diagnosis is usually made by transbronchial biopsy. Hepatitis is usually mild, but occasionally causes hepatic failure. CMV may be a harmless passenger in the gastrointestinal tract of patients. Its association with enteritis is strongly suggested by the coincidence of seroconversion and haemorrhagic lesions anywhere from the stomach to the rectum, causing a severe diarrhoeal disease and blood loss. A response to treatment with antiviral drugs supports the existence of this clinical entity. In the mouth and oesophagus of AIDS patients, CMV can cause large punched-out ulcers. 2 Severe choroidoretinitis causes progressive loss of sight, starting in one eye and then affecting the other. Large white exudates containing haemorrhagic areas occur. 3 Diagnosis Virus can be cultured from urine, throat washings or buffy coat during active replication, and IgM antibodies are detectable in serum by an immunofluorescence test. In histological sections 'owl's eye' cells are strongly suggestive of CMV infection. Management Intravenous ganciclovir, 5mg/kgb.d. for 14-21 days, is the treatment of choice for immunocompromised patients with CMV disease. AIDS patients with retinitis have a high risk of relapse with loss of vision, and maintenance treatment can be given with oral ganciclovir 1gt.d.s. Bone marrow toxicity is common and an alternative treatment is foscarnet 200mg/kg for 14-21 days, with monitoring of renal function and serum calcium. 4

Human herpes virus 6 infection Human herpes virus 6 (HHV6) has recently been identified in patients with AIDS and has subsequently been found to be widely distributed. It is the cause of roseola, a common febrile illness of young children characterized by the appearance of a rash when the fever and illness are resolving. The temperature is high but the child is relatively well. There is often cervical and postauricular lymphadenopathy. When the temperature starts to fall, or within 2 days, a maculopapular erythematous eruption appears on the trunk: this lasts for a few days. Blood count reveals neutropenia initially, which may be followed by mild leukocytosis. The illness resolves without complications.

Human herpes virus 8 (HHV8) or Kaposi's sarcoma (KS)-associated herpes virus HHV8 has been identified consistently in KS lesions of AIDS patients and it is now thought to be the cause of this spindle cell tumour. Epidemiological studies show that asymptomatic infection is common in Mediterranean and African countries where KS occurred independently of

HIV infection. It is likely that cofactors are required for the development of KS, but these have not yet been identified. Despite the relationship between KS and AIDS in homosexual men, transmission of HHV8 between individuals is likely to be similar to that of EBV, as infectious virions have been found in saliva. It is rarely detected in semen even though viral DNA is detectable in the prostate. Treatment of AIDS patients with antiretroviral drugs, particularly protease inhibitors, results in regression of KS lesions (see Chapter 11).

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POX VIRUSES Variola and vaccinia Variola virus is the cause of smallpox, an infection of low infectivity transmitted between humans by close contact. Immunization introduced globally using the refined vaccine containing vaccinia virus led to the eradication of smallpox in 1979, and only accidental laboratory infections have occurred since then. Vaccination against smallpox is no longer justified.

Orf virus infection Orf virus causes a single nodular lesion at the site of an abrasion which has been in contact with an infected lamb.

ENVELOPED SINGLE-STRANDED DNA VIRUSES PARVOVIRUS The association between infection with human parvovirus and disease has only been recognized since the 1980s. The virus was first noticed in sera from normal subjects during screening by electron microscopy (1975), but in 1983 it was reported to be the cause of erythema infectiosum ('slapped cheek disease' or 'fifth disease'). A more serious consequence is that the virus can cause aplastic crises in patients with sickle cell disease.

Clinical features of erythema infectiosum Parvovirus infection is probably transmitted between humans by nasopharyngeal secretions and causes a range of illness ranging from asymptomatic to a febrile systemic illness with a rash. After a mild prodromal illness consisting of fever, headache, upper respiratory symptoms and myalgia lasting 2-A days, a rash appears on the arms and chest, spreading peripherally, even to the palms and soles. The classic 'slapped cheek' appearance of erythema infectiosum is seen in less than half of infected patients. Elsewhere the rash is maculopapular and fluctuates in intensity. It often develops a lacy reticular pattern on the limbs

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and leaves a short-lived pale brown pigmentation as it fades over a week. The rash is frequently pruritic. Other features during the rash are generally mild, but include fever, malaise, headache and sometimes arthralgia, lymphadenopathy and splenomegaly.

Complications Complications are rare. Adult women may develop symmetrical peripheral polyarthritis, which can be the sole manifestation of infection. Although it usually resolves within 3 months it may continue for several years. Aplastic crises are not a feature of infection in patients who are otherwise normal haematologically, but when the red cell life is reduced, as in sickle cell disease or hereditary spherocytosis, arrest of erythropoiesis for 5-10 days causes a significant fall in haemoglobin level. The same effect has been observed in patients with advanced AIDS.

Diagnosis and management IgM serum antibodies detected by enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay (RIA) are diagnostic of recent infection and persist for about 2 months. A change in litre of IgG antibodies also indicates recent infection. Virus isolation is not feasible and detection of viral protein is reserved for research purposes. There is no specific treatment at present.

NON-ENVELOPED DOUBLE-STRANDED DNA VIRUSES

affects adults and often follows minor trauma to the eye. Type 8 is the usual pathogen. Haemorrhagic cystitis. Caused by types 11 and 21, haemorrhagic cystitis is a childhood infection. Adenoviruses are also uncommonly associated with diarrhoeal disease, intussusception, and meningitis or encephalitis. Diagnosis of adenovirus infection is usually made on clinical grounds. It can be confirmed by virus isolation or by identification of viral antigen by immunofluorescence where these techniques are available, or by detecting a rise in serum antibody titre. There is no effective antiviral treatment, but most disease is mild and self-limited.

PAPOVAVIRUSES The important members of the papovavirus group are papilloma or wart viruses and polyoma viruses. Palmar and plantar warts are benign infections, common in childhood, which often regress spontaneously with increasing age. They are caused by viruses which are distinct from the anogenital warts viruses; the latter are sexually transmitted (see Ch. 11, p. 456, and Ch. 10, p. 393).

Genital warts See Chapter 11 (p. 456).

ENVELOPED SINGLE-STRANDED RNA VIRUSES ORTHOMYXOVIRUSES

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ADENOVIRUSES

Influenza virus infection

Adenoviruses are a common cause of upper respiratory infection in children and cause a variety of other illnesses, depending on the serotype of virus and the age of the patient. Over 40 serotypes have been isolated from humans, and many of these are known to have pathogenic potential. Virus can frequently be isolated from the posterior pharyngeal lymphoid tissue of asymptomatic subjects, suggesting that it can remain latent for long periods. Upper respiratory infection. Common cold and pharyngitis occur in all age groups, and serotypes 1-6 are the usual cause. Lower respiratory infection. Tracheobronchitis and pneumonia are rare in children but young adults may be affected. This is one of the differential diagnoses of atypical pneumonia. Types 4 and 7 are the most common causes. Pharyngoconjunctival fever. An acute infection spreads among young children in close contact, often caused by adenovirus type 3. Epidemic keratoconjunctivitis. Epidemic keratoconjunctivitis is a more severe form of eye infection which

Influenza types A and B are the main viruses in this family, but there is also a type C virus. Influenza is an ancient disease characterized by regular winter epidemics, with occasional much larger outbreaks (pandemics) when there is a major shift in antigenic type against which there is little immunity in the population. Although the disease is normally mild and self-limiting, the elderly and those with chronic chest disease are susceptible to complications, resulting in a considerable mortality. Epidemiology Epidemics of influenza start with cases in children and spread to the adult population. As the epidemic progresses, vulnerable adults start to present in hospitals and the size of the epidemic becomes apparent when absenteeism causes problems at work and in schools. Epidemics usually peak within 3 weeks and last about 6 weeks. They occur in winter - December to April in the northern hemisphere and May to September in the southern hemisphere. In tropical countries virus isolates can be obtained year

round, but epidemics tend to occur after changes in weather, whereas in temperate climates it is rare to find the virus in the community between epidemics. Surprisingly, several variants of the virus are found to be circulating during an epidemic, but they are sufficiently similar to previously recognized viruses for some crossimmunity to exist. Variants that appear late in the course of an epidemic are sometimes the ones responsible for an outbreak during the following winter. Pandemics have occurred infrequently over the last century, in 1889, 1918, 1957, 1968 and 1977. They result from the emergence of new viruses in which there are major changes in the surface proteins, mainly neuraminidase and haemagglutinin, against which the populations of the world have no immunity. The mechanism for these changes is likely to be genetic reassortment and some evidence suggests that this occurs in animal reservoirs, such as birds and lower mammals. Two neuraminidases and three haemagglutinins have been detected at various times in the last century and these are recognized in the name given to a subtype of virus. For example, the virus responsible for the 1918 epidemic was H1N1, and another severe epidemic in 1957 was caused by H2N2. The severity of an outbreak is determined by the extent of change in antigenicity of the virus, so that if the neuraminidase and the haemagglutinin both undergo a major change, the severity of disease and the size of the epidemic are greater than if only one determinant changes. After a major antigenic shift causing a pandemic, smaller variations in antigenicity known as antigenic drift occur over a variable period (9-30 years in the past century) and the population gradually builds up immunity to the possible variants of the new virus subtype. The scene for the next major antigenic shift may be set by the level of herd immunity to the subtype variants, but other factors probably make a contribution also. Clinical features Influenza is transmitted by droplets of respiratory secretions and the incubation period is 1-3 days. Influenza A and B cause a similar illness, but influenza C only gives rise to sore throat. The onset of influenza is rapid, with symptoms of fever, including chills, sweats and sometimes rigors accompanied by malaise, anorexia, headache and marked myalgia. The severity of general symptoms varies greatly between individuals, from mild to prostrating. They are worst in the first 3 days and usually disappear within a week. Cough and sore throat are variable features which tend to increase as other symptoms subside and resolve over 2-3 weeks. On examination the patient is initially febrile, flushed and tachycardic, with minor nasal discharge. The pharynx may be inflamed and cervical lymph nodes palpable and tender. Complications The elderly are more vulnerable to all complications. The

most common is exacerbation of chronic bronchitis, and this is responsible for most adult admissions to hospital in influenza epidemics. Asthma is also exacerbated. Bacterial pneumonia, often caused by Strep, pneumoniae, Staph. aureus or H. influenzae, can occur in chronic bronchitics or patients with no previous history of chest disease, but it is more common in smokers. Viral pneumonia caused by influenza virus itself is a severe complication which usually occurs in patients with underlying disease of the chest or cardiovascular system, although in some epidemics it has affected previously healthy adults, suggesting that virus virulence is a factor. This type of pneumonia is bilateral, with opacities on the chest radiograph which do not correspond to clinical signs, low diffusing capacity and a progressive course. Other rarer complications include myositis, myocarditis, pericarditis, Guillain-Barre syndrome and encephalitis.

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Diagnosis Influenza virus can be cultured from respiratory secretions, but the diagnosis is more often made by serum antibody measurement using paired sera. When an epidemic is in progress a clinical diagnosis suffices. Management and prevention Zanamivir (Relenza) has been the subject of controversy, as governments have been unconvinced that it should be licensed for general use. It is a competitive inhibitor of viral neuraminidase which is active against a range of influenza A and B subtypes, giving it a clear advantage over amantidine which is only active against influenza A. Zanamivir, given by inhalation and intranasally, has been shown to be effective in reducing virus shedding, shortening the duration of symptoms, and in prophylaxis. Trials have not been completed in groups at highest risk from influenza, including the elderly, and the cost/benefit ratio has been judged too high to justify licensing the drug at present. Amantadine and rimantadine, which interact with the M2 membrane protein of influenza A, have more sideeffects than zanamivir and are rarely used. Comparative trials have not been carried out. Symptomatic treatment with analgesics such as paracetamol and maintaining adequate hydration are important. Aspirin should be avoided in children because of the danger of precipitating Reye's syndrome. Secondary bacterial infection causing bronchitis or pneumonia is the most serious complication which requires antibiotic treatment with co-amoxiclav (250 mg amoxicillin t.d.s.) or a macrolide such as erythromycin (250 mg q.d.s.) in penicillin-allergic subjects. If staphylococcal pneumonia is suspected, flucloxacillin (250mg q.d.s.) should be given. Inactivated viral vaccine containing the currently prevalent strains of influenza A and B is recommended for persons at special risk, especially the elderly and those suffering from chronic pulmonary, heart or renal disease, diabetes, and those with some forms of immunosuppres-

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sion. The vaccine is usually given in the autumn and confers about 70% protection for a year. O

PARAMYXOVIRUSES Para influenza virus infection There are four types of parainfluenza virus and the organisms are a common cause of mild upper respiratory infection in children under 2 years of age (Ch. 13). Types 1-3 occasionally cause more severe lower respiratory tract disease, such as croup and bronchiolitis. Although there is little antigenic variation in parainfluenza viruses, immunity is poor and reinfection causing mild disease is common.

Respiratory syncytial virus infection Respiratory syncytial virus (RSV) is the most important cause of lower respiratory tract infection in young children. Outbreaks occur annually, usually in late winter or spring, and about half of primary infections result in pneumonia, bronchiolitis or tracheobronchitis. Upper respiratory involvement is also common and otitis media is a frequent complication. Children over the age of 3 usually suffer milder disease, and adults are occasionally infected. Severe infection can occur in adults following bone marrow transplantation. RSV is highly infectious and is commonly transmitted to other patients in hospital. Respiratory isolation procedures should be applied and management is general support, with oxygen as required and maintenance of hydration. Successful therapy for RSV has been described in immunocompromised adults using ribavirin administered as an aerosol, but in practice this is difficult to apply.

Mumps Mumps is a systemic paramyxovirus infection which commonly causes inflammation of the salivary glands. It is transmitted by droplets from the mouth. Infection in childhood is common but infectivity is low, and many people reach adulthood without becoming affected. Clinical features The incubation period is about 18 days (Fig. 9.1, p. 261). Mumps is a mild disease in childhood and about one-third of children infected have no symptoms. In its mildest form there is fever with discomfort and swelling in the parotid glands, which lasts a week or less. In more severe forms there is considerable malaise, the glands are painful and there may be trismus. Other salivary glands are often inflamed and glands are sometimes involved sequentially.

1

292

MCQ 9.11

2

Fig. 9.7

Swollen parotid glands can be distinguished from lymphadenopathy because the angle of the mandible is obliterated by the former. The mouth is dry and there may be redness around the orifices of the parotid ducts, but there is no purulent discharge. About 20% of adult males develop orchitis in the course of mumps, but oophoritis is rare. Usually orchitis starts a few days after the onset of parotitis, but it may be earlier and may occur in the absence of parotitis. The swollen inflamed testicle is exquisitely tender and remains so for 3-4 days before gradually recovering. Orchitis is accompanied by fever and malaise, and the latter often persists for some weeks. Orchitis is bilateral in 15-30% of cases, but even in these patients sterility is extremely rare. Although some shrinkage of involved testicles may be detected shortly after the illness, this does not imply complete loss of function and it is important to reassure patients on this point. Mumps virus is highly neurotropic and involvement of the CNS is the most common complication of this infection. There are two distinct entities, meningitis and encephalitis. Lymphocytic meningitis occurs in about 5% of patients with mumps parotitis, but this figure underestimates its prevalence as it also occurs in the absence of parotitis. There is some seasonal variation in the clinical manifestations, meningitis with parotitis being more common in spring, whereas meningitis alone is seen more in summer. The time of onset of meningitis varies, but it usually becomes apparent a few days after parotitis. The CSF shows a lymphocytic pleocytosis and virus can be isolated from it. The course is invariably benign. Encephalitis is rare. It either occurs during parotitis as a result of direct viral invasion of the brain, or its onset is 7-10 days after that of parotitis, when it represents a postinfectious encephalitis. Most patients recover completely, but there is a mortality of 1-2%. Pancreatitis is rarely severe but may account for some of the abdominal symptoms in mumps. Some degree of abdominal pain is not infrequent and may be accompanied by vomiting. In severe cases there is marked abdominal tenderness and the serum amylase and lipase levels are elevated. Diagnosis A clinical diagnosis usually presents little difficulty, but if necessary the virus can be isolated from saliva and throat washings, or from CSF in cases of meningitis. Complementfixing antibody detection can be used to make a retrospective diagnosis. Management There is no specific treatment, but oral hygiene is important both for comfort and to prevent secondary infection. Orchitis requires testicular support and adequate analgesia. There is little evidence that corticosteroid treatment is beneficial in orchitis.

SUMMARY 5 Mumps

SUMMARY 6 Clinical features of measles

Fetal death possible if infection in first trimester

• • • • •

Gland involvement Parotid Submandibular Epididymo-orchitis Oophoritis Pancreatitis

65% 10% 25% (postpubertal) 5% (postpubertal) ?%

Meningitis Encephalitis

<10% 0.1%

Prevention Vaccination with a live attenuated vaccine was adopted as part of the routine programme in the UK from 1988. It is given in combination with measles and rubella in the second year of life.

Measles Measles is an easily recognized, highly infectious disease of childhood caused by measles virus, an RNA virus of the paramyxovirus group. Epidemiology Infection is spread by droplets coughed on to mucosal surfaces of the conjunctiva and nasopharynx, and because cough is a feature of the illness from the onset it is not surprising that infection spreads rapidly between non-immune subjects. One of the interesting features of the disease in older epidemics was the high mortality rate. It is not clear whether measles virus has changed to a more benign form or whether environmental factors are responsible, but the latter is more likely as the disease is still severe in Africa. The size of the pool of non-immune humans determines whether there is an epidemic of measles. In the past, epidemics have occurred in Britain every 2 years or so, but immunization has made this pattern less apparent. Pothogenesis Measles virus can infect many different cell types and during the incubation period, which is 8-11 days from infection to the onset of prodromal symptoms (Fig. 9.1, p. 261), the virus multiplies, becoming widely disseminated. It reaches most tissues, including skin, mucous membranes, lungs, gut, brain and lymphoreticular tissue. The lesions of measles, containing mononuclear and giant cells, are caused by a combination of viral cytopathic effect and non-specific and specific inflammatory reactions. The role of immune mechanisms is demonstrated by the modified or absent skin rash in immunodeficient subjects, who may nevertheless die from a giant cell pneumonia. Antibody is detectable in serum 24-48 hours after the onset of rash, and virus is rapidly cleared during this period.

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Incubation period 8-11 days Initial symptoms of upper respiratory infection Koplik's spots on buccal mucosa Rash spreads from face to trunk to limbs Complications (pneumonia, otitis media, encephalitis) more common in malnourished children

Clinical features In Britain measles is most common at the age of 3-5 years but the age is lower in underdeveloped countries. In the 2-4 days before eruption of the rash the features are similar to those of many upper respiratory infections. The patient feels unwell and has a fever, red eyes, swollen eyelids, a congested streaming nose, diffuse redness in the mouth and a hacking cough. Koplik's spots, 1-2mm white spots like a grain of salt on a red background, may be seen on the buccal mucosa. Their number varies from a few to hundreds, and they often persist after the rash appears. The worst of the illness is during the first few days after eruption of the rash, when there is a spiking fever and the child is irritable and miserable. Spots appear first behind the ears and on the forehead and then spread to the rest of the face, on to the trunk and out to the limbs over 24-72 hours. © This pattern of spread is characteristic, but the rash of rubella (German measles) spreads in the same direction. Measles spots are red macules and maculopapules initially a few millimetres in diameter, which enlarge and coalesce to form irregular blotches, the most striking of which are on the cheeks. As the rash fades and the patient starts to feel better there is transient brown staining of the skin and sometimes fine desquamation. At the height of the eruptive stage the mucous membranes and eardrums are red, and there is generalized lymphadenopathy, a barking cough and widespread crackles in the chest. Complications Major complications are rare in Britain today. All complications are more common in malnourished children, and severe skin desquamation with secondary bacterial infection, diarrhoea, appendicitis, laryngitis, stomatitis and major weight loss all occur frequently in Africa. Measles sometimes precipitates the onset of kwashiorkor. Secondary bacterial infection usually manifests itself 3-4 days after the rash and prolongs the illness. The timing is an important clue, as renewed fever heralds a third phase of illness. Bronchopneumonia and otitis media are examples. Giant cell pneumonia is rare and usually affects immunocompromised children, such as those with leukaemias. Febrile convulsions may occur as the temperature rises in the incubation period or at the beginning of the eruptive phase. Encephalitis is rare and varies in severity. It occurs in the convalescent phase and in fatal cases virus is not recovered from the brain, so encephalitis may be

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caused by an immune reaction to viral antigen in neural tissue. Subacute sclerosing panencephalitis (SSPE, p. 1426) is a progressive fatal form of encephalitis affecting older children who had measles many years before. High litres of measles antibodies and recovery of a measles-like virus from the brain suggest that it is related to measles. Diagnosis Clinical diagnosis of measles is usually straightforward. The rash of rubella has a similar distribution, but lesions are smaller and they tend to remain discrete. Rubella is a milder illness with a characteristic distribution of lymphadenopathy (occipital and posterior cervical). Laboratory confirmation of measles is rarely necessary, but measles virus can be cultured from nasopharyngeal specimens during the prodrome and for about 2 days into the eruptive phase. A blood count normally shows leukopenia, and neutrophilia suggests secondary bacterial infection. Antibody litres are measured by a complement fixation test. Management Most children with measles are looked after at home, but if hospital admission is required for social reasons or because of complications, the patient should be nursed in isolation. Antiviral treatment is not available at present and management is directed at providing comfort and maintaining hydration. Prophylactic antibiotics have no place, but appropriate antibiotics must be given for secondary bacterial infection. Important organisms in respiratory infection and otitis media are Strep, pneumoniae, H. influenzae and, less commonly, Staph. aureus. Therefore, the usual first choice of antibiotic is a broad-spectrum penicillin (e.g. amoxicillin) or erythromycin. Management of encephalitis is described on page 1423. Passive immunization with 500 mg normal human immunoglobin intramuscularly (250 mg for children less than 1 year old) attenuates or prevents clinical manifestations if it is given within 6 days of contact. This is useful in children under 18 months and in those made susceptible to severe forms of measles by immunosuppression. Protection lasts for about 3 weeks.

SUMMARY 7 Management of measles • • • •

General support including hydration Antibiotics for secondary bacterial infection Respiratory isolation Normal human immunoglobulin for children under 18 months if within 6 days of contact or immunosuppressed

1 294

MCQ 9.12

2

MCQ 9.13

FIG. 9.10 Notifications of, and deaths from, measles in England and Wales, 1940-2000 The impact of MMR vaccination is clearly visible.

Active immunization Live attenuated measles virus vaccine is given in the second year of life in Britain. In parts of the world where the disease is common in younger children immunization is recommended at an earlier age. A single subcutaneous or intramuscular dose gives prolonged protection. Contraindications are immune deficiency disease (primary or secondary), immunosuppressive therapy, and severe egg allergy. Atopy and febrile convulsions do not preclude use of the vaccine. The uptake rate for immunization has increased since the introduction of MMR vaccine in the UK and measles has become uncommon (Fig. 9.10), following the same pattern as in the USA. O

TOGAVIRUSES The togavirus group comprises the rubella virus, alphaviruses and flaviviruses. Rubella is the commonest togavirus infection in the western world. Alphaviruses are the cause of Eastern, Western and Venezuelan equine encephalitis. Flaviviruses cause dengue and yellow fever.

Rubella Postnatal rubella (German measles) is a mild illness occasionally complicated by arthritis or encephalitis. By contrast, infection in utero can have devastating effects on the fetus. Pathogenesis Rubella virus infects nasopharyngeal secretions, where it is found during subclinical as well as overt infection. During the viraemic phase it is disseminated widely and, as for

measles, the clinical illness corresponds in time with the development of immunity. The incubation period for rubella is 14-16 days. Clinical features Like measles, rubella is associated with fever, lymphadenopathy, rash and conjunctival suffusion, but it is a mild, short-lived illness which may be asymptomatic. The lymphadenopathy of rubella is characteristically suboccipital, postauricular and posterior cervical. It may persist long after the rash has faded. Although, as in measles, the rash starts on the face and behind the ears, spreading downwards and outwards over the trunk and limbs, the spots are paler red, circular macules which remain discrete and do not coalesce into brighter irregular blotches. The rash varies from hour to hour, fading and reappearing for up to 4 days. It is common to find petechiae on the soft palate (Forchheimer spots), but these are not diagnostic. Complications Arthritis is the only common complication of rubella. It usually affects young women, who develop polyarthritis of small joints, especially those of the fingers and wrists, although larger joints may be affected. It is easily confused with acute rheumatoid arthritis, especially in the absence of rash. It usually subsides within a few days but can last up to 3 months. Encephalitis and thrombocytopenic purpura are very rare complications. Congenital rubella Both the risk and the severity of damage to the fetus are closely related to the time of infection. Following infection during the first month of pregnancy over half of fetuses are affected, whereas by the fourth month only 5% have defects, although this is still twice the frequency in control groups. Minor damage can result from later infection. During the viraemic phase of the maternal illness rubella virus invades the placenta, causing villous placentitis, and then disseminates through the fetal circulation. The degree of damage is variable, even in twins infected at the same time. The common major abnormalities resulting from infection in the first trimester are cataracts, patent ductus arteriosus with or without pulmonary stenosis, and deafness. Rubella virus can be isolated from the baby's pharynx for several months, a much longer period than in acquired rubella. The virus is present in all other secretions, and these babies can readily infect nurses handling them. Diagnosis Serology is the mainstay of diagnosis in both congenital

SUMMARY 8 Clinical features of congenital rubella Cataracts Cardiac abnormalities - patent ductus, pulmonary stenosis. Deafness

and acquired rubella. In the haemagglutination inhibition (HAI) test, the virus agglutinates chick red cells. Serum antibodies inhibit this agglutination. A rise in total antibody titre or the presence of specific IgM antibodies indicates recent infection. In acquired infection antibody is detectable by HAI 14-16 days after infection and reaches a peak 6-12 days later. The fetus starts to produce IgM antibody at about the 20th week of life, and as only IgG antibody can cross the placenta the presence of IgM antibodies to rubella virus in the fetus or infant implies active infection. Rubella virus can be cultured from clinical specimens, but this is rarely used for diagnosis.

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Immunization Live attenuated virus vaccine is given routinely as part of the measles/mumps/rubella (MMR) vaccination to boys and girls aged 15 months. This was introduced in 1988 and replaces the policy of immunizing girls aged between 11 and 13 years. Vaccine virus can cross the placenta so it should not be given during pregnancy, and pregnancy should be avoided for 2 months after immunization. Exposure to rubella during pregnancy Definite exposure to rubella of a non-immune pregnant woman during the first trimester is an indication for termination of pregnancy. If the woman does not know whether she is immune to rubella, the following course of action is recommended: • If possible, establish by serology the diagnosis of rubella in the patient with whom the pregnant woman was in contact. Find out whether contact was close enough to allow transmission of virus. • Test the pregnant patient for rubella antibodies: - // positive by HAI within 14 days of exposure to rubella, the patient was immune previously and she can be reassured. - // negative by HAI then test a further sample 2-3 weeks from contact. If the second serum is positive or if IgM antibodies are detected, discuss risks and offer termination. Some women prefer to continue with the pregnancy despite the risk to the fetus. In this case intramuscular rubella immunoglobulin should be given as soon as possible after exposure. 2

FLAVIVIRUSES Dengue Dengue is an arthropod-borne (arbovirus) flavivirus infection characterized by an acute febrile illness with severe bone pain, rash and lymphadenopathy. The vectors are Aedes mosquitoes. The dengue virus is a 50 nm RNAcontaining flavivirus. Four serotypes are recognized, and these can be differentiated in a range of standard serological tests. The serotypes are closely related antigenically,

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FIG. 9.11 World distribution of dengue fever, 2000 (Source: Centers for Disease Control and Prevention)

but cross-protection between serotypes is lacking. The dengue shock syndrome and haemorrhagic fever occur in patients, particularly children, experiencing a second infection with a different Dengue serotype. Distribution and incidence Over the last three decades epidemics of dengue have occurred in all continents in the tropics, Africa, Asia, the Americas and the Pacific (Fig. 9.11), such that it is now the commonest mosquito-borne infection, and 50% of the world's population live in endemic areas. With the spread of dengue there has been a corresponding spread in the incidence of dengue haemorrhagic fever (DHF) which until the 1970s was confined to southeast Asia. The reasons for this spread are incompletely understood, but include the increase in travel worldwide distributing the serotypes to new areas, decline in mosquito control so that Aedes aegypti has proliferated, and the rise of densely populated periurban slums with no sanitary facilities except those that encourage the proliferation of A. aegypti. Transmission and epidemiology The most common vector is Aedes aegypti, a day-biting mosquito that breeds in small collections of water in tin cans, car tyres etc. peridomestically, but other species have more limited roles in transmission. Eight to 11 days after ingesting dengue virus in a human blood meal the mosquito is infective; it remains infective for the rest of its life. Peak biting times are the 2-hour periods after dawn and before dusk. Both sexes and all age groups are susceptible to dengue provided they have not been infected before with that serotype. Dengue haemorrhagic fever has been predominantly a disease of children, but with spread to new areas

1

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Fig. 9.8

second infections, and hence DHF, are occurring in older age groups. Pathology and pathogenesis After inoculation the virus replicates in local lymph node cells. Viraemia follows and reticuloendothelial cells in skin and other tissues become infected. Local inflammatory changes occur around small vessels in the skin. Dengue haemorrhagic fever occurs in children who have previously been exposed to infection with a different serotype of the virus, or who have acquired antibody passively from their mother. Immune enhancement causes more cells to become more heavily infected through immune complex binding to Fc receptors. Cytotoxic T-cell memory is activated, causing enhanced clearance of virus but also resulting in excess cytokine release, with tissue-damaging consequences: increased vascular permeability, causing hypovolaemia and coagulation defects owing to the release of cytokines with procoagulant properties. Clinical features The incubation period is about 7 days prior to the onset of high fever, headache, eye pains, backache and chills. Limb pain is often severe in dengue and this gives rise to its common name, 'breakbone fever'. A blanching erythematous macular rash may appear on the third or fourth day of the illness. 1 Lymphadenopathy may be present. Encephalopathy, cardiomyopathy and liver damage also occur. Leukopenia is usual in the peripheral blood. In dengue haemorrhagic fever the patient is more ill, and blood pressure falls as a result of transudation of fluid from the vascular compartment. This fluid can accumulate in the abdominal cavity or in the pleural spaces. Monitoring blood pressure, haematocrit and platelet count in addition to urine output and conscious level give warning of its onset. There may be spontaneous bleeding into the skin and at other sites. The loss of circulating blood volume causes shock, with low blood pressure, rapid pulse, restlessness and abdominal pain (the dengue shock syndrome), which can have a mortality of 50% if untreated.

Diagnosis Virus can be isolated from blood using Aedes or mammalian cell lines. Virus can also be identified in blood using the polymerase chain reaction, and IgM antibody or a rising antibody titre in paired sera obtained 10-14 days apart are serological indicators of the diagnosis, although the serological response may not be so clear-cut in areas where populations are exposed to other flaviviruses. Management Patients with uncomplicated dengue require supportive measures, such as attention to nutrition and hydration and relief of pain. Paracetamol, not aspirin, should be used for pain relief and as an antipyretic. Intensive management of severe dengue haemorrhagic fever can reduce the mortality from 10% to 1% without highly sophisticated facilities. Intravascular volume is restored with Ringer's lactate, giving a volume equal to daily requirements plus 5% of body weight, and monitoring pulse, blood pressure and respiration to avoid overload. Plasma protein fraction and dextran 40 may also be given to replace colloid losses. Haematocrit should be monitored to assess progress. The need for fluid replacement may last only 1-2 days. No specific antiviral treatment is beneficial. Control Live attenuated vaccines are under development. It is important that they contain all four serotypes of the virus to avoid the risk of dengue haemorrhagic fever. Vector control comprises the removal of mosquito breeding sites, which are often collections of water in tins, tyres, tubs and water storage vessels around homes, and larviciding.

Yellow fever Yellow fever is an acute arboviral (arthropod-borne) infection caused by the yellow fever virus, a flavivirus. The illness is characterized by high fever, jaundice and encephalopathy in its severe form. The disease occurs in focal outbreaks in Africa, the Caribbean and Central and South America. This condition is prevented by the 17D attenuated live vaccine strain, which should be given to travellers to endemic areas and to indigenous populations in outbreaks. There are infrequent occurrences of importation of yellow fever to Europe, which can present as PUO or viral haemorrhagic fever. Distribution and incidence Sub-Saharan tropical Africa (especially West Africa), the Caribbean islands (most recently Trinidad) and South America (Brazil, Peru, Bolivia, Ecuador, Venezuela and Colombia) are the areas affected by yellow fever. Relatively small numbers of cases occur every year in these areas, although cases in isolated areas may go unreported. Transmission and epidemiology Transmission is shown in Figure 9.12. In South America, and Central and East Africa, a jungle cycle involves

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FIG. 9.12 Cycle of transmission of yellow fever virus Infected humans bring the virus from the jungle. Mosquitoes can breed peridomestically in small collections of water such as puddles and water pots.

monkey-mosquito-monkey and maintains the virus in the mosquito reservoir. Haemagogus mosquitoes are the vector. The epidemiology in savannah and forest-savannah areas involves other Aedes species with humans and monkeys. The insect vector passes infection to the next generation of mosquitoes by transovarial transmission. Non-immune persons of all races, all ages and both sexes are susceptible to infection. Prior exposure to other flaviviruses produces some degree of cross-protection. Men are at particular risk of infection because of occupations that take them into forests. Pathology and pathogenesis The liver is the main organ involved and shows mid-zonal necrosis of hepatocytes. Councilman bodies result from the degeneration of hepatocytes. The kidneys show acute tubular necrosis which may relate to shock and hypovolaemia. There may be haemorrhage into mucous membranes and the skin, associated with the bleeding tendency that is common in yellow fever. The underlying pathogenic mechanisms are poorly understood. Clinical features There is a range of severity of disease, from mild to severe life-threatening illness. The latter constitutes a minority of all those infected. The incubation period is about 6 days before the onset of headache and fever. More severe illness is associated with marked limb pains. Proteinuria is usual. High fever, headache, severe limb and back pain, chills associated with fetor, haemorrhages in the gums, and nosebleeds are early features in severe cases. There may then be a short period of remission of symptoms for up to 24 hours before the recurrence of fever with vomiting and jaundice. Bleeding into the gut, skin and other sites is usual in severe cases. Occasional cases are seen with organ damage limited to the heart or kidneys, causing cardiac or renal failure. Bleeding and renal failure are the main causes of the high mortality (up to 50%) in severe cases. Resolution in severe cases can take from 3 days to 6 weeks.

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Diagnosis The clinical features in severe cases suggest the diagnosis, but in milder cases without evidence of organ dysfunction the diagnosis may not be made. Virus can be isolated most often from blood taken in the first 4 days of clinical illness. Rising antibody titres in paired sera may also give the diagnosis, but serological tests may not be easy to interpret in people exposed to related viruses. Differential diagnosis In mild cases the range of febrile illnesses to be considered is extensive and includes malaria, typhoid, the prodromal phase of viral hepatitis, leptospirosis and rickettsial diseases. The presence of jaundice with fever prompts consideration of leptospirosis, malaria, East African trypanosomiasis, typhoid, biliary tract sepsis and Marburg virus diseases. Ebola virus fever and Lassa fever are other causes of haemorrhagic fever, although marked jaundice is not usual. Laboratory features Anaemia, leukopenia and thrombocytopenia are usual features in more severe cases. Conjugated bilirubin levels and transaminases are high in jaundiced cases. Coagulation abnormalities comprise prolonged prothrombin time, reduced fibrinogen levels and detectable fibrin degradation products. Renal failure with proteinuria, oliguria and raised creatinine and urea may occur. Prevention and control All travellers to endemic areas - apart from pregnant women, infants under 1 year and immunosuppressed patients - should receive the attenuated 17D yellow fever vaccine. Patients with yellow fever should be nursed under mosquito nets to prevent mosquitoes becoming infected. Vaccination is used to help control epidemics. Other arthropod-borne (arboviral) infections There are a considerable number of arboviruses that affect humans. In these infections the main clinical manifestations are fever, chills, joint pain and a maculopapular rash. Mild forms of the diseases are frequent. Vaccines are not available. Infections may emerge in cities if stagnant water is infected by mosquito larvae. The primary virus hosts are birds. A recent outbreak of acute viral encephalitis in New York is an example. 1

VIRAL HAEMORRHAGIC FEVERS (VHF) In the patient who has acquired a febrile illness in Africa, consideration must be given to the possibility of infection

1

298

MCQ 9.14

TABLE 9.18 Risk assessment for VHF A Strong suspicion Patient left a known endemic area in the previous 3 weeks, particularly healthcare personnel from such an area. Contact of confirmed case Laboratory worker who handled VHF viruses B Moderate suspicion Patient left tropical Africa in the previous 3 weeks, but from a rural area or small town not considered endemic Where the onset and clinical course of the fever are consistent with VHF C Low suspicion Patient left a major city in tropical Africa in previous 3 weeks where risk of VHF is negligible

with one of the agents of VHF, Lassa fever, Ebola or Marburg. It is necessary to make an assessment of risk based on information about the area visited, contact with sick people etc. (Table 9.18). In an endemic area (Table 9.19) isolation and observation of the patient will be necessary, depending on the likelihood of some other clinical diagnosis. Public health authorities should be informed to arrange serological and virological testing, epidemiological investigation, and initiate additional measures. For a patient seen in a non-endemic area the risk assessment outcome will determine where the case is nursed; for A and B (Table 9.18) that will probably be a high security isolation unit, whereas for C side-room accommodation with strict barrier nursing precautions will be adequate. The viruses causing VHF, a group of clinically similar infections, are from the bunyaviridae, arenaviridae and filoviridae (Table 9.20). They are characterized in the most severe forms by a bleeding tendency with purpura, ecchymoses in the skin, bleeding from mucosal surfaces, and often bleeding into lungs, gut and other internal organs; haemoglobin levels fall rapidly. Disease onset is abrupt, with severe headache, rigors, myalgia, and an erythematous flush of the face and chest. Often patients have been treated for infections over the first 10-12 days with antimalarials initially, followed by an antibiotic for typhoid. Progressive renal failure can occur. Not all patients with these infections develop severe clinical disease: some have a febrile illness which settles without these severe features. Treatment in severe cases is supportive, with restoration of blood volume by transfusion with platelet support if possible, and dialysis if there is renal failure. Lassa fever is an exception in which ribavirin is known to be effective. In managing such patients it is essential at the outset to diagnose more common, treatable, causes of fever, particularly falciparum malaria.

Lassa fever This acute febrile illness was first described in patients who came from the village of Lassa in eastern Nigeria near the border with Cameroon. It is an arenavirus (RNA) infection characterized by high sustained fever, ulcerative pharyngitis and swelling of the neck in typical cases.

TABLE 9.19 The distribution of viral haemorrhagic fever viruses Lassa fever virus Ebola virus

Marburg virus Arenaviral haemorrhagic fevers in South America Hantaviral haemorrhagic fever with renal syndrome

Guinea, Liberia, Sierra Leone, Nigeria Congo, Gabon, Sudan, Cote d'lvoire, Uganda Reston strain in monkeys from Philippines (infectious but avirulent in humans) Uganda, western Kenya, ?Zimbabwe Brazil, Argentina, Bolivia Asia, the Americas, Europe

TABLE 9.20 Causes of viral haemorrhagic fever Type of virus

Bunyaviridae Hanta Crimean-Congo HF Rift Valley California encephalitis Arenaviridae Lymphocytic choriomeningitis Lassa Junin Machupo Guanarito Sabia Filoviridae Marburg Ebola

Disease HF with renal failure HF Fever (+retinitis in 10%); HF in 1% Encephalitis/meningoencephalitis Aseptic meningitis Lassa fever Argentine HF Bolivian HF Venezuelan HF Brazilian HF

HF HF

HF = haemorrhagic fever

Transmission and epidemiology Mastomys nataliensis, the multimammate rat, is the reservoir of infection and persistently excretes virus in its urine, which contaminates food eaten by humans. Person-toperson spread occurs through contact with body fluids. Infection can occur through cuts and needle-stick injury, or contact of body fluids with mucosal surfaces. In endemic areas, which include Nigeria, Sierra Leone, Liberia and other west African countries, there is a range in severity of disease with appreciable numbers of mild infections; severe infection occurs in 5-10% of cases with a hospital mortality of 15%. Children develop less severe disease than adults. Clinical features After an incubation period of up to 17 days there is a gradual onset of fever with anorexia, lethargy and headache. In the second week of illness ulcerative pharyngitis and swelling of the neck and face may occur. Vomiting, diarrhoea, cough and abdominal and chest pain also occur. A maculopapular rash may appear on the face, trunk

and upper limbs in the second week. Bleeding occurs in the third week and affects gums, nasal mucosae, gut and other sites. Fatal cases show declining renal function and oliguria, declining conscious level and secondary bacterial infections. Leukopenia, low albumin, raised urea and elevated transaminases with normal platelet counts are also evident. Neutrophil leukocytosis can be a feature later in the course. Platelet function is abnormal. An aspartate transaminase of greater than twice normal is associated with rising mortality.

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Diagnosis This may have to depend on clinical features in endemic areas, but virus can be identified in body fluids by electron microscopy, in cell culture and by PCR. Serological testing is also used. Management Supportive measures are used, with maintenance of fluid balance, analgesia and antipyretics, avoiding aspirin because of impaired platelet function. Ribavirin given intravenously reduces mortality if given in the first week of the illness: 30mg/kg as a loading dose, followed by 15mg/kg 6-hourly for 4 days, then 7.5mg/kg 8-hourly for a further 6 days. Close contacts should be treated immediately they develop a fever. Diagnosed cases in Europe and North America are managed in secure isolation facilities to give maximum protection to staff caring for the patient, but in endemic areas standard barrier nursing precautions are adequate. Oral ribavirin treatment may be given to staff and others exposed to the virus by needle-stick or other injury.

Marburg and Ebola virus disease These viruses also cause VHF. They are members of the filoviridae. Marburg was first recognized in 1967 as causing an outbreak among staff at a laboratory in Marburg, Germany, as a result of handling a recently arrived shipment of African green monkeys from Uganda. There were also cases in former Yugoslavia as a result of exposure to monkeys from the same shipment. The next outbreaks were of Ebola virus infection. These occurred in southern Sudan and in what was then Zaire in 1976; despite the similar temporal occurrence these outbreaks were caused by different strains of the same virus. Subsequently there have been outbreaks in Sudan, Gabon, Cote d'lvoire and Zaire. There were also outbreaks of disease in non-human primates. Epidemiology and transmission No reservoir has been identified for filovirus infection, though it is likely to be an animal. Chimpanzees and a range of monkey species die of the disease and so are not the reservoir. The average incubation period in one outbreak was 7 days. During the 7 months of the outbreak 80% died, with a decline in mortality over the 7 months. The mean duration from onset of disease to death was 10

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days. A quarter of all the cases were healthcare workers and this was largely due to contact with blood and body fluids. Reuse of contaminated needles and instruments and not wearing gloves for procedures were also factors in nosocomial transmission. Direct contact with body fluids from patients and with the bodies of dead patients were additional factors in transmission. Aerosol transmission was not thought to be a major factor. Subclinical infection is very uncommon. Seropositivity rates were only 2% in the nearby town and 9% in surrounding villages. Clinical features Three manifestations present relatively early in the course are conjunctival injection, a maculopapular rash, and sore throat with marked pain on swallowing. Severe muscle pain is often present. The rash appeared towards the end of the first week on flanks and in inguinal and axillary regions, then rapidly spread to cover the whole body apart from the face over hours. This is evident on white skins but not on black skins. Bleeding from mucosae and puncture sites, anuria, hiccup and tachypnoea were features indicating that death was likely in days, with defervescence over the last 2 days before death. Fever, asthenia, nausea, vomiting and diarrhoea - often dysenteric - and headache were additional common symptoms. Diagnosis Intense viraemia is the rule in cases, and so antigen detection using ELISA-based technology is the most valuable diagnostic technique, particularly when processing large numbers of samples. Serology, PCR and virus isolation are other methods for diagnosis. Management This is essentially supportive. Paracetamol and not aspirin should be used as antipyretic. Fluid intake and nutrition should be maintained and blood transfusion given where there is anaemia. In an endemic situation there may be very little that can be offered, and the major efforts need to go into protecting healthcare workers and family members from infection by caring for cases in hospital with strict barrier nursing precautions and attention to disinfection. No antiviral agents are effective in this infection. 1

RHABDOVIRUSES

Rabies Rabies is an acute encephalomyelitis caused by an RNAcontaining rhabdovirus. It is characterized by paroxysms of muscle spasm that particularly affect muscle groups associated with swallowing and inspiration, in response to attempts to drink water, as well as the sight, sound or mention of water. For practical purposes it is invariably fatal. Aetiology The rabies virus is an RNA-containing rhabdovirus which, with five related viruses, comprise the Lyssavirus genus. The virus can be grown in cell culture. Distribution and incidence Antarctica and Australasia are free of rabies, otherwise all continents are endemic; the UK, Scandinavia, Japan and Taiwan are free of the disease. The incidence of human rabies is difficult to estimate. Occasional cases occur in Europe and North America. It is a considerable health problem in Asia, Africa, and Central and South America. Transmission and epidemiology Rabies virus is inoculated in saliva by the bite of a rabid animal, most often a dog, less often a cat (Fig. 9.13). Licking abraded or cut skin can transmit infection. Virus can penetrate mucous membranes of the mouth and eyes. Endemic canine rabies is the major determinant of risk for human infection. All mammals can become infected, but transmission to humans is mainly related to biting animals, commonly stray dogs in the tropics. Wolves, jackals, mongooses, bats (insectivorous, vampire and fruit eating), monkeys and ungulates (sheep, cattle and deer) can all become infected and pose a greater or lesser degree of risk to humans. Apart from bats all species die of this infection. In Europe the red fox is the reservoir of infection. Vampire bats infect cattle in

FURTHER READING Peters C J, LeDuc J W, eds. 1999 Ebola: the virus and the disease. J Infect Dis 179; Suppl 1:288.

1

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Case 9.2

FIG. 9.13 Cycle of transmission of rabies The commonest routes of spread are shown in solid lines. Humans are usually infected by dog bites.

the countries of South America, causing considerable economic losses through cattle rabies. Human infection has been acquired directly from vampire bats and following exposure to aerosols containing virus excreted by bats in bat caves. Pathology Virus first penetrates skeletal muscle cells and then enters nerves through the fibres supplying muscle spindles and travels centripetally to infect nerve cells. Virus replication occurs and then ruptures cells, releasing virions to infect other neurons. Neuropathological changes are not gross. Collections of inflammatory cells are seen around small vessels; dead neurons and phagocytosis of degenerating neurons are seen especially in the medulla and the midbrain. Viraemia is not thought to contribute to spread of the virus; rather, it occurs through centrifugal spread via fibres of the autonomic nervous system to cornea, skin and salivary glands. Clinical features The incubation period is 20-60 days on average, ranging up to 1 year. Initial symptoms are headache, fever, insomnia, anorexia and paraesthesiae or altered sensation at the site of the bite or some peripheral site. After 2 or 3 days the patient may become markedly agitated, hyperexcitable, anxious, confused and lucid by turns. The earliest hint of hydrophobia may be evident at this stage, with rapid progression to overt hydrophobia, with involuntary contraction of the main and accessory inspiratory muscles in a sustained spasm brought on by attempts to drink water or at the sound, sight or mention of water. Variations of mood persist. Saliva may be continuously spat out as it cannot be swallowed. The spasms can be provoked by fanning air across the face. Cranial nerve palsies, paralysis and bizarre patterns of breathing follow. Ascending paralysis without hydrophobia occurs in a few patients, and this can pose problems in diagnosis. Death occurs in 7-14 days from respiratory failure or cardiac arrhythmias. Differential diagnosis Tetanus, other causes of ascending paralysis, and encephalitis and rabies hysteria are the main things to consider. Laboratory diagnosis Virus may be grown from saliva, nasal washings, CSF and urine. Viral antigen can be identified in skin biopsies, preferably taken from the hairy skin of the neck, where hair follicles contain peripheral nerves, or less easily in corneal impression smears using fluorescent antibody labelling techniques. The sensitivity of this method for antemortem diagnosis is not ideal. Corneal impression smears and skin biopsies for antigen detection should be refrigerated immediately after collection. In specialist centres PCR is available using reverse transcriptase PCR technology, and this method can detect virus in saliva. Blood and CSF should also be tested for rabies antibodies, and in the unvaccinated patient a positive test supports the diagnosis.

Prevention, control and treatment Correct management at the time of biting prevents rabies.

9

First aid The wound should be washed under running water for 5 minutes with soap or detergent. Where the wound is washed with soap all traces of this must be washed away if a quaternary ammonium compound is to be subsequently applied, as soap inactivates cetrimide. Primary suture and scrubbing of the wound should be avoided if at all possible. Alcohol 40-70% or an aqueous solution of iodine or a quaternary ammonium compound with known lethal effect on rabies virus, such as 0.1% cetrimide solution, should then be applied and the wound covered with a dressing. Tetanus prophylaxis should be given and antibiotics as indicated. The need for rabies vaccine must then be considered. • Low risk: following licks of the skin, abrasions or scratches, minor bites on covered areas of arms, trunk and legs, start vaccine (schedules given below) if animal is rabid or suspected rabid. If the animal is rabid at the time of exposure, or is wild or not available for observation, then vaccine plus rabies imimmoglobulin (RIG) should be started together. If the biting animal is a dog or cat and is healthy after 15 days of observation, then further vaccination can be stopped. • High risk: following licks of the mucosa, major bites, i.e. multiple bites, or bites to the head, face, fingers or neck by a suspect or rabid domestic or wild animal, or by an animal that is not available for observation, give vaccine plus rabies immunoglobulin. Again treatment can be stopped if the biting cat or dog is healthy at 15 days. Rabies vaccination The vaccine used now is human diploid cell vaccine (HDCV). • For pre-exposure vaccination (e.g. prior to travel etc.) the recommended schedule is three doses of 1.0 mL of HDCV given by deep subcutaneous or intramuscular injection (deltoid region, not gluteal region) on days 0, 7 and 28. • For low-risk cases HDCV should be given; for those who have not received full pre-exposure immunization give five doses of 1.0 mL of vaccine intramuscularly, starting on the day of biting, day 0, and thereafter on days 3, 7, 14 and 30. The vaccine is given by deep subcutaneous or intramuscular injection. If intramuscular, the injection is given into the lateral aspect of the thigh or the deltoid but not the gluteal region. For those who have had full pre-exposure vaccination, i.e. three doses of HDCV, two doses of vaccine are given on days 0 and 3-7. When RIG is needed it is given as detailed below. • For high-risk cases human RIG is given, 20iu/kg body weight, up to half infiltrated in and around the wound after cleansing and half given intramuscularly. In some parts of the world human RIG will not be available and equine RIG will be used. The dose is worked out on the

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basis of 40iu/kg body weight. As reactions to equine RIG are not uncommon a test dose should be given first. HDCV is given as five doses of 1.0mL of vaccine on days 0, 3, 7, 14 and 30 to those with no or incomplete preexposure vaccination for rabies. For those with full preexposure vaccination two additional doses of 1.0 mL of HDCV are given on days 0 and 3-7, RIG is not usually needed. While patients with established rabies can be kept alive by intensive care, the fatal outcome is unaltered. Postmortems carried out in patients managed in this way have shown extensive destruction of nervous tissues. Practical management in an endemic area comprises sedation and pain relief. Close contacts of cases should be vaccinated. The problem of controlling reservoirs of infection remains. The capturing and killing of stray dogs in endemic areas has reduced an important source of human rabies. Vaccination of household dogs and cats is a helpful measure but does not exclude the possibility of the animal contracting rabies. Good results have been obtained in the control of fox rabies in Europe by putting down baits containing an oral antirabies vaccine. The incidence of rabies in sentinel species has declined markedly. Advice about rabies vaccination etc. can be obtained in the UK from Virus Reference Division, Central Public Health Laboratory, Colindale, London NW9 5HT (Tel: 020 8200 4400).

NON-ENVELOPED SINGLE-STRANDED RNA VIRUSES PICORNAVIRUSES Rhinovirus infection Rhinoviruses are the most common cause of colds (p. 631). There are over 90 serotypes and reinfection with the same serotype can occur. Infection is usually confined to the nasal mucosa, but complications such as sinusitis and otitis media can occur as a result of mucosal swelling and

obstruction to drainage of secretions. Rhinoviruses can also cause exacerbations of chronic bronchitis but the mechanism for this is not clear.

Enterovirus infection Coxsackie A, Coxsackie B and Echoviruses, of which there are 24, 6 and 34 types, respectively, cause a wide variety of clinical infections, but overall most are asymptomatic. A febrile illness with upper respiratory symptoms is another common manifestation of infection with many different serotypes. More specific disease associations are shown in Table 9.21. Polio viruses types 1, 2 and 3 cause poliomyelitis, which is described on page 1426. Acute meningitis Enteroviruses are a common cause of lymphocytic meningitis (more than 70% of cases), which is a benign disease. Enteroviral meningitis is common in young children and rare over the age of 40. The clinical features are described on page 1422. Other neurological disease Encephalitis is a rare manifestation of enteroviral infection which may occur with or without meningitis. Flaccid motor paralysis is only seen with any frequency in poliomyelitis. Fever and exanthem A variety of skin rashes occur. Maculopapular eruptions associated with fever are more common with Echo than with Coxsackie viruses. Petechial or purpuric eruptions are uncommon. The most distinctive exanthem is the vesicular eruption of hand, foot and mouth disease caused by Coxsackie virus A16 (and occasionally others). Lesions are found in the mouth consistently, and on the palms, soles and extensor surfaces of the hands and feet. Vesicles are sometimes surrounded by a ring of erythema and lesions may be slightly tender. The child feels unwell for 1 or 2 days and has a fever, but recovers completely. Virus can be isolated from vesicles, throat washings or stools. Respiratory tract infection Most enteroviruses can cause non-specific upper respiratory infection, but group A Coxsackie viruses are the

TABLE 9.21 Enterovirus types and their disease associations Virus types most commonly associated

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Disease

Coxsackie A types

Coxsackie B types

Echo types

Acute meningitis Encephalitis Herpangina (pharyngitis) Hand, foot and mouth disease Pleurodynia (Bornholm's disease) Pericarditis/myocarditis Chronic meningoencephalitis in hypogammaglobulinaemics

Most One-fifth 2-6, 8, 10, 22 5,7,9,10,16 None None None

All Most None None 1-5 1-5 None

Most One-third None None None None One-third

common cause of herpangina, an acute painful vesicular eruption on the fauces and soft palate associated with fever, malaise and myalgia and lasting up to 10 days. Pleurodynia (Bornholm disease) Pleurodynia (sometimes known as epidemic myalgia) is an acute febrile illness that usually affects young adults and is characterized by 'pleuritic' chest pain; it is caused by infection with group B Coxsackie viruses which occurs mainly in late summer. The pain is due to infection of muscle and there is no pleural inflammation. About half of patients have pain in an area of the thorax but upper abdominal pain occurs in others, especially children, and this may mimic an abdominal emergency. Tenderness over involved muscles is the characteristic sign. Chest X-ray is normal. The illness is usually over in 5 days, but it may last up to 3 weeks and sometimes recurs. Non-steroidal antiinflammatory drugs such as ibuprofen 400 mg t.d.s. are helpful in treating the pain. Myopericarditis Enteroviruses, mainly group B Coxsackie, are an important cause of acute myocarditis and pericarditis in young adults. Usually the two conditions occur simultaneously, but one predominates in the clinical presentation. The clinical features are described on page 570.

SUMMARY 9 Management of rotavirus diarrhoea Clinical assessment No dehydration

Management Encourage ingestion of fluids orally Encourage normal feeding

Some dehydration (5-10% body weight lost)

ORS 80 ml/kg body weight over 4 hours + 400 ml ORS after each diarrhoeal stool + water to provide for insensible and renal losses

Severe diarrhea (>10% body weight lost)

Intravenous fluids (e. g. Ringer's lactate) 30 ml/kg over 30 minutes and then 70mL/mg over 2 hours

(Note: dehydration is not usually severe in adults with viral gastroenteritis)

Epidemic haemorrhagic conjunctivitis This epidemic form of acute conjunctivitis, which is associated with pain, subconjunctival bleeding and oedema of the eyelids, lasts about 1 week and is usually caused by enterovirus 70. The virus is highly infectious and is spread by contact and fomites rather than by droplet.

9

NON-ENVELOPED DOUBLE-STRANDED RNA VIRUSES REOVIRUSES Rotavirus diarrhoea Rotavirus diarrhoea is an acute dehydrating diarrhoeal disease caused by a 70 nm RNA-containing virus. This organism is the commonest cause of diarrhoea in children up to 2 years old in the tropics. It is spread by the faecal-oral route and possibly by droplet transmission. The infection occurs in both endemic and epidemic forms worldwide. Clinical features After an incubation period of up to 5 days (most often 2 days) anorexia, vomiting, diarrhoea and fever begin suddenly. There may also be a blocked nose and sore throat. The stools are watery and non-dysenteric. The illness is self-limiting, terminating in about 5 days in most cases. Moderate dehydration is the usual consequence of the illness, but a number of fatalities from severe dehydration have occurred. The organism may be found in faeces by immune electron microscopy and viral antigen detection using an enzyme-linked immunosorbent assay. Management Management comprises assessment of the degree of dehydration (see Table 9.14, p. 280) and replacement of that volume of fluid in the first 4-6 hours after presentation. Continuing fluid losses must also be replaced until diarrhoea ceases (see p. 280).

CHLAMYDIAL, MYCOPLASMA AND RICKETTSIAL INFECTIONS CHLAMYDIA Chlamydia are bacteria which contain both DNA and RNA (unlike viruses) but which are unable to replicate extracellularly (Table 9.22). They are Gram-negative and have a lipopolysaccharide endotoxin. Chlamydia psittaci, a common pathogen of birds and animals, can infect humans, causing psittacosis (ornithosis). Chi. trachomatis is transmitted between humans by sexual contact or from a mother's infected genital tract to her

newborn infant, causing conjunctivitis or occasionally pneumonia. Different serotypes of Chi. trachomatis cause lymphogranuloma venereum (LGV; see p. 457) and trachoma. The role of chlamydial infection in non-specific genital infection (NSGI) is discussed in Chapter 11 (p. 457).

Psittacosis Although ornithosis is a commonly used name for infection with this organism, this is a misnomer because a wide range of animals other than birds are infected by Chi. psittaci.

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TABLE 9,22 Chlamydial infections Type

Transmission

Disease

Clinical features

Chlamydia psittaci Chlamydia trachomatis Types A, B, C Types D-K

Zoonosis

Psittacosis

Pneumonia

Fingers, flies, fomites Sexual Mother-to-infant Sexual

Trachoma Non-gonococcal urethritis, salpingitis

Keratoconjunctivitis Urethritis, pelvic inflammatory disease, Reiter's syndrome, perihepatitis (rare) Conjunctivitis, pneumonia (rare) Suppurative inguinal lymphadenitis

Types L1, L2, L3

Lymphogranuloma venereum

Epidemiology Psittacosis occurs sporadically worldwide, but it is most common in people closely associated with birds. Infected birds are usually ill, but continue to shed organisms in excreta and feathers for months after recovery. Humans are infected by inhalation. Clinical features After an incubation period of about 2 weeks there is fever, malaise, headaches, myalgia and sometimes arthralgia. Dry cough and variable dyspnoea occur, with confusion and clouding of consciousness if severe hypoxia develops. There are few abnormal signs in the chest, although there may be fine crackles in the lower zones. The chest radiograph shows unilateral or bilateral patchy infiltrates, especially in the lower zones, but occasionally there is the appearance of lobar consolidation. Gastrointestinal symptoms occur uncommonly. Rarely the disease is complicated by aortic or mitral valve endocarditis. Abortion in pregnant women may occur. Diagnosis and management Diagnosis is suspected from the history and evidence for atypical pneumonia, and confirmed by testing for serum antibodies by immunofluorescent or complement fixation tests. Tetracyclines given for at least 10 days are the most effective treatment.

Trachoma Trachoma is a chronic infection of the conjunctiva of the globe and eyelids caused by Chl. trachomatis serotypes A, B, Ba and C. It is widespread throughout the tropics and subtropics, and is primarily a disease related to poor personal and public hygiene. It is one of the commonest causes of blindness in the world, with 500 million affected, 2 million blind and 100 million with severe visual impairment. Transmission and epidemiology The organisms present in ocular secretions infect other people by direct contagion on contaminated fingers or

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1

Fig. 9.9

4

Fig. 9.11

2

Fig. 9.10

3

MCQ 9.15

clothes. Lack of water for washing means that infected secretions are wiped on to hands and clothes. Flies may also carry the organisms from one person to another. Infection occurs early in life, and subsequently there are episodes of reinfection and secondary bacterial infection. Pathology and pathogenesis Acute inflammation is present in the conjunctiva. This progresses to a chronic state, with lymphoid aggregates around infected conjunctival cells. It is likely that damage due to trachoma is exacerbated by repeated bacterial infections. The tarsal plates fold inwards due to fibrosis (entropion) and the cornea is continually damaged by the inverted eyelashes, resulting in corneal opacity from scarring. There is evidence that cell-mediated immune responses to this intracellular pathogen are important in pathogenesis, with evidence of genetic factors determining the expression of reactivity. Clinical features The earlier features are hypertrophic follicles on the upper tarsal conjunctiva and at the corneoscleral junction superiorly. 1 With time and repeated reinfection this inflammatory response leads to fibrosis. The scarring disorganizes the arrangement of Meibomian glands, and their orifices are pulled away from the lid margin. The eyelid is inverted and sites of eyelash trauma on the cornea are seen. New vessels grow into the cornea (pannus formation) and corneal scarring follows. 2 Diagnosis Diagnosis is made on the appearances described above. Giemsa staining of scrapings from the affected conjunctiva shows intracytoplasmic inclusion bodies. Antigen can be detected by enzyme-linked immunoassay. Management and prevention Topical 1 % tetracycline eye ointment, applied two to four times daily for 3 weeks and repeated at 1-month intervals up to six times, is effective but it has been shown that a single dose of oral azithromycin, 20mg/kg, was as effective as 6 weeks of topical 1 % tetracycline eye ointment, though neither gave permanent cure and relapse is frequent. Continued trauma to the cornea must be prevented. Removal of the offending eyelashes helps. Surgical reconstruction of the eyelid may be needed.

Education concerning the importance of washing with soap and water is an important measure in preventing transmission. This depends on the availability of an adequate water supply sufficient for all domestic needs. The use of antibiotics in infected persons reduces the inflammation in the eyes and prevents progression of the disease while eradicating sources of infection for others. 0

MYCOPLASMAS Mycoplasmas are the smallest organisms able to grow in cell-free media, wherein they differ from viruses. They differ from bacteria in lacking a cell wall. Mycoplasma pneumoniae is an important cause of atypical pneumonia and a number of other clinical syndromes described in Chapter 13. M. hominis and Ureaplasma urealyticum can cause non-specific genital infection (see p. 457), prostatitis, pelvic inflammatory disease and postpartum fever. They are sensitive to tetracycline, the treatment of choice (p. 304).

RICKETTSIA Rickettsial infections comprise a group of acute infectious diseases caused by small bacteria which are transmitted by arthropods that in some cases act as reservoir and amplifying hosts. Fourteen rickettsial infections are currently recognized, eight have been described in the last decade, and there may well be more to be discovered. Some rickettsiae are currently regarded as non-pathogenic, but it may well be that all are pathogenic to some degree. The main groupings recognized are the typhus group of infections and the spotted fever group. The agent of scrub typhus has now been assigned to a new species, Orientalis tsutsugamushi. Current approaches to taxonomy have placed much reliance on homology between ribosomal 16S RNA sequences. The rickettsiae produce diseases with a range of severity from mild to severe and life-threatening. All are obligate intracellular parasites living free in host cell cytoplasm, not confined within a parasitophorus vacuole, and can only be grown in cells in vitro. They are Gram-negative organisms and, like Gram-negative bacteria, produce endotoxin which may contribute to the pathogenesis.

Typhus Distribution and incidence (Table 9.23) Typhus group Louse-borne typhus (Rickettsia prowazekii) occurs in louse-infested populations. These are usually relatively poor people living where night-time temperatures are low even though it may be hot in the day; people wear as much clothing as they can to keep warm, and do not change or

TABLE 9.23 Geographic distribution of the main rickettsial infections Epidemic typhus (R. prowazekii) Murine typhus (R. typhi) Rocky Mountain spotted fever (R. rickettsii) Mediterranean spotted fever (R. conori)

9

Highland regions: South America, Africa and Asia Texas (USA), Africa, Asia, Europe USA, Canada, Mexico, Panama, Costa Rica, Brazil, Colombia Countries of the Mediterranean littoral, sub-Saharan Africa, India, around the Black Sea, Vladivostok

wash their clothing. Body lice are frequent biters and feeders and are very sensitive to dehydration. If clothes are changed and washed then transmission of louse-borne typhus is prevented. Mountainous areas of South America, the Himalayas and highland regions of Ethiopia are endemic areas. Louse-borne typhus had become less common, but there was a large outbreak of 30000 cases in Burundi in relation to the civil war there, with large numbers of displaced persons crowded together in unsanitary conditions. In louse-borne typhus humans are the reservoir of infection, with latent infections recrudescing under the stress of displacement and war (Brill-Zinsser disease), infecting body lice which spread from person to person carrying the infection. Murine typhus (R. typhi) is widely distributed in warmer climates in Africa, Asia, Europe and southern parts of the USA. The rat flea spreads the infection. Spotted fever group Rocky Mountain spotted fever (R. rickettsii) occurs most often in the hills and mountains of the eastern seaboard and southern states of the USA. South American countries are also affected. African tick typhus affects the countries of North Africa, and eastern, central and southern Africa. The incidence is unknown. African tick typhus, caused by either R. conori (Mediterranean spotted fever) or R. africae, is the commonest imported rickettsial infection in the UK. Rickettsial pox (R. akari) infections occur in Asia, Asian regions of the CIS (former USSR) and Korea. With increased interest in rickettsiae, pathogens such as R. helvetica, first described from Switzerland, with a widespread distribution through Europe, R. sibirica in Siberia and China, and R. slovaca from the Balkan region, have been recognized. Transmission and epidemiology Typhus group Louse-borne typhus is transmitted by Pediculus humanus, the body louse (Fig. 9.14). The head louse does not transmit this infection. After taking a blood meal the louse defecates, and R. prowazekii in the faeces of an infected louse is scratched into the bite site or abrasions in the skin. 4 Humans are the reservoir for R. prowazekii, and infection

305

Reservoir Humans

Reservoir Small mammals

Reservoir Larval mites

Reservoir Ticks

Body louse

Fleas

Larval mite

Tick

Louse-bome typhus

Murine typhus

Scrub typhus

Tick typhus

FIG. 9.14 Transmission of rickettsial infections

passes from one person to another as the lice pass between people. The louse dies by 14 days after infection. Epidemic disease occurs when infection is introduced into a large group of people not previously exposed. Refugee camps present an ideal situation for such epidemics. Spotted fever group This is transmitted by the bite of infected ticks, which are also the reservoir of infection. Occupational and leisure activities, such as walking, camping, farming, lumber work and hunting, take people into tick-infested areas in North America. Tourism, tending animals and gathering wood take people into similar areas in Africa. Pathology and pathogenesis These organisms replicate within vascular endothelial cells of small vessels in many tissues, and vasculitic responses and blood vessel damage underlie the pathogenesis. R. rickettsii infection is more invasive than other organisms, and causes more severe illness owing to full-thickness vessel wall damage. The effect of blood vessel damage is a rash that may become purpuric and haemorrhagic, even ecchymotic in louse-borne typhus and R. rickettsii infection. Gangrene with loss of fingers and toes can occur in Rocky Mountain spotted fever. Leakage of protein-rich fluid from the vascular compartment into the interstitium causes hypovolaemia, hypotension and reduced tissue perfusion. Thrombotic lesions occur in a variety of organs, including the brain. Renal and liver damage from vasculitis occurs in severe cases. Clinical features Typhus group The incubation period is usually about 12 days, with a range of 10-14 days. Headache and mild fever are the usual initial symptoms, followed after 48 hours by a sharp rise in temperature to 40°C, which is sustained. Conjunctival suf-

1

306

Fig. 9.12

2

Case 9.3

3

Fig. 9.13

fusion is seen. Meningism and photophobia also occur. The rash occurs on about the 6th day and begins as red macular lesions on the axillary folds and trunk, spreading on to the limbs, with the palms, soles and face affected in the most severe cases. The rash may evolve through purpuric stages to form ecchymoses. Initial bradycardia progresses to tachycardia in hypotensive patients. Haemorrhagic manifestations and hypotension lead to renal involvement, with rising blood urea and falling urine output. Mild cases get better in the second week of the disease, but untreated severe cases may go into the third week before recovery begins. Death from shock, cerebral involvement or renal failure occurs in the second or third week. Mortality rates of 10-40% without treatment are recorded, and increasing age is associated with higher fatality rates. Brill-Zinsser disease is a mild form of louse-borne typhus caused by the recrudescence of latent infection, and in this condition recovery is the rule. Spotted fever group The incubation period is about 7 days for Rocky Mountain spotted fever (RMSF) and African tick typhus, and rather longer (around 13 days) in rickettsial pox. Fever and headache with generalized limb pains are usual early in the course. The clinical features are similar to those of typhus. There is early deterioration in those with severe RMSF. Death may occur between 3 and 6 days of onset, occurring in up to 25% of patients not receiving specific treatment in RMSF. African tick typhus is generally mild and selflimiting. Fever, systemic upset and headache are the usual presenting features. Rash may occur, causing macular lesions which have a widespread distribution on the trunk and limbs. The palms and soles may be affected. A black ulcerated eschar is usually found marking the site of the tick bite. Diagnosis The clinical features usually lead to suspicion of a rickettsial infection. This can be confirmed by serological tests using group-specific rickettsial antigens. The main differential diagnosis in RMSF is meningococcal septicaemia, which also requires urgent treatment. Laboratory features Severely affected patients with all forms of rickettsial disease will show generalized derangement of coagulation and evidence of liver and renal dysfunction. Platelet counts are low, in association with prolongation of the prothrombin time, reduced fibrmogen levels and elevated levels of fibrin degradation products. Anaemia is usual. Plasma albumin levels fall. Declining urine output indicates renal failure. Management Doxycycline (100 mg 12-hourly orally or i.v. for 7 days, or for 2 days after defervescence) is effective against all forms of rickettsial infection. Doxycycline 200 mg as a single dose is effective in epidemic typhus. Pregnant women and children under 8 years should receive chloramphenicol

(50mg/kg/day in divided doses for 7 days or for 2 days after defervescence; 25mg/kg/day in divided doses for infants under 1 month). Supportive measures Prompt administration of antibiotics is essential in RMSF and louse-borne-typhus. Additional management is essentially supportive, depending on the facilities available, and comprises restoring blood volume with infusions of plasma and fluids, and restoring coagulation mechanisms by fresh blood transfusions or fresh frozen plasma. Prevention and control Delousing is the main way to control louse-borne typhus. Thorough and regular washing of clothes in hot water with detergent kills lice and their eggs. DDT 10% or malathion 1% can be applied to clothed people with good effect. Appropriate clothing should be worn to prevent ticks reaching the skin. In tick-infested areas the skin should be carefully inspected at the end of the day. Any ticks that are found should be removed by gentle pulling to keep them intact. The duration of tick attachment, which can last 5 days, is important in relation to development of disease and strength of attachment, with 20 hours being the length of time needed to give a greater chance of infection.

Scrub typhus Scrub typhus (Orientalis tsutsugamushi) occurs throughout Asia and is probably one of the commonest causes of fever there. Studies in Malaysia showed that it accounted for 23% of patients with febrile illnesses presenting at rural hospitals. In most cases it is a self-limiting infection, with resolution in up to 14 days. Mortality has been reported in up to 60% of severe cases. It is transmitted by chiggers, the larvae of leptotrombiculid mites. Occupational exposure in rural areas (farming, animal tending, rubber plantation work etc.) and military personnel deployed in rural areas are associated with increased risk of infection. The incubation period is about 10 days (range 6-18). Fever, headache, chills and general body pains are the usual symptoms. Conjunctival suffusion, macular skin rash 1- pneumonitis and hepatosplenomegaly may occur, and cough with pulmonary infiltrate on chest radiographs is seen. An eschar at the site

of biting is often seen, with enlarged, tender regional adenitis. 2 Treatment with doxycycline is effective, with chlo- 9 ramphenicol as an alternative (see above). Resistance to these agents has been documented in northern Thailand. 3

Q fever Q fever is an acute illness caused by Coxiella burnetii; it is transmitted between animals by ticks and to humans from domestic animals by close contact, particularly with aborted placentas or with infected carcases in abattoirs or, more often, by inhalation of the endospores, which are resistant to desiccation and persist in the environment. Q fever has a range of clinical manifestations: atypical pneumonia, prolonged fever of undetermined cause, granulomatous hepatitis and culture-negative endocarditis. The main clinical features of acute infection are high fever with severe headache and myalgia, after an incubation period of about 20 days. Hepatosplenomegaly is common, with biochemical evidence of hepatitis and histologically granulomatous liver disease with very well denned granulomas that can suggest the diagnosis. Pneumonia is less common but may be severe and bilateral. Q fever may present as PUO (p. 274) with a prolonged course. Epididymo-orchitis can occur and so must be differentiated from brucellosis, which also produces prolonged fever. The natural history of the disease is to resolve spontaneously within 2 weeks in most patients, but a slower recovery with progression to chronic disease may occur. The main feature of chronic Q fever is endocarditis, which is usually fatal if left untreated (p. 574). Diagnosis Diagnosis is usually made by serology with positive responses to the phase II antigen in acute disease, IgM and IgG, and positive serology to the phase I antigen in chronic disease, with raised IgA litres suggestive of endocarditis. Laboratory handling of the organisms is dangerous. Treatment Doxycycline 100 mg twice daily for 14 days is the treatment of choice, but it is not known whether it prevents progression. Endocarditis is very difficult to eradicate by antibiotic therapy alone, and surgery is often required.

BACTERIAL INFECTIONS Despite the proliferation of antibiotics since the discovery of penicillin in 1941, bacterial infections remain a challenging problem. The continuing emergence of resistance to antibiotics, particularly but not exclusively in the hospital environment, is one aspect of the problem which is discussed earlier in this chapter (p. 264). Another is the rapid development of serious illness leading to multiorgan failure when antibiotics administered too late are relatively

ineffective. Gram-negative septicaemia is a classic example of this, and much research has been focused on the pathogenetic mechanisms involved, with recent advances defining the influence of cytokine release and highlighting the central role of nitric oxide in the vascular microenvironment. The disastrous consequences of failure to treat very early draw attention to the value of prophylactic measures, which are widely used in the form of antibiotics for surgery.

307

TABLE 9.24 Classification of bacteria

TABLE 9.25 Streptococci

Gram-positive cocci Streptococci Strep, pneumoniae Strep, pyogenes Strep, viridans group Anaerobic Staphylococci Staph. aureus Staph. epidermidis

Gram-positive bacilli Bacilli B. anthracis B. cereus Corynebacterium diphtheriae Listeria monocytogenes Clostridia (anaerobic) Cl. tetani Cl. botulinum Cl. perfringens Cl. difficile Cl. septicum

Gram-negative cocci Neisseria N. meningitidis (meningococcus) N. gonorrhoeae (gonococcus)

Gram-negative bacilli Enterobacteria Escherichia coli Klebsiella Proteus Salmonella Shigella Parvobacteria Haemophilus Bordetella Brucella Yersinia Pseudomonas P. aeruginosa Burkholderi pseudomallei Francisella tularensis Bartonella bacilliformis Cat-scratch bacillus Vibrios V. cholerae Campylobacter jejuni Anaerobic bacteria Bacteroides Fusobacteria

Mycobacteria Spirochaetes Treponema T. pallidum T. pertenue T. carateum Borrelia Leptospira icterohaemorrhagiae

Vaccines have been developed against some bacteria and this will be an area of rapid development during the lifetime of this edition of the textbook. A classification of bacteria is given in Table 9.24.

GRAM-POSITIVE COCCI

STREPTOCOCCI

308

B-Haemolytic streptococci are classified by the Lancefield grouping system, which detects polysaccharide antigens on their surface by a panel of antisera. Table 9.25 shows these

Group and name Group A S. pyogenes

Group B S. agalactiae Group D Enterococci, e.g. S. faecalis S. pneumoniae (pneumococcus) S. viridans group, e.g. S. milleri, mitior, mutans, salivarius, sanguis

Characteristics

Disease/syndromes

p-haemolytic Secrete enzymes, e.g. hyaluronidase, and toxins e.g. erythrogenic

Pharyngitis Scarlet fever Otitis media Sinusitis Erysipelas/impetigo Lymphangitis Puerperal sepsis

p-haemolytic Common vaginal commensal

Neonatal infection (puerperal sepsis)

B- or non-haemolytic Anaerobic Normal bowel flora Antibiotic resistance oc-haemolytic Common throat commensal More than 80 serotypes a- or non-haemolytic Dental commensals

Urinary tract infection Septicaemia Endocarditis Pneumonia Acute meningitis Otitis media/mastoiditis Endocarditis Cerebral abscess and empyema (S. milleri)

and other streptococci which are a-haemolytic or nonhaemolytic. Not all group D streptococci are P-haemolytic. Cutaneous streptococcal infections are described in Chapter 10.

Scarlet fever Scarlet fever is a febrile illness with a characteristic rash caused by infection with an erythrogenic toxin-producing strain of Strep, pyogenes. Infection is usually in the throat, but the skin or genital tract may be the primary site. It is now a much milder disease than it was 50 years ago. Its severity is probably determined by variations in the microorganism, but host factors also play a part. The same bacterium may be a harmless passenger in one subject, or produce a sore throat or scarlet fever in another. Host antibodies are largely responsible for these differences. Antibodies to the erythrogenic toxin prevent the rash of scarlet fever but not tonsillitis. Clinical features Infection is spread by droplets. After an incubation period of 2-4 days there is an abrupt onset of sore throat, pain on swallowing and fever. There is tender cervical lymphadenopathy. The tonsils are enlarged, congested, and often covered with exudate. The tongue is coated and initially red papillae are visible, but later the fur is lost, leaving the classic 'strawberry tongue' appearance. The rash (Fig. 9.15) appears on the face within 2 days. It is a diffuse erythema, often with perioral pallor (not specific for this con-

TABLE 9.26 Invasive disease due to Staph. aureus Site of infection

Disease

Skin

Impetigo Boils and carbuncles Surgical wound infections Septicaemia Pneumonia with abscesses Abscess Acute endocarditis

Blood Lungs Liver, bone and other Heart

9

Diagnosis and management Strep, pyogenes can readily be cultured from a throat swab, and the presence of neutrophilia helps to distinguish the condition from infectious mononucleosis, which can cause an identical appearance. Retrospective diagnosis can be made by measuring antistreptolysin O antibodies. Treatment with oral penicillin is commonly used, but may not eliminate streptococci unless given in high dose for 10 days. Eradicating the organism is less important since complications have become so uncommon. Erythromycin is an alternative agent for penicillin-allergic patients. FIG. 9.15 Scarlet fever rash

dition). On the trunk it is a punctate erythema which is less brightly coloured. Superficial peeling of the skin starts on about the 4th day. The illness resolves within a week, although the patient may continue to feel unwell for several more days. Complications Complications are uncommon in the temperate world, perhaps because of prompt treatment with antibiotics, but post-streptococcal glomerulonephritis is well recognized in the tropics and sub-tropics where infected insect bites, infected scabies etc. are common. Soft tissue infection due to this organism can be serious and life-threatening in the context of necrotizing fasciitis. This may occur without any obvious site of entry for the organism, but the process begins with localized pain in the muscle of the affected area. There is spreading cellulitis accompanied by severe haemodynamic disturbance with shock. Nausea, vomiting and diarrhoea may be present early in the course. Progressive increase in the severity of pain is a clinical indicator of this condition. Bullae can develop over affected skin. Outcomes differ but include tissue destruction, severe systemic illness, loss of the affected limb as a result of gangrene, and sometimes death. Prompt treatment with intravenous antibiotics should include clindamycin. Septic complications include otitis media. Late complications are rheumatic fever (p. 1069) or acute glomerulonephritis, which may develop 2-3 weeks after the infection.

STAPHYLOCOCCI

Staph. aureus and Staph. epidermidis are the clinically important staphylococci. Both are common skin commensals, but Staph. aureus is more virulent and is commonly associated with disease.

Staphylococcus aureus infection In most conditions where host susceptibility to infection is increased, Staph. aureus is an important pathogen. This applies particularly to the skin after surgical or accidental trauma and burns, and after skin infection such as chickenpox. More general predisposition is seen in diabetes mellitus, uraemia, alcohol excess, malnutrition and malignancy. When a surgical foreign body is present, for example an intravenous catheter, a heart valve or a prosthetic joint, both Staph. aureus and epidermidis can take root, with potentially disastrous consequences. There are two distinct mechanisms by which Staph. aureus can cause disease. Most often it is by direct invasion of tissues (Table 9.26), when some of the enzymes produced by Staph. aureus may be important in pathogenesis, e.g. catalase,coagulase,hyaluronidase. Less often, the major disease manifestations are the result of toxin secretion (Table 9.27). Management of deep Staph. aureus infections When Staph. aureus localizes in deep tissues it quickly causes acute inflammation and necrosis, leading to abscess formation. If an abscess can be seen on scanning (e.g. ultrasound, isotope or CT) it may be possible to aspirate pus as

309

TABLE 9.27 Staph. aureus toxin-mediated diseases Disease

Manifestations

Organism

Pathological effect

Site of infection

Staphylococcal scalded skin syndrome

Skin erythema; may progress to bullae, exudate, crusting, positive Nikolsky sign

S. aureus phage group II, often phage type 71 (produce epidermolytic exotoxins)

Split skin at stratum granulosum

Skin

Toxic shock syndrome

Diarrhoea and vomiting Hypovolaemia Erythema of mucosae and skin leading to peripheral desquamation Fever and myalgia

5. aureus phage group I, often phage types 29 and 52 (produce enterotoxin F, identical to exotoxin C)

Uncertain

Vagina, skin or other (occurs mainly in young women using tampons)

Food poisoning

Vomiting and diarrhoea

S. aureus phage group III (produce enteroxins A, B, C, D, E)

Uncertain

Food (toxin ingested)

both a diagnostic and a therapeutic measure. Antibiotic treatment is more likely to be successful if this can be achieved, and it may substitute for open surgery. In some sites, such as a heart valve, early surgery is essential because the valve is destroyed and a new one cannot be inserted if the surrounding valve root tissue has been destroyed. The decision whether to operate or aspirate and give antibiotics, or to give antibiotics alone, for a deep Staphylococcal infection is determined by the amount of pus formation, the accessibility of the site and the delicacy of adjacent tissue. For example, drainage of some CNS abscesses may lead to unacceptable damage, in which case the neurosurgeon would opt to try to sterilize the lesion with antibiotics in the first instance. Staph. aureus often produces pMactamase, particularly in hospital-acquired infections, and so treatment is usually started with a B-lactamase-resistant antibiotic such as flucloxacillin. Methicillin-resistant Staph. aureus (MRSA) is less pathogenic but it can cause deep-seated infection in vulnerable patients. The cutaneous syndromes of Staphylococcal infections are described on page 384. The management of septicaemia is discussed on page 274. Lung abscess is described on page 647.

Staphylococcus epidermidis infection Staph. epidermidis is a skin commensal. It is now clear that it causes serious infections in patients who are immunocompromised and in patients with intravenous cannulae, prosthetic heart valves, pacemaker wires, CSF shunts and other foreign materials in place for long periods. Staph. epidermidis produces B-lactamase and is usually resistant to a wide range of antibiotics, including methicillin. Resistance to methicillin is mediated by alteration to penicillin-binding proteins. The mainstay of treatment is vancomycin.

1

310

Fig. 9.14

2

MCQ 9.16

FIG. 9.16 Necrotic haemorrhagic lesions in meningococcal septicaemia, also showing the unusual features of gangrenous terminal phalanges

GRAM-NEGATIVE COCCI NEISSERIA Neisseria gonorrhoeae (gonococcus) infection is described in Chapter 11 (p. 458).

Neisseria meningitidis (meningococcus) infection There are three types of meningococcus - groups A, B and C - which are the most common cause of acute bacterial meningitis (p. 1413). They also cause septicaemia with or without meningitis (Fig. 9.16). Disease occurs sporadically or in epidemics, and the epidemiology is poorly understood.

FIG. 9.17 Incidence of meningococcal disease, England and Wales, 1989-2001 (source PHLS Meningococcal Reference Unit)

Meningococcal disease affects predominantly young children, although it can occur at any age. Its epidemiology varies between different countries, and particularly between Africa and European countries or the USA. In the meningitis belt of Africa it is a disease of young schoolaged children caused by serogroup A, which occurs in major epidemics at intervals of 8-10 years during the dry season, affecting 500/100000 people. In the UK, disease caused by serogroups B and, increasingly, C is endemic (Fig. 9.17), affecting 1-3/100000, with sporadic increases in incidence (hyperendemicity) in small areas from time to time, mainly during the winter months. About 50% of cases are in the under-5 age group. Clinical features Meningitis, which is the most common form of disease, is described on page 1415. It can occur with or without meningococcal bacteraemia, but it is important to recognize that meningococcaemia also occurs without meningitis in nearly 10% of cases. This can cause a range of illness, from almost asymptomatic bacteraemia to fulminant septicaemia with disseminated intravascular coagulation. The central feature is rash on any part of the body or mucous membranes which varies from maculopapular to petechial to ecchymotic. 1 In chronic meningococcal septicaemia there is persistent bacteraemia, together with rash, arthritis and low-grade fever. This may last for some weeks before progressing to more severe disease. Other syndromes rarely associated with meningococcal infection are pneumonia, pharyngitis, pericarditis, osteomyelitis and endophthalmitis. Diagnosis is made by blood cultures or Gram stain and culture of aspirates from skin lesions. Cultures from other sites may be indicated in particular situations, e.g. joint aspirate in arthritis.

Management and prevention Benzyl penicillin is highly bactericidal for meningococci and it should be the first choice of antibiotic. It is given intravenously at a dose of 2.4g 4-hourly initially in very sick patients, reducing to 1.2g after about 24 hours and then to 6-hourly (adults). If there is good evidence that the patient has penicillin sensitivity, cefotaxime or ceftriaxone can be used. Treatment is continued for 5-7 days. Nasopharyngeal carriage is not terminated by penicillin treatment, which should therefore be followed by rifampicin 600 mg b.d. for 2 days. This may need to change as resistance to rifampicin emerges, and an alternative would be a single dose of ciprofloxacin 500 mg. Polysaccharide vaccines are available against serogroups A and C meningococci but not against group B and there is a conjungate vaccine against serogroup C. The polysaccharide vaccines provide only short-lived protection but they are useful in curtailing the kind of limited outbreaks seen in European countries and the USA. Mass vaccination of villagers in Africa ahead of the spread of epidemics has been attempted, but it is more difficult to achieve success. 0

9

GRAM-POSITIVE BACILLI

BACILLI

Bacillus anthracis: anthrax Few cases of anthrax are seen in western countries but about 100000 cases occur in the world each year. The Grampositive rods of B. anthracis give rise to endospores in conditions unfavourable for replication, and these can survive for many years in the soil. Making use of this property they have been used in warfare in both world wars during the 20th century, and as a terrorist weapon on other occasions. The spores can contaminate the hides, hooves and bones of herded animals, and contact with these can cause cutaneous anthrax both in the endemic areas and in industrialized countries to which these animal materials are taken for processing. Bacilli are found in the tissues of animals dying of systemic infections. Transmission to humans is by skin contact with infected material such as hides or meat, by inhalation of spores or by ingestion of infected meat, causing skin, respiratory and gastrointestinal disease, respectively. Disease onset is within 5 days in all forms, and is usually about 2 days. Pathogenesis depends on the expression of virulence factors coded by two plasmids. Oedema toxin, lethal factor and protective antigen are the products of these plasmids. Endospores ingested by macrophages become vegetative and rupture macrophages, releasing organisms that replicate further in lymphatics and in the bloodstream, producing massive septicaemia, up to 108/mL. Expression of virulence factors is increased by elevated host temperature.

311

Cutaneous anthrax Cutaneous anthrax is the most common form of the disease and the most benign. A red macule or papule develops at the contact site, e.g. the neck of a meat carrier in a slaughterhouse. A pruritic vesicle develops, satellite lesions appear, and the whole evolves into an ulcer, then a black eschar. There is usually some surrounding oedema, but occasionally there is a severe local reaction with gross oedema, and general toxaemia ensures. Despite the size and appearances of the lesion it is painless unless secondarily infected. Inhalation anthrax At first there are mild general symptoms and a nonproductive cough. Improvement over a few days is followed by abrupt decline. The patient rapidly becomes very ill, with cough, fever, tachypnoea, cyanosis, tachycardia, vomiting and chills. Diffuse crackles are heard over the affected lung fields. The spleen may enlarge. There is massive enlargement and oedema of the neck and chest wall. Untreated, the patient often dies within 24 hours. There is an 80% mortality in this form. Gastrointestinal anthrax This may occur in clusters if a family or tribal group eat contaminated meat. Following ingestion, lesions can occur anywhere in the gastrointestinal tract, including the throat. There is diffuse abdominal pain, with rebound tenderness. Ascites can develop, and with this the abdominal pain declines. There are varying degrees of gastroenteritis with haemorrhage, and mortality is high. Symptoms resolve after about 14 days in those surviving. Haematogenous dissemination of organisms can sometimes cause meningitis with bloody CSF. Diagnosis Many cases probably go undiagnosed in the tropics and subtropics. The cutaneous form is probably most often diagnosed on the clinical appearances. Occupational exposure may be suspected from the nature of the patient's job. The severity of a pneumonic illness may prompt consideration of pulmonary anthrax. The organisms are readily found in Gram-stained smears from skin lesions and grow well in blood culture samples.

312

Management The cutaneous form may resolve without treatment. Penicillin V, 2 g/day in divided doses, is very effective. For more severe infections benzyl penicillin, 4.8-7.2 g in divided doses intravenously, is used. When the patient is allergic to penicillin, ciprofloxacin 400 mg twice daily intravenously or 500 mg twice daily by mouth, tetracycline 2 g/day or chloramphenicol lOOmg/kg/day in divided doses orally or intravenously can be used. The latter is given to children and pregnant women. Pulmonary or intestinal cases will require supportive care, with maintenance of oxygenation, giving normal saline, plasma or blood transfusions as necessary to maintain blood volume and hydration. Prevention is by elimination of the infection from

animals. Immunization is available when there is danger of occupational exposure. Vaccines are available for those who may be exposed to anthrax.

Bacillus cereus infection B. cereus is one of the causes of food poisoning (see Gastroenteritis, p. 278). Two illnesses are associated with different incubation periods. A short incubation period (1-6 hours), vomiting and abdominal pain caused by heatstable enterotoxin are often related to the ingestion of reheated rice. Longer incubation (8-16 hours), diarrhoea and abdominal pain are caused by a heat-stable toxin formed in the infected intestine. The treatment is directed at maintaining the patient's hydration. There is no specific therapy.

CORYNEBACTERIUM DIPHTHERIAE INFECTION

Corynebacterium diphtheriae is the cause of diphtheria, a toxin-mediated disease which is rare in countries with an effective immunization programme. Transmission is mainly person to person by nasopharyngeal droplets, but skin infection is also important in tropical countries. Pathogenesis C. diphtheriae (korynee - club, refers to the shape of the bacteria; diphtheria = leather, refers to the pharyngeal membrane) infects the nose, throat, larynx and trachea or the skin. It causes local inflammation, but its major effects result from the production of a protein toxin of MW 62000 which inhibits ribosomal polypeptide chain production by inhibiting elongation factor 2. The toxin is elaborated only by C. diphtheriae strains infected by a bacteriophage carrying the toxin production gene. Its main effects are on the myocardium and nervous tissue. Clinical features After an incubation period of 2-6 days there is a slow onset of malaise and fever, sometimes with mild sore throat. Immunized subjects develop disease at the site of infection but no toxin-mediated effects. In the unimmunized, at an early stage the predominant findings are profound weakness, restlessness and irritability, with fever, pallor and a rapid thready pulse. The pharynx shows the characteristic membrane which is adherent; attempts to scrape it off result in bleeding. In laryngeal diphtheria the membrane involves the larynx and trachea, causing respiratory obstruction which may require tracheostomy. The primary infection may also involve the nose, larynx or bronchi. ECG abnormalities suggesting myocarditis (flattening or inversion of T waves) or first-degree heart block appear after the first week and can progress to major dysrhythmias and circulatory collapse. Neurological complications start later, with paralysis of the palate, followed by the ocular muscles, then the pharynx, larynx and respiratory muscles, and lastly the limbs.

Diagnosis C. diphtheriae can be isolated from sites of infection but demonstration of toxin production takes several more days - too long to delay management decisions. Polymerase chain reaction for the tox+ gene has revolutionized management, as it can demonstrate the presence of the bacteriophage on the same day that a positive culture is obtained. Management and outcome Diphtheria antitoxin is administered without waiting for bacteriological confirmation in suspected cases, but it is no longer used for prophylaxis because of the danger of hypersensitivity reactions. The treatment dose is 1000030000 units i.m. for mild disease, increasing to as much as 100000 units for severe cases of more than 3 days' duration. For doses greater than 30000 units the remainder is given intravenously after an interval of 0.5-2 hours. Penicillin or erythromycin will eradicate the organism from the primary infection site but the patient must be isolated until the risk of cross-infection has been removed. Intensive nursing is required to protect the airway, and tracheostomy may be needed. ECG monitoring is used to detect dysrhythmias, and physiotherapy to preserve the range of movement in paralysed limbs. Contacts must be traced, treated if infected, and immunized. If the patient survives the acute illness, recovery from complications such as paralysis is complete. LISTERIA MONOCYTOGENES INFECTION

Listeria monocytogenes is a Gram-positive bacillus which is commonly dismissed as a diphtheroid contaminant on examination of CSF specimens. Microbiologists are now aware of its significance as a cause of serious disease, particularly in immunocompromised patients, pregnant women and neonates. The bacillus is a common contaminant of soft cheeses, especially if these are unpasteurized. It causes septicaemia, often associated with meningoencephalitis. Ampicillin or penicillin is the drug of first choice, with erythromycin in reserve for penicillin-allergic patients.

Epidemiology and pathogenesis Cl. tetani is found in human and animal faeces and its spores abound in soil. It is anaerobic and proliferates in ischaemic or necrotic tissue, usually in a poorly tended wound. In rural areas farm workers or gardeners are infected, but in cities the disease has been observed in drug addicts. Because immunization against tetanus toxin is standard in western countries, tetanus is rare. In poorer countries immunization is variable. Tetanospasmin is a neurotoxin which acts in several different ways. It inhibits the release of acetylcholine from nerve endings in muscle, but more importantly it interferes with synaptic reflexes in the spinal cord, causing disinhibition which results in muscle spasms. Clinical features The incubation period can be up to 3 weeks, depending on inoculation dose and site. Disease is most severe in the completely non-immune, in drug addicts and at extremes of age. The outcome is worst when the incubation period is short and there is rapid onset of the first spasm. The first (and sometimes the sole) sign of tetanus is often muscle spasm local to the wound; in most the CNS is involved, and trismus (lockjaw) heralds the onset of generalized tetanus. The patient notices difficulty in opening the mouth and swallowing, followed by stiffness in the neck, and back. Examination reveals the initial site of infection and 'risus sardonicus', the facial expression caused by trismus and contraction of facial muscles. The muscles of the back and abdomen become stiff, and painful spasms, provoked by sudden movement or noise, occur in the back muscles, causing opisthotonos. Autonomic involvement causes sweating and cardiovascular instability. Death is from exhaustion, aspiration or secondary infection.

Tetanus

Management Further toxin production is prevented by local debridement of wounds and treatment with metronidazole 500 mg intravenously 6-hourly. Human immunoglobulin containing antibodies to tetanus toxin in high titre is given to neutralize free toxin; 500 units are administered i.m. If surgery is indicated, it should be delayed for an hour after the administration of antibody. The patient is nursed in a quiet room to avoid stimuli likely to provoke spasms. Benzodiazepines such as diazepam are used to control spasms, as well as for their anxiolytic and amnesic effects. Neuromuscular block may be required, and then the patient is ventilated (see p. 737). Because prolonged ventilation is usual, tracheostomy is performed early. Nutrition is maintained enterally or parenterally. An attack of tetanus does not render the patient immune and a full course of immunization should be given after recovery.

Tetanus is a potentially fatal disease dominated by muscle spasm caused by an exotoxin, tetanospasmin, produced by Clostridium tetani.

Prevention Immunization with tetanus toxoid is the only way to

CLOSTRIDIA Clostridia are a group of obligate anaerobic bacteria that cause illness largely through toxins which act locally or enter the circulation. Clostridia are frequent wound contaminants without necessarily causing disease; when disease occurs, however, it is severe.

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prevent the disease altogether. A full course of toxoid confers immunity for at least 5 years. Neonatal tetanus can be prevented by immunizing the mother during pregnancy. Patients with wounds at risk from Cl. tetani infection are managed according to their state of immunity. All patients require local wound toilet. Fully immunized patients receive a booster dose of toxoid. Unimmunized patients with a wound considered susceptible to Cl. tetani receive human tetanus immunoglobulin, and active immunization with adsorbed tetanus toxoid is started simultaneously. Injection of long-acting penicillin, followed by a course of oral penicillin, is also indicated in these cases.

Botulism Botulism is a virulent form of food poisoning caused by heat-labile neurotoxins of Cl. botulinum. Disease follows ingestion of food containing toxin (usually tins of meat), ingestion of bacterial spores which germinate and produce toxin in the intestine, or contamination of a wound by spores which germinate there. The highly potent toxins interrupt cholinergic neurotransmission. There are seven antigenic types, A-G, but only A, B, E and F cause human disease. They consist of two polypeptide chains linked by a disulphide bond; the heavy chain binds to presynaptic receptors and the toxin is endocytosed. It inhibits acetylcholine release and the cell cannot release transmitters, so that there is motor paralysis and autonomic dysfunction. Damage to the synapse is permanent and repair requires the formation of a new synapse. These long-term effects of botulinum toxin are being used in the treatment of conditions in which there is sustained, inappropriate muscle contraction, such as torticollis. In the case of food-borne botulism the initial illness is an afebrile gastroenteritis that develops within 12-36 hours of ingestion in one-third of patients, but the remainder have only malaise and dizziness (with postural hypotension), progressing to extreme dryness caused by autonomic paralysis. Other neurological symptoms appear during the next 3 days: • Diplopia followed by bulbar signs • Symmetrical weakness of the limbs • Bulbar and respiratory muscle weakness may lead to inhalation pneumonia. Treatment is essentially supportive, with maintenance of the airway, including incubation or tracheostomy as required. Autonomic dysfunction does not usually cause severe problems (cf. tetanus). Antitoxin therapy is normally given although its value has not been established in controlled trials. Hypersensitivity reactions are common,

1 314

MCQ 9.17

particularly in those with a history of atopy, and skin testing is recommended. Trivalent horse antitoxin active against types A, B and E is given intravenously, 20 mL by slow infusion, followed by lOmL 2-4 hours later and further doses at 12-24-hour intervals if necessary. Infants who have ingested spores do not have circulating toxin, and antitoxin is of no benefit. Antibiotic therapy with penicillin or metronidazole is also of uncertain value, but wound debridement should be carried out in wound botulism. Recovery of muscle strength is extremely slow, occurring mainly in the first 3 months but continuing sometimes for up to a year. Prophylaxis with antitoxin may be needed in subjects thought to have ingested toxin. 1

Other clostridial syndromes Gas gangrene Cl. perfringens (welchii) is one of a number of gasproducing clostridia that contaminate wounds containing necrotic, anoxic material. Cl. perfringens produces 12 toxins, alphatoxin being the one associated with gas gangrene. It proliferates rapidly, producing myonecrosis. Gas infiltrates neighbouring tissues, causing crepitus. Toxins entering the circulation cause profound toxaemia, with a high mortality. Skin and soft tissue infections Local infections, often involving muscle, occur in amputated stumps, diabetic ulcers of the foot, decubitus ulcers, perirectal abscesses and abscesses at injection sites in drug addicts. Such infections frequently contain multiple organisms, including clostridia. Gut infections Pseudomembranous colitis is a diarrhoeal disease caused by toxins from strains of Cl. difficile which colonize the large intestine after antibiotic therapy. Cl. difficile produces two toxins, an enterotoxin (A) and a cytotoxin (B), both of which probably contribute to the pathogenesis of disease. Although the association with clindamycin therapy is well recognized, most antibiotics have caused this disease. It is particularly likely to occur in debilitated and elderly patients, but can affect any age group. It can be transmitted nosocomially, so patients should be isolated. The onset of watery diarrhoea (without blood), abdominal pain and fever is usually within a few days of exposure to an antibiotic, although it is delayed by 4-6 weeks in some cases. There may be severe systemic toxicity. In the majority of cases sigmoidoscopy reveals an inflamed mucosa covered by a white membrane, but this is absent in the 20% where only the ascending colon is involved. The diagnosis is confirmed by culture of the organism and identification of toxin in stool specimens, but as about 5% of healthy people carry the organism some laboratories just look for toxin. If symptoms continue after the offending antibiotic has been stopped, treatment is with oral metronidazole 400 mg

9

TABLE 9.28 Syndromes of enteric infection Organism

Toxins

Mechanism of action

Syndromes

ETEC

Heat labile Heat stable

Cholera-like; cyclic-AMP mediated Activates guanylate cyclase; cyclic GMP increases

EHEC (0157:H)

Shigella-like

?; toxic for Vero cells

Cholera-like Travellers' diarrhoea Infant gastroenteritis Haemorrhagic colitis Haemolytic-uraemic

t.d.s. for 7 days. Oral vancomycin has a slightly higher cure rate but is much more expensive than metronidazole. For severely ill patients who cannot take oral antibiotics, intravenous metronidazole 500 mg is given every 8 hours initially. Suppurative intra-abdominal infection caused by clostridia is particularly associated with carcinoma of the colon or pancreas. Neutropenic patients may develop severe enterocolitis caused by Cl. septicum.

GRAM-NEGATIVE BACILLI ENTEROBACTERIA The enterobacteria group comprises Escherichia coli (E. coli), Klebsiella, Proteus, Salmonella and Shigella. E. coli causes a wide variety of diseases, usually as a result of autoinfection. Urinary tract infection is the most common, but systemic infection is a major problem in hospitals. Septicaemia arises from the bowel when there is a bowel disease or when surgery has been carried out, or from the urinary tract as a complication of infection or surgery there. In neonates, E. coli is a common cause of septicaemia and meningitis. Several strains of E. coli cause gastroenteritis by a number of mechanisms; they are referred to as enteropathogenic (EPEC) (or alternatively enteroadherent - EAEC), enteroinvasive (EIEC), enterohaemorrhagic (EHEC) and enterotoxigenic (ETEC). EHEC and ETEC produce toxins (see Table 9.28). Klebsiella causes urinary tract infection, septicaemia and pneumonia. Kl. pneumoniae causes an acute severe cavitating pneumonia, most frequently seen in alcoholics (p. 638). Proteus is mainly associated with urinary tract infection. Salmonella is found in several hundred strains. Salmonellae other than S. typhi and S. paratyphi are amongst the most common causes of gastroenteritis related to food poisoning (see Gastroenteritis, p. 278). They cause disease by direct invasion of the intestinal mucosa, and some strains, e.g. S. typhimurium, cause septicaemia, but usually disease remains localized. Typhoid (enteric fever) is caused by S. typhi, and is described below. Four strains of Shigella are the cause of bacillary dysen-

tery, a form of acute diarrhoeal disease characterized by severe, bloody, purulent diarrhoea and abdominal pain.

Shigella dysentery Shigella sonnei and S. flexneri are the common organisms in the UK, the incidence of S. flexneri infection having increased in recent years; the other species are S. dysenteriae and S. boydii. Shigella infections occur worldwide, and epidemics are common where conditions are crowded and hygiene poor. Faecal-oral transmission results from lack of handwashing and the organism is highly infectious, ingestion of fewer than 200 organisms causing disease in healthy adults. The infection localizes in the colon, where the epithelium is invaded and becomes inflamed. There is an acute inflammatory exudate which produces diarrhoea containing large numbers of leukocytes. Enterotoxin production contributes to the intestinal damage, and the organisms may also produce a neurotoxin. Clinical features After an incubation period of 2-3 days there is a rapid onset of vomiting, abdominal colic and diarrhoea, which is usually bloody and purulent. Severity ranges from mild to fulminant. The most severe illness is caused by S. dysenteriae. Although the main illness is usually over within 1-2 weeks, diarrhoea and abdominal discomfort may persist for several weeks. Fever is common in the first few days and dehydration can occur rapidly, especially in children. Complications include haemolytic-uraemic syndrome (HUS), seen in children and the elderly, with a leukaemoid reaction in the blood frequently preceding the onset. Post-infective aseptic arthritis and Reiter's syndrome (conjunctivitis, urethritis and arthritis) are complications that vary in frequency in different epidemics but which are more common in HLA-B27 positive individuals. The diagnosis is made when organisms are cultured from faeces. Management Patients are managed as for any severe form of gastroenteritis, rehydration being the key factor (see Gastroenteritis, p. 278). This can usually be achieved using oral fluids, but if the patient is severely ill, and particularly if vomiting cannot be controlled, intravenous rehydration

315

may be required. Antibiotics are given as they shorten the duration of and ameliorate symptoms. They also reduce the risk of transmission, making a case for their use in milder disease, but plasmid-mediated resistance is common and transfers rapidly, so it is important to know the local antibiotic sensitivity pattern. Currently the first choice of antibiotic is ciprofloxacin 500 mg b.d. orally for 5 days. Other possibilities are co-trimoxazole, ampicillin or tetracycline. In the acute stage of invasive infection inhibitors of intestinal motility such as codeine phosphate and loperamide may exacerbate symptoms, and even precipitate toxic dilatation of the colon. Pain management can therefore be difficult, but regular paracetamol may help. Codeine is much more effective but it should be used only with great caution.

Typhoid Typhoid (enteric fever) is a serious, prolonged systemic infection with the Gram-negative bacillus S. typhi. Epidemiology Typhoid is endemic in many poor countries, and although uncommon in Britain (about 200 cases reported per year) it is an important cause of fever in returning travellers. Humans are the reservoir of infection and spread of infection is by contamination of water or food by human faeces. Epidemics usually occur when a common water supply is contaminated. Small outbreaks sometimes results when a chronic excreter of the organism works as a food handler. Pathogenesis Ingested organisms invade the small intestinal mucosa. In the absence of specific immunity, organisms phagocytosed by macrophages survive and proliferate. After an incubation period varying from 1 to 3 weeks (usually 10-14 days), determined by the infecting dose, septicaemia develops and foci of infection may be established in any organ. The gallbladder is an important site, as it is the source of chronic excretion when this occurs. Necrotic inflammation of Peyer's patches may be so vigorous as to cause intestinal perforation or haemorrhage. Clinical features In Britain typhoid usually presents as a pyrexia of insidious onset in a patient returning from abroad, often from the Indian subcontinent, although there have been small outbreaks in the United Kingdom related to take-away food outlets with a chronic carrier as the source. The classic stepwise rise in temperature is rarely seen but the untreated illness has a remorseless progression. Headache and dry cough are common in the first week, and

1

316

MCQ 9.18

the patient is often vague and withdrawn. Constipation is usual. In the second week the spleen is often palpable, and the elusive rash consisting of rose spots is seen in less than half of patients. The rash is sparse - fewer than a dozen spots in all - and consists of 1-2 mm pale red macules, which are hard to discern on a pigmented skin. By the third week diarrhoea may develop and the patient, now extremely ill, may lapse into coma. The overall mortality in untreated typhoid is about 10%, but with appropriate antibiotic therapy it is less than 5%. Spontaneous remission is often followed by relapse within 2 weeks. An unusual form of typhoid is encountered in patients infected with schistosomiasis, caused by S. mansoni or haematobium, in which fever is less dramatic but the illness more prolonged. Typhoid in children Typhoid is even more featureless in children than in adults, and presents as an abrupt severe septicaemic illness. The mental state is striking, the child initially being irritable but later frankly delirious. Febrile convulsions may be the presenting feature, and some degree of meningism is not uncommon. Diarrhoea is perhaps more frequent than in adults with typhoid, although intestinal infection with other organisms complicates the issue. Complications The most serious complications in the acute phase are intestinal haemorrhage or perforation. In severe cases there may be myocarditis or bone marrow suppression. Later complications are relapse, even after correct antibiotic treatment, in 15% of cases, and local sepsis in any organ as a result of septicaemia. Osteomyelitis is slow to cause symptoms. Chronic carriage Faecal excretion of S. typhi often continues several weeks after resolution of the illness and, rarely, patients excrete the organism for years. Chronic carriage is defined as excretion of the organism for more than 6 months after an acute episode. The organism is not detected in faeces during antibiotic treatment but reappears after therapy is stopped. The source of organisms in long-term carriers is probably the gallbladder, and gallstones readily become infected. Chronic excretion has obvious epidemiological consequences. Diagnosis The diagnosis is usually made by blood culture. The organism is not present in stools initially but can be isolated in

SUMMARY 10 Complications of typhoid • Relapse • Local sepsis, e.g. lobar pneumonia, meningitis, acute cholecystitis, urinary tract infection, osteomyelitis • Intestinal perforation and haemorrhage (2-3% with antibiotic therapy)

the second to third weeks. Bone marrow culture is particularly useful for identifying S. typhi in patients who have received antibiotics. It may also be cultured from urine in 30% of patients. Serology is rarely helpful in diagnosis. The blood count is helpful as neutropenia is common. Managemenf Patients must be nursed in isolation, preferably in an isolation unit, even though person-to-person transmission is uncommon. Intravenous fluids are given to correct dehydration. Currently ciprofloxacin 500 mg b.d. for 10 days is the drug of first choice. Treatment is started when there is a strong suspicion of the diagnosis and appropriate samples have been taken for culture without waiting for the results. Although duration and severity of symptoms, as well as mortality, are reduced by treatment, the response to treatment is not immediate. Controlled trials have shown the efficacy of dexamethasone 6 mg 6-hourly given to very toxic patients with typhoid. Relapse can be treated with the original antibiotic provided the organism was sensitive. Stools are collected for culture twice weekly after treatment to detect prolonged carriage. This is difficult to treat, but success has been reported with high-dose amoxicillin and ciprofloxacin for 4-6 weeks. Cholecystectomy may be necessary. Three negative stool specimens are considered to indicate that bacteriological clearance has been achieved. Perforation of the intestine is dangerous and carries a high mortality. Good results have been achieved by resuscitation followed by laparotomy, oversewing of single perforations or resection when a length of intestine is involved, and lavage of the peritoneum. When typhoid occurs in a patient with concurrent schistosomiasis the latter must also be treated to allow the antibiotic to be effective. Prevention A monovalent whole-cell heat-killed vaccine gives 75% protection against S. typhi for 1 year but causes local pain, fever and malaise in a high proportion of recipients after both primary vaccination and booster doses. This vaccine is no longer available in the UK. Another parenteral preparation containing Vi polysaccharide antigen is effective for 3 years. A live oral vaccine which uses the mutant strain of S. typhi,Ty 21a, gives similar protection after three doses but may not be as long-lasting. The protection may be overcome if the infecting dose of organisms is high enough, emphasizing the importance of clean water and thorough cooking in prevention.

Haemophilus infection

Haemophilus organisms are normal colonizers of the upper respiratory tract. H. influenzae is a major human pathogen; other Haemophilus species rarely cause disease, although H. parainfluenzae can cause illness similar to H. influenzae. A small proportion of H. influenzae isolated from humans are encapsulated and six antigenic types are recognized. The most important is type b, which can cause septicaemia and several clinical syndromes in children under 5 years old (Table 9.29). Older children acquire immunity to the capsular antigens. Untypable (nonencapsulated) H. influenzae are potential pathogens in the lower respiratory tract. Strains of H. influenzae have become increasingly resistant to antibiotics in recent years: 5-15% of strains are resistant to amoxicillin. This is particularly relevant to children with life-threatening diseases such as acute meningitis, in which a delay in treatment with the right antibiotic could be fatal. Resistance is mediated by pMactamases. Vaccine containing the polysaccharide capsular antigens has now been introduced in the UK for children below the age of 4 years, and this has greatly reduced the incidence of H. influenzae disease. Whooping cough (pertussis)

Whooping cough is a prolonged lower respiratory tract infection caused by the Gram-negative coccobacillus Bordetella pertussis. It is highly infectious and is transmitted by droplet. Epidemiology Spread of infection is entirely human-to-human and the disease is endemic, cases occurring continuously. Epidemics in susceptible children occur every 4 years in the UK (Fig. 9.18). Since reports of a possible association between pertussis immunization and encephalopathy in

TABLE 9.29 Diseases caused by H. influenzae Type

Disease

Type b

Acute meningitis Epiglottitis Septic arthritis Orbital cellulitis Pneumonia Exacerbations of chronic bronchitis Otitis media and sinusitis Conjunctivitis Rarely pathogenic

Salmonella paratyphi infection

S. paratyphi B is the most common paratyphoid infection in Britain. Other strains are called S. paratyphi A and C. Paratyphoid has a shorter incubation period than typhoid and is a milder disease with fewer complications. Diarrhoea tends to occur early, in contrast to typhoid. Treatment is with ciprofloxacin. 1

9

PARVOBACTERIA

Non-encapsulated

Other encapsulated types

Age

Up to 5 years

Any age

317

prolonged coughing spasms may cause convulsions. Minor complications are subconjunctival haemorrhages, periorbital bruising and frenal ulcer, all of which result from prolonged spasms of coughing.

FIG. 9.18 Incidence of whooping cough in England and Wales, 1940-2000 Note the effect of immunization on incidence. The death rate was falling before immunization was introduced (Communicable Diseases Surveillance Centre, Colindale).

1973, the rate of immunization has fallen off and epidemics have been larger. The disease may affect any age group but is most common in children under 5 years and most severe in those below 1 year. Pathogenesis The infection is concentrated in the bronchial walls, producing damage to the epithelium and accumulation of viscid mucus. Toxins produced by B. pertussis probably have a role in the tissue damage. Collapse of segments of lung distal to obstructed bronchioles is common. Clinical features After an incubation period of 7-10 days there is sometimes a prodromal illness that resembles a cold and lasts 2-3 days (catarrhal stage). This is followed by onset of the characteristic cough, with long spasms of coughing interrupted by rapid inspiration, which sometimes produces a whooping sound. This is often followed by vomiting. During a spasm of coughing the child becomes pink and then blue, and small babies may become apnoeic after a spasm. Between spasms the child looks and feels deceptively well. Whooping cough lasts about 2 months on average, and in the later stages the cough is mainly at night. It is distressing to watch small children rendered helpless by the spasmodic cough, and anxiety and disruption of sleep cause a major disturbance to family life. Complications Secondary bacterial infection causing pneumonia, or mucus plugging with segmental collapse, are the most common serious complications. Cerebral hypoxia during

1 318

MCQ9.19

Diagnosis Clinical diagnosis rests on recognition of the pattern of cough and is fairly simple when whooping is heard. However, in the early stages in babies and in adults the whoop may be absent. Laboratory support comes from the lymphocytosis and culture of B. pertussis from a pernasal swab; the latter is taken by passing a special swab through the nostril to the nasopharynx. Management Attentive nursing is the most important aspect of treatment, and parents need help and reassurance to learn to manage coughing spasms. Babies frequently feed poorly and lose weight, necessitating feeding through a nasogastric tube. The organism is sensitive to erythromycin, and early treatment with 125mg every 6 hours (up to 2 years) or 250 mg every 6 hours (over 2 years old) may be beneficial. Erythromycin can be used for secondary bacterial pneumonia if it has not already been started, or co-amoxiclav can be added. Prevention Pertussis vaccine is a crude preparation of killed organisms, but it is 80% effective in preventing whooping cough and often ameliorates the disease if not wholly preventing it. There is a small risk of convulsions after immunization (1 in 6000 doses) and a minute incidence (1 in 100000 doses) of encephalitis with lasting consequences. As there is severe morbidity and a small mortality in whooping cough epidemics the vaccine is strongly recommended. Prophylactic erythromycin treatment of close contacts has proved ineffective. 1

Brucellosis Brucellosis (undulant fever) is a septicaemic infection caused by Brucella abortus, Br. melitensis or Br. suis. Br. abortus is acquired from cattle, Br. melitensis from camels, llamas, sheep or goats (Malta fever), and Br. suis from swine. Most northern European infection is by Br. abortus acquired during occupational exposure in vets, farm workers and slaughterhouse employees, by ingestion of raw milk or by accidental infection in the laboratory. Most herds in the UK are brucella free, and pasteurization is an additional insurance against infection of milk. As a result of control measures the disease is now very rare in the UK but it remains a major problem in parts of Europe, the Middle East, and Central and South America. Brucellae are small Gram-negative coccobacilli which proliferate intracellularly. The incubation period of the disease is about 3 weeks.

Clinical features Some people have asymptomatic infections but the common presentation is an acute illness with persistent, swinging fever and profuse sweats. Back pain is common. There are no specific physical signs but 40% of patients have hepatosplenomegaly, 20% have splenomegaly only, and 20% have arthritis in one large joint. Less common manifestations are epididymo-orchitis, spondylitis, an erythematous papular eruption on the extremities, endocarditis, and neurological involvement with a range of manifestations, including meningitis, encephalitis or radiculitis. If no treatment is given the fever may persist for weeks or months, although it gradually declines, only to relapse again in many cases. A prolonged debilitating illness can be associated with depression. Depressed patients with moderate brucella antibody litres rarely have chronic brucellosis in the absence of a preceding history suggestive of acute brucellosis. Diagnosis There is neutropenia and lymphocytosis in the acute phase, and brucellae can be cultured from blood in 50-60% of cases and also from bone marrow in over 90% of cases. Complement fixing and agglutinating antibodies can be detected in rising titre following acute infection, and an ELISA-based serological test is also being used. Managemenf Inadequate treatment is associated with a high rate of relapse within 3 months, and some relapses occur despite the best known therapy. Doxycycline 200 mg daily combined with rifampicin 600 mg daily for 6 weeks, or doxycycline 200 mg daily for 6 weeks with streptomycin Ig intramuscularly daily for the first 3 weeks, gives the lowest relapse rates. Rifampicin is an enzyme inducer and may induce enzymatic breakdown of doxycycline reducing blood levels and hence its efficacy. Treatment is continued for 6 weeks in uncomplicated cases or 12 weeks in those with joint or spinal involvement. Endocarditis requires at least 12 weeks of therapy and probably surgical removal of the valve. In pregnancy rifampicin is given alone, and children less than 8 years old should receive co-trimoxazole plus rifampicin or streptomycin. There have been indications that rifampicin plus doxycycline has a greater relapse rate than streptomycin plus doxycycline. The explanation for this may be enzyme induction of doxycycline metabolism by rifampicin and so this effect could be overcome by increasing the doxycycline dose to ensure blood levels of the latter; this has not been tried. Because of susceptibility of brucella to other aminoglycosides such as gentamicin and netilmicin, these have been used for 5 to 7 days with good results although there are no controlled trials comparing these aminoglycosides with streptomycin. Some authors have suggested that for abscess, spondylitis, endocarditis and neurological disease treatment with three drugs, adding rifampicin to a doxycycline plus aminogly-

SUMMARY 11 Treatment of Brucellosis in adults Doxycycline 200 mg daily + rifampicin 600-900 mg daily

9

6 weeks uncomplicated 12 weeks complicated

or Doxycycline 200 mg daily + streptomycin 1g i.m. daily for first 3 weeks

6 weeks uncomplicated 12 weeks complicated

In patients with spondylitis Streptomycin 15mg/kg up to 1 g/day maximum i.m. (reduced dose in those under 50kg, over 40 years old or with renal impairment; drug level monitoring indicated in renal impairment) Children less than 8 years old Rifampicin 10-20 mg/kg/day for 8 weeks, together with cotrimoxazole for 6 weeks - every 12 hours, 6 weeks to 5 months, 120mg; 6 months to 5 years, 240 mg; 6-12 years, 480 mg.

coside regimen. For children, rifampicin plus co-trimoxazole can be used, adding an aminoglycoside when a third drug is needed. Preventive measures concentrate on elimination of brucellae from domestic animals, ideally by testing and slaughter of positive reactors, with compensation for the financial losses. Pasteurization of milk also prevents transmission, although in countries where the traditional custom is to drink milk and make other products using unpasteurized milk, changing these practices is immensely difficult. Vaccination of animals: the 19S strain of B. abortus in cattle or the Rev 1 strain of B. melitensis in sheep or goats is effective, but it should be noted that although these are attenuated strains for animals they are pathogenic for humans if accidentally injected.

Yersinia infection Yersinial infections are zoonoses. The important human pathogens are Y. enterocolitica and Y. pseudotuberculosis, which are enteric pathogens, and Y. pestis, the cause of plague. Y. pseudotuberculosis and Y. enterocolitica Infection with Y. pseudotuberculosis and Y. enterocolitica (see also p. 816) is less common in the UK than in some other European countries, notably Scandinavia and Belgium. The organism is a common commensal in the pharynx and tonsillar tissue of pigs, which are included in ground pig meat. Other foods, including milk and seafoods, have been incriminated in human outbreaks. Y. enterocolitica causes febrile enterocolitis in young children (less than 5 years old), but in adolescents an illness which is difficult to distinguish from acute appendicitis is caused by mesenteric adenitis. The latter is also the most common manifestation of Y. pseudotuberculosis infection. The presence of exudative pharyngitis may give a clue in

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Y. enterocolitica infection. Many laparotomies have been carried out for these self-limited infections, which may be partially responsive to gentamicin therapy (often given as blind treatment or as prophylaxis for surgery). Reactive polyarthritis and erythema nodosum are well-recognized complications which are more common with Y. enterocolitica.

Plague An acute severe infection caused by Y. pestis manifests by either lymphadenitis with suppuration (bubonic plague) or by necrotizing pneumonitis (pneumonic plague). It is a zoonosis. Aetiology The organism is a Gram-negative aerobic bacillus of the parvobacteria family. It grows well at 28°C. At 37°C it produces an antigen which inhibits phagocytosis. It has a lipopolysaccharide capsular endotoxin. Distribution and incidence Asia, Africa, the Middle East and the Americas (South America and the southern states of the USA) are endemic areas with comparatively small numbers of reported cases each year. The disease is probably under-reported. Plague is considered a re-emerging disease because the number of cases being reported to the WHO is increasing, and since 1994 it has reappeared in several countries such as Malawi, Madagascar, Mozambique and India, where it had not been experienced for 15-30 years. Also, the number of foci have increased in some countries, including the United States. The last pandemic started in 1894, and by the middle of the twentieth century public health measures had led to it being purely sporadic. Transmission The infection is transmitted to man by the bite of the rat flea (Fig. 9.19). The natural hosts are rodents and the vector is the rat flea, Xenopsylla cheopis, which takes blood meals from its rodent hosts. Infected rats die and the fleas leave the dead rats for other hosts. The organisms produce a coagulant which prevents the flea taking a full blood meal. The flea bites the host repeatedly, encouraging transmission. The coagulant is inactive above 28°C and transmission diminishes. Pathology

Necrosis and haemorrhage are the main features, together with marked inflammatory changes. An eschar is occasionally found at the bite site. Buboes are grossly enlarged, inflamed lymph nodes draining the site of the flea bite. The normal lymph node architecture is destroyed and necrotic, with large numbers of bacilli. The pathological changes in pneumonic plague are very similar, with haemorrhagic necrosis of lung tissue. 320

Clinical features The incubation period is 2-8 days before the onset of

FIG. 9.19 Cycle of transmission of plague

systemic upset, fever, chills and headache. Within 24 hours of this the patient finds a bubo, which is exquisitely tender. Any group of lymph glands can be involved. Tachycardia and high fever are usual, with hypotension and shock in severely affected patients. Purpura may occur. Pneumonic plague results from haematogenous spread of organisms to the lungs. Cough, chest pain and haemoptysis in a severely ill patient are usual features. Patchy shadowing is seen on the chest X-ray. Aerosol spread can occur from patients with pneumonic plague. Septicaemic plague has a high mortality. There is a neutrophil leukocytosis. Some degree of disseminated intravascular coagulation is common, although spontaneous bleeding is uncommon. Diagnosis The organism may be found in material aspirated from the necrotic centre of buboes and in blood films. Smears made on slides can be stained with Giemsa stain, which shows the Gram-negative coccobacilli. The organism grows readily on standard media. Antigen (F1) can be detected in sputum by the second day of symptoms using a dipstick test which is simple and highly practical. Management The high mortality in untreated plague (over 50%) has been altered by antibiotics. Streptomycin 15mg/kg twice daily i.m. for 10 days is the treatment of choice. Defervescence occurs by the third or fourth day. Tetracycline and chloramphenicol are alternative choices but there are reports of multiple resistance to antibiotics mediated by a plasmid. Supportive treatment is needed in those with low blood pressure and shock, with volume replacement using saline or plasma. Buboes should be aspirated.

Prevention and control A vaccine is available for those working with plague in the laboratory or in the field. Proven cases are not infectious unless there is pneumonic involvement, when isolation of cases, with respiratory precautions to avoid aerosol spread, is necessary. Antibiotics rapidly reduce infectivity. Vector control with insecticides and rat control will minimize transmission in towns and cities.

followed by chloramphenicol 10mg/kg four times daily, doxycycline 2mg/kg twice daily, and co-trimoxazole (trimethoprim 10mg/kg/day + sulfamethoxazole 50 mg/ kg/day) given for up to 20 weeks. The efficacy of maintenance therapy depends on full compliance over this long period. There is evidence to suggest that co-amoxiclav plus extra amoxicillin gives equally good results, as good as the conventional regimen, with fewer side-effects, though full compliance is again necessary over 20 weeks.

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PSEUDOMONAS TULARAEMIA Pseudomonas aeruginosa infection

Pseudomonas aeruginosa is an opportunist organism which rarely causes disease in immunocompetent subjects. It causes serious infection in patients with deficient immunity and in those who have had surgery. Septicaemia, osteomyelitis, infection of burns and pneumonia are examples. Skin changes due to Ps. aeruginosa are described in Chapter 10. Patients in intensive care units may become colonized superficially and treatment with antibiotics is often counterproductive, as resistance develops rapidly.

MELIOIDOSIS Burkholderi (Pseudomonas) pseudomallei is a Gramnegative aerobic bacillus with bipolar staining. It is found contaminating surface water, particularly in southeast Asia and northern Australia, although cases have been reported from a much wider geographical range. It has a very low host specificity and will infect a very wide range of animals, including humans. Infection occurs by ingestion or inhalation of contaminated water, or by contact of infected water with abraded skin. If health is good there may be subclinical infection, shown by seroconversion without systemic upset. Debilitating illness, for example diabetes mellitus and cirrhosis, and immunosuppression enhance susceptibility, and the development of clinical infection, which can be acute or chronic, may follow. After a 2-3 day incubation period there is fever, myalgia, vomiting, confusion or delirium. Diarrhoea may also occur, as may shock with features of endotoxic shock. Pustular skin lesions may occur. The lungs may be involved, with consolidation, cavitation and pus formation. Suppurative parotitis is seen in children. Chronic and relapsing sepsis may occur, with abscess formation affecting lymph glands, lungs, skin, liver, genitourinary tract and bones. Multiple small abscesses tend to form, producing multiple small cavities on liver ultrasound scanning. The organism is a dangerous pathogen which may be grown from pus, lymph gland biopsies, liver biopsy material and bone marrow aspirate. Serological responses using indirect haemagglutination (IHA) or complement-fixing antibody techniques are available. Antibiotic treatment comprises initial treatment with ceftazidime 2g t.d.s. intravenously for at least 2 weeks,

Francisella tularensis is a Gram-negative bacillus that infects a wide range of wild animals; humans are occasionally infected in rural areas of the northern hemisphere (North America, Sweden, Norway, northern Europe, Russia and Japan). Infection occurs by the bite of an infected deerfly or tick, by mucosal or skin contact with an infected animal, by inhalation, and by eating inadequately cooked meat. The effects in humans may be localized cutaneous pustular disease with regional adenopathy, a pneumonic illness, or a systemic illness sometimes with diarrhoea. Inapparent (subclinical) infections occur. The North American rabbit strain produces severe disease, with a mortality of up to 10% without treatment. Mortality is negligible (except for the American rabbit strain) even without treatment. The diagnosis is made by finding the organisms in material from infected tissues. Direct immunofluorescence may be used. Serological tests may also be used to detect antibodies to the organism by ELISA and agglutination techniques. Great caution is needed in handling specimens to avoid the risk of laboratory infection. Streptomycin (lOmg/kg twice daily for 14 days) is very effective. Tetracycline and chloramphenicol are effective. Patients need to be isolated until they have been on treatment for 48 hours to minimize the risk of cross-infection.

BARTONELLOSIS

Bartonella bacilliformis is a Gram-negative aerobic bacillus transmitted by the bite of the female sandfly Lutzomyia verrucarum. The disease is limited to the valleys of the western Andes, mainly in Peru, Colombia and Ecuador, between 2500 and 8000 feet above sea level. Humans are the reservoir of infection. There are two manifestations of the disease: haematological and cutaneous. After a 21-day incubation period there is sudden onset of systemic upset. The onset of fever is often followed by acute severe intravascular haemolysis, which may last up to 4 weeks before resolution. Several weeks to several months later the eruptive phase of the disease appears, with nodular lesions of various sizes over the body in the miliary form, or fewer nodular, deep lesions particularly

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concentrated on the extensor aspects of the limbs. Mucous membranes of the mouth and gut, and serous cavities can be affected. The organisms can be grown in blood cultures taken in the first week of the illness and can be readily found in Giemsa-stained thick and thin blood films, or in material obtained from skin lesions. Treatment with antibiotics kills the organisms and produces rapid defervescence and clearance of organisms from the blood. Penicillin, streptomycin and chloramphenicol are effective; the latter is recommended in view of the reported association between systemic salmonellosis and bartonellosis. Treatment is for at least 7 days. Bartonella quintana This organism, formerly known as Rochalimaea quintana, was recognized as the cause of trench fever among troops in the First World War. The vector is the body louse, and so infections can occur when levels of sanitation are low. The organisms are present in louse faeces and infection occurs by introducing B. quintana through skin abrasions by scratching. There is no identified animal host. The organism causes a range of febrile conditions, including a febrile illness lasting 4 days or so, a relapsing febrile illness with three to five episodes of fever, and a continuous febrile illness lasting up to 21 days. Despite the association with the First World War the condition occurs worldwide among communities where sanitation is poor. Doxycycline or erythromycin are the treatments of first choice. This agent and the related B. henselae have been recognized as the cause of cutaneous bacillary angiomatosis among patients with HIV infection (see Ch. 11). Infection of deep organs such as the liver produces similar lesions.

itself appear ill. The cat is probably infectious for about 3 weeks. Clinical features Most cases occur in children or young adults. There is gross enlargement of a single group of lymph nodes, which are usually tender. Lymphadenopathy develops about 2 weeks after the scratch and usually lasts for 2-4 months, but it may persist for up to a year. A papule may occur at the site of the scratch; it appears about a week after the scratch and persists for 1-3 weeks. Although most patients remain well, one-third have a low-grade fever for a few days and may experience malaise, headache and sore throat. Rare manifestations are conjunctivitis and preauricular lymphadenopathy (oculoglandular syndrome), encephalopathy, thrombocytopenic purpura, osteomyelitis and pneumonia. Diagnosis The diagnosis is usually based on the histology of excised lymph node with negative cultures for bacteria and mycobacteria. The Warthin-Starry silver impregnation stain may reveal the CSD bacilli but they are present in small numbers. There may be a mild neutrophil leukocytosis, but other tests are unhelpful. Antibody tests are being developed. Management Because the disease resolves spontaneously the only treatment usually required is analgesia if the lymph nodes are painful, and reassurance. Antibiotics do not help.

VIBRIOS

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CAT-SCRATCH DISEASE

Cholera

Cat-scratch disease (CSD) is a benign lymphadenopathy in a site determined by an area scratched by a cat, most often in the neck or axilla.

Cholera is due to infection with the Gram-negative bacillus Vibrio cholerae, which causes acute secretory diarrhoea with death due to dehydration.

Aetiology and pathogenesis Histology of affected lymph nodes reveals scanty small pleomorphic rod-shaped Gram-negative bacilli which are normally seen using the Warthin-Starry stain. These have now been identified as Rochalimaea henselae (possibly to be renamed Bartonella henselae) in most cases, although a small number may be a related organism called Afipia felis. The organism has been identified in lymph nodes from patients by culture, polymerase chain reaction for DNA, and by immunocytochemistry; serum antibodies are detectable in 84-96% of those affected. This organism is also one of the causes of the skin condition called bacillary angiomatosis which affects immunocompromised subjects such as AIDS patients (see Ch. 11). The infection is transmitted by scratching or licking by a young cat with chronic bacteraemia which does not

Aetiology V. cholerae is a curved Gram-negative motile bacillus. Two biotypes are recognized, the classic biotype and the El Tor biotype. The organism is present in vast numbers in the faeces of infected patients. The El Tor biotype tends to cause more asymptomatic and mild infections, which resolve spontaneously and leave the patient excreting vibrios to infect others. The organism is sensitive to desiccation but survives in saline waters. Vibrio cholerae 0.139 has been recently recognized in India and Bangladesh. Until that time the 0.1 serotype was the sole pathogenic organism and 0.2 to 0.138 were non-pathogenic. Distribution and incidence Distribution and incidence are shown in Figure 9.20. Cholera has been imported into European countries but

9

FIG. 9.20 World distribution of cholera 1994 (WHO)

no outbreaks have resulted, apart from that in Naples in 1974. Transmission and epidemiology Organisms are ingested in contaminated food and water. In India, Bangladesh and Pakistan, where cholera is endemic, it is predominantly a paediatric disease. In epidemic cholera all ages are affected. Individual susceptibility is governed by the infecting dose and by the gastric acid barrier. The 0.139 serotype affected adults and children in India and Bangladesh, indicating that there was no cross-protection between the usual serotype and the new one. Pathogenesis V. cholerae secretes an exotoxin which binds to the GM1 ganglioside, a glycolipid on the surface membrane of jejunal enterocytes (Fig. 9.21). The effects of cholera toxin are mediated by several mechanisms, one of which may be accumulation of cyclic AMP in the cell. Local neurohumoral stimuli may also contribute to the diarrhoea. The outcome is that the upper small intestine becomes a site of net secretion, with the accumulation of isotonic fluid containing Na+, Cl-, HCO3- and water. This fluid passes down the intestine and in the colon K+ exchanges for Na+ under the influence of aldosterone. Stooling rates of 500mL/h are common, and up to 1 L/h may be produced. The effect of cholera toxin lasts for the duration of the life of the enterocyte, which is 3-4 days; during this time the cell migrates from the crypt to villous tip, where it is desquamated into the gut lumen. There are no histological changes in the affected mucosa. Cholera is a secretory diarrhoea with no mucosal inflammation. Secondary changes in a range of tissues, e.g. kidney, occur as a result of hypovolaemia and shock. Clinical features The incubation period is about 2 days. Diarrhoea begins

FIG. 9.21 Mechanism of action of cholera toxin on intestinal cells A Attachment of cholera toxin to receptor on enterocyle. B Activation of cAMP - note different effects on villous and crypt cells.

suddenly, with vomiting during the first 24 hours of illness. Faecal residues disappear, and opalescent rice-water stools are passed. There are no pus cells in faecal smears. The abdomen may be distended and bowel sounds are increased. Stool losses are maximal within the first 48 hours of the illness and decline spontaneously thereafter, but death can occur from dehydration within 24 hours in the most severe cases. The clinical features are due to isotonic volume depletion (Table 9.14, p. 280). Haematocrit and plasma specific gravity rise with haemoconcentration. Hypoglycaemia may occur in young children and may be associated with convulsions. Loss of bicarbonate causes acidosis. There is prerenal uraemia. Colicky abdominal pain and slight fever are features of infection with the serotype 0.139. There is a considerable range in the severity of diarrhoea in cholera, particularly the El Tor biotype, which is the cause of many mild cases.

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Diagnosis Severe diarrhoea causing rapid progression to dehydration suggests that cholera is the cause in severe cases. Milder cases will not be diagnosed unless a stool is cultured or immediate dark-ground microscopy of a fresh faecal smear shows the characteristic morphology of V. cholerae. Differential diagnosis All the acute infective causes of diarrhoea need to be considered, including ingestion of staphylococcal enterotoxin, invasive bacteria such as Salmonella, Shigella and Campylobacter, which are usually readily distinguished because of the presence of systemic upset and colicky abdominal pain, and enterotoxigenic strains of E. coli. Rotavirus infection may also be difficult to distinguish from cholera.

the duration of both diarrhoea and faecal excretion of Vibrio cholerae. In pregnancy and childhood ampicillin or furazolidone may be given. Co-trimoxazole is also effective. Prevention and control Adequate clean water supplies and the safe disposal of faecal waste would do much to prevent the occurrence of cholera. Concurrent education of the population about the relationship between infective diarrhoeal disease and personal and general sanitation practices is essential. The widespread use of ORS early in the course of all diarrhoeal illness reduces mortality. Vaccination with the current killed vaccine is of no benefit, either for prophylaxis in the traveller or for the control of epidemics.

Management Mild to moderate dehydration can be managed with oral rehydration solution (ORS) (p. 280), but patients with severe dehydration need intravenous infusions, e.g. Ringer's lactate, to restore blood volume. The aims of rehydration are: • To replace estimated fluid losses in the first 4 hours after presentation; • To replace continuing intestinal fluid losses with equal volumes until diarrhoea stops. Frequent small amounts of ORS are better tolerated than less frequent large volumes, especially if the patient is vomiting. Additional fluid, such as water, fruit juice, tea or breast milk, but not ORS, should be given to allow for insensible losses and obligatory urinary losses. The glucose in ORS is not sufficient to counter hypoglycaemia and so extra sugar should be given orally. A solution prepared using rice flour as the source of glucose is capable of reducing faecal fluid losses by producing net absorption of sodium, glucose and water from the gut. Bowel sedatives merely paralyse smooth muscle, leaving fluid containing organisms and the toxin in the intestinal lumen, and should not be used in management. Tetracycline, 250 mg four times daily for 3-5 days, will reduce

SUMMARY 12 Managing dehydration in cholera

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Clinical assessment No dehydration

Management Encourage fluid intake Encourage normal diet

Some dehydration (5-10% body weight lost)

ORS 80mL/kg body weight over 4 hours + 400 mL ORS after each diarrhoeal stool + water to provide for insensible and renal losses

Severe dehydration (>10% body weight lost)

Ringer's lactate 30 ml/kg body weight over SOmin, then 70 ml/kg over 2 hours

CAMPYLOBACTER Campylobacter are curved rods morphologically similar to Vibrios but regarded as a separate genus, as they have different biochemical characteristics. There are six species, of which C. jejuni and C. fetus are important human pathogens. C. jejuni is a major cause of prolonged severe enterocolitis, frequently associated with bloody stools and abdominal pain and tenderness suggestive of peritonitis. It is now the pathogen most frequently isolated from patients with gastroenteritis and the incidence of infection peaks in late summer to autumn. Infection may be acquired from food or drinks, but there is often a relationship with domestic animals, a wide variety of which are normally colonized (e.g. dogs, fowl and cattle). In the tropics. C. jejuni can often be isolated from the faeces of asymptomatic subjects, but it frequently causes diarrhoea in children less than 5 years old, implying that asymptomatic infection occurs in those with some degree of immunity.

Pathogenesis The incubation period is up to a week, this and the severity of the illness being determined by the infecting dose of organisms. The infecting dose required to cause illness is about 104, but this may be reduced by conditions of low acidity in the stomach. Human bile encourages growth of the organism, and the small and large intestine are colonized and the mucosa is invaded. Although toxins are produced, they are not thought to contribute to pathogenesis. C. fetus sometimes causes bacteraemia but rarely C. jejuni, usually in the very young or elderly. Excretion in the stools continues for 2-3 weeks after infection in the absence of immunity, which causes more rapid clearance.

Clinical features Fever, headache and malaise begin 2-5 days after infection, shortly followed by diarrhoea, often with blood, cramping

abdominal pain and tenderness. The severity of pain and tenderness before the onset of diarrhoea sometimes suggests an abdominal emergency, such as appendicitis. The symptoms usually resolve within a week, but in a significant minority the duration is longer and there may be relapse in the absence of antibiotic treatment. Guillain-Barre syndrome is an uncommon complication of C. jejuni infection (about 1 in 2000 cases), although because the incidence of this infection is high it is linked to nearly 50% of cases of GBS.

Diagnosis The diagnosis is established normally by microscopy and culture of stools under microaerobic conditions, but occasionally blood culture is positive.

Management As with other forms of gastroenteritis, the first priority is rehydration and correction of electrolyte disturbances (see p. 280). Appropriate analgesia is required when abdominal pain is a prominent symptom. Drugs such as codeine phosphate which reduce gut motility should be used with caution in the acute phase. Simple analgesics (paracetamol) may be adequate. Antibiotics are indicated for severe cases when there is fever together with systemic symptoms. Erythromycin 40mg/kg/day in four doses may alleviate symptoms in children, and it terminates the excretion of organisms in the faeces. If treatment is clinically indicated before the organism has been identified, ciprofloxacin, 500 mg b.d. for adults, is more likely to improve symptoms and reduce the duration of illness, but there is increasing resistance to quinolones which necessitates local surveillance.

ANAEROBIC BACTERIA

Bacteroides fragilis is the most commonly encountered pathogenic anaerobe but many others are found among the normal flora of the gastrointestinal and genital tracts; these include other Bacteroides, Fusobacteria and some anaerobic cocci, such as peptostreptococci and microaerophilic streptococci. Anaerobic organisms often cause wound infection, abscesses and septicaemia in patients who have had abdominal surgery or intestinal perforation. Antibiotic sensitivity is restricted; metronidazole is very useful, as it is well absorbed orally or rectally and B. fragilis is usually sensitive to it. Clindamycin is also useful.

Mixed infections Infection may involve several different bacteria, including anaerobes. Abscesses associated with the bowel, especially the colon, or the vagina are examples. Some tissue infections, especially in debilitated patients, may also contain

multiple pathogens. Severe stomatitis, one form of which is known as Vincent's angina, commonly occurs in malnourished patients with poor dental hygiene. The pathogens responsible are members of the normal mouth flora, including anaerobes and spirochaetes which are sensitive to penicillin. Metronidazole is an alternative treatment. Necrotizing fasciitis is a rapidly spreading subcutaneous infection; it results in extensive necrosis, which may involve any part of the body. Type I is caused by mixed infection and type II by group A streptococci (see p. 386). Type I occurs particularly in diabetics, common sites being on the feet, spreading upwards, and on the perineum. Scrotal infection is called Fournier's gangrene. The organisms involved are mixed anaerobic bacteria, mainly Bacteroides or peptostreptococci. Treatment is by a combination of aggressive surgery and antibiotics aimed mainly at anaerobes, for example clindamycin plus ampicillin.

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MYCOBACTERIA Mycobacteria are classified as a group because they contain mycolic acids. They are bacilli which are mostly slow-growing and able to survive within macrophages. On staining by the Ziehl-Neelsen method they are acid and alcohol fast. The most important pathogens within the group are Mycobacterium tuberculosis and M. leprae. Tuberculosis is still relatively uncommon in the western world but a major problem in less developed countries. The disease is discussed fully on page 640. M. bovis is rarely incriminated now but can cause similar disease. Other nontuberculous mycobacteria, sometimes called atypical, such as M. kansasii, are less pathogenic than M. tuberculosis but can cause disease. M. avium intracellulare has become more familiar in recent years because it is one of the infections that afflict patients with AIDS. Mycobacteria other than M. tuberculosis are often resistant to standard antituberculous drugs, so their treatment presents difficult problems in immunocompromised patients.

LEPROSY Leprosy (Hansen's disease) is a chronic infection of the skin and cutaneous nerves caused by M. leprae. The manifestations in the patient may be localized or generalized, and are determined largely by the host response to the infecting organism. Aetiology Mycobacterium leprae is an acid-fast bacillus that cannot be cultured in vitro. Ziehl-Neelsen staining of smears of the organism differentiates viable (solid staining) from non-viable (granular) organisms. In humans the cooler superficial regions of the body are the preferred sites for

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Among those developing clinical disease there appears to be a racial variation in the type of leprosy occurring: up to 50% of cases in Asia have lepromatous disease, compared with 10% in Africa. The male-to-female ratio is 2:1 in adults and unity in children. Pathogenesis and pathology The host's cellular immune response determines the outcome of infection. If macrophages are able to kill the infecting organisms there is either no clinical disease or the lesions of indeterminate leprosy at most (Fig. 9.23). Those in whom the infection progresses further develop one of the forms of disease described in Table 9.30 and classified as one of the following: FIG. 9.22 Geographical distribution of leprosy

bacterial proliferation. The generation time is about 13 days. M. leprae was one of the first pathogenic bacteria to be identified, and yet in vitro culture remains elusive. Our knowledge of the organism's sensitivity to antimicrobial agents is gained from the response of mouse foot-pad lesions induced by injection of suspensions of M. leprae to antileprosy drugs given in water. It is known that M. leprae is a very hardy organism capable of surviving prolonged drying in the shade in south India, and capable of prolonged carriage in the noses of 5% of the general population and 16% of leprosy workers. Distribution and incidence Leprosy is mainly a disease of the tropics and subtropics (Fig. 9.22). It is relatively common in Africa and Asia, with a prevalence of 2-9 per 1000 in most areas and higher rates in a few countries. There are about 600000 new cases per year, including a considerable number of childhood cases, which indicates persistence of transmission. Lepromin skin test positivity rates in endemic areas are much higher than rates of clinical cases, suggesting that host factors do much to influence the outcome of the disease. The disease has almost completely disappeared from Europe, although cases do occur in Europeans who have had prolonged exposure in an endemic area. Transmission and epidemiology There is little evidence to support skin-skin contact as the route of infection. Aerosol spread from the upper respiratory tract of patients with multibacillary (lepromatous) leprosy is the likely source of infection. There is considerable variation in the course of infection from person to person, and the majority of those infected develop no clinical disease.

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1

Fig. 9.15

2

Fig. 9.16

4

Fig. 9.18

5

Fig. 9.19

3

Fig. 9.17

• • • • •

Tuberculoid (TT) Borderline tuberculoid (BT) Borderline (BB) Borderline lepromatous (BL) Lepromatous (LL).

It should be noted that the clinical disease is a biological continuum between the two polar extremes of pure tuberculoid and pure lepromatous. Few bacilli are found in the tuberculoid forms, whereas large numbers are found in patients with lepromatous leprosy. Host cellular responses to mycobacterial antigens determine the form of disease that develops, with delayed-type hyper sensitivity at the tuberculoid end of the spectrum and anergy at the lepromatous end. The borderline forms are immunologically unstable, and without treatment will deteriorate to the lepromatous end of the spectrum. The pathology of leprosy is a granulomatous response. At the lepromatous end of the spectrum the granuloma comprises macrophages laden with solid staining bacilli and globules of fatty products of bacillary metabolism, including phenolic glycolipid 1. This appearance of the macrophages is called foamy macrophages. Although lymphocytes are conspicuous by their absence from lepromatous lesions they are well represented in tuberculoid lesions. The earliest lesions in leprosy begin in cutaneous nerves in the Schwann cells which have phagocytic functions and ingest bacilli. The most marked damage to nerve trunks is seen in TT leprosy. At the lepromatous end of the spectrum the involved nerves are not so large. The auriculotemporal, ulnar, median, radial cutaneous, lateral popliteal and sural nerves are preferentially involved at sites where the nerve trunks are close to the skin and therefore cooler. The bacterial load and the morphology of the organisms need to be assessed, initially for classification purposes and subsequently to determine the response to treatment. Slit skin smears are obtained from the edges of lesions. Numbers of bacilli and their viability can be graded. Lepromin is a skin test antigen obtained from M. leprae. The antigen is injected intradermally and the test is read at 3 weeks; a nodule at the site of injection indicates a positive response, meaning delayed hypersensitivity and supporting a classification at the tuberculoid end of the spectrum.

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FIG. 9.23 Evolution of leprosy lesions with and without treatment (TT = tuberculoid; BT = borderline tuberculoid; BB = borderline; BL = borderline lepromatous; LL = lepromatous) (After Ridley D S 1977 Skin biopsy in leprosy. Ciba-Geigy, Basle.)

TABLE 9.30 Major features in leprosy Feature

Tuberculoid leprosy (TT)

Borderline leprosy (BB)

Lepromatous leprosy (LL)

Lesions Nerve involvement Numbers of bacilli Lepromin test Reactions Reversal Erythema nodosum leprosum (ENL)

Few (1-3) Local Fragmented only +++

More numerous Present in nerves of predilection Viable bacilli present in lesions -

Large numbers Diffuse, symmetrical, late in disease Vast numbers of viable bacilli -

-

+++

Two types of acute reaction are recognized in leprosy: • Erythema nodosum leprosum (ENL) is an immune complex-mediated vasculitis that occurs in LL patients and, less often, in BL, either during treatment or in the untreated patient. There is inflammation with oedema and a prominent infiltrate of neutrophils. • A reversal reaction indicates a change in cellular responsiveness to the infecting organism, either increasing (after starting treatment) or decreasing responsiveness. Skin lesions and affected nerves become more inflamed. The swollen lesion resolves completely in time, becoming smaller in 'upgrading' and bigger with 'downgrading'. Clinical features Indeterminate leprosy Indeterminate leprosy is manifest as a hypopigmented macule on a dark skin, and as a slightly reddened macule on a light skin, with either normal or mildly reduced sensation. The lesions may regress spontaneously or progress to one of the stages described below. Tuberculoid leprosy Tuberculoid leprosy (TT) is characterized by a hairless, hypopigmented anaesthetic lesion with a flat centre and a well-defined raised edge with minimal inflammation. 1 The skin of the lesion does not sweat. Single lesions are usual, but up to three may be found. Common sites are the extensor aspect of the arms, around the elbow and the

+++

knee. A thickened cutaneous nerve supplying the affected area may be felt. 2 To feel an enlarged nerve the examining fingertip should be moved to and fro over the nerve trunk at right-angles to the direction of the nerve. Neural TT leprosy occurs with a single thickened nerve as the only physical sign. Borderline tuberculoid leprosy Borderline tuberculoid (BT) lesions are similar to those of TT but more numerous and asymmetrically distributed. The edges of the lesions are inflamed and irregular. 3 The nerves preferentially involved in leprosy are usually thickened and damaged, causing anaesthesia, loss of function and deformity to a variable extent in hands and feet. Penetrating ulcers in the soles of the feet, burns and skin sepsis are often present. There may be osteomyelitis of the bones of the feet caused by an infected penetrating ulcer. Borderline leprosy Borderline leprosy (BB) produces multiple lesions that vary in form, size and shape. Papules, plaques and lesions with elevated wide outer rims and depressed, well-defined anaesthetic centres are seen. The lesions may be hypopigmented or hyperpigmented. 4 There is diffuse involvement of the peripheral nerves. Borderline lepromatous leprosy Borderline lepromatous leprosy (BL) causes numerous asymmetrically distributed inflamed or hyperpigmented lesions, which may be papules, nodules or plaques. 5 Sen-

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sation over the lesions may be normal. Vague macules that vary in size are present in some patients. Peripheral nerves may only show slight enlargement. Lepromatous leprosy Lepromatous leprosy (LL) is associated with numerous symmetrically distributed skin lesions. 1 At the earliest stage, numerous slightly reddened hypopigmented macules and nodules occur. Without treatment these evolve into papules and plaques. The eyebrows are lost and the skin of the face and ears becomes diffusely thickened (leonine facies). Involvement of the nasal mucosae may block the nose and cause a bloodstained nasal discharge. Destruction of the nasal cartilage may occur later. Iritis and keratitis are often present. The voice may alter because of inflammation and thickening of the laryngeal mucosa. Testicular atrophy and gynaecomastia occur because of testicular damage. Bilateral oedema of the legs is often present. Nerve involvement occurs late in the course of the disease. Renal failure due to glomerulonephritis and amyloid disease are late complications in LL. Reactional states In reversal reactions the skin lesions and involved nerves become more inflamed and swollen. These reactions may also be accompanied by swelling of the face, hands and feet. Involved nerves become very tender, often with further deterioration in function. This type of reaction may persist for 2-3 months before subsiding. ENL produces acute inflammation of existing skin lesions in BL. The lesions become swollen and painful and slowly evolve through a livid appearance to residual hyperpigmentation of the affected skin. Bullae form over some lesions; these ulcerate and are slow to heal. New papules appear in LL cases, typically on the extensor aspects of the limbs. They may evolve over 2-3 days, through a bullous stage, to indolent ulcers which are slow to heal. Uveitis, lymphadenitis, orchitis and neuritis are also features of ENL. Diagnosis Diagnosis is based on the clinical features, characteristic histology, a positive lepromin test (at the tuberculoid end of the spectrum) and acid-fast bacilli in slit skin smears taken from the edge of lesions and other sites, the earlobes, elbows and knees (BB, BL and LL). In pure neural leprosy the diagnosis can be made from a biopsy of a few fascicles of an affected distal cutaneous nerve with no motor function, such as the radial cutaneous nerve at the wrist, or the sural nerve. Management

Multidrug therapy is now the rule and the current WHO

328

1

Fig. 9.20

2

4

Figs 9.23, 9.26

MCQ 9.20 5

3

Fig. 9.27

Figs 9.21, 9.22

TABLE 9.31 Treatment of leprosy Type Paucibacillary Tuberculoid (TT) and borderline tuberculoid (BT) Multibacillary Borderline (BB), borderline lepromatous (BL), lepromatous (LL)

Drugs Rifampicin, 600 mg monthly, supervised + dapsone, 100mg daily, unsupervised both for 6 months Rifampicin, 600 mg monthly, supervised + dapsone, 100mg daily, unsupervised + clofazimine, 300 mg monthly, supervised + clofazimine, 50 mg daily, unsupervised All drugs are continued for 2 years from time of diagnosis and thereafter until slit skin smears contain no bacilli

recommendations are set out in Table 9.31. These drugs are generally well tolerated. Dapsone occasionally causes haemolysis. Clofazimine may stain the skin a rather reddish hue. Mild upgrading reactions may be controlled with aspirin or non-steroidal anti-inflammatory drugs. More severe reactions that threaten nerve function require oral steroids. ENL may be controlled by steroids, but sometimes thalidomide is needed. The patient needs careful instruction regarding the care of hands and feet, prevention of cracking and infection of the skin of the feet and appropriate footwear. Where the cornea is exposed as a result of facial nerve palsy, early lateral tarsorrhaphy is essential to prevent corneal damage. Tendon transplants may help in managing foot and hand deformities. Prevention and control There is still a considerable stigma attached to leprosy; this is based on ignorance. Education of the public regarding the disease and the efficacy of treatment is being attempted. BCG vaccination reduces the incidence of leprosy. Currently there are efforts to define protective antigens which may result in a genetically engineered vaccine. 2

MYCOBACTERIUM ULCERANS

M. ulcerans causes chronic ulceration, usually on an exposed area of the body, often the lower limbs. The condition has a wide distribution in the tropics and is often called Buruli ulcer. The pathogenesis of M. ulcerans disease is related to its unique ability to produce a tissuedamaging toxin, mycolactone, recently characterized as a macrolide molecule which causes cell death by apoptosis. Histology shows numerous acid-fast bacilli within extensive areas of necrotic fatty tissue with little inflammatory reaction. The organisms can be grown in Lowenstein-Jensen medium at 30-33°C. Clinical lesions begin as a subcutaneous nodule which ulcerates through the skin.

© Subcutaneous extension produces an ulcer with markedly undermined edges. Patients (most commonly children aged 5-15) are systemically well unless there is secondary bacterial infection. Long-term complications are determined by the site of the lesion; facial ulcers can destroy an eye; limb lesions may require amputation; scars around a joint lead to contractures. The disease is a major cause of morbidity in West Africa. Standard treatment is surgical and excision of early lesions is usually curative. Established ulcers require extensive debridement to remove all infected tissue, followed by grafting. Antibiotics have not been shown to be effective despite in vitro sensitivities, but there have been few formal trials. Local heat may encourage healing, as the bacteria are killed by temperatures over 33°C. Many topical treatments have been tried but there is little evidence about their benefit. Recent evidence suggests that topical nitric oxide treatment may be beneficial. When the lesion affects a region near to a joint, active and passive movement of that joint must be encouraged to prevent contractures.

SPIROCHAETES Syphilis, caused by infection with Treponema pallidum, is primarily transmitted sexually and is discussed in Chapter 11 (p. 458).

YAWS Yaws is a chronic infection due to Treponema pertenue; it is characterized by a primary site of skin infection, with later dissemination to other cutaneous sites and periosteum. Unlike syphilis, cardiovascular and nervous systems are not affected and congenital infection does not occur. Distribution, incidence and transmission Following mass eradication campaigns yaws became very uncommon, but there has been a resurgence of cases in South America, west and central Africa, Indonesia and the Pacific region. The organism must be introduced into the skin by contact between an infective lesion and an abrasion in the skin of the recipient. Clinical features 4 The primary papillomatous lesion or 'mother yaw' develops at the site of infection. This lesion is highly infectious. Other forms are a localized area of dry papules or a localized maculopapular rash. Regional lymph nodes are often enlarged. Secondary infectious lesions appear within a few weeks, either before or after the primary lesion has healed. Rashes continue to appear over the next 5 years. Condylomata form at moist sites, and are highly infectious. Later periostitis may occur, affecting fingers, tibia (causing sabre

tibia) and nose (a destructive lesion called gangosa). Painful, deep fissures in the soles of the feet also occur.

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Diagnosis and management The organisms are readily found in serous material from primary and secondary lesions examined by dark-ground microscopy. Serological tests for syphilis are positive. Penicillin aluminium monostearate is very effective given once only in a single dose of 1.5 g (0.75 g for children under 10 years). Tetracycline (2.0g/day in divided doses for 14 days) can be used in those allergic to penicillin, apart from pregnant women and children under 8 years, who should receive erythromycin for 2 weeks.

ENDEMIC SYPHILIS (BEJEL) Endemic syphilis is due to non-venereal infection with an organism that is intermediate between T. pallidum and T. pertenue. It is present in the desert regions of North Africa and the Middle East. Infection probably occurs by personto-person spread among children and older women who look after children. The first lesions are mucous patches in the mouth. Later, moist raised lesions of various sizes in axillae, groins, perineum and between the buttocks are seen. Hyperkeratotic lesions, like those of yaws, affect palms and soles. Bone involvement (periostitis) is associated with pain in the knees and shins. Destructive lesions of the nose, similar to gangosa in yaws, may occur. Congenital transmission does not occur, and late disease affecting the cardiovascular and nervous systems is very rare. Treatment with penicillin aluminium monostearate, as in yaws, is effective.

PINTA Pinta is a treponemal infection caused by T. carateum. Geographically it is localized to the drier regions of Central and South America. Transmission occurs by direct contagion from infectious skin lesions, and breaks in the skin may be a route of entry for the organism. The primary skin lesion is a papule sited on the extremities, around which smaller, similar lesions appear. 5 Spirochaetes may be found in serous material expressed from the erythematous and violaceous lesion. Serological tests for syphilis are positive. Treatment is with a single dose of benzathine penicillin (1.5g intramuscularly, or 0.75 g for children under 10 years).

RELAPSING FEVER Relapsing fever is an acute infectious illness caused by Spirochaetes of the genus Borrelia. Borrelia recurrentis is the cause of louse-borne relapsing fever, and a range of other species cause the tick-borne variety.

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Aetiology and transmission Borrelia are spiral organisms which can be identified in peripheral blood smears using Giemsa and Leishman stains; they can also be readily identified using dark-ground microscopy and cultured on artifical media. Humans are the reservoir of infection of louse-borne relapsing fever. The human body louse, Pediculus humanus, is the vector. Sudden mass migrations of people grouped together in adverse conditions encourage the spread of lice and louse-borne diseases, relapsing fever and typhus. Tick-borne relapsing fever is a sporadic zoonosis in humans in areas where there is a cycle of transmission between ticks and wild rodents. The disease has a worldwide distribution, except for Australia and the Pacific region. Pathogenesis and pathology During the incubation period spirochaetes divide intravenously. Platelets are sequestered, intravascular coagulation occurs, and a bleeding tendency results. After 4-5 days of symptoms there is a crisis associated with massive phagocytosis of Borrelia, helped by opsonizing antibody. Following the crisis there is an afebrile period during which numbers of organisms expressing different surface antigens build up and symptoms recur. This can occur up to five times. The spleen, liver, heart and brain are the main sites of pathological lesions, which consist of macrophages surrounding and ingesting large numbers of organisms. Clinical features After an incubation period that varies from 4 to 18 days the illness begins suddenly with rigors and a fever which rises rapidly to 40°C. Headache, joint pains, anorexia, malaise, nausea and vomiting are usual features, with mental confusion frequently present. Hepatosplenomegaly is common, with jaundice present in some patients. A petechial rash, most prominent on the trunk, is seen. Bleeding from the nose, the respiratory tract or the gut may occur, as may focal neurological signs. The first febrile period lasts about 5 days before spontaneous defervescence. This follows a severe febrile paroxysm with cold extremities, a rising pulse rate and blood pressure, and tachypnoea. An afebrile period lasting about 7 days recurs before the first relapse. Tick-borne disease is milder than louse-borne disease. In both, death can occur during the initial rigor or during defervescence. Diagnosis Organisms can be found in Giemsa-stained peripheral blood smears. 1 Dark-ground microscopy can be used to demonstrate the motile spirochaetes in a fresh blood smear.

1

330

Fig. 9.28

2

MCQ 9.21 3 Fig. 9.29

Management Antibiotics kill spirochaetes readily. Tetracycline can be used in patients over 8 years old. Erythromycin can be used in pregnant women and young children. Louse-borne relapsing fever requires a single dose of 500 mg of either drug. Tick-borne relapsing fever requires treatment for 10 days. Supportive care is needed, particularly in patients with louse-borne disease, as they can develop severe reactions, including Jarisch-Herxheimer, after being treated. Central venous pressure monitoring is essential if facilities are available. Hypoxia is corrected by giving oxygen continuously. Vitamin K is given if the prothrombin time is prolonged. Prevention Delousing by washing with soap and water, followed by dusting with 10% DDT, is effective. Clothes should be washed with soap in water at 55°C to kill lice and nits (lice eggs), which are found in the seams of clothes. Lice cannot survive on a person who has two sets of clothes worn on alternate weeks.

LYME DISEASE Lyme disease is caused by infection with Borrelia burgdorferi, transmitted by the tick Ixodes dammini. It is described on page 1160.

LEPTOSPIRAL INFECTION Infection with Leptospira icterohaemorrhagiae is discussed on page 879. 2

ACTINOMYCOSES Actinomyces species, despite their name, are bacteria which are often confused with fungi because of their filamentous appearance and their propensity to produce chronic suppurative infection with sinuses discharging purulent material. Most human disease is caused by Actinomyces israelii, an oral commensal, and occurs in the presence of chronic lack of dental hygiene. The characteristic pathological feature is that tissue boundaries are crossed and bone is infected. There is a fibrotic reaction around suppurating areas which accounts for the induration detected in palpable lesions. Three major forms of disease occur: cervicofacial, thoracic and disseminated actinomycosis. In cervicofacial actinomycosis the characteristic lesion is a painless swelling below the border of the mandible, bluish, fluctuant and slowly enlarging. Sometimes the abscess is painful and is usually apparent long before there is any spontaneous discharge. Thoracic actinomycosis may result from aspiration of oral debris, or may occur after thoracic surgery; it is easily

SUMMARY 13 Actinomycosis • • • • •

Cervicofacial form associated with poor dental hygiene Thoracic form may follow surgery Abdominal form is usually ileocaecal Discharging sinuses occur Prolonged penicillin treatment is needed

confused with carcinoma. The chest radiograph shows unilateral consolidation, with evidence of chest wall involvement. Nowadays the disease is usually diagnosed before discharging sinuses develop. Actinomycosis may be disseminated haematogenously and lesions may occur at almost any site. The abdomen is the most common, usually in the ileocaecal region. Because of the chronic course and the difficulty of diagnosis, sinus or fistula formation is still seen in abdominal actinomycosis. Other rare sites of infection are the pelvis, CNS and bones. Diagnosis and management Microscopy of tissues reveals the Gram-positive organisms, with surrounding acute or chronic inflammatory reaction and foamy macrophages. The organism can be cultured from tissues and, rarely, from blood. Penicillin is the drug of choice and prolonged treatment in high dose is necessary. Intravenous administration of 2.4-3.6 g every 6 hours for 4-6 weeks is followed by oral treatment with amoxicillin 500 mg every 8 hours for at least 6 months. Tetracycline, erythromycin and chloramphenicol are alternatives in penicillin-allergic subjects. Relapse is uncommon if this rigorous approach is adopted. Surgery is rarely required but may have to be considered in severely ill patients who fail to respond to medical therapy, and possibly in those with CNS disease.

MADURA FOOT This is a descriptive term for a group of chronic infections of the subcutaneous tissues and bone of - usually, but not invariably - the limbs. Two groups of organisms cause this condition: • Actinomycetes cause 60% of cases; these are bacteria and respond to antibiotics. • True fungi such as Madurella mycetomatis, which are almost totally unresponsive to antifungal drugs. These two groups of organisms are found in the soil and enter the skin by penetrating injuries. Pathology and clinical features The main features are chronic inflammation with microabscesses and granulomatous reactions around collections of the organisms. The organisms spread slowly along fascial planes and not via lymphatic or haematogenous routes.

Collections of organisms forming adjacent to bone produce local resorption, and small lytic areas visible on X-ray. 3 There are also areas of reactive sclerosis. Sinuses form and organisms are extruded. There is swelling of the affected area, with often prominent subcutaneous nodules. The time course is slow, and although there may be recollection of a penetrating injury, such as a thorn going deeply into the foot in childhood, there is often no such history and presentation may occur years after the patient has left an endemic area.

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Investigations and management The most important investigation is an adequate surgical biopsy of diseased tissue, which must usually go down to bone. This specimen is divided to give samples for histology and culture for the two groups of organisms. Actinomycetoma responds well to prolonged courses of antibiotics. Co-trimoxazole is effective (two tablets twice daily for 9 months, with streptomycin 1 g intramuscularly daily for the first 2 months). Dapsone, 100mg daily, is an alternative to co-trimoxazole. Pigmented grains fungi may respond to ketoconazole, whereas non-pigmented species are treated with itraconazole. Madurella mycetomatis has responded to ketoconazole 200 mg twice daily, and Aspergillus nidulans, A. flavus and Fusarium species have responded to 100 mg twice daily, in prolonged courses. Surgical removal of diseased tissue in addition to antifungal agents is recommended for some fungal infections.

NOCARDIOSES Nocardiosis is a systemic infection caused by species of Nocardia (N. asteroides and, less often, N. brasiliensis and N. caviae). N. brasiliensis is the common cause of actinomycetoma in the tropics and subtropics. Nocardia are higher bacteria which exist in a filamentous and coccobacillary form, depending on culture conditions. Aetiology, pathogenesis and epidemiology Nocardia are aerobic, filamentous branching Gram-positive bacteria and grow well on standard culture media. The organisms are found in rotting vegetation and infection is acquired by inhalation in most cases, although inoculation via the skin occurs. Initial pulmonary lesions may lead to dissemination of infection by the bloodstream. Necrosis and suppuration are the typical pathological changes. Adults are most often affected. Infection occurs mainly in immunosuppressed individuals. Clinical features Acute and sometimes fulminant or chronic suppurative pulmonary disease occurs in nocardiosis. Fever, cough with viscid sputum, night sweats and weight loss are usual features. Pleural thickening and empyema may develop, and the affected lung may cavitate. Haematogenous dissemination to cause brain abscess, kidney lesions, bone lesions and subcutaneous sepsis is reported.

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Actinomycetoma due to Nocardia presents with longstanding swelling of the extremity, most often the foot or ankle, and sinuses discharging on to the skin.

diagnosis and can give information about the response to treatment. An adequate deep biopsy will give the best chance of isolating the organism concerned.

Diagnosis Diagnosis depends on finding the organism in discharges, exudates, bronchial washing or biopsy sections. Nocardia grow well on media used for growing tubercle bacilli and on Sabouraud's medium. Serological tests are helpful in

Management Co-trimoxazole is effective (two double-strength tablets every 8 hours). Prolonged treatment is the rule, with relapse being less common after 3 months, medication. Minocycline (100-200 mg twice daily) is also effective.

SYSTEMIC MYCOSES Mycoses are infections caused by organisms that are classified morphologically as yeasts or filamentous fungi. Yeasts are round or oval and reproduce by budding. Filamentous fungi grow by branching and longitudinal extension of hyphae. This is not a simple distinction, as several organisms can grow in either form, depending on conditions. 1

CANDIDA INFECTIONS The range of diseases caused by Candida albicans is very broad. It is a common commensal of the oral and vaginal mucosae at one extreme, and at the other it can cause pneumonia, endocarditis, septicaemia and death. Candida can become a pathogen on damaged skin, in severely ill patients, in patients who have specific immune deficiency (especially AIDS), and in patients receiving

SUMMARY 14 Candida infections Skin

Secondary infection of damaged skin Mucocutaneous candidiasis (specific T cell deficiency)

Oral

Broad-spectrum antibiotic use Topical corticosteroids (e.g. inhalers for asthma) Immune deficiency (e.g. AIDS) Severe illness

Vaginal

Antibiotics or contraceptive pill Spontaneous (no immune deficiency)

Pneumonia

Due to severe illness with secondary immune deficiency

Septicaemia

Severely ill patient; multiple antibiotics Intravenous cannulae Neutropenia

1

332

Figs 9.30, 9.31

2

Fig. 9.32

broad-spectrum antibiotics when the local microbial ecology is disturbed. Both cell-mediated and humoral immunity participate in control of Candida. Inherited deficiency of T-cell function causes severe but localized disease. In combined immune deficiency the infection becomes disseminated. Severely ill patients under intensive care frequently have a mixed immune deficiency and are also receiving antibiotics that predispose to Candida infection. Disseminated infections are also seen in intravenous drug abusers. Cutaneous and mucosal surface candidiasis is described in Chapter 10. Diagnosis of systemic Candida infection Candida septicaemia is often a terminal event and over half of patients are diagnosed at postmortem. Clinical signs are usually minimal, but there may be endophthalmitis with fluffy yellow/white retinal spots resembling cottonwool spots, or small abscesses may be detected elsewhere, such as in the liver, where ultrasound-guided biopsy or aspiration can clinch the diagnosis. Pulmonary infiltrates may occur on chest X-ray, with Candida in bronchial washings. Isolation of Candida from a single site on one occasion does not necessarily indicate serious infection, even when it comes from a blood culture. The judgement that Candida is responsible for disease manifestations remains clinical. In view of the difficulty in diagnosis, treatment is given for disseminated Candida infection if Candida is cultured from more than one site in a severely ill patient in whom there is new evidence of infection (e.g. fever) but bacterial infection is judged to be unlikely. Management Fluconazole is the first choice for disseminated candidiasis. It is given intravenously, 400 mg by infusion initially, followed by 200 mg daily until oral therapy can be substituted. Maintenance treatment is needed until antibiotics are stopped. Toxicity is very uncommon. If there is no response to this drug amphotericin B is substituted, starting at 0.25 mg/kg daily infused over 1 hour, increasing rapidly to about 0.8 mg/kg daily. The maximum dose is limited by sideeffects such as fever, uraemia and bone marrow toxicity. For management of local Candida infections and the emergence of drug resistance, see pages 391 and 453.

ASPERGILLUS Aspergillus is a less common fungal pathogen which can cause disseminated disease in terminally ill patients. However, its more common manifestations are a range of respiratory diseases, the nature of which is determined by the immune response of the host (see Ch. 13). 2

CRYPTOCOCCOSIS Cryptococcosis (torulosis) is a systemic infection with the yeast-like fungus Cryptococcus neoformans. The organism is commonly found in soil contaminated by bird droppings, notably those of pigeons. Disease occurs following inhalation of the organism, but it is unusual in immunocompetent people and currently is seen most often in patients with AIDS (Ch. 11, p. 448). Clinical features CNS infection causes chronic meningitis with very lowgrade symptoms on presentation. Cranial nerve palsies may cause visual abnormalities, loss of acuity or diplopia, or facial weakness and numbness. The course is slow or rapidly progressive, depending on the patient's immune status. Corticosteroid therapy accelerates progression. Respiratory infection usually occurs in the absence of CNS involvement. It is more chronic and may regress spontaneously. Skin lesions are found in 10% of patients. The face and scalp are the most common sites of the painless lesions, which are variable nodules, sometimes ulcerating. Diagnosis Routine culture is often negative. In the CSF little abnormality is found, apart from a few cells, mainly lymphocytes, mildly reduced glucose compared with the blood, and slightly raised protein. The organisms are shown by India ink preparations, but the most sensitive method of diagnosis is by detection of antigen in CSF and sometimes in blood. Management Treatment is started with fluconazole 400 mg daily, by mouth if the patient is not vomiting, or intravenously at the same dose. If there is no response after 2 days amphotericin B is substituted, giving up to 1-1.5 mg/kg/day until there is a clinical response, and then reducing to three times weekly to a total dose of 1-2.5g (see Candidiasis).

HISTOPLASMOSIS Histoplasma capsulatum is a common environmental fungus found in the soil in a filamentous form, but when it infects humans it behaves as a yeast. It multiplies rapidly in soil containing the droppings of birds and bats, and humans are usually infected by inhalation of spores in

infected dust. Infection has been shown to be common by skin test surveys in the eastern central part of the USA, but there are also scattered areas of infection in both temperate and tropical areas of the world. H. capsulatum var. duboisii is a variant found in central Africa. H. capsulatum infects macrophages, and the pathogenesis of disease is similar to that of tuberculosis. Delayed hypersensitivity skin tests show that the majority of infected individuals are asymptomatic. Clinical features of H. capsulatum Acute pulmonary infection in normal hosts causes febrile illness with headache, often accompanied by cough and chest pain, with malaise, myalgia and weight loss. Erythema nodosum or multiforme may occur. Symptoms usually last less than a week, but occasionally severe infection is seen following a large infecting dose and it may even be fatal. Radiological changes occur in only 25% of acute infections, with scattered pulmonary infiltrates and hilar and mediastinal lymphadenopathy. The histoplasmin skin test is not helpful in diagnosis, but a complement fixation antibody test may be useful. Treatment is often not required but, now it is established that the azole drugs, ketoconazole and itraconazole, are beneficial, they can be given more easily than amphotericin B and with less risk of toxicity, and they may make patients feel better earlier than if they receive no treatment. Ketoconazole (400 mg daily) or itraconazole (200 mg daily) is given by mouth for 3-6 weeks. Amphotericin B (0.8mg/kg daily) is reserved for severe illness. Concurrent prednisolone therapy, tapering from 60-80 mg/day, is given if there is a marked hypersensitivity reaction to the infection. Chronic pulmonary histoplasmosis affects normal individuals with structural defects of the lung. Infection of emphysematous lesions causes chronic destructive disease in the lung apices, similar to tuberculosis. Fever may be accompanied by night sweats; one-third of patients have chest pain. Diagnosis requires repeated sputum cultures. Antibody and skin tests are usually unhelpful. Treatment is with ketoconazole, 400 mg daily for 6-12 months, or longer if there is evidence of relapse. Itraconazole is more expensive but may cause fewer side-effects. The need for treatment is judged on the basis of clinical severity. Disseminated histoplasmosis is a rare and often fatal manifestation of infection in immunocompromised hosts. It may be acute, subacute or chronic, depending on the age of the patient (acute is more frequent in infants) and the degree of parasitization of macrophages (more severe parasitization causes more acute disease). Fever, hepatosplenomegaly, anaemia, leukopenia, thrombocytopenia and interstitial pneumonia are most common in the acute disseminated form. Intestinal ulceration, Addison's disease, meningitis and endocarditis occur in the subacute form, and oropharyngeal ulcers occur in chronic disseminated disease. Diagnosis is by histology and culture of relevant tissues, and treatment is as for the other forms

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of the disease. Amphotericin B is reserved for the most severe cases where the prognosis is poor, and it is the first choice of treatment for progressive disseminated histoplasmosis associated with AIDS, which does not respond satisfactorily to ketoconazole.

Histoplasma capsulatum var. duboisii H. capsulatum var. duboisii infection occurs in Africa. The route of infection is poorly defined; asymptomatic pulmonary infection, with later spread to the skin and bones or inoculation into the skin, is a possibility. Skin, subcutaneous tissues and underlying bone can be affected, causing: • Superficial, cutaneous granulomas (papules or ulcers) • Subcutaneous granulomas and abscesses • Osteomyelitis with discharging sinuses which heal intermittently. Smears from exudate or discharges show numerous large yeast cells. Histological sections of infected tissue show giant cell granulomas with the large yeast cells. Treatment with ketoconazole (400 mg daily) or amphotericin B may be needed in lesions that show no signs of regression.

COCCIDIOIDOMYCOSIS Coccidioidomycosis is a fungal infection caused by Coccidioides immitis. Its distribution is confined to arid areas of the western hemisphere, including the southwestern USA, Central America and some countries of South America. Dust contaminated with fungal spores is the source of infection. Granulomatous responses occur around fungal spherules, and suppurative lesions with leukocytes characterize the tissue response to endospores. The host response to the organism determines the outcome of disease. Asymptomatic infection occurs in about three-fifths of patients and is detected by skin testing. A smaller number of those infected present with respiratory symptoms, cough, fever and chest pain, with malaise, muscle pains, night sweats and chills. A macular erythematous rash, erythema nodosum and erythema multiforme also may be seen (p. 407). Radiographic appearances include pneumonitis, hilar adenopathy and pleural effusion. In most of these patients the disease resolves spontaneously. In some cases pulmonary infiltrates and systemic symptoms persist, sometimes with cavitation. The diagnosis is made by finding the endospore of the organ-

1

334

MCQ 9.22

ism in material from affected lung. There is a considerable risk of laboratory infection with this organism. Serological tests are an aid to diagnosis. Dissemination of infection from an initial site of pulmonary disease may occur. Pregnant women show an increased incidence of dissemination. All tissues and organs of the body may be affected. Meningitis is one of the most severe manifestations of disseminated infection. Amphotericin B is used in treatment. The main difficulty lies in deciding which patients will benefit from treatment. Persistent, symptomatic pulmonary infection and disseminated infection require chemotherapy.

PARACOCCIDIOIDOMYCOSIS Paracoccidioidomycosis, or South American blastomycosis, is unrelated to Coccidioidomycosis. It is caused by Paracoccidioides brasiliensis and occurs exclusively in the area between Mexico and Argentina. The natural environment of the pathogen is uncertain. Its mode of acquisition is probably through inhalation. Clinical features, diagnosis and management Adults usually present with progressive respiratory symptoms, sometimes accompanied by ulcers in the mouth and nose, dysphagia, voice changes, skin lesions and cervical lymphadenopathy. Diagnosis is usually made by culture or histology, and treatment is with imidazole (particularly itraconazole), sulphonamides or amphotericin B.

BLASTOMYCOSIS Blastomycosis is a primarily pulmonary disease caused by the dimorphic fungus Blastomyces dermatitidis. It is much less common than histoplasmosis and occurs mainly in the eastern USA. The organism has been isolated from soil, and infection may be by inhalation of dust. Clinical features Primary infection may be asymptomatic, or it may lead to an acute pneumonia which either resolves spontaneously or progresses to chronic pulmonary disease, which may be confused with tuberculosis. Extrapulmonary manifestations are caused by haematogenous spread from the lungs, and the most common is skin disease with verrucous or ulcerative lesions. Diagnosis is by demonstration of the yeasts in sputum or other specimens, or by culture of the organism. Amphotericin B is the mainstay of therapy, but imidazoles have been used successfully.

SPOROTRICHOSIS

MUCORMYCOSIS

Sporothrix schenckii is a dimorphic fungus found in soil, on plants and on plant debris. Infection is uncommon and is seen in the Americas and Africa. Disease usually results from traumatic inoculation into the skin, and the common form is a red painless papule at the site which enlarges and forms a granulomatous plaque that commonly ulcerates. Further lesions often appear proximally along the course of the lymphatic channels, which are often palpably thickened by inflammatory infiltrate such that they could be mistaken for thrombosed superficial veins, and in regional lymph nodes. Disseminated disease is rare and usually only occurs in immunosuppressed patients. Diagnosis is by culture of the organism from skin lesions. Cutaneous lesions are treated with a saturated solution of iodine, 5-10 drops t.d.s. orally and gradually increasing to 50 drops t.d.s. for up to 3 months, and extracutaneous disease with amphotericin B. Itraconazole can also be used.

Mucormycoses are a group of similar diseases caused by members of the order Mucorales. The organisms are common in the environment, often growing on fruit or bread. They cause disease almost exclusively in immunosuppressed patients.

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Clinical features In rhinocerebral disease in an uncontrolled diabetic the fungus invades the palatal, nasal and paranasal sinus mucous membranes, and destructive lesions spread directly back towards the brain. Black necrotic lesions are visible, and from these a variety of secondary bacterial pathogens are often isolated. Pulmonary, cutaneous and intestinal disease may occur. Diagnosis is made by examination of scrapings and biopsies, and cultures are often negative. Successful treatment depends on management of the underlying cause. Amphotericin B is the only useful drug in treatment, but the response is often poor. 1

PROTOZOAL INFECTIONS

Protozoa are single-cell organisms that have adapted to a range of ecological niches in the human host (Table 9.32). They are an important cause of human disease, especially in the developing world.

PROTOZOAL INFECTION OF THE GUT

GIARDIASIS Infection with the flagellate protozoan Giardia lamblia can cause asymptomatic infection or diarrhoeal disease of variable severity, from mild to severe with malabsorption. Aetiology The parasite is a flagellate, pear-shaped protozoan (Fig. 9.24) which is found in the lumen of the upper small intestine. Some trophozoites encyst, to be passed in the faeces. The cyst is infective and can survive for 2 months at 8°C in water. It is resistant to normal levels of chlorination, and sand filtration is used to clear municipal water supplies of this and other parasites. The parasite can now be grown in culture. Distribution ana1 incidence The distribution is worldwide, although it is more common in the tropics. It is endemic in the countries of eastern Europe. Epidemics have occurred at daycare nurseries, on cruise ships and in towns in the USA. Giardiasis has

occurred in children in inner-city populations in Britain, and can cause diarrhoea in the elderly. Transmission ana1 epidemiology Spread is by the faecal-oral route. As few as 10 cysts will cause infection, and 1000 cysts consistently cause infection. Contaminated food and water are vehicles of infection. Person-to-person spread is common in childhood, particularly when children are not toilet trained. Mothers are often infected by changing the nappies of an infected child. Any circumstances in which standards of personal and public hygiene (such as water treatment) are low lead to transmission. In the tropics children are most often infected, although both indigenous and visiting adults can develop symptomatic disease. Male homosexuals and retarded children are other risk groups. Hypogammaglobulinaemia and reduced gastric acid secretion are host factors that increase susceptibility. Pathology and pathogenesis The main abnormalities relate to the function and morphology of the upper small intestine. Markedly symptomatic patients have impaired absorption of fat, o-xylose and vitamin B12, and lactose maldigestion. The jejunal mucosa is abnormal, with a ridged or convoluted mucosa, reduced villous height with increased crypt depth, and an increased infiltrate of plasma cells in the lamina propria. Subtotal villous atrophy may occur with giardiasis but is uncommon. Patients with mild or no symptoms have

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TABLE 9.32 Classification of protozoa Gut protozoa Giardia lamblia Cyclospora cayetanensis Cryptosporidium Entamoeba histolytica Balantidium coli Isospora belli Sarcocystis Non-pathogenic gut protozoa Entamoeba coli Entamoeba hartmanni Endolimax nana lodamoeba butschlii Chilomastix mesnili Blastocystis hominis Entamoeba dispar Genital tract protozoa Trichomonas vaginalis Tissue and blood protozoa Toxoplasma gondii Pneumocystis carinii Plasmodium species

Babesia species Trypanosoma gambiense, rhodesiense and cruzi Leishmania species Free-living protozoa causing human disease Naegleria fowleri Acanthamoeba

normal jejunal morphology and function. Lactose maldigestion may be present. The pathogenesis is not well understood. The parasite itself may damage the enterocyte surface membrane to impair function and fat digestion intraluminally. Jejunal colonization with bacteria may also contribute to some of the mucosal dysfunction. Antigiardia IgA from the mucosa and in bile may control parasite numbers. Clinical features The incubation period is usually about 10-14 days, although it can be much longer. Many patients with giardiasis are asymptomatic or have minimal bowel upset. Acute giardiasis is characterized by the sudden onset of anorexia, nausea, abdominal distension, discomfort and diarrhoea with frequent yellow, offensive, frothy stools by day and night. Lethargy is often severe and weight loss is usual. After about 3 weeks there may be the beginnings of spontaneous improvement. This may progress to complete resolution over a month, but some patients remain mildly symptomatic, often because of continuing lactose intolerance. Some patients remain markedly symptomatic and fail to regain lost weight or continue to lose weight. The abdomen is distended and bowel sounds are prominent. The stools 1

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MCQ 9.23

FIG. 9.24 Scanning electron micrograph of Giardia lamblia (Reproduced by kind permission of Dr David Warhurst.)

are yellow and offensive. Testing confirms malabsorption. Children are occasionally brought to medical attention because of failure to thrive. Giardiasis has been reported as a cause of chronic diarrhoea in elderly persons in the UK. It is not a major cause of diarrhoea in AIDS. Diagnosis Diagnosis depends on finding the parasites. Stool microscopy shows cysts in most patients, although examination of several samples may be necessary. Trophozoites may be found in diarrhoeal stools. When the parasite is not found and symptoms are marked, investigation of intestinal morphology and function is indicated. Jejunal juice and jejunal mucus obtained at the time of biopsy can be examined for trophozoites. Giardia may be seen in the intervillous space of the sections of the biopsy. Giardia antigens can be detected in stools by immunological techniques. Differential diagnosis Other causes of gastroenteritis are discussed on page 278. Cryptosporidiosis causes self-limited diarrhoea in healthy persons (see below). Cyclosporiasis causes a similar acute illness (see below) Campylobacter species can cause a small bowel type of diarrhoea but usually cause systemic upset. The differential diagnosis of malabsorption syndrome is discussed in Chapter 15. Laboratory features Laboratory investigations show malabsorption of fat, Dxylose and vitamin B12 in severely affected patients. DXylose malabsorption and lactose maldigestion may also be present in those with mild symptoms. Occasional patients are seen who have marked malabsorption and folate deficiency. Barium follow-through examinations show nonspecific changes, with dilatation of small bowel loops and thickened mucosal folds in patients with malabsorption.

SUMMARY 15 Giardia

SUMMARY 16 Treatment

Anorexia Lethargy Weight loss Diarrhoea Yellow mushy to watery stools Abdominal distension Sulphurous eructation Foul-smelling flatulence

First choice Tinidazole 2g single dose with evening meal Repeat 1 week later Precautions: no alcohol for 48 hours after dose, as it can make people 'woozy'. Also, patients should not ride a bike, drive a car or operate any dangerous machines for 48 hours after doses

Note: These are typical symptoms; in an acute severe case there is a range of severity, as indicated in the text.

Management Tinidazole is effective and can be given in a single dose of 2g (50mg/kg) which can be repeated after 1 week. A cheaper alternative is metronidazole, 2g as a single dose on 3 successive days. A second course after 10 days may increase the cure rate. Both drugs cause nausea and a metallic taste in the mouth, and have a disulfiram-like interaction with alcohol. Asymptomatic giardiasis in pregnancy need not be treated. When there is symptomatic disease in pregnancy associated with weight loss or failure to gain weight, then metronidazole (200 mg three times a day for 10 days) may be given. Symptoms due to giardiasis improve rapidly after treatment. Dietary measures are sometimes helpful for continuing gut symptoms. Avoidance of alcohol, spicy foods and lactose is often helpful. Repeat stool microscopy 6-8 weeks after treatment provides a test of cure. Abnormalities in intestinal structure and function disappear over 6-12 weeks after treatment. Prevention and control Travellers in areas where the tap water is not safe to drink should avoid salads, uncooked foods, unpeeled fruits and ice cubes in drinks. Sterilization of drinking water with 2% tincture of iodine (0.5 mL/L of water and allow to stand for 30 minutes) may be necessary. Treatment of asymptomatic cyst excreters is worthwhile, particularly in a non-endemic area, as it reduces the risk of transmission to others. 1

CYCLOSPORIASIS Cyclospora cayetanensis is a coccidian protozoan parasite which has been recognized as a cause of acute and persisting diarrhoea. The organism is an intracellular pathogen that infects the enterocytes. It has a complex lifecycle involving sexual and asexual forms, similar to that of Toxoplasma gondii. Infection occurs by ingestion of oocysts. It causes an acute small bowel type of diarrhoea with features suggesting malabsorption. It is not associated with systemic upset, dysentery or a faecal cellular exudate. It is likely to have a widespread geographic distribution

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Second choice Metronidazole 2g single dose with evening meal for 3 days Repeat 1 week later Same precautions Third choice Mepacrine 100 mg tds for 7 days Causes abdominal discomfort: stains the skin yellow Contraindicated in patients with psoriasis If the above fail, try albendazole 400 mg bd for 5 days

throughout the world. The diagnosis is made by finding the oocysts, which contain four sporozoites in the mature form, in faeces which stain a pinkish colour with a modified Ziehl-Neelsen method. Treatment with co-trimoxazole, two tablets twice daily for 7 days, is effective.

CRYPTOSPORIDIOSIS Cryptosporidiosis is an infection of the gastrointestinal tract with the sporozoan parasite Cryptosporidium. It causes enteritis in humans and a range of other animals. It is a zoonosis with a worldwide distribution. Its life cycle is complex, with asexual and sexual cycles. Infection is by the faecal-oral route. Ingested oocysts are disrupted in the intestinal lumen, liberating four sporozoites which enter the apical regions of intestinal cells within a membrane-bounded vacuole. Trophozoites develop from the sporozoites and undergo asexual reproduction. Merozoites liberated by schizogony can undergo further asexual cycles, or become gametocytes which fuse to form oocysts which are passed in the faeces. Transmission and epidemiology Many reports recognized this organism as a gut pathogen causing persistent watery diarrhoea in immunosuppressed patients, especially those with AIDS. Other studies showed that Cryptosporidiosis was associated with diarrhoea in 4-9% of otherwise healthy children and adults. Children at nursery school may transmit infection person to person. Susceptible animals include calves, lambs, goats and birds, although a history of contact with animals is often absent. Clinical features An acute watery diarrhoeal illness, often with offensive

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stools, is the usual history. There may be fever and vomiting. The disease is self-limiting, with a median duration of about 12 days, but prolonged diarrhoea with weight loss occurs in patients with humoral and cellular immunodeficiency states, especially AIDS (p. 446). Diagnosis and management Faecal smears stained by the modified Ziehl-Neelsen technique show the pinkish-red-staining oocysts. Other forms of the parasite are seen at the luminal surface of enterocytes in intestinal biopsies. In most patients the disease is self-limiting and symptoms resolve spontaneously in 10-12 days. There is no effective drug therapy for the chronic infection seen in AIDS patients though diarrhoea may regress with the institution of effective anti-retroviral treatment. Rehydration, nutritional support and symptomatic treatment may be needed. Handwashing is the most important factor in limiting the spread of infection by the person-to-person route. FIG. 9.25 Scanning electron micrograph of Entamoeba histolytica

AMOEBIASIS

(Reproduced by kind permission of Dr David Warhurst.)

The different manifestations of amoebiasis have long been a paradox. The following have been recognized:

not with non-invasive strains has been developed. These findings give support to the view that there are two separate species, one consistently a pathogen, E. histolytica, and the other a commensal, E. dispar.

• Non-invasive, asymptomatic and confined to the lumen of the colon, with amoebic cysts in the stools; • Invasive ulcerative colonic disease (amoebic dysentery) with amoebic trophozoites in stools and scrapes from the ulcers; • Invasive, causing amoeboma; • Invasive, causing amoebic liver abscess (ALA). Hitherto all these forms have been ascribed to infection with Entamoeba histolytica, but research over the past two decades has produced evidence for the existence of two separate species accounting for invasive and non-invasive conditions, respectively. Aetiology Entamoeba histolytica has two forms, a motile trophozoite (Fig. 9.25) and an encysted trophozoite. The motile trophozoite is found in the stools of a person with amoebic dysentery and contains ingested red cells. The cyst is the infective form. It is resistant to the chlorine in potable domestic water supplies. Sand filtration is the best method of removing cysts from water. Isoenzyme analysis of strains from patients with invasive disease and persons who excrete cysts only has shown two separate patterns that segregate invasive from non-invasive organisms. Subsequently a DNA probe which hybridizes with invasive amoebae but

1

338

Figs 9.33, 9.34

2

Distribution and incidence Amoebiasis has a worldwide distribution. It is common in those areas of the world where standards of sanitation are low. Most instances of invasive disease occur either in endemic areas or in travellers who have recently been exposed. Occasional cases are seen in people who returned from endemic areas years before, or who have never left a country such as Britain. Transmission and epidemiology Faecal-oral spread by ingestion of amoebic cysts in contaminated food and water, or on fingers or other direct personal contact, is the route of infection. With the new classification of amoebae noted above we now need information about the prevalence of Entamoeba histolytica, particularly the frequency of excretion of cysts. People excreting cysts are the source of infection to the community. There is an ELISA-based technique for detecting E. histolytica. Asymptomatic amoebiasis (E. dispar) is not uncommon in male homosexuals in Britain with transmission by person-to-person spread. It is also common in the tropics and subtropics. Amoebiasis is more common in adults than children. Men are affected by ALA more often than women, but dysenteric disease occurs in both sexes. Invasive amoebiasis can be more severe in pregnancy.

Fig. 9.35

Pathology and pathogenesis There are no pathological changes in E. dispar cyst

excreters. Their amoebae live on the colonic mucosa but do not invade. There is now a need to review the pathological findings in asymptomatic E. histolytica cyst excreters. These individuals maintain infection in communities without apparently being diseased themselves. In amoebic dysentery trophozoites invade the colonic epithelium and lyse host cells, causing necrosis. Areas of the mucosa are excavated, leaving multiple flask-shaped ulcers. 1 Amoebae are found in the slough and in the advancing edge of the lesions. The rectum and caecum are commonly affected areas, but the extent can vary from localized proctitis to a pancolitis with a diffusely inflamed ulcerated mucosa. 2 The mucosa over a variable length of the colon is occasionally sloughed off and passed per rectum, leaving exposed denuded submucosa. Amoeboma is an uncommon late complication that occurs after amoebic dysentery has resolved. The lesion consists of a mass of granulation tissue containing few amoebae. The caecum is a usual site, but any part can be involved and lesions may be multiple. ALA results from the haematogenous spread of amoebae from the colonic mucosa via the portal vein. Amoebae reach the liver, and on contact with amoebae liver cells are lysed. The affected area enlarges progressively and the necrotic cells liquefy in the abscess cavity, which may be unilocular or multilocular. A single abscess in the right lobe is usual. The pus is typically odourless, pinkish-brown, sterile on culture and with few pus cells. A carbohydrate containing lectin on the surface of amoebae helps attachment to epithelial cells. The mechanism of cell damage then appears to be the result of insertion of a large permanent ion channel into the host cell membrane, and the host cell dies rapidly. This ion channel is referred to as an amoebapore. Clinical features No symptoms are attributable to the commensal amoeba. In patients with amoebic dysentery symptoms vary according to the extent and site of colonic involvement. The usual symptoms are abdominal discomfort and increased frequency of bowel action, with softer stools. Blood may be noticed in the stools: sometimes flecks of blood or bloodstained mucus on the outside of stools, and sometimes overtly bloodstained stools. Physical signs usually consist of mild colonic tenderness. Sigmoidoscopy may show the typical appearance of scattered ulcers surrounded by mucosal erythema with normal mucosa intervening, but the mucosa may be diffusely inflamed and ulcerated. With increasing extent of colonic disease, symptoms and signs are more marked. When sloughing of areas of the mucosa occurs loss of protein-rich fluid from the denuded mucosa is marked. Acute onset of diarrhoea with systemic upset is almost certainly not due to amoebic dysentery, even if there is blood in the stools. It tends to have a more indolent onset with, in some patients, the development of more severe symptoms and signs as the extent of colonic involvement increases.

Dehydration, anaemia and septicaemia may occur in severe disease, and perforation, toxic dilatation and significant haemorrhage may complicate the clinical course. Rarely the superficial part of the mucosa may be sloughed over a variable length of colon and passed per rectum. Occasionally ulceration can extend from the anal canal to affect the perianal skin. Late complications of amoebic dysentery are colonic stricture and amoeboma, where a mass of granulation tissue forms in response to the presence of relatively few amoebae. Localized pain and blood in the stools are usual symptoms, and one or more masses may be felt in the abdomen or rectally.

9

Symptoms and signs in ALA Symptoms and signs in ALA relate to the site and size of the abscess. There may be no history to suggest past or present intestinal amoebiasis, and many patients do not have amoebic cysts in their stools. Fever, sweats, lethargy and anorexia are usual early symptoms and examination may reveal no abnormal physical signs, or only tenderness on springing the right lower ribcage. With larger abscesses pain becomes a more prominent feature related to the site of the abscess. Abscesses sited laterally or superiorly cause chest pain which may be pleuritic, or referred pain in the right shoulder indicating diaphragmatic irritation. Rigors occur with multiple large abscesses. Some patients have no systemic symptoms. The liver may be enlarged and tender, with a localized tender mass on the surface. With superiorly sited abscesses there may be dullness to percussion and impaired movement at the right lung base. Left lobe abscesses may present with symptoms and signs related to the epigastrium or left hypochondrium. Complications The main complication in ALA is extension outside the liver (Fig. 9.26). Spread to the brain may occur, producing a necrotizing abscess-like lesion. Rarely the skin of the chest or abdominal wall is involved after percutaneous rupture of ALA. Diagnosis Cyst passers are usually diagnosed when stool microscopy is carried out during screening after overseas travel or residence, investigation of diarrhoea due to some other microbial pathogen, or examination of other groups at risk of infection, e.g. male homosexuals. Serological tests for amoebiasis are negative. Antigen detection tests can be

SUMMARY 17 Amoebiasis • Cyst passers. Asymptomatic. Cysts in stools. • Amoebic dysentery. Diarrhoea, dehydration, anaemia. Motile trophozoites in faeces and scrapes from ulcers. • Amoebic liver abscess. Fever, pain, tenderness. Ultrasound shows abscess. Positive serology.

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CASE STUDY 9.3 TRAVELLERS' DIARRHOEA

A 26-year-old man had travelled extensively in India over a 4-week period. He presented to an infectious disease unit in London 21 days after his return with increased frequency of bowel action that had begun in the third week of his stay. He was passing stools that were softer than normal and which for the previous week had contained obvious external blood. There was no abdominal pain, appetite and weight were normal and he experienced no systemic upset. Abdominal examination was normal. On rectal examination the mucosa felt slightly granular and a limited sigmoidoscopy showed an inflamed mucosa to 15 cms, with haemorrhagic areas and some obviously ulcerated areas. Questions 1. What is the differential diagnosis? 2. What further investigations should be performed?

FIG. 9.26 Sites of spread of amoebic liver abscess

1

340

Figs 9.36, 9.37

2

MCQ 9.24

Comment This history is in marked contrast to that of in Case study 9.1 (p. 279), which was invasive bacterial infection. The history is very suggestive of amoebiasis. Abdominal examination was normal. The endoscopic features are typical. Nonspecific inflammatory bowel disease (ulcerative colitis or Crohn's disease) could present like this and histological findings would be diagnostic. He could have postinfective gut symptoms and be bleeding from a colonic polyp, and so had amoebae or another source of bleeding not been found then colonoscopy would be the next step. Schistosoma mansoni affects the colon but only rarely causes rectal bleeding. This parasite occurs in Africa, the Middle East and South America, but not in India. In older patients presenting with rectal bleeding whether they have travelled to tropical areas or not colonic cancer always needs to be excluded

and colonoscopy is essential where no immediate source is found. A rectal biopsy was taken and a scraping from an ulcerated area and mounted on a slide in saline for immediate microscopy. A faecal smear was made from flecks of bloodstained mucus on the stool specimen provided, and microscopy of this showed motile trophozoites with ingested red cells. In the cellular exudate there were red cells but very few pus cells. The rectal scrape also showed motile trophozoites with ingested red cells. Histological examination showed an ulcerated mucosa with amoebic trophozoites in the surface layers. He was treated with tinidazole 2g as a single dose with food daily for 3 days, followed by diloxanide furcate 500 mg tds for 10 days.

used to identify E. histolytica cysts; most of those detected are E. dispar. Some cysts are, however, untypable using the currently available kit. Amoebic dysentery is diagnosed by finding motile trophozoites with ingested red cells in faecal smears or scrapes from ulcerated colonic mucosa. Amoebae can be seen in the edges of ulcers in rectal biopsies, where they are seen as large cells at the edges of ulcers and in slough. They are PAS-stain positive. Serological tests for amoebiasis (e.g. indirect fluorescent antibody test, or IFA) are positive in 60% of cases, and so diagnosis cannot depend on serology but rather upon finding the parasite. With amoeboma, cysts may be found in the stools. Colonoscopy allows the lesion to be visualized and biopsied. Serology for amoebiasis is positive in over 90% of cases and is a reliable test in this situation. Diagnosis of ALA depends on the clinical features suggesting an intrahepatic lesion and strongly positive amoebic serology (found in over 95% of cases). Cases seen early in the course of disease occasionally have a negative IFA but have a definitely positive test 7 days later. Additional investigations Intestinal disease With increasing extent of colonic involvement there is

increasing exudation of protein-rich fluid into the gut. Plasma albumin levels fall; normochromic, normocytic anaemia and a raised ESR develop. These investigations are normal in more localized disease. Plain abdominal X-rays are useful in giving an indication of the extent of the inflammatory process, indicated by the extent of colon devoid of faecal shadows. Barium enema studies show non-specific features with ulceration in dysentery. Amoeboma appears as one or more mass lesions causing narrowing of the colon, simulating colon cancer, and so if cancer is not demonstrated in biopsies from a stenosing lesion amoebic serology should be performed to prevent resection of something that would respond to metronidazole or tinidazole. Amoebic liver abscess There is neutrophil leukocytosis, a normochromic, normocytic anaemia and raised ESR. Bilirubin levels are usually normal, but aminotransferase levels are slightly raised; alkaline phosphatase levels are raised and plasma albumin levels are low. A chest X-ray will show elevation of the diaphragm above an abscess in the right lobe superiorly, and sometimes basal linear atelectasis or consolidation or pleural effusion. Ultrasound and CT scanning give more accurate information about an abscess, and its precise site and size. 1 Ultrasound can be repeated to assess changes and to guide the insertion of a needle for percutaneous aspiration. Differential diagnosis Intestinal disease Shigella, Salmonella, Campylobacter and Yersinia infections may all cause colitis, but the onset of symptoms is rapid in these infections and pus cells predominate in the faecal cellular exudate. Non-specific inflammatory bowel disease, Crohn's disease and ulcerative colitis must be considered. Amoebic infection should be rigorously excluded in a patient who could have been exposed to amoebiasis in the past, before treatment for inflammatory bowel disease, as steroids may promote rapid progression of invasive amoebiasis with perforation and death. Where the distinction cannot be made then treatment for both conditions may be appropriate. Carcinoma of the colon, pericolic abscess, Crohn's disease of the colon, tuberculosis of the ileocaecal region or colon, and schistosomiasis are possible causes of a colonic mass. Amoebic liver abscess Subphrenic and intrahepatic pyogenic abscess and infected hydatid cyst cause similar symptoms and signs. Often the history is more acute and the patient more toxic, with chills and rigors. Pyogenic liver abscess may be secondary to some other focus of intra-abdominal infection. Hepatocellular carcinoma and bacterial infection of a hydatid cyst may present like ALA, particularly when the carcinoma has undergone necrosis or there has been bleeding into it. Management The drug treatment of amoebiasis is set out in Table 9.33. Patients who can be shown to harbour E. dispar do not

TABLE 9.33 Drug treatment of amoebiasis Clinical situation

Drug

Cyst passer (E. histolytica)

Diloxanide furoate for 10 days 500 mg 3 times a day (8mg/kg3timesaday) Metronidazole 800 mg 3 times a day for 5-10 days (40mg/kg per day in 3 divided doses) or Tinidazole 2g (50mg/kg) single daily dose for 3 days (abscess) or 5 days, (dysentery amoeboma) followed by Diloxanide furoate 500 mg 3 times a day (8mg/kg3timesaday)

Amoebic dysentery Amoeboma Amoebic liver abscess

9

need treatment. Symptoms and signs improve rapidly within 48 hours. Surgical treatment of amoebic dysentery is rarely needed, except where large areas of mucosa are sloughed; in this case resection of the affected colon can be life-saving. When ALAs are very large, pointing or likely to rupture, percutaneous aspiration is needed. This is done using a large-bore needle inserted under local anaesthetic, if possible under ultrasound guidance. Variable amounts of fluid can be removed. Amoebae are sometimes found in the material aspirated from the edge of the abscess. Aspiration has a low morbidity. Rupture of ALA dramatically increases the mortality, which is low in uncomplicated cases. Prevention and control The provision of clean water and safe disposal of faecal waste would do much to prevent transmission. Patients with invasive amoebiasis should always receive diloxanide furoate to eradicate any pathogenic amoebae remaining in the gut lumen. Where water supplies are not treated, boiling and filtering drinking water is advised. Tincture of iodine (2%) is effective in killing amoebae, used as above. Salads, unpeeled fruits and ice cubes are possible sources of infection and should be avoided in endemic areas. 2

BLASTOCYSTIS HOMINIS The pathogenicity of this organism is questioned. There do appear to be some infected patients whose diarrhoea settles with eradication of the organism after a single dose of tinidazole 2g on two occasions a week apart. However, there are also patients excreting B. hominis whose diarrhoea persists after eradication, and in others the organisms persist despite resolution of the diarrhoea. The organism is very commonly found in healthy individuals with no gut problems.

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BALANTIDIUM COLI INFECTION The ciliate Balantidium coli is the largest protozoan parasite in humans. It can be seen with the naked eye in cultures. It is a parasite of pigs, and humans who have close contact with pigs become infected. In most cases it causes no disease. Occasional cases of enteritis due to B. coli affecting the small and large intestine are reported. Death occurs as a result of bacterial peritonitis after ulceration and perforation of the gut. Metronidazole is effective in symptomatic cases.

Trichomonas infection is discussed in Chapter 11 (p. 462).

ISOSPORA BELLI INFECTION

NAEGLERIA FOWLERI INFECTION

Isospora belli is a sporozoan parasite of the gastrointestinal tract in humans. It has a worldwide distribution and humans are the only reservoir of infection. The life cycle has asexual and sexual phases. Infection occurs by ingestion of oocysts containing sporozoites, which are released in the small intestine and invade epithelial cells; there they undergo asexual reproduction, or schizogony. The host cell ruptures, releasing merozoites which invade other epithelial cells and reproduce asexually to form oocysts. These are released into the gut lumen by the normal desquamation of epithelial cells and passed in the faeces. Infection occurs by ingesting oocysts in contaminated food and water. Most infections cause no symptoms. Some cause a diarrhoeal illness, with weight loss, pale stools, lethargy and low-grade fever. Patients with immunodeficiency syndromes, including AIDS, exhibit chronic diarrhoea with more marked symptoms. The diagnosis is made by finding oocysts in stools, in jejunal juice, and in stained sections of jejunal biopsies. Co-trimoxazole, two tablets twice daily for 10 days, appears to be effective. Longer courses of treatment may be needed in patients with immunodeficiency.

Naegleria fowleri is a free-living amoeboflagellate, 6-9 mm in diameter, which causes the rare primary amoebic meningoencephalitis. It is found in water from hot springs as well as in ponds and pools, and has a worldwide distribution. Amoebae in fresh water are carried into the nasal passages by activities such as swimming. They adhere to areas of the nasal mucosae and then migrate through the cribriform plate along the nerve fibres. The amoebae replicate asexually and spread through the subarachnoid space. The olfactory bulbs show massive invasion with amoebae and necrotic changes. There is a superficial encephalitis of the affected area. Abscess formation can also occur. In the meninges there is a prominent fibrinous and purulent reaction that is most marked over the inferomedial regions, with particular involvement of the basal subarachnoid cisterns.

SARCOCYSTOSIS

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of muscle cysts, and thorough cooking of meat prevents infection.

The two parasites of humans are Sarcocystis bovihominis and S. suihominis, which have cattle and pigs as their respective intermediate hosts. They have a worldwide distribution, with high infection rates in cattle and pigs. However, the infection is probably uncommon in humans. The parasites have a complex lifecycle involving both asexual and sexual reproduction. Abdominal discomfort, distension, nausea and diarrhoea occur within hours of infection, and sporocysts are found in the stools 14-18 days later. Diagnosis is by finding the small numbers of cysts shed in the faeces. Treatment with pyrimethamine and sulfadiazine or nitrofurantoin has been successful in patients with chronic symptoms. Freezing meat reduces the infectivity

GENITAL TRACT PROTOZOA

FREE-LIVING PROTOZOA CAUSING HUMAN DISEASE

Clinical features Patients are often children or young adults. Fever, headache, nausea, vomiting and lethargy are usual early features, followed by deterioration of conscious level. Neck stiffness is usual. Papilloedema may be present. Lumbar puncture in shows features suggesting acute pyogenic meningitis. The CSF is turbid, with a very high neutrophil count. Protein levels are very high and sugar levels are reduced or normal. The amoebae are readily seen on phase contrast microscopy from a direct smear of CSF. They can be grown in special culture media. Management Amphotericin B for 6 weeks at least, depending on the response, is effective in treatment, possibly in combination with miconazole. The high mortality in this condition is probably related to delay in diagnosis and initial trials of antibiotics as for pyogenic meningitis.

ACANTHAMOEBA INFECTION Acanthamoebae are free-living amoebae commonly found in soil and water in tropical and temperate regions. Infec-

tion may occur by ingestion or inhalation of cysts, which are very light and may be distributed on the wind. A considerable range of clinical features have been reported for this infection. Cerebral abscess, granulomatous meningoencephalitis, meningitis and involvement of the scalp, orbit and middle ear have occurred. Acanthamoebae have most often been identified in corneal ulcers, and the increased use of contact lenses has perhaps increased the frequency of amoebic keratitis. The amoebae are difficult to kill. They have been known to cause a radial keratitis, with spread of the organisms alongside nerve fibres, seen on confocal microscopy of the cornea. Lung involvement has also been reported. Amoebae may be identified in smears from CSF or from corneal ulcers, or in stained tissue sections. A modified Field's stain is effective in showing the amoebae. Amphotericin B is used in systemic infections. 0.1% hexamidine isethionate, dibrompropamidine isethionate and chlorhexidine have all been used with varying degrees of success for corneal lesions. There appears to be little correlation between in vitro and in vivo activity of compounds.

NON-PATHOGENIC GUT PROTOZOA There are a number of protozoa that infect humans but cause no disease. These are listed in Table 9.30. When they are found in patients with abdominal symptoms, the symptoms should not be ascribed to these parasites and further investigations should be undertaken.

TISSUE AND BLOOD PROTOZOA TOXOPLASMOSIS Toxoplasmosis is caused by Toxoplasma gondii. It is a zoonosis, the definitive host in the lifecycle being cats (Fig. 9.27). Primary human infection is acquired by ingestion of oocysts derived from animal excreta or from undercooked meats such as pork or mutton, the pig or sheep having acted as an intermediate host. Infection is common, 20-40% of adults in Britain having antibodies. The most serious effects are seen after congenital infection or in immunocompromised patients. Pathology and pathogenesis Trophozoites released at the site of entry multiply and spread via blood and lymphatics to all tissues. They can invade any cells, and intracellular proliferation leads to cell death. Development of immunity results in restriction of proliferation and the organism is eliminated, or forms tissue cysts. Cysts 10-200 mm in diameter, containing several thousand organisms, may remain in the tissues for life. Depression of CMI results in reactivation.

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FIG. 9.27 Transmission of toxoplasmosis Infection can occur in either sex and at any age. Reactivation causes disease in immunosuppressed patients.

Clinical features Congenital infection Congenital infection usually follows primary asymptomatic infection of the mother during the third trimester of pregnancy. The effect on the fetus may be spontaneous abortion, stillbirth, premature birth, or normal birth with subsequent illness. The latter is most frequent and results in disease of the eye, usually bilateral choroidoretinitis, or of the brain, with hydrocephalus, microcephaly, cerebral calcification or convulsions. Fever, lymphadenopathy, hepatosplenomegaly and rash may also occur. Acquired infection Asymptomatic infection is common in adults, but there may be a mild chronic febrile illness with lymphadenopathy. Often a group of enlarged lymph nodes in a single area is the only finding, although more diffuse adenopathy may occur with splenomegaly. Sore throat does not occur. Choroidoretinitis is now recognized as a manifestation of acquired infection. Reactivation in the immunosuppressed patient Most toxoplasmal disease in patients with deficient immunity is caused by reactivation of latent cysts. The most common manifestation, especially in AIDS, is necrotizing lesions in the brain, often presenting as intracerebral mass lesions. Primary infections in the immunocompromised host cause disseminated infections. This has been recognized in cardiac transplantation when a seropositive donor is the source of a heart for a seronegative recipient. This is prevented by chemoprophylaxis. Myocarditis and possibly pneumonitis also occur. Diagnosis This is by serology. The Sabin-Feldman dye test, indirect haemagglutination or fluorescent antibody test (FAT) are used to measure IgG antibodies, and an ELISA is also available for measurement of IgM antibodies. Histology of affected lymph nodes shows reactive changes which are

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not specific for toxoplasmosis. The organisms are rarely seen in tissue sections. Diagnosis of cerebral lesions is by CT or MRI scan. 1 A/loncrgfemenf

Treatment of acquired infection in normal adults does not affect outcome and is rarely required. Severe infections are treated with the synergistic combination of pyrimethamine 50 mg daily and sulfadiazine 1.0-1.5g every 6 hours by mouth for 3 weeks, together with folinic acid 15 mg daily, as pyrimethamine is a folic acid antagonist and can cause bone marrow suppression. Clindamycin 600 mg every 6 hours orally or i.v. can be used as an alternative to sulfadiazine in the event of toxicity. Patients with AIDS may need a longer course of treatment and the cerebral lesions are monitored by CT or MRI. These patients also require maintenance therapy with pyrimethamine 75 mg twice per week and sulfadiazine 1.5g twice daily once a satisfactory response has been achieved. Tissue cysts are not killed by this treatment, but they may be susceptible to azithromycin or atovaquone. 2

PNEUMOCYSTIS CARINII INFECTION

sive interstitial shadowing. The diagnosis should be suspected in immunosuppressed patients, especially those with AIDS, and confirmation is obtained from examination of bronchial washings obtained at bronchoscopy or in sputum induced using nebulized hypertonic saline. Management The treatment is adequate oxygenation and ventilatory support when necessary, and chemotherapy with either high-dose co-trimoxazole (four tablets four times a day) or pentamidine given by intramuscular injection or slow intravenous infusion in 250 mL of normal saline or 5% dextrose over 1-2 hours. Corticosteroids are added in moderate or severe cases. Fever, rash and leukopenia have been seen in AIDS patients after about 7-10 days on co-trimoxazole, and a change to pentamidine may be necessary, as treatment for at least 21 days is required. Pentamidine side-effects include renal and hepatic failure and prolonged hypoglycaemia. There is a 20% mortality in AIDS patients in their first episode of Pn. carinii, irrespective of treatment. Prophylaxis with co-trimoxazole for this infection has been effective in patients with acute leukaemia. Primary prophylaxis in AIDS patients with the combination of an antifolate and a sulphonamide/sulphone is of value, and nebulized pentamidine has also been used successfully.

Pneumocystis carinii is a common organism that is found worldwide. Although previously classified as a protozoan, evidence suggests that it may be fungal in nature. It infects the lungs and causes no problems in normal human hosts. The organism is found in autopsy material from healthy people in up to 4% of cases, and serological studies in Europe have shown up to 75% seropositivity in healthy children. The reservoirs of infection and the mode of transmission are poorly defined, but it seems likely that personto-person droplet infection occurs. It causes interstitial pneumonitis in premature and young infants, in children with protein-energy malnutrition, in immunosuppressed patients during treatment for haematological malignancies, and in AIDS patients in the west. It is uncommon in AIDS in Africa. In normal lung the organisms are found singly or in clusters on the alveolar septal wall, with no surrounding host response. When there is pneumonitis large numbers of parasites are found in the alveoli, with desquamation of alveolar cells and accumulation of proteinaceous material in the alveolar spaces. Clinical features and diagnosis The clinical features of Pn. carinii pneumonia are progressive dyspnoea, cough, fever and weight loss. Chest examination is often normal; chest radiographs may be normal initially but progress fairly rapidly to show exten-

1

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Fig. 9.38

FIG. 9.28 World distribution of malaria, 2000 Chloroquine-resistant malaria occurs in all areas.

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FIG. 9.29 Malaria in the UK, 1981-2000, showing the progressive rise of falciparum importations (Communicable Diseases Surveillance Centre, Colindale and Malaria Reference Laboratory, PHLS.)

MALARIA Malaria is an acute febrile illness characterized clinically by paroxysms of fever, the consequence of rupture of infected red cells due to asexual reproduction by species of Plasmodium (schizogony). Plasmodium vivax, P. ovale and P. malariae are associated with morbidity but no major mortality, but P. falciparum causes both morbidity and considerable mortality. The infection is transmitted by the bite of the female anopheline mosquito. Distribution and incidence Malaria occurs widely throughout the tropical areas of the world, in the Americas, Africa, Asia and the Pacific area (Fig. 9.28). Falciparum malaria is particularly common in tropical Africa, where it causes at least 1000000 deaths per year, mainly in children. The resurgence of malaria in the Indian subcontinent was led by a rising incidence of vivax malaria in the 1970s, and now falciparum infection is more widespread in the region. Ovale malaria is predominantly a west African disease. Malariae malaria is the least common form. Malaria is imported into temperate regions by tourists, people employed overseas, business travellers and immigrants. The numbers of cases have risen progressively over the past 20 years (Fig. 9.29). Transmission and epidemiology Life cycle The life cycle of malaria is shown in Figure 9.30. Vivax and ovale life cycles are similar, with primary exoerythrocytic schizogony (EES) in hepatocytes leading to infection of the peripheral blood with merozoites. These enter red blood cells (RBCs) and undergo erythrocytic schizogony (ES) every 48 hours; this is benign tertian and ovale tertian malaria. Some of the sporozoites produce latent forms, the hypnozoites, within liver cells, which produce EES and then ES up to 2 or 3 years after infection, i.e. relapsing malaria.

FIG. 9.30 Life cycle of malaria

Falciparum malaria has no hypnozoite form, and so the infection is cured when parasites are cleared from the blood by treatment. ES has a periodicity of less than 48 hours ('subtertian'). Malariae parasites also lack the hypnozoite stage but can cause reappearance of parasitaemia (parasites in peripheral RBCs) up to 20 or more years after infection. Small numbers of parasites persist in RBCs to

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cause this. The periodicity of ES is 72 hours (quartan malaria). Vivax, ovale and malariae parasites invade 1-2% of RBCs at most. Falciparum parasites invade any proportion of RBCs, accounting for the severity of disease and the high mortality. Host A baby born of an indigenous mother in an endemic falciparum area will be protected against infection during the first year of life by maternal antimalaria IgG crossing the placenta in the last trimester of pregnancy. After the first year the child is fully susceptible. Without chemoprophylaxis the child experiences repeated attacks of malaria, and by the age of 4 or 5 years will have acquired protective immunity, which persists as long as they remain in the endemic area. Parasites are often found in the peripheral blood of an asymptomatic child, so that there is disease immunity without immunity to reinfection; indeed, reinfection is necessary to maintain antigenic challenge and the immune status. The immunity declines if an individual leaves the endemic area. Maternal immunity declines during pregnancy, particularly in primiparae, with transplacental transfer of IgG. Anaemia, fever and intense parasitization of the placenta make miscarriage, premature labour and low birthweight common, especially in areas such as West Africa, where there is heavy seasonal transmission with a high risk of infection. Where transmission is not so intense, effective immunity is not built up and all ages in the exposed population are at risk. Any individual, of any age, from a malaria-free area may contract severe malaria. Splenectomy enhances susceptibility to maleria to a considerable degree. Sickle cell trait haemoglobin C trait, and the heterozygous state for glucose-6-phosphate dehydrogenase (G6PD) deficiency protect against severe malaria. Vector Climatic factors have a profound influence on the transmission of malaria through effects on survival and reproduction of the mosquito population, and on the development of the parasite in the vector. Mosquitoes survive up to several months and their lifespan is not affected by malaria parasites. Ambient temperatures in the range 20-30°C, with a relative humidity of 60% or more, are ideal. In most areas of tropical Africa malaria is transmitted all year round, with upsurges of incidence with the dramatic increase of anopheline numbers during rainy seasons. In Asia transmission is seasonal with the rains. Sporogony will not occur below 16° or above 33°C. The vector species vary considerably in different localities. Anopheles gambiae is one of the most efficient vectors because of its long lifespan and preference for biting humans rather than other animals. 1

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Fig. 9.39

Additional routes for transmission of malaria are: • Transplacental, which is uncommon • Transfusion associated, which is uncommon in Europe and North America but common in endemic areas • Syringe transmitted, among intravenous drug abusers. Mention should be made of 'airport malaria', which has been documented in a range of temperate countries, including the UK and France. Malaria can occur in people who have never been to an endemic area and who are not at risk as a result of transfusion, shared syringes etc. Such cases have occurred around airports, and it is thought that malarious mosquitoes that have been carried on international flights survive in the temperate country and bite individuals there, infecting them and causing disease. Pathogenesis and pathology The pathogenesis of falciparum malaria is complex and incompletely understood. The initial step is adhesion of the merozoite to the erythrocyte membrane. Glycophorin A, the major glycoprotein on erythrocyte membranes, is a receptor for binding specific surface proteins of falciparum merozoites. RBCs deficient in glycophorin A are resistant to invasion. The Duffy blood group antigen is a specific receptor for invasion by P. vivax merozoites, and the absence of this antigen among populations from west Africa explains the absence of vivax infections there. Changes in the parasitized RBC result in sequestration of RBCs containing mature falciparum trophozoites in the postcapillary venules. 1 Parasitized cells are less flexible than normal cells. In addition, as the parasite matures the RBC becomes deformed and knobs develop on its surface. These knobs are an expression of a parasite-derived adhesion-promoting molecule which binds to molecules such as ICAM-1, VCAM-1 and thrombospondin expressed on the vascular endothelium of the postcapillary venule. This adhesion phenomenon explains why mature trophozoites and schizonts are usually absent from peripheral blood films. Maximum numbers of adherent RBCs are found in venules in brain, liver, spleen, kidney and lung. The placenta is heavily parasitized with chondroitin sulphate A serving as a specific receptor for adhesion of infected RBCs. The trophozoite matures into the schizont and at schizogony the RBC membrane bursts, releasing merozoites, malaria antigen, malaria pigment and RBC cytoplasmic constituents. The cycle continues, progressively building up the numbers of parasitized RBCs. How these changes lead to altered consciousness in cerebral malaria is not clear. CT of the brain in patients with cerebral malaria has not shown oedema, although among children in Kenya intracranial pressure recording has shown raised pressure. Diffuse irreversible vascular obstruction is also an unlikely cause, in view of the normal cerebral flow and complete recovery without neurological deficit in most survivors. CSF lactate levels are increased in cerebral malaria, which may indicate some degree of anaerobic cerebral glycolysis. At the molecular level, high levels of TNF and other cytokines are found in the

blood of patients with the most severe forms of malaria, especially cerebral malaria. The extent to which these molecules cause severe malaria is not yet known. It is recognized that quantitative differences in cytokine production, particularly TNF, are genetically determined, indicating possible inherent predisposition to severe disease. Renal damage occurs because of prerenal and renal factors. Acute tubular necrosis is the usual effect of severe malaria on the kidney. This may occur both with and without severe intravascular haemolysis. Vessels in the heart are parasitized but cardiac function is well preserved. Reduced peripheral vascular resistance and dehydration from sweating, vomiting and reduced fluid intake may contribute to hypotension. In cerebral malaria post mortem the brain shows swelling with small haemorrhages throughout the white matter. The spleen is enlarged and has a slate-grey hue over the normal red colour. Centrilobular necrosis is seen in the liver with the accumulation of malaria pigment in Kiipffer cells. The pulmonary venules contain large numbers of parasitized RBCs. Pulmonary oedema of the ARDS type occurs but the cause is not understood. The placenta is usually heavily parasitized. The anaemia of malaria has several causes, which include rupture of parasitized RBCs in schizogony; sequestration of RBCs in tissue venules; destruction of parasitized and non-parasitized RBCs in the reticuloendothelial system (especially the spleen); haemolysis due to the presence of malaria antigen, antibodies and complement on RBCs; and marrow suppression. Abnormalities of coagulation are usual, with low platelet counts due to peripheral consumption and consumption of clotting factors. Disseminated intravascular coagulation does occur in a few patients with severe malaria but is probably not a major factor in pathogenesis in most severely ill patients. Clinical features Vivax and ovale • After an incubation period of about 13 days (vivax) or 18 days (ovale), prodromal symptoms begin with headache, fever, shivering without rigors, and general aches. These last for up to 3 days before the first paroxysm of coldness, then extreme heat, then defervescence with a profuse sweat. • Forty-eight hours later the full paroxysm occurs, with a feeling of extreme coldness and a rigor beginning in the late afternoon. Headache, nausea and vomiting are usually present. The temperature is high, the pulse rapid and low in volume, and the skin is cold. This phase lasts for 45 minutes to 1 hour. When the rigor ceases, peripheral dilatation occurs; the patient feels very hot and thirsty. The pulse is rapid and of full volume. The skin is hot and dry. This lasts about 1 hour and defervescence follows, with a profuse sweat. The symptoms settle completely and the patient will usually sleep. The following day there may be a little weakness. One day later the malaria paroxysm recurs. Daily paroxysms occur when

parasite broods are undergoing schizogony on successive days. • Untreated, the paroxysms continue for 6 weeks and die out spontaneously, only to recur 2-3 months later. By the time symptoms have been present for a week the spleen is usually palpable and there may be mild anaemia. Rupture of the enlarged spleen is reported in vivax malaria.

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Malariae malaria The incubation period is usually about 28 days. Nonspecific prodromal symptoms last for 2-3 days before the onset of the first paroxysm, which is accompanied by a rigor. The periodicity of symptoms is every 72 hours. The spleen is enlarged when symptoms have been present for 7-10 days. Falciparum malaria • The incubation period is about 12 days, range 9-17 days. • Headache, anorexia, nausea, vomiting, weakness and fever are prominent symptoms. • The periodicity of symptoms is less than 48 hours, and periodicity is an unreliable clinical feature, being present in only 30% of cases. • The patient feels ill all the time, with exacerbation of symptoms at the time of paroxysms, which are similar to those described above but usually more severe. • Convulsions occur in children. Vomiting and diarrhoea are sometimes prominent features in the history. Herpes simplex vesicles may appear on the lips during the illness. Complications Complicated malaria occurs in falciparum infections. • Altered consciousness in the presence of falciparum malaria must be taken as a clinical indication of cerebral malaria. Neck rigidity is not a feature, although mild neck stiffness may be present. Raised intracranial pressure is not seen and focal neurological signs are uncommon. Generalized convulsions occur in children and adults. • Hypoglycaemia occurs in children, pregnant women with severe malaria and, less often, in adults with severe infection. • Jaundice may be a prominent physical sign in some patients with severe malaria. Haemolysis can cause this, but tender hepatomegaly and abnormalities of liver function suggest liver involvement. • Some degree of uraemia is common, but this resolves after treatment. Uraemia with oliguria indicates renal involvement. • Pulmonary oedema can result from overhydration, but can also occur in the patient whose infection is coming under control. • Blackwater fever, due to acute massive intravascular haemolysis, became less common after chloroquine replaced quinine for prophylaxis and treatment of malaria, suggesting that quinine itself contributed to pathogenesis. It does, however, occur in people who have not taken quinine. The urine is black, the haemoglobin

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SUMMARY 18 Main features of malaria • • • • • • • • •

Fever Chills and rigors Headache Vomiting Diarrhoea sometimes Jaundice* Anaemia* Falling urine output* Passing black urine*

* Indicative of severe infection.

falls rapidly and jaundice appears. Hypotension and tachycardia are usual, and renal failure may follow. • Gram-negative septicaemia has been reported in patients with severe malaria and may be responsible for hypotension. Late complications Tropical splenomegaly syndrome (TSS) occurs in areas of endemic falciparum malaria. There is considerable splenomegaly, a lesser degree of hepatomegaly, anaemia and pancytopenia. Malaria antibody titres are high, with polyclonal elevation of serum IgM. Quartan nephrotic syndrome is related to P. malariae infections, and presents with gross oedema and proteinuria in children aged 4-6 years. The histological features are segmental endothelial proliferation with obliteration of capillary loops by periodic acid-Schiff (PAS)-positive material. There is segmental thickening of the basement membrane. Progression of the glomerular lesion leads to diffuse glomerulosclerosis. Immunoglobulins and complement are deposited in the glomerulus, and P. malariae antigen is detectable in 25% of biopsies. The prognosis is poor, with progressive deterioration in renal function. Treatment of malaria and chemoprophylaxis do not influence the course of established disease.

TABLE 9.34 Differential diagnosis of malaria Fever alone Any cause of pyrexia of unknown origin (see p. 274)

Fever and renal failure Septic shock Leptospirosis Viral haemorrhagic fevers

Fever and jaundice Yellow fever Typhus Leptospirosis Biliary sepsis Septicaemia

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Fig. 9.40

Fever and impaired consciousness Meningitis Encephalitis Brain abscess

2

Case 9.4

Diagnosis The clinical diagnosis of malaria is based on the history of a febrile illness after exposure in an endemic region. Differential diagnosis is shown in Table 9.34. Cases in non-endemic areas present most often in the first 3 months after leaving the endemic area. Persons who have taken mefloquine as malaria prophylaxis may experience attacks of malaria up to 3 months after returning from the endemic area. Ovale and vivax infections may present later, and the latency in malariae malaria may be prolonged. The diagnosis is confirmed by the finding of parasites in stained blood films. If falciparum malaria is diagnosed, the percentage of RBCs parasitized should be determined and the film should be carefully examined for schizonts, which may be seen in the blood film from patients with severe malaria. Severe malaria is defined parasitologically as over 5% of RBCs parasitized, although complicated malaria can occur with fewer; clinical assessment is therefore very important. Because of binding of RBCs containing mature ring forms to vascular endothelium, the peripheral blood film in falciparum malaria is an uncertain guide to the severity of infection. Low initial parasitaemia can rise dramatically within hours when schizogony of sequestered parasites occurs. The blood is positive on the first occasion in most cases. The peripheral blood film gives only a guide to the severity of infection. If the parasitaemia is high the interpretation is straightforward but, if low, parasitaemia is not always indicative of mild malaria as many RBCs containing maturing parasites may be sequestered in deep venules, and so parasitaemia alone may not give a true picture of the severity of infection. A blood film should be made and examined as soon as the diagnosis of malaria is considered. 1 It is not necessary to wait for fever to occur. An antimalarial drug taken before blood films are obtained may clear the blood of parasites. If necessary, further blood films should be made and examined once or twice daily until the febrile illness either is diagnosed or resolves. During a period of observation in hospital, prophylactic antimalarial drugs should be stopped to give the best chance of demonstrating parasites. It may be necessary to start treatment as soon as blood films have been taken or on the basis of clinical diagnosis if laboratory confirmation is not readily available or the patient is very sick. Microscopy of stained blood films has been the gold standard for malaria diagnosis and in skilled hands is 100% specific and very sensitive, capable of detecting parasitaemia as low as 0.0001%. However, expertise is very variable and antigen detection methods for malaria diagnosis have been developed and can be used as an adjunct to microscopy. These depend on using monoclonal antibodies to various parasite epitopes. Compared with expert microscopy these methods have a 90% sensitivity in detecting parasitaemias in the range 0.01-0.001%, i.e. 50-500 parasites per microlitre of blood.

Laboratory features Laboratory investigations are normal or mildly abnormal in vivax, ovale and malariae malaria, but consistently abnormal to some degree in falclparum malaria. Haemoglobin levels may be normal or slightly reduced at presentation, but fall thereafter. Reticulocyte counts may be low before and after treatment, while haemoglobin levels are falling, suggesting a period of marrow suppression, followed by reticulocytosis with rising haemoglobin. Platelets are low in falciparum malaria, sometimes as low as 20 x 109/L, but other coagulation tests are usually normal. Occasional patients do have coagulopathy with spontaneous bleeding. Plasma sodium levels are low in falciparum malaria and urea may be raised. Globulin levels rise and albumin falls. Abnormalities in liver function tests are frequent, and there may be a minor elevation in both total and unconjugated bilirubin in mild infections or greater elevation in more severe falciparum. Azotaemia is common in falciparum malaria but oliguria is not. Elevation of urea and creatinine may reflect the hypercatabolic state of severe malaria, but urine output must be monitored as renal failure, most often due to acute tubular necrosis, is well recognized in severe malaria. Serological tests for malaria have no place in diagnosis of individual cases but may be helpful in assessing previous exposure. 2

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Management Drug treatment Vivax, ovale and malariae. The aim of treatment is to stop further ES cycles (Table 9.35). There is usually a prompt response following chloroquine treatment of vivax, ovale and malariae malaria. Where radical cure of relapsing malaria is required G6PD levels should be checked and, if normal, primaquine given. When there is severe G6PD deficiency, primaquine should not be given because of the risk of severe haemolysis; chemoprophylaxis can be given to prevent relapse, e.g. pyrimethamine (25mg weekly). Primaquine is not recommended in pregnancy and a chemoprophylactic should be given. Falciparum. P. falciparum malaria is a serious infection demanding urgent treatment. Quinine is the drug of first choice for treatment because chloroquine resistance is now so widespread. The route of administration must be chosen carefully. When the patient is vomiting, is clinically ill with fever >39°C, is hypotensive or has specific complications of malaria, or has more than 2% of RBCs parasitized or schizonts in the peripheral blood, intravenous treatment is needed. The dosage regimens used are set out in Table 9.35. Impairment of renal or hepatic function will prolong

TABLE 9.35 Treatment of malaria Type of malaria

Drug

Dose

Additional treatment

Vivax and ovale

Chloroquine base

Malariae Falciparum Chloroquine-resistant or sensitivity unknown Mild

Chloroquine

600 mg (10mg/kg) stat, then 300 mg (5mg/kg) 6 hours later, then 300 mg (5mg/kg) daily for 2 days As above

Primaquine. 7.5 mg twice a day for 14 days (children 250ug/kg per day) Nil

Quinine salt

700 mg max (10mg/kg) 3 times a day for 7 days orally

or Malarone (atovaquone 250 mg + proguanil 100mg) or Mefloquine Quinine salt

4 tablets once daily for 3 days (reduced dose for children)

Fansidar. 3 tablets as a single dose for adults: reduced doses for children Nil

Severe

Known chloroquine-sensitive Mild Severe

Chloroquine base Chloroquine base

1,5g (125mg/kg) in 2 divided doses 6-8 hours apart Initial loading dose 1400 mg max (20mg/kg) in 250-500 ml of fluid in over 4 hours then 700 mg max (10mg/kg) by i.v. infusion in 250-500 ml fluid over 4 hours given 8-12-hourly until the patient can take oral quinine giving a total of 7 days treatment As above 300 mg (15mg/kg) given by i.v. infusion in 250-500 ml fluid, repeated 12-hourly Change to oral Chloroquine as soon as the patient's condition permits

Nil Fansidar as above

Nil

Note: (1) Loading doses of quinine should not be given to patients who have previously received quinine or therapeutic doses of mefloquine: in that case standard doses of i.v. quinine should be given. (2) Blood glucose levels must be monitored during intravenous quinine therapy as it can stimulate insulin release and hypoglycaemia.

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CASE STUDY 9.4 COLLAPSE AND DYSPHASIA A 61-year-old man had travelled for 3 weeks in southern Africa visiting Zambia, Zimbabwe and South Africa. He had been in South Africa for a week before his return to UK. He had taken no antimalarial chemoprophylaxis. He became unwell 4 days before his return flight, with shiveriness, headache and anorexia. Towards the end of his flight from Johannesburg he collapsed, and on arrival was admitted to hospital. He was found to be very drowsy, with dysphasia and a divergent squint. He was febrile, 38°C, with no other localizing signs in the nervous system. Examination was otherwise unremarkable.

Questions 1. What is the differential diagnosis? 2, What further investigations would be needed?

It was thought that he had a stroke. Six hours later his sister visited and gave the information that he had just returned from an African holiday; blood films were then examined for malaria. These were positive, showing 11% asexual parasitaemia with schizonts, typical of falciparum malaria. Also on review deep jaundice was apparent, not noted previously. At this time his conscious level had declined further and he showed withdrawal responses to painful

stimuli. There were no retinal haemorrhages. Chest and cardiovascular examination was normal, BP 125/70. A urinary catheter was inserted and 59 mL of urine drained. Additional investigations showed Hbl2g/dL, with an increased white cell count at 15.3 x 109/L and low platelets, 13 x 109/L; coagulation screen normal; bilirubin 306 mmol/L, alanine transaminase 50 uL, albumin 37g/L, sodium 128 mmol/L, urea 27.6 mmol/L, creatinine 292umol/L.

Question 3. What Would be your immediate steps in management?

The patient was sedated, intubated and ventilated. Comment This case is typical of severe falciparum malaria, which very often occurs against a background of no prior chemoprophylaxis. The rapidity of progression of disease, particularly in the final hours before hospital admission, is in contrast to the much more indolent course of the vivax malaria case described below. The high level of parasitaemia is typical of falciparum, but the presence of schizonts in the peripheral blood is not usual and is indicative of more severe disease. Usually severe

the half-life of the two main schizonticidal drugs, and so the dosage regimen may need to be modified, reducing the amount given and, if necessary, the frequency of administration after 48 hours of medication. As soon as the patient's condition has improved sufficiently, oral treat1

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MCQ 9.26

malaria is associated with high parasitaemias, but this is not invariable and severe disease can be seen in patients with less than 2%. This patient had cerebral malaria with renal failure due to acute tubular necrosis. Although platelets were low there was no bleeding. Management comprises termination of parasite replication and supportive care until the disordered physiology starts to return to normal. Great care is needed with fluid balance to avoid overhydration, with the risk of pulmonary oedema, and intraoesophageal Doppler is a valuable means of assessing fluid status, giving 200 mL boluses of colloid to optimize systolic ejection parameters. Quinine 1400mg was given as a loading dose over 4 hours, with 700 mg 12-hourly thereafter until all asexual parasites had been cleared, when a single dose of three Fansidar tablets was given. A six-unit exchange transfusion was carried out. Blood sugar was monitored during the quinine infusion. Haemofiltration was commenced. He was unconscious for 12 days before starting to wake up. Haemofiltration was required for 3 weeks. This man returned to his normal work. One of the concerns is how much irreversible cerebral damage occurs after cerebral malaria. In adults the clinical impression is surprisingly little, but 5-10% of children surviving this condition in East Africa do have residual cerebral abnormalities, e.g. cortical blindness, deafness.

ment should be given. Tinnitus, deafness and headache are common side-effects of quinine, and if they are very troublesome the frequency of administration of the drug can be reduced. Quinine alone is used in pregnancy (Table 9.35). Quinine alone will not cure falciparum malaria and is followed by a single dose of Fansidar (pyrimethamine plus sulfadoxine) as in Table 9.33. Doxycycline, 100 mg daily for 7 days, or lesser doses, is an alternative for older children and adults. Mefloquine, 20mg/kg up to a maximum of

1.5g, in two divided doses 6-18 hours apart, can be given as sole treatment. Malarone (a combination of atovaquone 250 mg plus proguanil 100 mg per tablet) is effective in mild falciparum malaria, giving four tablets as a single dose with food or a milky drink at the same time daily for 3 days. The problems of multiple drug resistance in strains of P. falciparum are maximal in southeast Asia. Compounds derived from Artemesia annua, qinghaosu, are very important in treatment. Although these drugs produce rapid defervescence and parasite clearance there is a relatively high recrudescence rate for monotherapy, and so to use them most effectively they must be given with another drug, for example artemether plus lumefantrine. Atovaquone and proguanil are combined in malarone (see above). It has been proposed that in order to try to maintain the efficacy of currently available antimalarial drugs combination therapy should become the rule, giving both selected drugs together from the beginning. Chloroquine is generally well tolerated by mouth; nausea and blurring of vision are transitory side-effects. Upper abdominal discomfort may occur after taking the drug. Pruritus is common in Africans taking chloroquine. This is not associated with a rash and is not a manifestation of allergy. Chloroquine can be used in pregnancy. The route of administration is determined by the severity of the illness, judged by the criteria detailed above. Additional measures Patients with severe or complicated malaria should be managed in an intensive care unit. Apart from effective malaria chemotherapy, management is essentially supportive. When the patient is unconscious intubation is necessary to secure the airway. Convulsions should be controlled with diazepam. There is no specific additional treatment. Dexamethasone is contraindicated and at present there are no grounds for recommending the use of mannitol. Hypoglycaemia has been reported in severe cases, both before and during treatment with quinine, particularly in young children and pregnant women. Quinine causes insulin release. Blood sugar should be monitored regularly and 50% glucose given i.v. as needed. Dialysis is needed when there is renal failure. Attention to fluid balance is essential to prevent fluid overload. Pulmonary oedema can occur because of fluid overload, but can also occur without evidence of heart failure - an adult respiratory distress syndrome picture. Mechanical ventilation may be needed when pulmonary oedema occurs. Transfusion is indicated when there is acute intravascular haemolysis and when the haemoglobin falls below 7.0g/dL. Fresh frozen plasma and platelet transfusions are given when there are major clotting defects requiring correction. Whole blood exchange transfusion, six units in adults, appears to be effective in reducing parasitaemia as well as removing plasma containing immune complexes, cytokines, malaria antigen and products of red cell schizogony in severely ill patients, and is indicated when more than 30% of RBCs are parasitized and at lower levels of parasitaemia when complications are present. Although

there are no controlled trials demonstrating its efficacy there is logic to it and it should be considered where supplies of adequately screened blood are available.

9

Management of other complications Quartan nephrotic syndrome has a poor prognosis, with progressive deterioration of renal function to end-stage renal failure. Fluid restriction, diuretics and albumin infusions may be helpful in relieving the oedema and fluid retention. The idiopathic tropical splenomegaly syndrome is treated with maintenance antimalarial chemoprophylaxis. With this, the splenomegaly regresses, haematological indices improve, and abnormal serological findings return towards normal. Cessation of chemoprophylaxis may cause relapse. Prevention and control For the traveller to endemic areas prevention comprises the avoidance of mosquito bites and chemoprophylaxis. Everything possible must be done to prevent mosquito bites (p. 272). With the increasing problems posed by drugresistant malaria, these measures occupy a central place in prophylaxis and their importance must be stressed to travellers and residents in endemic areas. This applies particularly for infants, children and pregnant women. Chemoprophylaxis in pregnancy prevents maternal anaemia, prevents the abortifacient effects of fever due to malaria and prevents intrauterine growth retardation. The use of permethrin-impregnated bed nets is very effective in reducing attacks. Permethrin has a residual insecticidal effects lasting 6 months before retreatment is needed. The drugs currently used for chemoprophylaxis are listed in Table 9.36 but up-to-date information should be obtained by those advising travellers to endemic areas. A malaria vaccine remains elusive. As indicated above, there is clear evidence for effective antidisease immunity in populations in endemic areas but this needs to be maintained by constant antigenic challenge. It is likely that any vaccine developed will comprise antigens from several stages of the parasite lifecycle, but the sporozoite stage seems to be important in stimulating immunity. Eradication is no longer perceived as an achievable goal and control is the current aim. Insecticide resistance among mosquitoes, particularly to the cheapest compound, DDT, and chloroquine resistance among falciparum parasites, have contributed to the problems of controlling malaria. The main methods used are: • Reduction of vector breeding sites • Larviciding pools that cannot be drained • Spraying insecticides inside houses and on other sites where mosquitoes rest • Treating cases in humans. 1

FURTHER READING ON MALARIA White N J et al. Averting a malaria disaster. Lancet 1999; 353: 1965-1967. World Health Organization. Severe falciparum malaria. Trans Roy Soc Trop Med Hyg 2000; 94: suppl 1.

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TABLE 9.36 Prophylactic regimens against malaria in adults (Reproduced with permission of the PHLS Communicable Disease Surveillance Centre) Regimen Areas of chlomquine resistant P. falciparum: Mefloquine* Proguanil plus chioroquine Pyrimethamine-dapsone (Maloprim)+ plus chioroquine Doxycycline++ Atovaquone-proguanil (Malarone)** Areas without drug resistance: Chioroquine Proguanil

Dose for chemoprophylaxis

Usual amount per tablet (mg)

1 tablet weekly 2 tablets daily plus 2 tablets weekly 1 tablet weekly§ plus

250 (228 in US) 100 150 (base) 12.5(pyrimethemine) plus 100 (dapsone) 150 (base) 100 250 (atovaquone) plus 100 (proguanil)

2 tablets weekly 1 tablet daily 1 tablet daily

2 tablets weekly 2 tablets daily

150 (base) 100

All antimalarials to be avoided in severe hepatic and renal impairment. Chioroquine doses are given as the base. Folate supplements should be given to those taking proguanil or Maloprim when pregnant. * Avoid during pregnancy, during lactation and avoid pregnancy for 3 months after stopping it. Do not prescribe mefloquine if there is a history of epilepsy, depression or severe, psychiatric disorder. Appropriate for up to 1 year abroad. Caution in cardiac conduction disorders. + Best avoided in the first trimester of pregnancy. (Maloprim is only available for travellers who have epilepsy and cannot take alternatives.) + Contraindicated during pregnancy and lactation and for children less than 12 years. § Never exceed one tablet of pyrimethemine/dapsone (Maloprim) weekly. ** Licensed for up to 28 days in malarious area. Do not give in pregnancy. Begin 1-2 days before departure. Continue for 1 week after return.

FIG. 9.31 World distribution of trypanosomiases

matic infections also occur. Prodromal features include headache, malaise and gastrointestinal upset prior to the onset of fevers and rigors, with jaundice, haemoglobinuria and renal impairment in B. divergens infections. B. microti produces a more prolonged but less severe illness. Increasing age is associated with more severe clinical illness. The laboratory diagnosis is made by finding organisms similar to malaria parasites in Giemsa-stained peripheral blood films. Treatment with clindamycin, 600 mg 6-hourly intravenously or intramuscularly (20mg/kg/day in children), and quinine, 600 mg 8-hourly (10mg/kg 8-hourly in children) is effective in treatment of severe B. microti infections. For all severe cases intensive supportive therapy to maintain circulation, organ perfusion and oxygenation is essential. The efficacy of drug therapy in B. divergens is less certain.

TRYPANOSOMIASES African trypanosomiasis (sleeping sickness)

BABESIOSIS Babesia are intracellular protozoa that invade, divide asexually within, and finally rupture host erythrocytes. There are 70 species, affecting a wide range of vertebrates including cattle (B. diver gens) and rodents (B. microti). The parasites are transmitted by the bite of hard-bodied (ixodid) ticks. Babesia are widely distributed geographically, with reports of cases in humans from many countries, including Scotland and the USA. Babesia may occur concurrently with Borrelia burgdorfei infection. The incubation period is up to 4 weeks, less in patients who have had a splenectomy. There is a considerable range in the severity of infection, from mild to severe. Asympto-

1

352

Fig. 9.41

2

Fig. 9.42

Infection with Trypanosoma gambiense causes an initial febrile illness which progresses slowly to a chronic phase dominated by infection of the CNS, causing neuronal death and a variety of organic neurological syndromes. Neurological involvement occurs early in T. rhodesiense infections, within weeks of inoculation of parasites and, untreated, there is rapid deterioration and death. The two species cannot be distinguished on morphological grounds. Various species of tsetse fly, Glossina, are the vectors. Distribution and incidence The specific names of these parasites suggest a West African (T. gambiense) or East African (T. rhodesiense) origin for the infections, but there is a considerable overlap of the distribution of the two species in Central Africa (Fig. 9.31). The total numbers of cases are far fewer than malaria, but rhodesiense infections have a considerable economic impact as valuable farming and grazing lands

cannot be used because of the high risk of infection. There have been increases in both forms recently with imported cases seen in Europe.

Epilepsy occurs. In the terminal stage the patient is scarcely reusable, unable to swallow or feed him/herself. Bronchopneumonia is a common cause of death.

Transmission and epidemiology Tsetse flies become infected by ingesting trypanosomes in a blood meal. Once infected, a fly remains infective for life. About 1 % of flies in an area are infected. Humans are the reservoir in gambiense infections, whereas a variety of wild mammals, including bush buck and hartebeest, are the reservoir of rhodesiense infection, and humans are an incidental host. Transmission of gambiense trypanosomiasis occurs in wooded areas around rivers and streams that are water sources for local populations. Blood transfusion and transplacental transmission are also possible routes of infection.

Diagnosis Diagnosis depends on finding trypanosomes. Early in the course of infection with either species, parasites may be found in peripheral bloodfilms.0 There are usually many more parasites in rhodesiense than in gambiense infections. Repeated examinations must be made to detect the low levels of parasitaemia in gambiense infection. Gambiense parasites may be seen in bone marrow smears. Smaller numbers of parasites can be detected in smears of the buffy coat. Material aspirated from a lymph node can be smeared on a slide and stained. CSF must also be examined. The cell count is determined and the stained deposit examined for trypanosomes. An increased white cell count (>5/mm3) and/or an increased CSF protein (>250mg/L) indicates CNS infection in a patient with parasites in the blood or tissues. Serum immunoglobulin concentrations are increased, with IgM levels being very high. Increased CSF IgM indicates nervous system involvement. Serological tests do not have diagnostic value for individual patients.

Pathology and pathogenesis There is an early marked inflammatory response at the site of inoculation and in the lymphoid tissues of the body, lymph glands, liver and spleen. Trypanosomes may be seen in tissue sections. Rhodesiense infections progress rapidly to involve the heart and brain. Myocarditis and pericarditis are common. An obliterative endarteritis with vascular occlusion is found in the CNS, causing the degenerative changes. The neuropathological features include thickening of the meninges, which are infiltrated by lymphocytes and plasma cells. This infiltrate extends into brain substance in a perivascular distribution. The parasites continuously shed surface antigens which evoke antibody responses in the host, but the antigens change sequentially, a possible mechanism of evading host immune responses. Autoantibodies to brain and heart may cause tissue damage. Disseminated intravascular coagulation can occur in rhodesiense infections. Clinical features With both species, fever, chills and weakness are usual initial symptoms, beginning about 10 days after the bite. An inflamed lump is present at the bite site - the trypanosomal chancre 1 - and there is regional adenopathy. On white skins it is possible to see transient irregular areas of circinate erythema in both types of disease. Posterior auricular and posterior cervical adenopathy develop after 1-2 months of infection in gambiense infections. Unpleasant dysaesthesia follows squeezing of the calf muscles. Hepatosplenomegaly is often present in both infections early on. Jaundice occurs in rhodesiense infections. Purpuric rashes on the extremities are occasionally seen in severe rhodesiense infections. Neurological involvement appears within weeks of infection in rhodesiense infections, but it may be months or years later with T. gambiense. Indifference, lassitude, personality changes and altered behaviour are early features. Sleep rhythm is reversed. The basal ganglia, cerebellum and brainstem regions are most affected, producing tremor, incoordination, and problems with speech, balance and walking. Parkinsonian features may be prominent.

Management Suramin is used to kill parasites in blood and lymph nodes, and cures patients early in the disease. After an initial test dose of 100-200 mg given by slow intravenous infusion to ensure that the drug does not cause anaphylaxis or cardiovascular collapse, 1g doses are given by slow intravenous infusion on days 1, 3, 6,14 and 21. Pentamidine is the first-line drug for use in T. gambiense infections, giving 3-4mg/kg of pentamidine base daily by slow intravenous infusion or intramuscularly until 7-10 doses have been given. Sterile abscesses can occur at sites of intramuscular infection. Pentamidine stimulates insulin release from the pancreas, with the consequent risk of hypoglycaemia. Although pentamidine is used for early disease there is evidence that it crosses the blood-brain barrier and has worthwhile actions in early neurological disease in rhodesiense infections. Melarsoprol treatment regimens are complicated. Treatment is given intravenously. There is a significant incidence of arsenical encepholopathy with its use. For T. gambiense the drug is given in doses of 3.6mg/kg, maximum 180mg, for 3 days, repeating the series after a week without drug in patients with 6-19 WBC/cu mm CSF, and giving a third series for those with > 20 WBC/cu mm. For T. rhodesiense the regimen builds the dose up slowly from 0.36mg/kg (day 1), 0.72 (day 2), 1.1 (day 3), 1.8 (days 10,11 and 12), 2.2 (day 19), 2.9 (day 20), and 3.6 to a maximum of 180mg (days 21, 28, 29 and 30). The incidence of reactive arsenical encephalopathy is reduced by giving prednisolone 1 mg/kg before and throughout treatment. Eflornithine is effective in CNS disease due to T. gambiense with none of the arsenical toxicity, and should replace melarsoprol in this infection; initial treatment is with

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400mg/kg/day in divided doses, 6-hourly for 14 days, followed by 300mg/kg/day in divided doses for 30 days. This amounts to a lot of drug! Examination of blood films, IgM levels, CSF and the patient's condition is helpful in assessing the response to treatment. Improvement in the patient's condition and resolution of the abnormalities indicate a good response. Relapse is indicated by a rise in the CSF protein or cell count, and further treatment should be given. When patients are treated early, complete recovery is the rule. In more advanced cases treatment arrests progression of the disease. Prevention and control Appropriate clothing in endemic areas is essential to minimize the area exposed to biting. Tsetses can bite through thin material. Pentamidine has been used as a prophylactic agent against gambiense infection in those heavily exposed. Efforts to control vectors by destruction of habitats and trapping flies may be helpful.

American trypanosomiasis (Chagas' disease) Aetiology American trypanosomiasis is an infection caused by T. cruzi, which exists in several forms during its lifecycle. The trypomastigote is found in the blood and has similar appearances to the African trypanosome. Amastigotes are found within host cells. Human blood forms are ingested by the vector species of reduvid bug, 1 when it takes a blood meal. The bug defaecates infective faeces on the skin after taking a blood meal, and the metacyclic forms enter the host through the bite or other skin abrasion, or through the conjunctiva if the faeces are carried to the eye on fingers. Distribution and incidence American trypanosomiasis is most common in the countries of South America among people living in poorly constructed housing, as the bugs live in roof thatch and cracked mud walls. Many people are infected in South America, with about 6000000 cases in Brazil, although not all those infected develop disease (see Fig. 9.28). Transmission and epidemiology Contact with infected bugs (the most important source), transplacental infection and blood transfusion are the routes of infection (Fig. 9.32). Infection in bugs is maintained from a reservoir of T. cruzi in dogs. Infection of children in the first decade of life is common. The bugs live in the thatch and cracked mud walls of basic village housing.

1 Fig. 9.43

354

4

MCQ 9.27

2

Fig. 9.44

3

Fig. 9.45

Animal reservoir (e.g. dog)

Proliferates in gut

TRIATOMID BUG HUMAN Trypomastigotes enter histiocytes and divide asexually

Cells rupture, releasing more trypomastigotes

Trypomastigotes released and invade other cells AUTONOMIC CELLS INVADED AND DENERVATION RESULTS FIG. 9.32 Lifecycle of Trypanosoma cruzi

Hundreds if not thousands of bugs can be found when these houses are demolished. Chagas' disease is essentially a disease of the rural poor. Pathology and pathogenesis Trypanosomes invade cells, including myocardial and gut smooth muscle cells. Rupture of the cell releases trypomastigotes and evokes inflammatory responses in the surrounding tissues. The trypomastigotes circulate, invade other cells, and replicate as amastigotes. Phagocytic cells in any tissue, as well as heart muscle, skeletal and smooth muscle and CNS, are among the tissues involved. Pericarditis and cardiomegaly are often present. A meningoencephalitis can occur in acute disease. The heart and the gut are the organs severely affected in chronic Chagas' disease. The heart is enlarged, with apical ventricular aneurysm commonly present. Thrombus is often present in the atrial appendage and in the ventricles. There is diffuse myocardial cell necrosis, with fibrosis and involvement of the conducting system. Parasympathetic plexuses of the gut are destroyed, causing dilatation of the intestine, frequently the oesophagus or colon (the mega-syndrome). Involvement of the conducting system of the heart is common and may be the only evidence of disease. Evidence of disease may come on at any time, even decades after infection. The pathogenesis of the disease is complex. There are several different strains of T. cruzi, some of which cause the cardiac and mega-syndromes. Other strains cause lifelong infection but no disease. Autoimmune mechanisms are probably involved in damaging tissues. Clinical features Acute infection may be inapparent in young children, but in older children and adults there may be an acute febrile illness. The patient may find a lump in the skin marking the site of the infected bite and initial parasite replication (the chagoma). Unilateral periorbital oedema indicates a conjunctival route of infection. Local adenopathy and hepatosplenomegaly are found.

Cardiomegaly, heart failure, arrhythmia and conduction defects indicate myocarditis in the acute illness. This may cause sudden death. Meningoencephalitis may occur. The local signs at the bite site, hepatosplenomegaly and fever subside in 6 weeks. Chronic Chagas' disease presents with heart and gut disease. Right- and left-sided cardiac failure are common. There may be signs suggesting pulmonary or systemic embolization from thrombus in the cardiac chambers. Conduction abnormalities are often present and may cause Stokes-Adams attacks and sudden death. Megaoesophagus causes dysphagia and aspiration pneumonia in the most severely affected. 2 Megacolon causes constipation and faecal impaction. 3 Volvulus of the sigmoid megacolon may occur. Diagnosis Acute infections can be diagnosed by finding parasites in the peripheral blood film. Trypanosomes may also be found on microscopy and culture of CSF, even when evidence of CNS involvement is lacking. Xenodiagnosis is also used to make a specific parasitological diagnosis. Laboratoryreared bugs, known to be free of infection, are fed on the patient, up to 20 bugs being used. They are then kept in the laboratory, dissected after 3 weeks and the hindgut examined for metacyclic forms. The polymerase chain reaction offers a valuable technique for detecting low levels of infectious agents and has been adapted for use in Chagas' disease. Serological tests are usually positive in both acute and chronic cases by indirect imrmmofluorescence, indirect haemagglutination and complement fixation techniques, and may be the only indication of infection. Management Treatment is unsatisfactory. Two drugs are available, nifurtimox and benznidazole. Both will clear the blood of parasites in the acute phase, but prolonged follow-up suggests that neither gives a radical cure. There is now evidence from a prospective randomized controlled study that benznidazole treatment, 8mg/kg body weight in divided doses for 3 weeks given to children with positive serology, will reduce the frequency of development of ECG changes during follow-up and, with time, be followed by a decline in antibody litres. In adults with positive serology nonrandomized studies have shown a reduction in the frequency of development of ECG changes during follow-up after benznidazole therapy. However, the extent to which these findings indicate a definite benefit for treatment is still uncertain. Control of arrhythmias and heart failure is all that can be done for cardiac disease in the chronic phase. Relief of obstruction at the oesophagogastric junction by dilatation or surgery may help the patient with megaoesophagus. A dilated segment of small or large intestine can be excised. Prevention and control Brick-walled houses with corrugated iron roofs would prevent the transmission of Chagas' disease. Residual

spraying of existing houses with y-benzene hexachloride is a useful method of vector control. 4

9

LEISHMANIASIS The Leishmania are obligate intracellular protozoan parasites that infect humans and other mammals, including dogs, foxes, gerbils and rats. Infection is transmitted by the bite of infected sandflies. The generalized lifecycle is shown in Figure 9.33. These organisms invade the mammalian host, parasitize cells of the reticuloendothelial system and evoke granulomatous responses in infected tissue. Genetic factors controlling the host cell-mediated responses determine the outcome of infection, with only a proportion of those infected developing clinically apparent disease. The geographical distribution is shown in Figure 9.34. Two forms of disease are recognized. Cutaneous leishmaniasis denotes infection with species of Leishmania that affect primarily reticuloendothelial cells in the skin, whereas visceral leishmaniasis denotes infection with a species that primarily infects reticuloendothelial cells of deeper tissues (Table 9.37). The species causing cutaneous disease are geographically distinct between the Old and the New World.

Cutaneous leishmaniasis Cutaneous leishmaniasis is a granulomatous infection of the skin caused by various species of Leishmania, resulting in one or more chronic ulcerating skin lesions (Fig. 9.35). In time, the ulcers usually heal with scarring.

Proliferation in gut

SANDFLY

Promastigotes regurgitated or contaminate mouth parts while feeding

Ingestiqn of parasitized cellwithamastigotes

HUMAN

Rupture of host cell. Other reticuloendothelial cells invaded

Reproduction by binary fission

FIG. 9.33 Generalized lifecycle of Leishmania

Promastigotes taken up by reticuloendothelial r.fills

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FIG. 9.34 World distribution of leishmaniasis FIG. 9.35 Cutaneous leishmaniasis producing ulcerating skin lesions

(copyright S.G. Wright)

TABLE 9.37 Forms of Leishmania infection Location

Cutaneous leishmaniasis

Visceral leishmaniasis

Old World

Leishmania tropics Leishmania major

Leishmania donovani

Leishmania aethiopica Leishmania infantum Leishmania mexicana

Leishmania infantum

New World

Leishmania chagasi

Leishmania braziliensis Leishmania peruviana

Aetiology The organisms causing cutaneous leishmaniasis are listed in Table 9.37. Morphologically they are identical, but distinctions can be made using polymerase chain reaction (PCR) methods. Distribution and incidence The incidence is difficult to estimate, as many self-healing cases never come to medical attention. World Health Organization figures put the incidence at 100 cases per 10000 of the population in endemic areas (Fig. 9.31). Transmission and epidemiology Female sandflies of the genera Phlebotomus (Old World) and Lutzomyia (New World) transmit these infections by their bite. Apart from L. tropica (transmitted in towns and cities, with humans as the reservoir), these are zoonotic infections; humans are infected when they move into areas where there is a mammal-sandfly cycle. Urban infections tend to be more common among children. Pathology and pathogenesis Promastigotes change to amastigotes after inoculation into

1

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Fig. 9.46

the skin and are phagocytosed by macrophages, where they replicate (Fig. 9.30). 1 The local granulomatous reactions produce a subcutaneous nodule and then the overlying skin ulcerates. The lesion persists as long as amastigotes proliferate within macrophages. This occurs despite the presence of sensitized T lymphocytes, shown by a positive delayed hypersensitivity reaction to a leishmanin skin test antigen. In most infections healing occurs spontaneously with time. It is likely that factors that contribute to TNF production, often genetic, determine the natural history of infection. Clinical features Persisting cutaneous ulceration on an exposed part of the body continuing for more than a month is the usual feature. The ulcer is painless and may crust over, only for the crust to separate again. There may be small nonulcerated satellite nodules around the primary lesion, and in both Old World and New World forms there can be involvement of draining lymphatic channels, which may be both palpably thickened and the sites of secondary lesions along their course. Lymph nodes on these lymphatics can be enlarged. Secondary bacterial infection is surprisingly uncommon. These infections will heal spontaneously in 2-8 months, leaving a residual scar. Recidivans leishmaniasis caused by L. tropica infection is characterized by a chronic relapsing course in spite of T-cell immunity. In contrast, diffuse cutaneous leishmaniasis causes numerous nodular or plaque-like lesions which tend not to ulcerate. These patients represent a kind of 'lepromatous' cutaneous leishmaniasis (p. 326). It is caused by L. aethiopica in Africa and L. mexicana in Central and South America. Leishmanin tests are negative. The South American species cause lesions similar to those of L. major (Fig. 9.35). L. braziliensis causes an initial ulcerating skin lesion which heals, but may subsequently produce a recurrence of disease with destruction of tissues at a mucocutaneous junction (mucocutaneous leishmaniasis). This can occur at the time of presentation with the primary skin

lesion, or months or even a year or so later. Another feature of cutaneous disease is the tendency to form lesions at the sites of chronic inflammation in the skin or at sites of trauma. For example, cutaneous leishmaniasis can develop in the perianal region, when there is recurrent perianal sepsis. Laryngeal disease due to leishmania has also been recognized. Diagnosis Parasites can usually be found in Giemsa-stained smears of material from slit skin smears, material aspirated from the edge of the lesion, or touch impression smears from the surface of a biopsy. Material from the biopsy can also be cultured in Novy-McNeal-Nicolle (NNN) medium. PCR on DNA extracted from biopsies or from cultured material can be used to make the diagnosis or to characterize the species complex involved. Serological tests for leishmaniasis are positive at low litre in most forms of cutaneous leishmaniasis. Differential diagnosis A variety of infective disorders can cause indolent ulceration. Among these are • • • • • • • • •

Yaws Tertiary syphilis Lupus vulgaris Histoplasma duboisii Diphtheritic ulcers (desert sore) Sporotrichosis Blastomycosis Malignant ulcers Tropical ulcers.

Diffuse cutaneous leishmaniasis can be mistaken clinically for lepromatous leprosy unless the causative organism is demonstrated in skin smears. Management The treatment of cutaneous leishmaniasis is unsatisfactory, not least because the commonly used drug, sodium stibogluconate, 20mg/kg, has to be given by daily intravenous injection for 20-30 days. Intralesional antimonials, in Old World disease, and y-interferon have also been used. Sodium stibogluconate (Pentostam) is the first choice of drug for both Old and New World leishmaniasis, and usually results in healing in most types of disease. Diffuse cutaneous leishmaniasis is often resistant and pentamidine is the alternative drug. Amphotericin-B is also very effective, given as a solution rather than in the liposomal formulation which is very effective in visceral disease (see below). Prevention and control Among Old World cutaneous leishmaniasis cure is usually associated with immunity to reinfection with the same strain, but vaccination is not yet available. Destruction of the burrows of rodent vectors can be successful in removing reservoirs. Removal of sandfly breeding sites around houses and spraying with insecticides will help to control

peridomestic transmission. Protection against the bites of sandflies may be helpful, e.g. mosquito nets and insect repellants, although the insects will bite through a shirt.

9

Visceral leishmaniasis (kala-azar) Visceral leishmaniasis, an infection caused by L. donovani, is spread by the bite of an infected female sandfly and can cause a prolonged febrile illness with wasting, hepatosplenomegaly and lymphadenopathy. In South America visceral disease is caused by L. chagasi, which is probably identical to L. infantum which causes visceral as well as cutaneous disease in the countries of the Mediterranean littoral. Distribution, incidence and transmission The areas affected are shown in Figure 9.31. This condition is endemic in countries of southern Europe and Mediterranean islands that are regularly visited by tourists. Infections acquired in these areas are seen in the UK. Leishmaniasis has been recognized as an opportunist infection in AIDS in southern European countries. A major epidemic has been continuing over 10 years in the southern Sudan. Children are commonly affected in the endemic areas. Subclinical cases probably exceed clinical cases by 5 to 1. Endemic, epidemic and sporadic forms of the disease occur. All ages and both sexes are susceptible to infection. The dog seems to be an important reservoir throughout the endemic areas. Humans are the reservoir for L. donovani in northeastern and eastern India. The vectors are female sandflies of the genus Phlebotomus in the Old World and Lutzomyia in the New. These insects, guided by scent plumes, bite at night. Pathology and pathogenesis Promastigotes transform to amastigotes when they are injected into the skin and ingested by phagocytic cells. Amastigotes replicate asexually within macrophages and are carried to lymph nodes draining the site of the bite; they then disseminate to macrophages in other tissues, particularly the liver, spleen, nodes and marrow. There is progressive enlargement of liver and spleen. Wasting of the muscles and low plasma albumin are metabolic responses to the infection. The malnutrition will impair immune responses to the parasite and to other diseases such as tuberculosis or pneumococcal pneumonia, which may complicate the patient's illness. Leishmanin tests (a delayed hypersensitivity skin test) are negative before treatment and become positive after cure. Clinical features The incubation period is very variable, from 2 weeks to 2 years or more. Latent infections are common and are particularly likely to give rise to disease in the context of AIDS. Early symptoms are lethargy, sweats, and fever, with a typical pattern of two peaks in a day. Within weeks of onset the liver and spleen are palpable and progressively enlarge. Body weight falls. Lymphadenopathy may be

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found. Emaciation is obvious in more long-standing cases. Darkening of the skin of hands, feet, face, and abdomen is common in eastern India ('kala-azar' means 'black sickness' in Hindi). Poorly nourished patients should be carefully examined for coexisting tuberculosis or other infection, such as pneumonia. Investigation shows anaemia and pancytopenia due to hypersplenism, low plasma albumin and high globulin (e.g. 50g/L) with polyclonal elevation of IgG. Serological tests for leishmaniasis are positive in most cases. Parasites are readily found in patients with co-existing AIDS. Diagnosis The clinical features, together with exposure in an endemic area, suggest visceral leishmaniasis. The parasites are usually found on examination of Giemsa-stained smears of bone marrow aspirate, which should also be put into NNN culture medium. 1 Percutaneous splenic aspiration has a high yield of positive results (95%); it can be done safely in a cooperative patient whose prothrombin time is not more than 3 seconds prolonged and whose platelet count is 40 x 109/L or more. Again, material should be cultured and used for making smears. Management For many years sodium stibogluconate has been the drug

of first choice, giving 20mg/kg intravenously daily for 30 days, though longer courses may be needed. Liposomal preparations of amphotericin B are very effective, much less toxic than the conventional formulation, and can be given for shorter courses, 2-3mg/kg/day for 10 days, while 4mg/kg/day for 5 days plus an additional dose at day 10 is very effective. Relapse occasionally occurs; the options are to give more sodium stibogluconate for longer periods, or to give a second-line drug, e.g. pentamidine or amphotericin B. One of these is certainly needed if there is no response to a second course of sodium stibogluconate. Preliminary results with miltefosine, an anticancer drug, are promising. Although there may be good responses to treatment in patients with AIDS, relapse is likely as parasites are unlikely to be eradicated. However, there is little experience to date of antileishmanial treatment given with concurrent highly active antiretroviral treatment (HAART), and the improvements in CD4 counts seen with HAART may possibly allow parasite killing. Prevention and control Prevention is difficult. Where humans are the reservoir, finding and treating cases and insecticiding homes may help in control. Control of canine reservoirs can be of help. Vaccines are under study but not yet in clinical use.

HELMINTH INFECTIONS

A large number of helminthic parasites affect humans (Fig. 9.36). Humans are the definitive host in most instances, and the sexual phase of the lifecycle takes place in the human host. A classification is given in Table 9.38. Less commonly humans are an inadvertent intermediate host, infected either with larvae that do not develop any further because they are in the wrong host, e.g. Toxocara canis, or with larvae that are unlikely ever to be consumed by the definitive host, as with hydatid disease. The lifecycles of these parasites differ markedly. Faecal-oral transmission by ingested eggs or percutaneous infection by infective larvae are characteristic of the soilassociated gut nematodes. In contrast, the filariases have blood-sucking insect vectors in which they develop to infective larvae that will infect humans when later blood meals are taken. The lifecycles of the trematode platyhelminths are more complex, involving more than one intermediate host in many instances. The climatic conditions favouring transmission are warmth and humidity. These factors promote the survival of the soil-transmitted helminths and the insect vectors of

1

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Fig. 9.46

TABLE 9,38 Classification of helminth infection Nematodes (roundworms) Human intestinal Ascaris Ancylostoma Necator Strongyloides Enterobius Trichuris

Filariai Onchocerca Wuchereria Brugia Loa loa

Animal intestinal Trichinella Toxocara

Trematodes (flukes) Schistosoma Clonorchis Opisthorcis Fasciola Fasciolopsis Paragonimus Cestodes (tapeworms) Human intestinal Taenia species Diphyllobothrium Hymenolepis

Larval tissue cestodes Taenia solium (cysticercosis) Hydatid (Echinococcus)

the filarial parasites. Local traditions in food preparation and consumption are important in the transmission of a number of parasites, such as eating raw meat or lightly cooked or raw fish and crabs. Among sheep and goat

9

FIG. 9.36 Example of helminths A Rhabditiform larvae of Stmngyloides stercoralis passed in faeces (copyright S.G. Wright). B Adult roundworms, Ascaris lumbricoides. The larger female is about 15cm long. C Taenia saginata, the beef tapeworm, after expulsion from the gut (copyright S.G. Wright).

herding communities where dogs are used, definitive and intermediate hosts of Echinococcus granulosus are brought together, and it is common for sheep and goat offal containing hydatid cysts to be fed to dogs. Dog faeces containing E. granulosus eggs contaminate the environment around houses, with the consequent risk of infection of humans, particularly children. It is apparent that the burden of infection is not evenly distributed in communities. There is a small group, often children, with persistent heavy infections, and it is among this group that the morbidity and any mortality of helminthiasis are seen. Studies have shown adverse effects on nutrition and growth, and there are associations between intestinal helminthiasis and impairment of intellectual development, although a causal link has not been shown. These effects have been well shown for Ascaris lumbricoides and for Trichuris trichiuria, particularly in the setting of the trichuris dysentery syndrome. Additional studies are extending these observations to consider a similar role for schistosome infection. In addition, the availability of ultrasound scanning and endoscopy has allowed recognition that migration of ascarids into biliary and pancreatic ducts is more common than hitherto realized. The filarial worms produce disease as a result of inflammation caused either by adults in main lymphatic channels, e.g. Wuchereria bancrofti, or by larval microfilar-

iae dying in the skin in Onchocerca volvulus infection. Additional morbidity in onchocerciasis is the result of onchocercal larvae dying in the cornea to cause the ocular complication sclerosing keratitis, which can progress to blindness. The chemotherapy of helminthic infections has become progressively simpler. The benzimidazoles - tiabendazole, mebendazole and albendazole - are broad-spectrum antihelminthics active against the soil-transmitted helminths. The incidence of side-effects decreases in the order given, the most marked side-effects occurring with tiabendazole, which should be avoided unless absolutely necessary. Praziquantel has actions in a range of cestode and trematode infections, with a low incidence of side-effects. It is the first drug to be effective in cysticercosis.

NEMATODES HUMAN INTESTINAL NEMATODE INFECTION Ascariasis Ascariasis is infection of the gut lumen with the nematode parasite Ascaris lumbricoides.

359

Aetiology The adult female worm measures up to 400mm long by 6mm wide at its thickest (Fig. 9.36B). The male is up to 300mm long by 2-4 mm. They live for about 1 year. Both are a greyish-white colour. The female lays up to 200000 eggs per day. The worms do not attach themselves to the gut mucosa but maintain their position by actively moving against the flow of intestinal contents. The eggs survive well in warm moist soil but are killed by heating to 50° C. Distribution and incidence Ascariasis is common in the tropics and subtropics, and up to 90% of people may be infected. Poor or absent sanitation and frequent faecal contamination of the environment with vast numbers of Ascaris eggs lead to a high frequency of infection, often with large worm loads in children. Transmission and epidemiology Eggs are ingested in food or water or from fingers, and the larvae are released in the small intestine. They enter the mucosa and then blood vessels to reach the lungs, where they leave blood vessels and enter air spaces. Here they undergo two further moults and then ascend the bronchial tree to the pharynx. They migrate down the oesophagus and through the stomach to reach the small intestine. An excess of infections is found in a small proportion of the population, the reasons for which are uncertain. However, among this group there is evidence of undernutrition, perhaps because of the effect of the worm bulk creating a sense of satiety, with consequent reduction in food intake. Pathology No intestinal mucosal lesions are attributable to the adult worms. Pulmonary infiltrates with eosinophils are found during the larval migratory phase of the lifecycle, but this rarely has a clinical correlate. Clinical features Symptoms due to the migrating phase of ascariasis are very uncommon. Pulmonary infiltrates on X-ray, eosinophilia and restrictive pulmonary function defects can occur. This can be seen when humans are infected with the pig ascaris, Ascaris suum. There are also few symptoms attributable to established infection. Worms may be vomited, or passed with the stools, or may even emerge from a nostril. Bolus obstruction of the small intestine occurs, particularly in children with very heavy infections. A mass of matted worms in a segment of gut can cause intestinal obstruction, volvulus and infarction. Occasionally an adult worm will migrate

1

360

Figs 9.47, 9.48

into the common bile duct, causing pain, obstructive jaundice and ascending cholangitis, or into the pancreatic duct to cause pancreatitis. Ascarids can also migrate through intestinal suture lines to cause leakage from an anastomosis. Ascaris egg granulomas are occasionally found in the peritoneal cavity, presumably related to ectopic development of an adult female.

Diagnosis Diagnosis is made by finding eggs in faecal samples. The complications of ascariasis are usually diagnosed on surgical exploration or endoscopic examination. Eosinophilia is uncommon, apart from at the stage of tissue migration. Management Mebendazole (100 mg twice daily for 3 days) or albendazole (400 mg as a single dose) is effective. Both drugs are relatively expensive. Piperazine hydrate elixir (750 mg of hydrate per 5mL) is effective. The dose depends on age and weight. Where a mixed infection of ascaris and hookworm is being treated with piperazine and tetrachlorethylene (TCE) for hookworm, it is usual to treat the ascaris first, as TCE may stimulate ascaris migration into biliary or pancreatic ducts. Prevention and control The use of latrines would prevent infection. Regular administration of drugs, e.g. albendazole, in affected communities is being used. Faecal contamination of the environment and the use of human faeces as fertilizer on crops encourage transmission. Before use as fertilizer, faeces can be treated with sodium nitrate or calcium superphosphate to kill the eggs of gut parasites. Education of the community about the control efforts, and their active cooperation, are essential to the success of control programmes.

Hookworm This is infection of the gut with either Ancylostoma duodenale or Necator americanus. Both grip the wall of the mucosa with their mouth parts and take a small amount of blood from the host each day. A relatively small number of people develop disease related to hookworm infection. Aetiology The worms are about 9 mm long. The female Ancylostoma produces 30000 eggs per day and Necator 9000 eggs per day. Eggs must be passed into warm, moist soil for the ovum to develop into the larval stage. The lifecycle is shown in Figure 9.37. Larvae of Necator grow in the lungs. Ancylostoma larvae can be ingested with food and develop in the gut lumen without tissue migration. Epidemiology Both species occur worldwide where temperature and soil conditions are suitable. Ancylostoma eggs are capable of resisting desiccation to some extent. Infection rates of 80-90% are common in endemic rural areas. The use of

Growth of larvae

Larvae penetrate alveoli, pass via the trachea to the pharynx and are swallowed

Larvae in upper small intestine, mature to adult stage

Venous circulation to heart and lungs Larvae penetrate skin HUMAN

Egg passed in taeces

SOIL Eggs mature and hatch in soil FIG. 9.37 Lifecycle of hookworm

untreated faeces as fertilizer on crops accounts for the high infection of farm workers.

(TCE), giving 0.5mL/kg to a maximum single dose of 5.0mL. Eradication of the worms is not the priority if anaemia is present. Packed cell transfusion may be needed after giving diuretics. Where there is heart failure, diuretics and cautious blood transfusion with packed cells are needed. Exchange transfusion is another way of correcting anaemia without risking the adverse effects of fluid overload. Later, iron stores will need replacing.

9

Prevention and control Safe disposal of faeces prevents transmission. Where night soil must be used to fertilize crops, prior chemical treatment kills ova (see Ascariasis, above). Wearing shoes or sandals also prevents infection. A diet with meat as a regular constituent would prevent anaemia, but in the tropics and subtropics this is often beyond the means of many families and so vegetables with a high content of ferrous iron, e.g. soya beans, should be introduced into the diet. Regular deworming is increasingly used.

Cutaneous larva migrans Pathogenesis and pathology Each worm takes a small amount of blood from the host. Nutrients are removed by the parasite and the residue passes into the gut, where it can be digested and absorbed. Iron deficiency anaemia occurs when iron losses exceed intake and iron stores are depleted. Anaemia may be severe, with haemoglobin levels of less than 5.0g/dL. Hypoalbuminaemia is usual at this stage, but malabsorption does not occur. Clinical features No symptoms are attributed to hookworm infection. Hookworm anaemia appears to cause few symptoms until oedema due to hypoproteinaemia develops. Salt and water retention exacerbates the oedema and causes some degree of exertional dyspnoea. The findings are those of severe iron deficiency anaemia, with mucosal pallor and koilonychia. Some patients present with high-output congestive cardiac failure. Diagnosis and investigation Diagnosis is confirmed by finding eggs in the faeces. Worm burden can be assessed from 24-hour faecal egg outputs. Hypochromic microcytic anaemia is present. It is important to distinguish between iron deficiency and p-thalassaemia trait, which is common in the tropics. Eosinophil counts can be normal or increased, though they are often markedly raised during the phase of migration.

Management Mebendazole (100 mg twice daily for 3 days) or albendazole (200 mg twice daily for 2 days) is effective. Bephenium hydroxynaphthoate granules (5.0g) are given on an empty stomach. The cheapest treatment is tetrachlorethylene

The hookworm parasite of dogs and cats, Ancylostoma braziliensis, produces eggs which are passed in the animal faeces; they hatch in warm, moist soil conditions to release larvae which mature to the infective stage and can penetrate the skin of humans. The larvae cannot follow their usual migration in humans and instead meander around in the subcutaneous tissues close to the site of entry until they die. This can go on for several months. The feet are the most common site for this condition, but any part in contact with contaminated soil or sand can be affected. This is often seen in people who have recently had a tropical beach holiday. Occasionally the infective hookworm larvae of Ancylostoma and Necator will produce the same appearance. The appearances are readily recognized. A red papule marks the tip of the track produced by the migrating worm, and is in fact a little way behind the migrating worm. A raised, red, serpiginous track, about 3 mm across, stretches out behind. 1 The affected skin is itchy and may be blistered. Secondary bacterial infection can occur. Sometimes when the lesion is deeper in the skin a subcutaneous nodule is all that can be felt, with none of the signs described. The lesion can be active for several months. The larvae can migrate through the fabric of a swimming costume and so lesions are seen on areas that have been covered. The diagnosis is made on the appearances. Treatment with oral albendazole, 400 mg daily for 3 days, is effective, as is a single dose of ivermectin 200u,g/kg body weight, though with more numerous worms longer treatment is needed. Tiabendazole topically as a 5% cream applied twice daily for 7 days is also effective. Following effective treatment worm migration ceases and the track will slowly disappear. Secondary bacterial infection requires antibiotic treatment.

361

Migration via blood to lungs and then to gut

Adults in gut

Autoinfection through anal mucosa and perianal skin

Rhabditiform larvae in gut

Invasive infective larvae HUMAN SOIL Free-living larvae Sexual reproduction FIG. 9.38 Lifecycle of Strongyloides stercoralis

Strongyloidiasis Strongyloidiasis is an infection of the small intestine with the nematode parasite Strongyloides stercoralis, which is distributed worldwide but flourishes particularly in a hot humid climate. Most people are asymptomatic. A small number have cutaneous manifestations, and immunosuppressed patients may develop massive systemic invasion with filariform larvae. A particular characteristic of this helminth is its capacity to produce prolonged infections for decades after exposure as a result of autoinfection (e.g. former prisoners of war of the Japanese in Thailand and Myanmar). Aetiology Strongyloides stercoralis adult females are small (2mm long) and are found in the intestinal lumen, where they insinuate their anterior ends between the villi. The lifecycle is described in Figure 9.38. A variation of the lifecycle involves rhabditiform larvae developing into filariform larvae during transit down the gut. These larvae penetrate the rectal or anal mucosa or the perianal skin, and then enter the usual migratory tissue phase. It is this variation of the lifecycle that gives rise to prolonged infection, because filariform larvae develop into new adults that maintain infection. When it occurs in immunosuppressed patients very large numbers of filariform larvae develop and give rise to the massive autoinfection syndrome. Transmission and epidemiology Transmission and epidemiology are broadly the same as those of hookworm but tend to be focal, depending on soil

362

1

Fig. 9.49

2

Fig. 9.50

4

MCQ 9.28 5 Fig. 9.51

3

conditions. The occurrence of autoinfection in Strongyloidiasis allows infection to persist for 30 years or more, successive generations of adults maintaining infection. It has wide distribution in the tropics but is particularly common in Asia. Pathology The migrating larvae in the lung evoke some degree of eosinophilic pneumonitis. Markedly raised eosinophil counts are usually seen during the phase of migration, and lesser but elevated counts persist in established infection. Adult larvae provoke a mild inflammation in the gut. Maiabsorption may occur but the mechanism is not understood. Diarrhoea, hypoproteinaemia and oedema of the small bowel wall occur in children. 1 Massive autoinfection with filariform larvae can occur in immunosuppressed patients who are taking steroids or are taking steroids with cytotoxics as part of chemotherapy for tumours, with dissemination of larvae to the gut, lungs and CNS, and concurrent septicaemia from the gut. There is a clear relationship between infection with HTLV-1 infection (see p. 1237), Strongyloidiasis and massive autoinfection. Clinical features Most patients are asymptomatic and the diagnosis is made by stool microscopy finding rhabditiform larvae (see Fig. 9.36A) or in the investigation of eosinophilia. Some patients present with a transient, linear or serpiginous urticaria that comes and goes within 40-60 minutes. Lesions are seen on the trunk, buttocks and upper thighs. This is caused by subcutaneous migration of infective filariform larvae, larva currens 2 (cf. Cutaneous larva migrans, above). Intermittently rhabditiform larvae develop into infective filariform larvae during their passage down the intestine, and these then invade the rectal wall and perianal skin causing autoinfection. The massive autoinfection syndrome occurs most often in people on steroids or immunosuppressive drugs. Fever, abdominal distension, diarrhoea, vomiting and ileus are common presenting symptoms. There may be signs of meningitis. Dyspnoea, cyanosis and pulmonary infiltrates indicate pulmonary involvement. Septicaemia with organisms from the colonic microflora is common. There is a range of disease severity, and the earlier it is recognized and treated the better the outlook though, overall the prognosis tends to be poor. Diagnosis Diagnosis is usually made by finding rhabditiform larvae in stools or juice obtained from the duodenum by intubation. Eosinophilia is usual in normal persons but absent in patients with massive autoinfection. Larvae are readily found in sputum, jejunal aspirate or faeces in massive autoinfection.

Case 9.5

Management Albendazole (400mg twice daily for 3 days) is effective and

causes few side-effects. There is evidence to suggest that ivermectin, 200ug/kg as a single dose may be more effective. Treatment with albendazole is continued for 7 days or longer in massive autoinfection. There is no experience with ivermectin given over days, but adverse reactions to the drug are not common. Occasionally in those very severely affected the parenteral veterinary preparation of ivermectin has been given with good effect, though relapse is all too common and some form of maintenance therapy is often needed, e.g. intermittent ivermectin. Intensive care is also needed for these patients. Prevention Safe disposal of faeces would prevent S. stercoralis infection, and wearing sandals would help to prevent skin-soil contacts. Treatment with cytotoxic or immunosuppressive drugs for leukaemia, lymphoma and other malignancies, reactional states in leprosy or organ transplantation should be preceded by albendazole or ivermectin treatment in patients from or in the tropics. 3 4

Threadworms Infection with the intestinal nematode Enterobius vermicularis causes pruritus ani. Children are most often affected, but adults can also become infected. The lifecycle is described in Figure 9.39. The full cycle can take 14 days. Transmission Autoinfection maintains the parasite in the host. Personto-person spread is the likely route of infection in children and other family members, or by handling pyjamas, sheets or towels with adherent eggs. Clinical features Intense pruritus ani is the usual symptom of this infection and often disrupts sleep. When symptoms are present the worms may be seen on the perianal skin. In females vulvovaginitis and vaginal discharge may occur. Diagnosis Diagnosis is made either by identifying a female worm obtained from the perianal skin or the faeces, or by finding eggs. The perianal skin should not be washed before the swab is taken. Eosinophilia does not occur. Management A number of drugs are available and it is usual to treat the whole family. Mebendazole (100 mg as a single dose, fol-

SUMMARY 19 Effects of nematode infection on child health • Growth impairment • Increasing evidence for impaired intellectual function

Airborne dust

9

INGESTION Sexual reproduction in small bowel

Scratching

Adult worms Deposit of eggs on perianal skin

Gravid females migrate down colon and through anus

FIG. 9.39 Lifecycle of threadworm

lowed by a second dose 2 weeks later) is effective. Piperazine citrate (65mg/kg to a maximum dose of 2.0g/day for 6 days, repeated after 3 weeks) can be used. Pyrvinium pamoate (5mg of base/kg as a single dose) is also used. In addition to chemotherapy it is helpful to prevent ringer sucking and nail biting. The importance of handwashing after going to the lavatory and before eating should be stressed. Occasionally one child is chronically afflicted by enterobiasis, and this causes both child and family great distress. This may occur in families that are particularly careful about washing. Reassurance is needed that this is not uncommon, and that enterobiasis is occasionally difficult to treat.

Trichuriasis Trichuriasis is infection of the intestinal lumen with the nematode Trichuris trichiura. Most patients are asymptomatic. Malnutrition is associated with heavy infections, causing symptomatic disease which can include stunting of growth and rectal bleeding. Eggs are swallowed and the larvae hatch. They mature during their transit down the small intestine, and adults are found in the terminal ileum and colon. The eggs mature in soil and are ingested. The adult worm has a long thin anterior end and a short thick posterior end. This appearance is described by the common name of the parasite, the whipworm. The thick posterior end grips the colonic mucosa. 5 Clinical features Most people are asymptomatic and eggs are found on faecal microscopy. Malnourished children may become infected with large numbers of these worms, and diarrhoea with blood in the stool may result. These children often have stunted growth. On proctoscopy large numbers of worms can be seen adhering to the rectal mucosa. Rectal prolapse is sometimes seen in these malnourished children. It is difficult to know if the worm burden is the cause or the result of malnutrition. Diagnosis and management Diagnosis is made by finding eggs in faecal smears or concentrates. Mebendazole (100mg twice daily for 3 days) is effective. A marked catch-up in growth occurs in stunted children after their infection is cleared.

363

Microfilariae penetrate stomach wall. Migrate to thoracic muscles. Mature to infective larvae in fly's thoracic muscles

FILARIAL INFECTION The filariae are a group of helminthic parasites whose adult and larval forms are found in humans, the sole reservoir for all but one filarial species. Transmission occurs by the bite of blood-sucking insects. The first-stage larvae, microfilariae, develop into infective third-stage larvae by two further moults in the vector. The infective microfilariae migrate out from the insect's mouth parts on to the skin when the insect is taking a blood meal, and then enter the skin through the puncture site. Development from infective larva to the adult takes up to 6 months. The adult worms are very long-lived; shedding of microfilariae begins about 6 months after infection and lasts for many years. The severity of disease relates to the burden of adult worms in the host.

BLACKFLY HUMAN Microfilariae in skin and eyes

Sexual reproduction in subcutaneous nodules containing male and female microfilariae released

Third-stage larvae mature in subcutaneous tissue to adult form

FIG. 9.40 Lifecycle of Onchocerca

Onchocerciasis Infection with the filarial parasite Onchocerca volvulus causes chronic intense pruritus with a papular eruption due to the death of microfilariae in the skin. Death of microfilariae in the eye causes a range of ocular disease; microfilarial death in the cornea over a prolonged period results in scarring of the cornea and unilateral or bilateral blindness. 1 Microfilarial death in the retina causes choroidoretinitis, and in the optic nerve optic atrophy. 2 The latter two complications are relatively rare. Aetiology and transmission Infective larvae escape on to the skin from the proboscis of an infected Simulium blackfly when it takes a blood meal, and enter the skin through the bite site (Fig. 9.40). The infection is maintained in the vectors when adult blackflies ingest microfilariae in blood meals. These develop into infective larvae over about 9 days. In humans the larvae develop into adults over 6 months and then start to shed microfilariae into the skin. These migrate out from the adult, and only when the larvae die do symptoms start to occur. Adult worms survive for up to 15 years and may shed microfilariae for most of that time. Distribution Tropical Africa and Central America are the main endemic areas, with foci of disease in Yemen, Colombia, Venezuela and the northern Amazonian region of Brazil. In Africa, two distinct areas are affected: the savannah area throughout West Africa, where ocular involvement is common, and the tropical rainforest area where ocular involvement is less common (Fig. 9.41).

364

1

Fig. 9.52

2

Figs 9-53-9.54 3 Fig. 9.55

4

Fig. 9.56

5

Figs 9.57, 9.58

FIG. 9.41 World distribution of filariasis Onchocerciasis distribution is very local and not uniform over the areas shown.

Epidemiology The distribution of the disease relates closely to the ecology of the Simulium vector, which requires fast-flowing freshwater streams and rivers for breeding. Most human cases occur in people who live close to such water sources and use them to collect water, wash clothes or play. Pathology and pathogenesis The changes in the skin and eyes are caused by the death of microfilariae. Following an acute response to microfilarial death there is granuloma formation and fibrosis. Over a number of years the result is destruction of elastic fibres, fibrosis, and thickening in the affected skin. Microfilariae die in the cornea, leading to irreversible corneal scarring. Worms also may die in the iris and ciliary body, causing uveitis with secondary glaucoma as a further complication. Choroidoretinitis and optic atrophy are also recognized. Some heavily infected patients have no symptoms, whereas others have marked symptoms and signs. Anti-

body and eosinophils are the important effector cells in killing microfilariae.

Clinical features The earliest symptom is pruritus, which may be made worse by a hot bath. Examination shows a papular eruption with excoriation. When the arm or leg is affected the limb may be obviously swollen in the early phase of the infection. As this process goes on over years there is destruction of the elastic fibres in the skin, giving the appearance of premature ageing. 3 In Yemen a variant of onchocerciasis called sowda occurs in which there is marked hyperpigmentation of the affected limb. 4 Regional glands are often enlarged and non-tender. The lateral corneoscleral junction should be examined with a slit lamp for keratitis, which appears first as small diffuse white spots. Slit-lamp examination may show microfilariae in the anterior chamber. The posterior segment of the eye should be examined for retinal lesions. The adult worms are found in nodules that consist of the adult female surrounded by fibrous tissue of host origin. 5 These nodules are felt over bony prominences such as the skull, shoulder blades, ribs, pelvic girdle and knees. When they are not palpable they must lie deep to scapulae and muscles of the gluteal region, for example. The papular rash is less apparent in chronic cases where fibrosis has produced inelastic thickened skin. There may be patchy destruction of the pigment layer in a black skin, giving a 'leopard skin' appearance. Destruction of the elastic fibres of skin in the inguinal region creates pouches containing enlarged inguinal glands, and predisposes to inguinal hernia.

bamazine (DEC). Ivermectin is given in a single dose of 200 ug/kg body weight; most adults receive 9 mg. There may be some local swelling of affected skin, but much less than that with DEC. Like DEC this drug only kills microfilariae, not adult worms, and so relapse is likely in about 50% of cases over the next year; these patients are then retreated. Diethylcarbamazine is given with a starting dose of 50 mg, increasing the dose on alternate days to a maximum of 200 mg thrice daily for 21 days. When there is marked local reaction with exacerbation of ocular involvement, topical or systemic steroids may be needed. Severe and even fatal reactions are seen in malnourished and sick patients given DEC, and so it is essential that intercurrent infection and nutritional status are improved before DEC is given. Suramin (Antrypol) is effective against adult worms and microfilariae but is used mainly for its ability to kill adult worms when ocular involvement is present. Anaphylaxis to the drug can occur and the drug is nephrotoxic. Excision of onchocercal nodules is recommended, particularly those on the head and shoulders. Early trials suggest that doxycycline may have a role in treatment, as it kills Wolbachia, bacteria within Onchocerca volvulus filariae, on which they are dependent for survival (Figs 9.42 and 9.43).

9

Prevention and control The Onchocerciasis Control Programme in West Africa has been very successful in reducing transmission of the

Diagnosis The parasitological diagnosis is confirmed by examining skin shavings from affected areas for microfilariae. These can be obtained using a needle and scalpel blade, but skin snips taken using a corneal punch is perhaps easier for the patient. Eosinophilia and a positive serological test for filariasis are usually found in the peripheral blood but are not diagnostic for onchocerciasis. Differential diagnosis Scabies and lichen planus are common or relatively common itching skin diseases in the tropics and should be considered. Nodules and ocular disease are not found, and the appearance and distribution of lesions in both conditions is different. Loa loa infection (p. 368) causes transient soft tissue swelling that produces short-lived pruritus. The lymphatic filarial infections cause unilateral limb swelling with regional adenopathy but no pruritus or papular rash. Treatment Ivermectin is now the drug of first choice because it exacerbates clinical signs much less than does diethylcar-

FIG. 9.42 Immunohistology, midbody cross-section of 'live' female Onchocerca volvulus filaria in onchocercomas Numerous bacteria are stained red in the hypodermis (arrows); some are visible as individual red dots. Note that the bacteria are located over the whole width of the hypodermis, in contrast to mitochondria (see Fig. 9.43), which also stain with antihsp60 antibodies because they have the chaperone hsp-60. Note the presence of normal embryogenesis, such as morulae (single arrow head), coiled embryos (double), and microfilariae (transverse sections, triple arrowheads). (Reproduced with permission of Dr A. Hoerauf and Professor D.W. Buttner.)

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Microfilariae mature in mosquito thoracic muscle to become infective larvae

MOSQUITO HUMAN

Microfilariae shed by female in lymphatics enter bloodstream FIG. 9.43 Immunohistology, midbody cross-section of 'live' female Onchocerca volvulus filaria in onchocercomas Worm from a doxycycline-treated patient 8 months after the end of doxycycline treatment (100 nig P.O., daily for 6 weeks). No bacteria are detectable in the hypodermis. There is only some staining in areas towards the cuticle (c), where mitochondria (also expressing hsp-60) are located (arrow). Uteri (u) contain only remnants of degenerated embryonic stages (coiled embryos, single arrowheads, degenerated mf, double arrowheads). (Reproduced with permission of Dr A. Hoerauf and Professor D.W. Biittner.)

disease by the application of insecticides to vector habitats and by treating cases. The success is evidenced by a striking reduction in infection rates among children, but the costs involved are considerable. Insecticide resistance may become a serious handicap to further progress.

FURTHER READING Hoerauf A, Volkmann L, Hamelmann C et al 2000 Endosymbiotic bacteria in worms as targets for a novel chemotherapy in filariasis. Lancet 355:1242-1243

Lymphatic filariasis Lymphatic filariasis is a group of filarial infections in which adult worms, found in major abdominal lymphatic vessels, shed microfilariae which are carried to the bloodstream. In contrast to onchocerciasis, it is the adults that cause the pathological changes resulting in lymphoedema. This occurs in a relatively small proportion of those infected. The three species involved are Wuchereria bancrofti, Brugia malayi and B. timori. Geographical distribution of W. bancrofti is shown in Figure 9.41.

1

366

Fig. 9.59

2

Adults develop in lymphatic channels

FIBROSIS AND INFLAMMATION CAUSED BY ADULTS IN LYMPHATICS -> ELEPHANTIASIS FIG. 9.44 Lifecycle of lymphatic filariasis

Aetiology and transmission W. bancrofti (Fig. 9.44) females measure 80-100 mm long by 0.3mm. The males are smaller, 40-50 mm long. The adults live in lymphatic channels and the female sheds about 50000 sheathed microfilariae per day; these are carried to the bloodstream in lymph. They circulate in the blood and are taken up by mosquito vectors of the genera Culex, Anopheles and Aedes. The infective larvae moult twice after they enter a human host when the insect bites. W. bancrofti exhibits periodicity of microfilaraemia throughout most of its geographic distribution, releasing microfilariae during the night hours; maximal counts are at about 1 am, in close relation to the nocturnal feeding habits of the mosquito vectors. Subperiodic strains release microfilariae throughout the 24-hour period. Brugia malayi and B. timori have similar adult morphology and a similar lifecycle. Distribution ana1 incidence (Fig. 9.41) Bancroftian filariasis has the widest geographical distribution, covering tropical Africa, Asia east of Pakistan as far as eastern China, Indonesia, the Philippines, Papua New Guinea, the Caribbean and the northeastern regions of South America (all periodic forms). Subperiodic forms are widely distributed in southeast Asia and the Pacific. Current estimates indicate that about 905 million people live in endemic areas, about 10% of whom are infected. Of these, 90% have W. bancrofti. Two-thirds of all those infected live in China, India and Indonesia.

Fig. 9.60

Pathology and pathogenesis Obstructive lymphoedema of the arms, breasts, genitalia

or legs is the main outcome of inflammatory changes in the main lymphatic channels elicited by the presence of adult worms. Adult worms may be found in lymphatics or lymph nodes. Distal to this obstruction the lymphatics are dilated. Inflammatory changes in the epididymis can be an early manifestation of the host response to W. bancrofti. Similar histological features occur in infection with Brugia species, but these most often affect the legs. In established infections episodic non-bacterial lymphangitis and lymphadenitis occur, evoked by allergy to filarial antigens. Eosinophils, giant cells, dead adult worms and fibroblasts are seen in the affected lymphatics and glands. Established lymphoedema predisposes to and is exacerbated by bacterial cellulitis and lymphangitis. Minor cuts and abrasions and tinea pedis are routes for entry of streptococci and staphylococci. Bacterial infections add to the irreversible changes caused by the filarial obstruction of lymphatic channels. In the chronic phase lymphatic channels are obstructed by fibrosis with distal lymphoedema. There is fibrosis in the lymphoedematous tissue. Clinical features Many infected people have no symptoms related to the disease. The earliest feature is often generalized painless swelling of the leg. There is no rash, and inguinal glands may be normal. The swelling is worst in the evening and declines while the patient is recumbent overnight. This occurs within months of infection, before microfilariae are shed, which indicates a response to adult worms. Without treatment this swelling may progress to the chronic lymphoedema of filariasis. Filarial lymphangitis is another presentation of filariasis. Lymphatics are red and tender, and inguinal glands are swollen and painful. The lymphangitis may spread distally in a limb, which is the opposite of spread in bacterial lymphangitis. Epididymitis, which may or may not relapse, is another manifestation of the same process. The end stage is non-pitting lymphoedema with thickened, lichenified skin. 1 The penis, scrotum or labia may be involved. The breast is sometimes involved. Infection with Brugia species tends only to affect the lower limbs. Filarial abscesses can develop along the line of lymphatic channels, more often proximally in the limb. These rupture and discharge, and the ulcerated area heals well. W. bancrofti infection may cause intermittent chyluria, in which anastomoses between intestinal and renal lymphatic channels are open; these are due to more proximal obstruction in main lymphatics leading to the cisterna chylae and thoracic duct. An uncommon presentation of filariasis is referred to as tropical pulmonary eosinophilia (TPE). It occurs with both bancroftian filariasis and with Brugia malayi infections. It takes 6 months before TPE develops with bancroftian infections, but only 3 months with Brugia. The manifestations of this condition are almost entirely pulmonary. Dyspnoea with cough, predominantly nocturnal, is the major

symptom. There may also be some night sweats. Wheeze is not a usual feature. Chest X-rays may show a fibronodular pattern and peripheral blood eosinophil counts are markedly raised (6.0 x 109/L is not uncommon), with strongly positive filarial serology. Day and night bloods are free of microfilariae. It is thought that this is a manifestation of hypersensitivity on the part of the host's immune system to the microfilariae, resulting in retention and destruction of the nocturnally released larvae within the pulmonary vasculature.

9

Diagnosis Diagnosis is usually made on the history, physical signs and marked peripheral blood eosinophilia when patients are seen at the early lymphoedema stage. Later, when there is relapsing lymphangitis or epididymitis, microfilariae are found in the blood, 2 maximally at 1 am in the periodic forms, and by day and by night in the subperiodic forms. When there are many microfilariae they are readily found in stained blood smears. Filtration of blood through a filter to retain the microfilariae may demonstrate parasites in lighter infections. In patients with scrotal nodules, ultrasound scanning can sometimes visualize adults which are motile, the 'filarial dance sign'. The adult parasites may have died out in patients with end-stage disease, and so parasites cannot be found. Serological tests are not specific for filarial infections and cross-reactions with Strongyloides are common, so that a positive test should stimulate a further search for parasites. In TPE the history, with relevant exposure in endemic areas plus marked eosinophilia plus strongly positive filarial serology, are the features required for diagnosis.

Differential diagnosis Tuberculosis, malignancy and chronic bacterial lymphangitis may all cause lymphoedema in the tropics. Management Diethylcarbamazine (DEC) is used, as for onchocerciasis (p. 364) though 12 days' therapy is sufficient. Reactions due to death of worms do occur. Lymphoedema is best controlled by elevation of the affected limbs at night and pressure bandaging. Albendazole and ivermectin are also effective. Surgery to excise the lymphoedematous tissue is not satisfactory and is only a final resort. Prophylactic penicillin V, 250 mg twice daily, is helpful in patients who have had repeated attacks of bacterial lymphangitis. Meticulous care of the feet, and particularly the skin between the toes, is essential. Staphylococci and streptococci are the common causes of bacterial infection in the affected limbs. TPE responds to DEC in the same dosage regimen, though it may be necessary to give prednisolone as well to inhibit exacerbations of pulmonary symptoms. Prevention and control Traditionally these have depended on vector control and

367

treating cases. Recent work in Indonesia and Kenya has shown that low-dose DEC can be used to control the infections.

Loiasis Loiasis is a filarial infection characterized clinically by transient soft tissue swellings at sites of adult Loa loa worm death or migration of adult worms across the eye, subconjunctivally. Chrysops flies are the vectors. Aetiology Loa loa adults measure about 60 x 0.5mm (female) and 30 x 0.4mm (male). They migrate freely in subcutaneous tissues. 1 Six months after infection adults have developed and fertilized females start to shed microfilariae, which are found in peripheral blood during the daytime. Chrysops flies ingest microfilariae in blood meals. Development to adult worms takes place in subcutaneous tissues, and shedding of microfilariae begins by 90 days after infection. Adults live for up to 15 years. Epidemiology The endemic areas (Fig. 9.41) cover the tropical rainforest regions of West and Central Africa, extending as far east as the southern Sudan and Uganda. The vectors live in the forest canopy and descend to lower levels to feed. The prevalence in some populations is 100%. Animal reservoirs do not play a part in the cycle of transmission. Clinical features Transient itchy soft tissue swellings up to 7cm across, on the limbs or less often the face, are a common presentation; these are called 'Calabar swellings' and are most often seen in people who have lived in endemic areas for a relatively short time. In indigenous residents of endemic areas a more typical presentation is migration of an adult worm across the globe of the eye beneath the conjunctiva, causing local irritation, a feeling of movement and some alarm. 2 Occasionally a worm dies immediately beneath the skin, producing a linear swelling in the skin. Problems can arise in patients who have large numbers of microfilariae in the peripheral blood (over 25-50/mm3), beginning a short time after starting treatment with DEC. Encephalitis or encephalomyelitis can occur, probably because of dead microfilariae occluding vessels of the brain and spinal cord. Cerebral oedema and granulomatous reactions around microfilariae are found in fatal cases. Diagnosis The diagnosis is confirmed by finding typical sheathed microfilariae in peripheral blood samples taken during the day. 3 When there are few microfilariae, millipore filtra-

368

1

Fig. 9.61

2

Fig. 9.62 3 Fig. 9.63

4

MCQ 9.29

5

Fig. 9.64

tion of blood may show parasites (see above). Eosinophilia in the peripheral blood is usual and a positive serological test, e.g. filaria indirect fluorescent antibody test, provides only indirect evidence of infection. Management DEC (p. 365) is the most active drug in the treatment of loiasis. It kills microfilariae well and adult worms more slowly. While the patient is on DEC, Calabar swellings may appear. Also, worms dying close to the skin may be seen. When microfilariae counts are above 25-50/mm3 DEC cannot be given alone because of the danger of precipitating cerebral complications. Removal of microfilariae from the circulation is recommended. Whole blood exchange transfusion, or apheresis using a blood separator, can be used to remove large numbers of microfilariae. This makes it safe to give DEC. Prednisolone in doses of 40-60 mg/day, beginning 24 hours before starting DEC and continuing till the top dose is reached, is usually more convenient. Prevention and control Measures for the control of loiasis have not been successful. Vector control is difficult. Mass chemotherapy is not appropriate because of the need for individual supervision of treatment in people with heavy infections, and because of the coexistence of onchocerciasis in the same endemic areas. Other measures include protection from biting by clothing and the use of insect repellants. 4

ANIMAL INTESTINAL NEMATODE INFECTION' Trichinosis Aetiology Trichinella spiralis is a nematode parasite with very low host specificity that will infect over 100 species of animals, particularly carnivores. Human infection occurs by consumption of undercooked meat containing encysted larvae (Fig. 9.45). These hatch in the human gut and mature to the adult stage. Fertilized females shed viviparous larvae for up to 14 weeks until the adults are expelled. The larvae penetrate the gut mucosa to reach the circulation and are disseminated to all the tissues, where they excite inflammatory responses. Larvae encyst and survive in skeletal muscles. 5 Distribution, incidence and transmission T. spiralis is widely distributed in nature through the Americas, Asia, Africa and the Arctic. Sporadic cases and epidemics occur. Outbreaks also occur in Europe. All ages and both sexes are susceptible but children seem to have milder attacks, probably related to a lower infecting dose of larvae in their smaller meals. Exposure to infection is more likely among those nationalities whose cuisine involves eating raw or lightly cooked meats. Smoked sausages made from wild boar are common sources of infection in European countries.

positive. Differential diagnosis includes polyarteritis and other causes of eosinophilia. Eats infected food

Encysted larvae eaten in raw or undercooked pork

A/loncrgemenf Albendazole 400 mg twice daily for 10 days will eradicate adult warms from the gut and thus cut off the production of invasive larvae. There is evidence that anthelminthics affect larvae in the tissues. Steroids may be needed when inflammatory responses in the tissues are very marked.

Larvae moult in intestinal mucosa to become adults in gut

Prevention and control Thorough cooking or freezing (-15°C for 20 days) of meat will prevent trichinosis. Public health measures include boiling pig swill and inspecting meat.

PIG

HUMAN

Larvae encyst in striated muscle Larvae invade intestinal mucosa and travel to muscles via lymphatics and blood vessels FIG. 9.45 Lifecycle of Trichinella spiralis

Pathology Granulomas form around worms dying in the tissues. Focal interstitial myocarditis is found in the heart, with a marked infiltrate of eosinophils. A non-suppurative meningitis with granulomas and capillary thromboses is seen in fatal cases. Invasion of the eye muscles may contribute to the periorbital oedema. Skeletal muscles show encysted larvae, myositis with marked eosinophil infiltrate, and patchy degeneration of muscle fibres. Calcification may occur in the capsule of the cyst or in the larvae by 6 months after invasion, but larvae can remain viable in muscle for 10-15 years. Clinical features Four main features of the disease are fever, orbital oedema, myalgia and eosinophilia. Bowel upset is variable. Vomiting occurs, and the alteration in bowel habit may be diarrhoea or constipation. In the phase of muscle invasion the affected muscles are tender on movement. Fever, urticaria, splinter haemorrhages in fingers and toes, difficulty with swallowing and difficulty with breathing may all be present. Invasion of the nervous system can cause a meningitislike picture. Fits, paralysis, disturbed conscious level, difficulty with balance and personality disorders may occur. Heart failure can result from severe cardiac involvement. Symptoms due to reactions to larvae in the tissues start to resolve gradually from about 14 days onwards in milder cases, but can take several months to settle completely. Diarrhoea and a malabsorption syndrome have been described. Diagnosis Trichinosis is suspected clinically and confirmed by examination of muscle biopsy for encysted larvae. Muscle biopsies can be obtained under local anaesthetic using a Trucut needle and are examined immediately, squashed between microscope slides. Eosinophil counts are very high and muscle enzymes are raised. Trichinella serology is strongly

9

Toxocariasis Aetiology Toxocariasis is caused by infection with larval forms of Toxocara canis or T. cati, which are primarily parasites of dogs and cats. The adult worms are found in the gut lumen and eggs are shed in the faeces. Humans are infected by ingesting eggs, and the larvae released burrow into the gut wall to enter vessels and disseminate. Larvae mature outside the host over 14 days and then are infective to the definitive host or to humans. Distribution, incidence and transmission The distribution is worldwide in dogs and cats, although there is considerable variation in the frequency of animal infection and contamination of the environment. Studies in Britain showed that 17% of soil samples were contaminated with toxocara eggs. Moist soil conditions are more suitable for transmission than hot, dry conditions. Children are most often infected. Infection is likely to occur when fingers are contaminated with soil or sand containing eggs during play and then put in the mouth. Dog faeces deposited in public parks, especially around playgrounds, represent a potential source of infection. Dog breeders and people who work in kennels are at risk of infection. Toxocariasis due to T. cati is much less common. Pathology and pathogenesis Disease in humans relates to the number of infecting larvae and the host response. Clinical manifestations are due to dying and dead larvae, which evoke granuloma formation with eosinophils, macrophages and lymphocytes. The eye, brain, liver, spleen and lungs may be involved in toxocariasis, but granuloma formation may occur in any organ of the body. Clinical features Ocular toxocariasis and visceral larva migrans (VLM) are two clinical presentations of this disease, which is often a subclinical infection. Unilateral visual impairment is the usual symptom in ocular toxocariasis. Lesions directly on the visual axis will cause severe impairment. A child may

369

develop a squint. The granuloma can form in relation to the lens and ciliary body, or on the retina itself. A cataract may develop secondary to a granuloma affecting the ciliary body. Visceral larva migrans is due to a heavy infection with larvae. Fever, anorexia, chills, night sweats and weight loss are usual features. Examination shows hepatosplenomegaly as the main physical sign. Pneumonitis may also be present. There is usually a marked eosinophilia in the peripheral blood in VLM, but eosinophilia is less common with ocular disease. Serological testing is valuable, the ELISA technique using a toxocara secretory antigen being a sensitive and specific test. Differential diagnosis Toxoplasmosis usually causes bilateral choroidoretinitis with destruction of the retina. 1 Lymphoma, tuberculosis and sarcoidosis are usually considered in the differential diagnosis of VLM, although the gross eosinophilia is against the former conditions and supports a helminthic infection. The toxocara antibody test is strongly positive. Management DEC is the usual treatment, giving initial doses of 50 mg and doubling the dose on alternate days till the maximum (lOmg/kg/day in three doses for 21 days) is reached. Ocular disease is not specifically affected by DEC because the worm is dead. There may be some spontaneous improvement as inflammation and granuloma size reduce. DEC is given in these cases to kill any worms that are still migrating. Prevention and control Regular deworming of dogs, particularly pregnant bitches and puppies, reduces the numbers of eggs contaminating the environment. Dog owners should try to ensure that their dogs defaecate somewhere where the faeces will not contaminate open spaces, playgrounds and parks.

Dracunculiasis (Guinea worm infestation) Dracunculus medinensis, the Guinea worm, is a tissue nematode widely distributed through Africa and Asia. Humans are infected by drinking water containing minute crustaceans of the Cyclops genus infected with Guinea worm larvae. The larvae penetrate gut tissues and migrate through host tissues, maturing to the adult stage. The female is fertilized by the male, which dies, and the gravid female migrates out into a limb, producing a painful, fluid-filled blister about 3cm across which then bursts and about 5 cm of the female protrudes. 2 Vast numbers of larvae are released from the worm. Patients often put

370

1

Fig. 9.65

2

4

Figs 9.68, 9.69

Fig. 9.66

3

Fig. 9.67

the affected limb into cold water to relieve the pain; this stimulates the discharge of larvae, providing the opportunity for larvae to continue the lifecycle by infecting other cyclops. The diagnosis is made on the clinical appearances. Treatment comprises relief of pain, treatment of secondary bacterial infection with antibiotics, and administration of tiabendazole. This does not have any direct effect on the worm but reduces inflammation around it, allowing it to be gently wound out of the subcutaneous tissues on a stick. O Control of Guinea worm is a realistic prospect using very simple methods. Cyclops can be filtered from drinking water using simple filters with nylon mesh of appropriate pore size. These can be made locally from materials that can be supplied by Ministries of Health. Village communities can all be involved in disseminating information about the disease, making the filters, and how to avoid disease by simple water filtration.

TREMATODES Schistosomiasis Infection with digenetic flukes of the genus Schistosoma affects the bladder and urinary tract (S. haematobium) or intestine (S. mansoni, S. japonicum). These worms cause disease because of the host's response to eggs retained in the tissues. The severity of disease relates to the number of eggs in the tissues, which is proportional to the worm burden. Aetiology Eggs are passed in stools or urine; those deposited in still or slow-flowing fresh water hatch to release the ciliate miracidium, which can survive for up to 48 hours before it dies (Fig. 9.46). During this time it must find an aquatic snail of the appropriate genus: Biomphalaria for S. mansoni, Bulinus for S. haematobium, and Oncomelania for S. japonicum. Cercariae are released from the snail and these penetrate the skin of a suitable host, almost always human, becoming schistosomules during penetration. These migrate via the blood vessels to the pulmonary vasculature, where some traverse the pulmonary circulation to enter the systemic circulation. Schistosomules of mansoni and japonicum mature in the hepatic branches of the portal vein, and by 6 weeks after infection they are mature. They migrate out of the liver against the flow of blood in the portal vein to small veins around the colon and small intestine. The colon is mainly involved in mansoni infections, and both colon and small intestine are involved in japonicum infections. The lifecycle of S. haematobium is similar, but maturation takes place in pelvic veins. The worm pairs migrate into small branches of the internal iliac vein, principally around the bladder, although other pelvic structures such

Schistosomules reach venous circulation via lungs. Become sexually mature and mate

9l

Male and female migrate to lay eggs in vesicle veins (S.haematobium) cr intestinal veins (S.mansoni, S.japonicum)

Blood and lymphatics

Eggs reach water in urine (S.haematobium) or faeces (S.mansoni, S.japonicum) HUMAN

Cercariae penetrate skin

FRESH WATER Eggs hatch, liberating ciliate miracidia SNAIL

Sporocysts rupture on to external surface of snail, releasing cercariae

Miracidia penetrate foot piece of one of several species of snail (intermediate hosts), where sporocysts form

Cercariae develop within sporocysts FIG. 9.46 Lifecycle of schistosome parasites

as the prostate and seminal vesicles in men, and the uterus and adnexal structures in women, may be involved. Adult worms survive for about 7 years on average, but survival of over 30 years has been reported. Distribution and incidence The distribution is shown in Figure 9.47. There is considerable overlap in the endemic areas of haematobium and mansoni, but japonicum has a distinct Asian distribution. The prevalence and incidence of infection vary considerably, with rates up to 70% or more in the endemic areas. Infection rates tend to be highest in children and decline with increasing age. Transmission and epidemiology Freshwater contact is the major factor in infection and maintenance of transmission. Children are infected early in life by playing in infected water. They are also likely to urinate and defecate in and around pools and streams, further enhancing the local intensity of transmission. The highest rates and intensities of infection are found in the second and third decades of life. Pathology and pathogenesis The pathological changes relate to the presence of eggs in the tissues. Eggs laid in the small branches of veins may: • pass through the wall of the viscus to reach the exterior in faeces or urine

FIG. 9.47 World distribution of schistosomiasis

• be retained in the tissues • embolize through vessels to lodge in presinusoidal branches of the portal vein in mansoni and japonicum infections, or in pulmonary arterioles in haematobium infections. The egg excites a granulomatous response with macrophages, lymphocytes, plasma cells and eosinophils. Granuloma formation is important for the transition of the egg through the mucosa to the lumen of the viscus. The chronic inflammation they may cause in the epithelium may be a factor in carcinogenesis of the bladder (haematobium). Eggs retained in the tissues within granulomas gradually break down until all that may remain is remnants of the egg case. The granuloma heals by fibrosis. Early in the course of infection exuberant granuloma formation can cause colonic polyps in mansoni and japonicum infections, and bladder polyps in haematobium infection. These resolve after treatment and may also resolve spontaneously. Fibrotic polyps and strictures are not often seen in mansoni infection, although they are more common in japonicum infection. Haematobium infection causes fibrosis of the bladder, which is often shrunken, with a thick wall. Bladder stones may form and cystitis is common. Unilateral or, less commonly, bilateral ureteric strictures cause obstructive uropathy. Stones may form in the dilated ureters. Distortion of the ureterovesical junction may allow vesicoureteric reflux of urine with associated recurrent pyelonephritis. Squamous cell carcinoma of the bladder is common in highly endemic S. haematobium areas. It is suggested that schistosomiasis acts with dietary factors to produce malignancy. This has not been found in S. mansoni infection or in S. japonicum, despite earlier reports from China. Mansoni and japonicum eggs embolize to the liver. The granulomas that form around eggs 4 add to the volume of the liver and increase its size, and obstruct the flow of blood through the portal circulation in the liver, causing congestive hepatosplenomegaly in those with heavy worm burdens. Granulomas resolve with local fibrosis, and when

371

this process goes on over years periportal fibrosis results, causing irreversible portal hypertension. The anatomy and architecture of the hepatic lobules are not altered and there are no regenerating nodules, therefore cirrhosis is not caused. In the lungs granulomatous reactions in the vessels cause fibrosis and pulmonary hypertension. Involvement of the CNS occurs in S. japonicum, S. mansoni and S. haematobium, in descending order of frequency. Disease of the central nervous system is most probably the result of an ectopic worm pair laying eggs in or around the brain or spinal cord. Mansoni and haematobium infections are associated with spinal cord and cauda equina lesions. Clinical features Cercarial invasion of the skin may cause a local irritant papular eruption, but this is uncommon. Most patients have no symptoms related to the phase of migration and maturation. Occasionally non-immune people develop the Katayama syndrome with the phase of worm migration. There is malaise and lethargy, and fever, profuse sweats, muscle pain, abdominal pain, joint aches, unproductive cough, urticaria, swollen eyelids and hepatosplenomegaly occur in more severely affected patients. These symptoms begin 3-4 weeks after exposure and persist for up to 3 months, with reducing severity. Chest X-rays may show coin lesions caused by worms dying in vessels and evoking local inflammatory reactions. Marked eosinophilia is common. Eggs are not found until 3-6 weeks after infection. S. mansoni and S. japonicum Many infected patients go through life without any symptoms related to this infection. Rectal examination is normal; sigmoidoscopy is normal or shows scattered mucosal haemorrhages. Occasional patients present with anaemia and oedema because of bleeding and protein loss from schistosomal polyps. The most common physical sign in infected patients in endemic areas is hepatomegaly, which correlates with the intensity of infection in the first two decades but not in older age groups. Similar findings are noted in S. japonicum infection. Abdominal pain and subacute intestinal obstruction occasionally occur in the rare patient who develops fibrotic strictures in the colon or, less often, the small intestine. Hepatosplenomegaly with congestive splenomegaly suggests end-stage schistosomal hepatofibrosis. These patients often present with haematemesis and ascites. Portosystemic encephalopathy is not a usual feature after variceal bleeding in schistosomiasis. Severe pain over a grossly enlarged spleen may indicate splenic infarction.

372

1

Fig. 9.70

2

Fig. 9.71

4

Fig. 9.74

5

MCQ 9.30

3

Fig. 9.72, 9.73

S. haematobium Dysuria, frequency and haematuria occur in some patients at the start of egg laying. More commonly, the presenting symptom is terminal haematuria, i.e. the last drops of urine passed are bloodstained. Physical examination is usually normal. Most people have light infections and suffer no long-term adverse effects. Reversible granulomatous polyps and obstructive uropathy occur in the early stages of heavier infection. This appears to be spontaneously reversible, and is certainly reversible after treatment. Those with heavy infections develop fibrotic and obstructive complications which can cause recurrent urinary tract infections, stone formation, and finally renal failure. 1 In these patients the infection is associated with an increased risk of bladder cancer. Excretion urography often shows bladder polyps and obstructive uropathy, either unilateral or bilateral, in older children and teenagers. Chronic infection causes 'sandy' patches on the trigone as a typical cystoscopic finding. 2 Calcification in retained eggs is seen in the bladder wall as a rim of calcium in the pelvis on a plain abdominal X-ray. Tramline calcification in the ureter may also be seen. Other manifestations Pulmonary involvement may be subclinical up to the stage when significant pulmonary hypertension develops. Right heart failure develops, and this is difficult to treat. Cutaneous involvement is indicated by a collection of subcutaneous papules. In haematobium infection the skin of the scrotum and perineum may be affected. 3 Symptomatic involvement of the CNS is uncommon. Intracranial disease occurs with S. japonicum infections, with a frequency of 2-4%. It is much less common in mansoni and haematobium infections. Focal signs and jacksonian epilepsy may occur with involvement of the cerebral hemispheres, whereas posterior fossa lesions are associated with raised intracranial pressure, cerebellar signs and brainstem compression. Lesions of the spinal cord may present with features suggesting cord compression, transverse myelitis or spinal artery occlusion. Granulomas may also form around the cauda equina. The occurrence of focal signs in the neuraxis in a patient in or from an area endemic for schistosomiasis should prompt a search for schistosome eggs in stools and urine that would indicate active infection. Eosinophils in the CSF suggest the possibility of schistosomiasis affecting the CNS. The empirical use of antischistosomal drugs plus steroids also need to be considered. Diagnosis Diagnosis is made by finding schistosome eggs. Eggs of S. mansoni and S. japonicum are found in concentrates of faecal samples. Eggs of S. haematobium are found in the centrifuged deposit of terminal urine samples. Eggs of all three species may be found in rectal snips. Squash preparations can also be made from fragments of bladder mucosa obtained at cystoscopy.

Eosinophilia is a common finding in the peripheral blood but occurs in several helminthic infections. Serological tests can be helpful. An ELISA for antibodies to schistosome egg antigens is useful because it indicates that infection has progressed to the stage of ovideposition. The test takes 18 months at least to revert to negative after treatment, and so is not helpful in assessing cure. Excretion urography, isotopic renography, ultrasound and CT scanning give anatomical and functional detail of the urinary tract in chronic schistosomiasis. Colonoscopy and barium enema can be used to examine the colon in more detail. Ultrasound scanning of the liver demonstrates the presence of periportal fibrosis. 4 Chest radiographs show dilatation of the pulmonary arteries and right ventricular hypertrophy in pulmonary hypertension. MRI or CT allow localization of schistosomal lesions of the neuraxis. Eosinophilia in the CSF supports the diagnosis of CNS involvement in schistosomiasis. Management Three safe, effective drugs are available for use in schistosomiasis (Table 9.39). Their safety in pregnancy has not been confirmed, and so treatment should be delayed until after delivery unless there are urgent indications for prompt treatment. All cases should be treated, even the advanced ones, as further ovideposition causes further urinary tract, intestinal, liver or pulmonary damage. Ideally, stools and rectal snips should be examined for viable ova 3 months after treatment. Prevention and control Control measures are expensive and require a change in the behaviour pattern of the exposed population. Education regarding the reasons for the measures is essential. Dams and irrigation projects for the improvement of the

SUMMARY 20 Schistosomiasis

9

• Infection by exposure to freshwater pools, lakes • Invasion usually inapparent: occasionally itching at sites of invasion (swimmer's itch) • Worm burden determines morbidity and mortality • Tissue damage is caused by host granulomatous response to retained eggs • Bladder (S. haematobium): polyps, strictures, fibrotic and contracted bladder squamous cell carcinoma associated with heavy prolonged infections • Intestine (colon S. mansoni; colon and small intestine S. japonicum) Polyps and stricture in gut uncommon • Liver: schistosomal hepatofibrosis causing portal hypertension, congestive splenomegaly, hypersplenism with variceal bleeding and ascites • Ectopic disease related to the site of a worm pair with CNS disease is the most serious manifestation

economy of an area may create new habitats for snail hosts of schistosome parasites. Molluscicides can be used, but are expensive and may have detrimental effects on other water creatures. Regular, community-based treatment with praziquantel has reduced morbidity. 5 Clonorchiasis

Aetiology Clonorchis sinensis is a hermaphroditic trematode parasite of the biliary tract in humans. The adult fluke is 10-25 mm long by 3-5 mm wide. The lifecycle is shown in Figure 9.48. Transmission ana1 incidence Fishponds into which human faeces are poured as fish feed are an important source of infection, as eggs, snails

TABLE 9.39 Drug treatment of schistosomiasis Drug

Active against

Dose

Side-effects/contraindications

Oxamniquine*

Schistosoma mansoni

West Africa and South America 15mg/kgx1 (adult) 20mg/kgx1 (child) Elsewhere 20mg/kg per day x 3

Occasional febrile episode 5 days post treatment

Metrifonate*

S. haematobium

7.5mg/kgx3 (2 weeks between doses)

Anticholinesterase actions may prolong neuromuscular blockade after surgery. Avoid elective surgery for 3 days post treatment and provide ventilatory support after emergency surgery within 48 hours of administration

Praziquantel*

S. mansoni S. haematobium S. japonicum

40mg/kgx1

Dizziness, nausea and occasional vomiting beginning 1 hour after dosing, lasting up to 4 hours

20mg/kgx3 (4 hours between doses)

*The safety of these drugs has not been confirmed in pregnancy; treatment should be delayed until after delivery unless there are urgent indications for prompt treatment.

373

FIG. 9.48 Lifecycle of Clonorchis and Opisthorcis

and fish are conveniently found together. The disease occurs in Asian countries. Dogs and cats are also important hosts. Pathology The worms obstruct small branches of the biliary tree, and bile accumulates in cysts proximal to the obstruction. Hypertrophy of the bile epithelium with adenomatous proliferation occurs. Later there is cellular infiltrate of the bile duct wall with chronic inflammatory cells. Pigment stones and biliary sludge form. Flukes obstructing the pancreatic ducts can cause pancreatitis. Long-standing heavy infections are associated with malignant change in the adenomatous hyperplasia, leading to cholangiocarcinoma. Clinical features Clinical features relate to the worm burden. Mild infections cause no symptoms. Upper abdominal discomfort, diarrhoea and weakness occur with heavier infections; with the heaviest worm burdens upper abdominal pain, diarrhoea, weight loss, obstructive jaundice, hepatomegaly, cholangitis and Gram-negative septicaemia occur. Diagnosis The eggs are found in faeces or in duodenal aspirate. Eosinophilia is usual in the peripheral blood. Endoscopic retrograde cholangiopancreatography or percutaneous transhepatic cholangiography shows dilated branches of the biliary tree, and the worms appear as filling defects.

1

374

Fig. 9.75

FIG. 9.49 Lifecycle of Taenia species

Management Praziquantel is the treatment of choice, giving 25 mg/kg on three occasions 4 hours apart on one day. When there is obstructive jaundice with cholangitis and septicaemia, relief of biliary obstruction, vigorous treatment of the bacterial infection and circulatory support for the patient are needed. Prevention and control Transmission can be interrupted by safe disposal of faecal wastes. Usually this involves a major change in social habits, which is difficult to achieve. Thorough cooking of fish before it is eaten prevents infection, as does freezing fish, -10°C for 5 days, and salting in 10% saline.

Opisthorciasis Opisthorcis viverrini and O. felineus have similar lifecycles to that of C. sinensis, and in humans they parasitize the intra- and extrahepatic branches of the biliary tree (Fig. 9.49). Raw, pickled, smoked and undercooked fish are the sources of infection. The pathological changes and consequences are those of chronic irritation and obstruction of the biliary tree, with ascending cholangitis in severely affected patients. Cholangiocarcinoma occurs in O. viverrini patients. The diagnosis is made by finding eggs of the parasite in stools or duodenal aspirate. Praziquantel is used for treatment as for clonorchiasis.

Fasciolidsis Fascioliasis is an infection of the biliary tree with the

hermaphroditic trematode Fasciola hepatica. It is primarily an infection of sheep. The lifecycle is similar to that of Clonorchis (Fig. 9.46). Aetiology and distribution The parasite measures 3 x 1.5cm. 1 Eggs are released in the biliary passages and pass to the exterior in the faeces. The miracidium hatches in fresh water and penetrates the tissues of a freshwater snail (Lymnaea species). After a cycle lasting 4 months in the snail, cercariae are released. These encyst on the leaves of watercress and other types of aquatic vegetation. Humans are infected by eating watercress with encysted metacercariae. Maturation to the adult stage in bile ducts takes about 4 months until egglaying starts. Sheep are the normal hosts of this infection, and human infections are likely wherever sheep are herded in wet pasturelands. Pathology There is hepatic parenchymal necrosis in the phase of migration through the liver. The liver tissue regenerates. The worm burden determines the severity of disease. In the bile ducts there is chronic inflammation, with regenerative hyperplasia of the epithelium and some degree of duct obstruction. Clinical features Pain in the liver area, fever, chills, tender hepatomegaly and marked eosinophilia are usual features during the tissue migration phase. Upper abdominal discomfort and hepatomegaly are present in mild to moderate infections, whereas heavy infections may cause obstructive jaundice and cholangitis as well. Diagnosis Eggs of the parasite are found in stools or duodenal aspirate, though they can be difficult to find in relatively light infections. Endoscopic retrograde cholangiopancreatography may show filling defects in the biliary tree and flukes may be extracted from ducts using a stone basket. Eosinophilia is usual and serological tests for this infection are usually positive. Management and prevention Triclabendazole, 10mg/kg b.d. x 1 day, or bithionol, 40 mg/kg in 2 divided doses on alternate days for 15 dosage days, are effective. Watercress production must be separate from sheep pastures. Wild watercress should not be sold for human consumption.

when these are eaten uncooked. After about 3 months the adult has matured in the small intestine; egg production begins and lasts for most of the 6-month lifespan of the adult. Upper abdominal discomfort, diarrhoea, preprandial upper abdominal pain relieved by food, and symptoms and signs of intestinal obstruction may occur, more marked symptoms being found with heavier infections. Eggs are found in the faeces. Tetrachloroethylene is effective in treatment. Praziquantel may prove to be effective.

pj

Paragonimiasis Paragonimus westermani is a hermaphrodite fluke usually found in the lungs but occasionally in other sites, e.g. CNS. It has a wide distribution in South America, West Africa, south east Asia and the Pacific. Human infection occurs when raw or undercooked freshwater Crustacea with metacercariae encysted in their muscles are eaten. The development cycle outside the host involves a freshwater snail: from the snail the cercaria is released and then finds a suitable crustacean host. In humans the metacercaria excysts and penetrates the full thickness of the gut wall to enter the peritoneal cavity. The phase of tissue migration continues with the parasites reaching and crossing the diaphragm to enter the lungs. Where the worm finally comes to rest in lung tissue it elicits first a cellular response and then fibrosis, so that the worm is enclosed but for a connection to an airway. Dead worms calcify. Radiological appearances comprise pleural thickening, infiltrates at the site of recent invasion, nodular lesions (encysted adults), fibrosis and finally calcification. Eggs released by the worms are coughed up or swallowed. Cough productive of sputum, dyspnoea and chest discomfort are usual features. Bacterial infection of the affected area causes fever, systemic upset, purulent sputum and haemoptysis on occasions. Abdominal organs and brain are affected less often. Diagnosis and management Eggs are found in the sputum in most cases. Serological tests are available. Praziquantel is effective in doses of 25 mg/kg given three times daily for 3 days.

CESTODES

HUMAN INTESTINAL CESTODE INFECTION Taenia saginata

Fasciolopsiasis Fasciolopsis buski is the largest trematode parasite, measuring up to 7.5cm long by 3.0cm wide. It has a wide geographic distribution throughout eastern Asia, with a reservoir of infection in pigs. The metacercariae are found on bamboo shoots or water chestnuts, and infection occurs

Human infection with T. saginata is common in Africa, the Middle East, Asia and South America. The infective stage is the cysticercus in beef, and humans are infected by eating rare or undercooked beef (Fig. 9.46). The cyst is released in the gut and the scolex everts from the cyst. It adheres to the gut wall and proglottids start to develop. Each segment

375

has testes and ovaries, and is self-fertile. The worm may be 5-10 m long. The distal segments are full of eggs. Lengths of worm are passed in the stools, and when defaecation occurs in pasture, cattle may eat the gravid segments and develop cysticercosis bovis. The infection causes no symptoms in humans although often a variety of vague abdominal symptoms have been attributed to it. Occasionally a patient will present with pruritus ani and find segments in underwear, the motile segments having wriggled out of the anus. The diagnosis is confirmed by examining segments. T. saginata segments have 15-20 lateral branches to the uterus. The eggs are occasionally found in the stools or on the perianal skin, but are identical in saginata and solium infections (see below). Treatment with praziquantel (10-20 mg/kg as a single dose) is effective in 96% of patients. Niclosamide is also effective. Both praziquantel and niclosamide destroy the scolex and it is not present in the expelled worm remnants. If segments have not been passed by 4 months after treatment the infection is cured. Thorough cooking of meat and freezing meat to -10°C for 10 days kills cysticerci. Meat inspection is also an effective control measure.

Taenia solium The lifecycle is the same as that of T. saginata, except that the pig is the intermediate host (Fig. 9.46). Infection with T. solium in adults causes no symptoms. The segments are distinguished from those of T. saginata by the small number of lateral branches of the uterus: 7-13. Treatment is the same as for T. saginata, with the addition of an antiemetic prior to dosing and a purge 2 hours after dosing. Thorough cooking of pork or freezing to -10°C for 10 days prevents infection. Cysticercosis is discussed below in the section on larval cestodes.

Diphyllobothrium iatum

376

The fish tapeworm has a more complex lifecycle than the other intestinal cestodes: coracidia released from eggs infect water fleas (copepods). Further development takes place in fish that eat the copepods, and in bigger fish that eat plerocercoid-infected fish. Mammals are infected by eating the plerocercoid-infected fish. Digestion releases the plerocercoid, which adheres to the gut wall and starts to produce proglottids. Proglottids break up, releasing eggs which are passed in the stools. Humans are infected by eating uncooked fish. A variety of abdominal and general symptoms are attributed to this infection, including abdominal discomfort, fatigue, weakness, sensations of hunger and diarrhoea. It is associated with deficiency of vitamin B12 and, less commonly, with overt megaloblastic anaemia. When the worm is sited in the upper gastrointestinal tract it can take up both free and intrinsic factor-bound vitamin B12. Features of vitamin B12 deficiency appear when body stores are exhausted.

The diagnosis is made by finding eggs or, less often, typical segments in faecal samples. Purging may provide a sample of segments. Praziquantel gives a high cure rate. Niclosamide is also effective. Thorough cooking of fish and freezing fish to -10°C for 48 hours kills plerocercoids.

Hymenolepiasis Hymenolepis nana and H. diminuta are two species of small tapeworm. H. nana is predominantly a parasite of humans, with person-to-person transmission, whereas H. diminuta is predominantly a rodent parasite, with humans as an occasional host. Children are most often infected with H. nana. Heavy infection causes abdominal pain, anorexia, diarrhoea, irritability, pruritus ani and urticaria. Eosinophilia is found in heavy infections. Treatment with praziquantel (15 mg/kg as a single dose) is effective. H. diminuta has a more complex lifecycle involving an insect intermediate host that ingests eggs with rodent faeces. Most infections cause no symptoms and are diagnosed when eggs are found in faeces. Treatment with niclosamide is effective.

LARVAL CESTODE INFECTION Cysticercosis Infection with the intermediate state of the T. solium parasite (see above) can occur in two ways: • By ingestion of the eggs of the worm, which hatch in the gut to release the cysticercus; • By regurgitation of gravid segments into the stomach to initiate the process of egg digestion and release of cysticerci. The cysticerci released by either route of infection then invade host tissues. The first route is more likely. Occasionally patients are seen with a vast number of cysticerci in a wide range of sites, in those instances it is most likely that the patient has swallowed a proglottid. The development of subcutaneous lumps is a common presentation. Uniocular disturbances of vision occur with cysticerci in the eye. The most serious consequences occur in cerebral cysticercosis, causing epilepsy, raised intracranial pressure and localizing signs related to space occupation. Frequently numerous cysts are found in the brain. The diagnosis is based on the geographic history, a positive serological test for cysticercosis on serum, and the finding of cystic lesions by CT or MRI (Fig. 9.50). In endemic areas where CT is not available the diagnosis would be made on the clinical picture. Antibodies to cysticerci can be detected in CSF, which contains increased amounts of protein, a normal glucose and a normal or increased cell count. Skeletal muscles are often involved in cysticercosis. Usually this causes no symptoms, and calcified cysticerci are seen on X-rays. There may be muscle pain at the

9

FIG. 9.50 MRI scan of cerebral cysticercosis, showing cystic lesions

time of invasion. If cysticerci are found at any site in the body a CT brain scan should be done to detect cerebral involvement. Praziquantel, 50mg/kg/day in divided doses for 10-14 days, and albendazole, 20mg/kg/day in divided doses for 14 days, are both effective in killing cysticerci, and when this happens surrounding inflammation may increase enhancing neurological signs. For this reason steroids are started prior to treatment with either drug to reduce these effects. This should be carried out in a centre where neurological expertise is available. Two-thirds of cerebral cysts disappear after treatment, and clinical improvement follows. The efficacy of drug treatment in this condition has not been proven in prospective studies.

FURTHER READING ON CYSTICERCOSIS Del Brutto O et al 1993 Therapy for neurocysticercosis: a reappraisal. Clin Infect Dis 16:730-735

Hydatid disease Aetiology and distribution Echinococcus granulosus is a tapeworm of dogs. The lifecycle is shown in Figure 9.51. The ingested eggs release the onchosphere, which penetrates the gut mucosa and spreads by vascular or lymphatic channels to other organs, most often the liver, with lung, spleen, brain, eye, bone and other tissues infected less often. Cyprus, Turkey, Middle Eastern countries, the Turkana area of Kenya, and South America are among the endemic areas. Clinical features The clinical presentation is very variable. Unexplained painless hepatomegaly is fairly common, but an expanding cyst can cause right upper quadrant abdominal discomfort.

FIG. 9.51 Lifecycle of Echinococcus granulosus

Rupture of the cyst may produce pleuritic discomfort, abdominal pain and tenderness, and allergic manifestations such as urticaria and anaphylaxis. Rupture of hydatid cysts is infrequent, although the consequences of release of daughter cysts to seed the peritoneal cavity are serious. Pulmonary hydatids may be symptomless and may be found on chest X-ray. They may rupture spontaneously. Hydatid material, membranes and scolices with booklets may be coughed up and disseminate endobronchially to seed the lungs bilaterally, causing numerous small cysts in both lung fields. Bone and joint hydatids cause pain, swelling, and sinuses that discharge hydatid material. The latter may follow surgical exploration. The cyst wall may calcify. Diagnosis There may be blood eosinophilia and positive serological tests, but a viable cyst may be present without eosinophilia or positive serology. Ultrasound and CT scanning (Fig. 9.52) allow accurate localization and measurement of hydatid cysts in internal organs. Bone hydatid produces areas of lucency surrounded by sclerosis. Joints are destroyed. Management Management is difficult. Albendazole is given in doses of 400 mg twice daily for 12 weeks and appears to be effective. However, surgical treatment is probably needed for most cases. There is increasing experience with percutaneous aspiration of cysts under ultrasound guidance. Solitary pulmonary hydatids can often be excised with the relevant segments or lobe. Excision of hepatic hydatids is

377

able, vigorous antibiotic treatment is needed first, followed by safe surgical drainage of the cysts. Hydatid disease of bone is very difficult to treat, as it causes pain and destruction of affected areas. Neither drug treatment nor surgery is very effective, although on occasion, when disease is limited to the femur, total excision of the affected bone with prosthetic replacement, including hip and knee joints, can be carried out.

FIG. 9.52 CT scan showing hydatid cysts in the liver

more difficult. Surgery for hydatids of the CNS requires great care to avoid rupture. Complications Secondary bacterial infection of a hydatid cyst is not uncommon. Amoebic abscess, pyogenic abscess and perihepatic sepsis must be considered in the differential diagnosis when liver cysts are concerned. Gallium scanning may help to indicate bacterial infection and blood cultures should be taken. Amoebic serology is strongly positive in amoebic liver abscess. When infected hydatid cyst is prob-

378

Prevention and control Regular deworming of dogs, killing of stray dogs, and safe disposal or boiling of offal are important control measures. These measures, plus effective communication of the dangers of hydatid disease among populations in Iceland and New Zealand, have controlled the disease.

FURTHER READING ON INFECTIOUS, TROPICAL AND PARASITIC DISEASES Cook G C 1996 Manson's tropical diseases, 20th edn. London: W B Saunders Lambert H P, Farrar W E 1982 Infectious diseases illustrated. London: W B Saunders Mandell G L, Douglas R G, Bennet J E, Dolin R 1994 Principles and practice of infectious diseases, 4th edn. New York: Churchill Livingstone Strickland G T, ed. 2000 Hunter's tropical medicine, 8th edn. London: W B Saunders

Skin Disease Cameron T C Kennedy and Robin A C Graham-Brown

Biology of the skin 379 Examination of the skin 381 Dermatological diagnosis 381 Dermatological therapy 382 Bacterial diseases 384

Internal malignancy and the skin 420 Sunlight and the skin 426 Pigmentation 427 Pressure sores 428 Leg ulceration 429

description of those skin diseases that are either common or important. Diseases presenting as changes in the skin but whose major impact is on other systems, are discussed in other chapters. Because of the great importance of the visual aspects of dermatology, a colour atlas or, whenever possible, patients, should be viewed in conjunction with the text. Therapy is considered in terms of general principles.

BIOLOGY OF THE SKIN The skin is a protective barrier between a hostile environment and internal tissues. Its principal functions are to reduce the loss of water, electrolytes and other solutes, and the entry of unwanted molecules, microbes and radiation. It has a complex and specialized sensory innervation and contains a network of antigen-processing cells. The cutaneous vasculature and sweat glands are vital to heat regulation. Vitamin D is synthesized in the skin. By virtue of its smell, colour and texture, the skin has psychological and sexual roles. The skin is composed of three layers: epidermis, dermis and fat (Fig. 10.1).

Superficial fungal diseases 389

Acne vulgaris 431

Viral diseases 393

Hyperhidrosis 431

Arthropods and the skin 394

Hidradenitis suppurativa 432

Psoriasis 395

Rosacea 432

Epidermis

Eczema and dermatitis 399

Pruritus 433

Ichthyosis 405

Alopecia 433

Reaction patterns 405

Hirsutism and hypertrichosis 434

Blistering diseases 410

Nails and disease 435

Miscellaneous disorders of unknown cause 413

Psychological causes of skin disease 436

Skin changes in diabetes 415

Genodermatoses 436

The epidermis is a stratified epithelium comprised mainly of keratinocytes, which are of ectodermal origin. These divide in the basal layer, where they are separated by the basal lamina from the dermis, progressively produce the sulphur-rich fibrous protein keratin, and become flattened and dead by the time they reach the surface. These cells have a lipid-rich envelope and are linked to one another by specialized cell junctions, notably the desmosomes, and in health the horny layer is tough, flexible and relatively impermeable. At the surface they are constantly shed as squames. Removal of the horny layer virtually destroys the barrier function of the skin with respect to water and solutes. The effectiveness of the horny layer is reduced if its production is faulty (e.g. in psoriasis), if the water content drops below a critical level (e.g. chapping), or if it is damaged (e.g. by detergents and lipid solvents). Resident in the epidermis are the melanocytes, Langerhans' cells and Merkel's cells.

Drug eruptions 416

Skin disorders are a common reason for seeking medical advice (Table 10.1). Apart from diseases that primarily affect the skin, many systemic diseases may produce dermatological manifestations. When a skin disease is widespread and interfering with skin functions, systemic consequences follow - sometimes, as in untreated pemphigus vulgaris, with fatal results. More limited skin diseases can cause distress or hardship. The psychological impact of readily visible skin lesions, even if biologically trivial, should not be underestimated. Another common problem associated with skin disorders is fear (often not expressed) that a skin disease is contagious, or a manifestation of cancer. This chapter gives a brief account of the biology of the skin, the principles of diagnosis and therapy, and then a

• Melanocytes migrate early in fetal life from the neural crest and become established along the basal layer, so that there is approximately one melanocyte per 10 basal keratinocytes. Via their dendritic processes, the yellow or brown-pigmented protein melanin is passed in membrane-bound particles, called melanosomes, into the keratinocytes; here most of it is distributed over the surface of the nucleus that faces the sun. Melanin absorbs ultraviolet radiation and thus helps protect against DNA damage. In its absence, in albinism, skin cancer on exposed sites is common at an early age.

379

TABLE 10.1 Prevalence of skin diseases* Rates of consultation (general practice) per 1000/year All skin diseases Alopic dermatitis and related conditions Contact dermatitis and other eczema Viral warts Psoriasis Urticaria Chronic ulcer Malignant neoplasms Some comparisons Asthma Osteoarthritis Irritable bowel Diseases of stomach (functional) Rheumatoid (and other inflammatory) arthritis

229 43 27

18 11

9 4 1.4

91 58 32 22 11

* Date from Morbidity Statistics from General Practice, Fourth National Study 1991-2. OPCS, HMSO, 1995.

FIG. 10.1 Cross-section of the skin

RECENT ADVANCES IN MEASURING DISABILITY IN SKIN DISEASE An important new approach to the assessment of skin disease has been the application of techniques that measure the impact of the process on the quality of life (see Further Reading). Such methods are being used in other branches of medicine too, and can help doctors: • Gain an understanding of what having a chronic skin disease such as psoriasis or eczema is really like; • Gauge the usefulness of treatments in terms of improvements in life quality (which may improve the ability to judge therapy in terms of risk/benefit ratios and cost-effectiveness); • Compare the effects of skin disease with other medical problems and apportion resources.

FURTHER READING Finlay AY 1997 Quality of life measurement in dermatology: a practical guide. Br J Dermatol 136:305-314. Anderson RT, Rajagopalan R 1997 Development and validation of a quality of life instrument for cutaneous diseases. J Am Acad Dermatol 37:41-50.

1

380

MCQ 10.1

• Langerhans' cells, also dendritic, are of bone marrow origin. They are located in the mid-epidermis, function as antigen-trapping and antigen-presenting cells, and can migrate to regional lymph nodes. Together with lymphocytes, they constitute a vital outpost of the immune system. • Merkel's cells, best recognized on electron microscopy by their dense-cored granules, are closely associated with sensory nerve endings, and may represent a mechanoreceptor system. They are most numerous on the lips, on digital pads and in hair follicles. The epidermis is separated from, and attached to, the dermis by a basal lamina, across which all nutrients must pass. A component of the basal lamina is the target of immunological attack in the blistering disease bullous pemphigoid (p. 411).

Dermis The dermis is a three-dimensional fibrous tissue network of collagen and elastin associated with water-rich glycosaminoglycans, in which are embedded the blood and lymphatic vessels, neural elements and epidermal appendages - sweat glands, sebaceous glands and hair follicles (Fig. 10.1). The dermis is manufactured by fibroblasts, and other cells seen in normal tissue include dermal phagocytes and mast cells. The dermis has viscoelastic properties,

allowing body movements without permanent distortion, yet considerable mechanical strength. It is essential to the wellbeing and repair of the epidermis. The superficial part of the dermis, containing capillaries and nerve endings, is more loosely woven than deeper layers, and projects into the undersurface of the epidermis as papillae. Blood flow through the skin can be greatly in excess of nutritional demands, and skin vasculature contributes to thermoregulation and the maintenance of blood pressure. There are networks of blood vessels at the levels of the deep fascia, the fat-dermis junction and in the papillary dermis, where capillary loops follow the contour of the dermoepidermal junction. There are also numerous arteriovenous shunts that allow blood to bypass capillaries, thereby conserving heat. Vascular control is by autonomic nerves and chemical mediators. The skin is also provided with an extensive plexus of lymphatics, which act both as a drainage system for lymph and in the recirculation of lymphocytes. There are afferent sensory nerves subserving touch, pain, temperature and itch, and also the specialized Meissner and Pacinian corpuscles, which are probably mechanoreceptors. The autonomic supply is sympathetic, with adrenergic, cholinergic and purinergic terminals. Collagen and elastin disorders are described on page 71.

Epidermal appendages Eccrine sweat glands consist of secretory coils connected by straight ducts to the surface. There is a rich blood supply and a predominantly cholinergic sympathetic innervation. Because of the sodium-resorptive properties of the ducts, sweat is hypotonic. The basal level of fluid loss through the skin of about 600mL/day can be greatly increased in response to the need for heat loss. Apocrine sweat glands are found in the axillae, anogenital regions, on the breast and on the scalp. They open into hair follicles and on to the skin surface. Their secretion is low in volume, and after bacterial alteration it has a characteristic odour. Very similar glands produce wax in the ears and occur on the eyelids. The pilosebaceous follicles produce both hairs and sebaceous glands. In humans hair is largely of cultural and sexual significance. There are three types: lanugo, which covers the fetus; vellus, which is fine and short; and terminal hair, which is coarse and occurs on the scalp, eyebrows, axillae and pubic regions. A residual protective value of hair is seen when its absence in bald males is accompanied in later life by sun-induced neoplasms. An important characteristic of hair follicles is their cyclical activity: for each follicle a period of active growth (anagen) is followed by a transition period (catagen) and then a resting phase (telogen), when the hair is shed and a new hair begins. Individual follicles are normally asynchronous, hence humans do not moult. Nails are hard plates of keratin which protect the ends of the digits and facilitate many of the functions of the hands. 1

FURTHER READING ON BIOLOGY OF THE SKIN

10

Eady R A J , Leigh I M, Pope F M 1998 Anatomy and organisation of human skin. In: Champion R H et al, eds. Textbook of Dermatology, 6th edn. Oxford: Blackwell Science, pp. 37-111.

EXAMINATION OF THE SKIN It is essential to examine all the skin, together with the mouth, genitalia, hair and nails, in a good light. The skin should be palpated as well as inspected, to appreciate the thickness of lesions and of the whole skin. Being touched can help some patients to shed a 'leper complex'. Skin lesions should be described in terms of: • The individual characteristics (shape, colour, etc.) • Their arrangement in relation to each other (if any) • Their distribution. The terms used have precise meanings (Table 10.2). Distribution The following points should be noted: • Is the rash localized, regional or generalized? • Is there symmetry? Endogenous disorders are often symmetrical. • Is there localization by exposure to light, cold or some other environmental factor? • Has non-specific trauma, e.g. scratching, caused new lesions (Koebner's phenomenon), as in psoriasis and lichen planus? • Is there an underlying anatomical basis, e.g. the vascular or nerve supply, the flexures or hair follicles? Many conditions have characteristic patterns of distribution, the basis for which is obscure, e.g. dermatitis herpetiformis on elbows and knees, scalp, shoulders and buttocks.

DERMATOLOGICAL DIAGNOSIS There is a great variety of dermatological diagnoses. However, the practised observer can describe changes that suggest a diagnosis or differential diagnostic group. The history is important, narrowing the possibilities (Table 10.3). Diagnostic procedures and investigations may be useful. Diascopy When the skin is pressed with a microscope slide or Perspex spatula, purpura (which does not blanch) can be distinguished from erythema (which does). Nikolsky sign The Nikolsky sign involves the production or extension of a blistering process by the combination of pressure with a

381

TABLE 10.2 Terms used to describe skin lesions Skin lesion Appearance Erythema Macule Papule Plaque Nodule Vesicle Bulla Pustule Weal Angioedema Purpura

Telangiectasia Atrophy Sclerosis Ulcer Excoriation Crust Scaling Burrow

Definition Redness due to vasodilatation Flat, circumscribed, impalpable area of colour change. There may be scaling, as in pityriasis versicolor Small (less than 0.5cm), solid, elevated lesion, most of which is above the plane of the skin Elevated lesion with relatively large surface area in relation to height Large (greater than 0.5cm diameter) solid lesion Blister less than 0.5cm diameter Blister greater than 0.5cm diameter Elevation of the skin containing fluid and leukocytes, usually yellow or green in colour, but not necessarily infective Elevation due to dermal oedema, lasting minutes to several hours Massive oedematous reaction in loose dermis or subcutaneous tissue Extravasated red cells (see Diascopy, p. 381). Small purpuric lesions are called petechiae, large ones ecchymoses. They are not obliterated by pressure. The colour varies from red, through purple and brown, to yellow, depending on the age of the lesion Permanent dilatation of capillaries Thinning, often with loss of normal skin markings, and increased transparency Hardening due to changes in the dermis Loss of (at least) the epidermis Scratch mark Dried exudate Desquamating horny layer Irregular linear elevation of horny layer, characteristic of scabies

Shape and arrangement Linear In a line Annular Ring-shaped Erythematous ring or rings separated by relative pallor with a Target purplish centre Herpetiform Clustered, like herpes simplex Zosteriform Clustered and following a dermatome Reticular Net-like

sliding action. It is characteristic of pemphigus and some other blistering diseases.

382

Wood's light Wood's light is produced by a long-wave UV lamp, which shows red fluorescence with erythrasma, green fluorescence with some common scalp fungal infections, and pale yellow fluorescence with pityriasis versicolor. It enhances the pallor of vitiligo and is helpful in screening for the ash-leaf macules of tuberous sclerosis.

TABLE 10.3 Taking a history History of the skin eruption When and where did the problem start? Has it spread, and how? Has it changed in character? What was it like if different before? Does it itch? Does it come and go? What has been used or taken for it (prescribed and self-medication)? Have any other medications - oral, injected or topical - been used? Is there any relation to sunlight? Any past history of skin disease? Does anyone the patient knows have anything similar? What does the patient think is the cause? Background Age, sex, race. Pregnant? Pubertal? General medical, past and family history Personal and family history of eczema, asthma or hay fever Social history: occupation, hobbies, travel Any known allergies?

Biopsy Biopsies are carried out for histopathology and, when relevant, immunological studies, microbiological culture and electron microscopy, cell culture and molecular biological studies such as gene analysis. Mycological techniques Mycological techniques are described on page 389. Patch testing Patch testing is described under 'Contact

dermatitis'

(p. 400). Scabies mite scraping Scabies mite scraping is described on page 395.

DERMATOLOGICAL THERAPY Dermatological treatment includes topical and systemic pharmacy, physical modalities such as liquid nitrogen cryotherapy, ultraviolet radiation, radiotherapy, laser and surgical procedures, and dietary measures. Topical therapy is the traditional province of the dermatologist.

Vehicles Active ingredients are applied to the skin in a vehicle (Table 10.4). A vehicle may be used therapeutically: a lotion to cool and dry, a cream to soothe, an ointment to moisturize dry skin, and a paste to protect. When an active ingredient is included, the vehicle must

TABLE 10.4 Composition and properties of vehicles for topical treatment Vehicle

Composition

Properties

Lotion

Liquid (water or alcohol)

Cools inflamed skin. Useful in hairy areas. Miscible with exudate

Shake lotion

Water + powder

Powder increases area for evaporation, so has cooling properties

Cream

Water + grease + emulsifier

Aqueous phase gives some cooling effect and miscibility with exudate. Grease increases hydration. Properties will vary depending on whether the emulsion is oil-in-water or water-in-oil

Ointment

Grease

Moisturizes dry skin by trapping water passing through the epidermis. Hydrophobic (e.g. vaseline) or hydrophilic (e.g. lanolin)

Paste

Grease + powder

Moisturizing and protective

Dusting powder

Powder

Reduces friction. Absorbs water

deliver it appropriately and maintain its integrity against oxidation and bacterial contamination. Therefore vehicles, especially creams, often contain preservatives and stabilizers. Some preparations contain substances to enhance drug penetration, e.g. urea. When adverse reactions to topical agents occur, it should be remembered that not only the active ingredient but also the components of the vehicle should be considered as possible causes. For most active ingredients the major barrier to penetration is the horny layer. Penetration is greater through facial and genital skin and flexures (e.g. axillae, crural folds) and is increased by occlusion (e.g. by rubber gloves), diseases that alter the horny layer (e.g. eczema and psoriasis), and pharmaceutical penetration enhancers such as urea. In contrast, when the horny layer is very thick, as on the palms and soles, there is reduced penetration.

TABLE 10.5 Potency of topical corticosteroids Group

Potency

Examples

1 2

Very high High

3 4

Moderate Low

Clobetasol propionate Betamethasone valerate Hydrocortisone butyrate Clobetasone butyrate Hydrocortisone

10

TABLE 10.6 Adverse effects of topical steroids Adverse effects

Factors increasing risk

Pituitary-adrenal axis suppression; growth suppression in children

Potency group 1 Potency groups 1 and 2 with occlusion Widespread skin inflammation Infancy Hepatic failure

Spread of skin infection

Overt infection Body folds

Atrophy (thin, red, fragile skin)

High risk sites, e.g. face, body folds Occlusion Prolonged and continuous use

Striae (stretch marks)

Potency groups 1 and 2 Body folds

Increased hair growth (hypertrichosis)

Potency groups 1 and 2 Prolonged use

Peri-oral dermatitis

Face

Exacerbation of skin disease on withdrawal

Psoriasis Facial dermatoses

tration, the vehicle, and also by factors favouring increased absorption. Adverse effects (Table 10.6) are very unlikely with topical 1 % hydrocortisone.

Other topically used drugs

Topical corticosteroids

A selection of drugs used topically is shown in Table 10.7.

Topical corticosteroids have anti-inflammatory and other actions, with useful suppressive effects in a number of skin disorders, but they do not cure disease. They can worsen skin infection and modify physical signs, and the more potent preparations easily produce side-effects. In general, the efficacy of topical steroids goes hand in hand with the ability to cause side-effects, and a preparation of the lowest potency that is effective should be used (Table 10.5). Applications are usually once or twice daily, with bland creams or ointments at other times if necessary. Efficacy is determined by the steroid molecule, its concen-

Cryotherapy Many benign and some malignant skin lesions can be quickly and successfully treated by accurately applied low temperature. The most satisfactory agent is liquid nitrogen, whose temperature is -196°C, applied on a cottonwool swab, by a spray or a probe. The procedure can be painful and is often followed by swelling and blistering, but longterm cosmetic results are generally good. Hypopigmentation and some sensory loss can be troublesome consequences.

383

TABLE 10.7 Some topical preparations used in skin diseases Topical drug

Use

Tars Dithranol Calcipotriol Benzoyl peroxide Adapalene Metronidazole Calamine Aminobenzoic acid esters Salicylic acid

Chronic eczema, psoriasis Psoriasis Psoriasis Acne Acne Rosacea Pruritus Sunscreens Viral warts, other localized hyperkeratotic conditions Viral warts Scabies Some dermatophyte infections Some dermatophyte and yeast infections; seborrhoeic dermatitis Dermatophyte infections Candidiasis Localized superficial Gram-positive bacterial infection Some herpes simplex and zoster infections

Podophyllum Permethrin Compound benzole acid ointment Antifungal imidazoles Terbinafine Nystatin and amphotericin B Antibiotics, e.g. fusidic acid, mupirocin Aciclovir

BACTERIAL DISEASES Bacterial infection can produce skin lesions at or near the portal of entry, as in impetigo. Lesions may also be due to organisms deposited in the skin during septicaemia, bloodborne spread of a toxin, and hypersensitivity phenomena, such as the vasculitic Osier's nodes and splinter haemorrhages of subacute bacterial endocarditis's. Normal intact skin is colonized by diphtheroids and nonpathogenic staphylococci and, in some sites such as the anterior nares, axilla and perineum, by potentially pathogenic Staphylococcus aureus. In moist areas there are often some Gram-negative bacilli. Overt infection nearly always follows some kind of injury, albeit trivial. If it is associated with some obvious pre-existing skin lesions, such as eczema, it is referred to as secondary infection. Host factors, particularly the immunological status, are important in determining the degree and extent of infection. Some skin diseases, such as hidradenitis suppurativa, are a non-specific reaction to bacteria, which, although contributory, are not the primary cause. The types of staphylococcal and streptococcal skin infection are shown in Table 10.8. 1

384

1

MCQ10.2

2

Fig. 10.1

3

Fig. 10.2

4

Fig.10.3

RECENT ADVANCES IN DERMATOLOGICAL THERAPY There have been a number of important advances in the treatment of skin diseases in the last 5 years. • The introduction of newer 'azole' derivatives (itraconazole, fluconazole) and the allylamine terbinafine has resulted in a wider range of more effective and safer systemic options for the treatment of cutaneous (and other) fungal infections. • Ciclosporin, which suppresses T-lymphocyte activity, has an established role in the therapy of severely affected patients with psoriasis and atopic dermatitis, and can be effective in several other skin diseases in which immune dysfunction is important, e.g. pyoderma gangrenosum. Other drugs with immunomodulatory effects useful in dermatology include tacrolimus (similar in action to ciclosporin) which can be used topically (e.g. for atopic dermatitis) and thalidomide (helpful in Behcet's syndrome and cutaneous lupus erythematosus). • The vitamin D3 analogues can now be regarded as first-line agents in the management of plaque psoriasis. Examples include calcipotriol and tacalcitol. • Retinoids are the most important cell-signalling molecules in dermatology. Two newer retinoids of clinical value are tazarotene for psoriasis and adapalene for acne vulgaris. • Better laser technology has improved the results of treatment for vascular lesions such as port wine stains. Other lasers are used to eliminate tattoos and some pigmented lesions.

Impetigo Impetigo (Fig. 10.2) is a primary superficial bacterial skin infection, initially vesicular or bullous and later crusted. It may only involve the openings of hair follicles and is caused by Staph. aureus, Streptococcus pyogenes group A, or both. In some tropical regions the streptococci can cause nephritis. Bullous impetigo is usually due to phage group II staphylococci. Impetigo occurs predominantly among children and is highly contagious. Spread is mainly from skin to skin, although in streptococcal cases infected individuals may acquire the disease from pharyngeal colonization. Trauma, for example from scratching insect bites, and infestation commonly predispose to the infection. Exposed parts are mainly affected. The early lesions are clear or turbid blisters which soon become crusts, often golden yellow, with a surrounding zone of erythema. In bullous impetigo there are larger blisters with no erythema. The lesions tend to heal centrally but spread peripherally. Regional lymphadenopathy is common. Diagnosis is by Gram stain and culture of a swab, which will help to distinguish impetigo from other lesions such as tinea and varicella.

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FIG. 10.3 Staphylococcal scalded skin syndrome This shows characteristic crusting and radial fissuring around the mouth. FIG. 10.2 Impetigo: ruptured flaccid blisters and crusts on a red base

TABLE 10.8 Staphylococcal and streptococcal bacterial infections of the skin Due to direct bacterial infection Staphylococcus aureus Impetigo Ecthyma Follicular infections Streptococcus pyogenes Impetigo Ecthyma Erysipelas Cellulitis Necrotizing fasciitis

Due to toxin

Due to hypersensitivity

Staphylococcal scalded skin syndrome Toxic shock syndrome Staphylococcal scarlatina Scarlet fever

Erythema Vasculitis Erythema nodosum

Treatment Gentle removal of crusts is helpful. If localized, a topical antibiotic, such as fusidic acid or mupirocin, is adequate. For widespread impetigo, oral flucloxacillin (or erythromycin if the patient is allergic to penicillin) is required. Improvement of hygiene may be advisable, e.g. not sharing towels.

Ecthyma Ecthyma is a vesiculopurulent condition similar to impetigo, but the infection extends deeper, producing ulceration 2; it is caused by Strep, pyogenes, often with Staph. aureus. The condition is common in hot, humid climates, affects mainly children and the elderly, and is often associated with poor hygiene and/or insect bites. The initial vesicular lesion soon becomes a punched-out ulcer with an overlying crust. The legs are commonly affected. The differential diagnosis includes ecthyma gangrenosum 3, caused by Pseudomonas septicaemia (see below),

and other causes of ulcers (p. 430). Treatment is with a penicillinase-resistant antibiotic, such as flucloxacillin or erythromycin. If there is surrounding cellulitis penicillin should be added.

Staphylococcal scalded skin syndrome Staphylococcal scalded skin syndrome is a generalized skin reaction to bloodborne Staphylococcal epidermolytic toxins, which cause a split in the superficial epidermis; unlike impetigo, there are no organisms in the accumulating fluid. It is caused by a focus of infection of Staph. pyogenes of phage group II, which may be cutaneous but can be elsewhere. Children, especially infants, are most susceptible (Fig. 10.3). Clinical features A few days after the initiating Staphylococcal infection there is a sudden onset of widespread tender erythema with fever. Twelve hours or so later there may be widespread flaccid bullae, and the horny layer begins to detach in sheets. 4 Differential diagnosis Toxic epidermal necrolysis due to drugs (p. 417) can be distinguished by the histology of a blister roof, which shows a deeper level of split in the epidermis in the drug-induced type, and by the history. Treatment Treatment is with parenteral flucloxacillin (or equivalent), and careful attention to fluid balance and temperature regulation.

Erysipelas Erysipelas (Fig. 10.4) is a dermal infection, usually with group A streptococci. There is often a recognizable portal of entry, such as a fungal infection between the toes or a fissure at the corner of the mouth. There may have been a previous upper respiratory tract streptococcal infection. The onset is often sudden, with fever, malaise and rigors,

385

FIG. 10.5 Cellulitis Spreading soft tissue infection due to B haemolytic streptococcuslor which the portal of entry was a venous leg ulcer.

Cellulitis

FIG. 10.4 Erysipelas: tender erythema and oedema

together with a bright red, tender swelling. The face and lower legs are common sites. The skin becomes oedematous and a well-defined, raised, sometimes blistering edge advances rapidly. There are often red streaks due to lymphangitis. Diagnosis Leukocytosis is usual. Surface culture is useless, but the organism can sometimes be cultured from aspirated fluid. There is usually an antibody response to streptococcal proteins, with rising litres of antideoxyribonuclease B; antistreptolysin O is less often elevated. Differential diagnosis Acute contact dermatitis and angioedema of the face may simulate erysipelas but do not produce fever. Herpes zoster, before the outbreak of vesicles, is associated with pain or paraesthesiae. Erysipeloid (p. 387) occurs in meatand fish-handlers, and systemic symptoms are much less severe. Complications Erysipelas is usually self-limiting but can produce suppurative and widespread infection. There is involvement of the lymphatics, and this predisposes to persistent swelling (lymphoedema) and recurrent attacks. Treatment The treatment of choice is penicillin, parenterally in severe infections, unless contraindicated by hypersensitivity, in which case erythromycin or another macrolide should be suitable.

1

386

Fig. 10.4

Cellulitis is a deeper dermal/subcutaneous infection than erysipelas, usually with group A streptococci. In practice there is no absolute distinction between erysipelas and cellulitis. There is usually an obvious portal, e.g. a leg ulcer (Fig. 10.5) or wound, or oedema of lymphatic, venous or renal origin. There is spreading erythematous oedema as in erysipelas, but without the sharply denned edge or vesiculation. There may be similar constitutional symptoms and lymphangitis. Untreated, gangrene may occur. Treatment is the same as for erysipelas, unless the cellulitis is caused by bacteria other than group A streptococci.

Necrotizing fasciitis Necrotizing fasciitis (streptococcal gangrene) is a necrotizing process usually caused by group A streptococci; it involves the deep fascia and vessels within it, with secondary death of overlying skin. This uncommon process can occur in healthy subjects, but arterial insufficiency and diabetes predispose. Necrotizing fasciitis usually begins like cellulitis, but after about 2 days the area becomes purplish, haemorrhagic bullae appear, and there is tissue death. 1 Untreated, there is a high mortality. The diagnosis is often based on clinical suspicion alone, but streptococci can commonly be found in exudate or the blood. Treatment by urgent and adequate surgical debridement is essential. There has been some debate over the antibiotic of choice in necrotizing fasciitis, with some recommending vancomycin or clindamycin. However, most authorities recommend high-dose intravenous benzylpenicillin, with vancomycin being reserved for the penicillin-allergic individual.

Progressive bacterial synergistic gangrene Progressive bacterial synergistic gangrene is gangrenous ulceration due to synergistic infection with microaerophilic

streptococci and Staph. aureus, usually associated with an abdominal or thoracic operation wound. One to 2 weeks after surgery there is a slowly spreading area of ulceration which has a rim of gangrenous skin surrounded by purplish erythema. The main differential diagnosis is pyoderma gangrenosum (see p. 407). Treatment is by surgical debridement plus i.v. highdose penicillin, gentamicin and metronidazole. For the penicillin-allergic patient, clindamycin and gentamicin are recommended.

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Follicular infections A furuncle (boil) is an acute necrotizing infection of a follicle. A carbuncle is more extensive, involving contiguous follicles and the tissues around them. Infection of the hair follicle opening is termed superficial folliculitis. The usual infecting organism is Staph. aureus, and there is often nasal, axillary or perineal carriage of the organism. Friction, as at the nape of the neck, and moisture, as in the flexures, are important predisposing factors. Obesity, poor hygiene, widespread skin disease, immune deficiency and diabetes mellitus may predispose in severe cases. Superficial folliculitis can be non-infective; causes include contact with oils and other irritant chemicals. Furuncles are tender red papules or nodules, which become pustular centrally and often heal with some scarring. Furunculosis may be chronic, as in sycosis barbae, a pustular eruption due to Staph. aureus that occurs on the male face. Carbuncles are often associated with fever and malaise, and with an underlying systemic illness such as diabetes or immune suppression. Follicular infections can produce bacteraemia and, rarely, bony and cerebral abscesses, and endocarditis. Swabs should be taken from pus and from the anterior nares, axilla and perineum of both the patient and household contacts (potential reservoirs of infection) in chronic cases. Differential diagnosis The differential diagnosis includes dermatophyte infection (the fungi can be demonstrated by microscopy and culture of hairs) and pseudofolliculitis, a non-infective papulopustular condition on the face and neck caused by cut hairs growing back into the skin. The latter is very common in black people because their hair is tightly curled. Acne vulgaris (p. 431) can usually be distinguished by the presence of comedones, and the pustules are sterile. Hidradenitis suppurativa is discussed on page 432. In anthrax (see Ch. 9) there is a haemorrhagic crust and vesicular margin, and a swab will establish the diagnosis. Treatment Furuncles and carbuncles may need incision and drainage. Superficial staphylococcal folliculitis should respond to flucloxacillin (or an equivalent) for 1-2 weeks, but chronic cases may need treatment for longer, and treatment of

FIG. 10.6 Erythrasma Well-defined brownish erythema which fluoresces pink by Wood's light.

reservoir sites, e.g. chlorhexidine for the skin and mupirocin for the nose.

Erythrasma Erythrasma (Fig. 10.6) is a common surface infection caused by Corynebacterium minutissimum. Sharply defined red or reddish-brown patches, sometimes with slight scaling, are seen in the axillae, groins, toe webs, and sometimes other body folds. There are usually no symptoms. The diagnosis is readily made with Wood's light; the affected skin fluoresces pink. Most cases respond to a topical imidazole, e.g. clotrimazole, but if the condition is widespread oral erythromycin for 10 days may be more effective.

Erysipeloid Erysipeloid is an acute cutaneous infection with Erysipelothrix insidiosa. This Gram-positive bacillus causes infection in several animals and in salt-water fish. Transfer to the skin occurs mainly to veterinary surgeons, butchers, fish-handlers and housewives.

387

The hand is the common site. A few days after inoculation there is a well-defined, slowly spreading, dusky erythematous oedema with little or no general upset (in contrast with erysipelas). Treatment is with penicillin or tetracycline.

Pseudomonas infection of the skin Pseudomonas aeruginosa is not normally found on the skin but can become pathogenic, with the production of a characteristic bluish-green pus and a fruity odour in circumstances of increased moisture. Examples may be found at the base of the nail in those whose hands are often immersed in water, in toe spaces, beneath dressings for ulcers, and very importantly on raw surfaces following burns. Prior eradication of Gram-positive flora may also predispose. A pruritic pseudomonas folliculitis can be acquired from contaminated whirlpool baths. Localized infection usually responds to simple antiseptic measures, such as acetic acid, silver nitrate or silver sulfadiazine, together with drying. Pseudomonas septicaemia can produce solitary or widespread vesicles with surrounding red haloes. Subsequent necrosis, often with haemorrhage into the tissues, producing black crusts, is known as ecthyma gangrenosum. The lesions, as well as the blood, should yield Pseudomonas on culture, and prompt treatment can be life-saving.

Mycobacterial and treponemal diseases Tuberculosis (see also p. 640) leprosy (p. 325) and syphilis (p. 458) all have important cutaneous manifestations. Cutaneous tuberculosis Involvement of the skin by Mycobacterium tuberculosis is relatively uncommon in developed countries but is often seen in the developing world, where the overall prevalence of tuberculosis is much higher. The condition still needs to be considered in the west, particularly in those who have migrated from the Indian subcontinent and Africa. Many descriptive terms have been applied to the wide variety of clinical presentations that can occur, and to some extent these reflect the mode by which the skin may be affected: haematogenous spread from a deep source (most lupus vulgaris); direct spread from underlying organs, e.g. lymph nodes, bones, respiratory or gastrointestinal tract (scrofuloderma, tuberculosis cutis orificialis); direct inoculation from outside (some lupus vulgaris, tuberculosis verrucosa cutis and warty TB). The commonest form is lupus vulgaris, which presents as an area of indurated, reddish-brown skin, characteristically on the head and neck (Fig. 10.7), although lesions may

1

388

Fig. 10.5

FIG. 10.7 Typical lupus vulgaris involving ear and cheek

occur elsewhere. The lesions gradually spread and have a tendency to produce scar tissue, which results in distortion of normal anatomy and loss of hair follicles in hair-bearing areas. When the microorganism is inoculated directly into the skin, lesions sometimes have a warty surface. Tuberculosis may result in a number of skin changes in which the microorganisms are not directly involved (known as tuberculides}: • Erythema nodosum (see p. 407), in which the lesions usually appear in association with primary infection; • Erythema induratum (or Bazin's disease), in which the nodular, ulcerative lesions appear on the lower legs, involving the calves as well as the shins; 1 • The rare papulonecrotic and lichenoid forms. Investigation of suspected cutaneous tuberculosis involves biopsies for histology and culture and a search for involvement of internal organs (see Ch. 13). Treatment should be with standard antituberculous chemotherapy (p. 645), even if a deeper focus is not found. Atypical mycobacterial infections The skin may become infected by direct inoculation of other mycobacteria, especially Mycobacterium marinum, an organism responsible for a systemic infection in fish. An indurated nodule or nodules appear, usually on the hand or arm of a fish-fancier (Fig. 10.8). In some patients, further nodules appear along the lines of lymphatic drainage (socalled sporotrichoid spread). Occasionally lesions may be more widespread, especially in those who catch the organ-

10

FIG. 10.8 'Fish-tank granuloma' These lesions are caused by mycobacteria acquired from fish.

ism from swimming. Biopsy for histology and culture should be performed, but the tissue must be incubated on special media at low temperature for the organism to grow. Lesions often resolve spontaneously, but this is a slow process and therefore treatment with antibiotics may be indicated. Various drugs have their advocates: minocycline, co-trimoxazole and rifampicin are all considered to be effective. Treatment should be for about 6 weeks.

Fungal infections involving the skin are broadly classified into superficial and deep. The former include the ringworm fungi (dermatophytes), candidiasis and pityriasis versicolor. Except for Candida, these fungi rarely invade deeper than the horny layer of the epidermis. Nails and hair, as well as the skin surface, may be involved (see Fig. 10.12, p. 391). The clinical manifestations depend partly on the infecting species, on the body part affected, and on the host response to substances diffusing from the fungi into the skin. Deep fungal infections are discussed in Chapter 9. Diagnosis Diagnosis is by microscopic examination of scrapings to show fungal hyphae, and species identification is by culture. The dermatophytes are grown on Sabouraud's medium. With skin lesions scale is collected by scraping with a blade, hair is plucked and clippings are taken from nails. Material is sent to the laboratory dry in folded paper. Microscopy is performed on small samples after clearing with a few drops of 30% potassium hydroxide. For some species of scalp dermatophyte infection and for pityriasis versicolor the Wood's light is valuable (p. 382).

Tinea The fungi that cause the characteristic annular lesions

FIG. 10.9 The annular lesions of tinea (ringworm)

known as tinea or ringworm (Fig. 10.9) are also known as dermatophytes, as they have the ability to digest keratin. There are three genera - Trichophyton, Microsporum and Epidermophyton - and numerous species, which are recognized by their culture characteristics. Humans are the primary host for some (the anthropophilic species), but with others the fungi are incidental pathogens to humans, being primarily animal parasites (zoophilic) or found in soil (geophilic). The immune response is most marked against zoophilic species, and these tend not to recur. With very inflammatory ringworm there can be so-called 'id' reactions, owing to the immune response. These are widespread, often follicular, papular lesions which do not contain fungi. Probably for similar reasons, a vesicular eruption on the hands can be associated with ringworm of the feet. The distinctive appearance of ringworm infections can be greatly modified by topical steroids. Treatment Successful treatment requires attention to sources of reinfection and measures to deal with acutely inflamed macerated skin, such as aluminium acetate soaks, as well as specific antifungal preparations. Topical agents, including Whitfield's ointment, and various imidazoles are suitable for localized skin infection. The most rapid, effective and expensive agent is terbinafme. Oral terbinafine is the treatment of choice for hair, nail, widespread and chronic skin infections, but is not yet licensed in the UK for use in children. Itraconazole and griseofulvin are alternatives. A weak topical steroid, together with antifungal therapy, may be useful if there is much inflammation. Tinea pedis Tinea pedis is a dermatophyte infection of the feet, some-

389

FIG. 10.10 Tinea pedis Macerated hyperkeratosis and scaling in the lateral toespace.

times with concurrent bacterial infection. This very common, often chronic condition is frequently acquired where bathing facilities are shared, and infection is favoured by maceration. It is much commoner in males than in females. The most common pattern is an itchy, inflamed, fissured, moist toe space, usually between the fourth and fifth toes (Fig. 10.10). It is often unilateral. A vesicular pattern may occur involving the instep, dorsum of the foot or sides of the toes. A very chronic pattern may be seen, with hyperkeratosis and fine white scaling accentuating skin creases on the soles. 1 Tinea pedis may be accompanied by cellulitis. Tinea pedis can resemble eczema, contact dermatitis, candidal infection and psoriasis. Endogenous eczema and psoriasis are more likely to be bilateral. Most toe space infections respond to a topical antifungal agent, but extensive involvement of the soles needs oral treatment. Regular cleansing of communal bathing facilities and prophylactic use of antifungal powders help reduce transmission of infection. Tinea cruris Tinea cruris is a dermatophyte infection of the groins and adjacent skin. Like tinea pedis, with which it is often associated, tinea cruris is much more common in males. Itching is very common. There is inflammation, with a well-defined margin which is scaly, vesicular or occasionally pustular, often with central clearing. The differential diagnosis includes candidiasis, in which there is a less well defined edge and outlying tiny pustules. Erythrasma is not usually inflammatory. Intertrigo, an inflammatory process common in the obese, in which friction sweating and minor bacterial infection cause erythema

1

390

Fig. 10.6 2 Fig. 10.7

FIG. 10.11 Tinea corporis Ring-shaped lesions with erythematous scaly borders and some central clearing.

TABLE 10.9 Types of tinea capitis Representative species

Wood's light fluorescence

Patchy baldness, with broken-off hairs and scaling of the scalp

Microsporum canis

Blue-green

Microsporum audouini

Green

Puppies, kittens Humans

Patchy baldness with black dots

Trichophyton tonsurans Trichophyton violaceum Trichophyton verrucosum Trichophyton schoenleinii

-

Humans

-

Humans

-

Cattle

Dull green

Humans

Clinical pattern

Kerion Favus

Source

in body folds, can mimic tinea cruris, but scrapings will be negative. Eczema and psoriasis can usually be recognized by their characteristic appearances on non-flexural skin elsewhere. For limited infection treatment with a topical imidazole is sufficient. For extensive involvement, topical steroidtreated cases, or when therapy fails, however, oral therapy is needed for 3-6 weeks. Tinea corporis Tinea corporis is often of animal origin, and is then selflimiting. Lesions are usually multiple and often, but not always, ring-shaped (Fig. 10.11). Because the appearances are so variable, scrapings should be taken from any red, scaly rash that cannot be readily diagnosed. If the disease is limited in extent, a topical agent is usually sufficient; if widespread, then oral terbinafine or itraconazole is preferable. Tinea capitis Many different fungal species can infect hair and scalp skin (Table 10.9). In the UK, tinea capitis is nearly always a

10

FIG. 10.12 Distal thickening and yellow discoloration due to fungal infection FIG. 10.13 Candidiasis, a superficial fungal infection

disease of children. Affected hairs may break off a few millimetres above the scalp, producing short stubble, or flush with the scalp, giving bald patches with black dots in dark-haired patients. 0 When there is a marked degree of inflammation, producing an appearance like that of a carbuncle, the lesion is called a kerion, and in this circumstance there may be concurrent staphylococcal infection. An appearance known as favus is now very rare in the UK. In this form yellowish cup-shaped crusts develop, together with hair loss. Both kerion and favus can produce permanent alopecia. Fungal infection can be distinguished from other causes of patchy hair loss by microscopy and culture.

Tinea of the hand A diffuse hyperkeratosis with fine powdery accentuation of the palmar creases, usually of only one hand, is the commonest pattern of tinea of the hand. If there is diagnostic doubt, scrapings should be taken.

Tinea of nails In many cases nail infection (onychomycosis) occurs in conjunction with fungal disease elsewhere. Predisposing factors include previous trauma and poor peripheral circulation. The toenails are more commonly affected than fingernails. The changes spread proximally from the free edge. The nailplate becomes discoloured and usually thickened, and may crumble away. It may also separate from the nailbed (onycholysis) (Fig. 10.12). Confirmation of the diagnosis by microscopy and culture of clippings should precede treatment. The differential diagnosis includes psoriasis, in which there is often a distinctive pattern of fine pitting. Candidal infection produces changes that begin proximally. Eczema can simulate fungal infection. Treatment is with oral terbinafine or griseofulvin.

Candidiasis Most human candidal infection is caused by Candida albicans (Fig. 10.13). This yeast is a common commensal in the

TABLE 10,10 Some factors facilitating candidal infection Local Maceration of skin Topical steroids Dentures Poor oral hygiene High oral carbohydrate levels

General Debility Extremes of age Immunosuppression by drugs or disease, particularly HIV Broad-spectrum antibiotics Corticosteroids Diabetes mellitus Iron deficiency Cushing's syndrome Hypocalcaemia/hypoparathyroidism Pregnancy

gastrointestinal tract, mouth and vagina, but not on the skin. However, it may become pathogenic (Table 10.10). Unlike the dermatophyte fungi, Candida invades living tissue. In some circumstances serious systemic infection can occur (see also p. 332). Some of the clinical patterns of candidal infection of the skin and mucosal surfaces are shown in Table 10.11. When infection is widespread and refractory to treatment this may be due to an immune deficiency. The skin lesions in such patients often resemble ringworm, and nails as well as nailfolds tend to be affected. There are several clinical/genetic types. In group I there is a well-defined major primary immune defect, e.g. Swiss-type agammaglobulinaemia. Group II comprises those cases without such a clear-cut primary immune defect. Subgroups include: • The Candida endocrinopathy syndrome, with hypoparathyroidism and Addison's disease being the commoner associated organ-specific autoimmune diseases • Autosomal recessive • Autosomal dominant

391

TABLE 10.11 Clinical patterns of Candida infection Type Oral Thrush Atrophic candidiasis Chronic hyperplastic candidiasis Angular stomatitis Skin Flexural

Anogenilal Vulvo-vaginitis Balanitis

Nails Paronychia Onychia

Pattern of infection

Features

White patches (Fig. 10.9) Painful red atrophic mucous membrane Thickened white adherent plaques Soreness and fissuring at the angles

Can be scraped off to reveal inflamed mucous membrane Common with antibiotic treatment and dentures Needs differentiating from leukoplakia Occurs in folds, usually due to ill-fitting old dentures

Sore, red, marginated skin, often with outlying pustules

Due to maceration

Itchy, sore with curd-like discharge Tiny red papules and pustules on glans and prepuce

Commoner in pregnancy

Painful swollen nail folds with loss of adhesion of cuticle Thickened, discoloured nails

Maceration predisposes. May have poor peripheral circulation Uncommon, often associated with immune detects

Usually from sexual partner

• Diffuse (severe) mucocutaneous candidiasis • Late-onset candidiasis, in which thymoma and HIV infection should be considered. Treatment of Candida infections Any remediable predisposing factors should be dealt with. Locally active agents include nystatin, amphotericin B and the imidazoles. For chronic oral candidiasis prolonged treatment is often necessary. Oral agents, including itraconazole and fluconazole, are usually required for chronic mucocutaneous candidiasis, a common problem in patients with symptomatic HIV infection. Long-term treatment is required.

Pityriasis versicolor Pityriasis (tinea) versicolor (Fig. 10.14) is a superficial infection caused by the mycelial form of the commensal yeast Pityrosporum orbiculare (also known as Malassezia furfur).

1 MCQ 10.3 2 Figs 10.8,10.9 392

FIG. 10.14 Slightly scaly macules of pityriasis versicolor; brown on a white skin (A) and pale on a tanned skin (B)

For most patients who have the disorder it is assumed that there has been a change in the pathogenicity of their surface commensal yeasts. Young adults are the most affected, and it is seen more in the tropics and subtropics. The distinctive hyper- and hypopigmentation is due to the diffusion into the epidermis of azelaic acid, a fatty acid from the fungus, which affects the melanocytes. Clinical features The upper trunk, arms and neck are the commonest sites. Lesions are macular and sharply demarcated, and have fine scaling. They may become confluent over large areas. On sun-protected 'white' skin the patches are skin-coloured or pale brown, but after sun exposure and in darker races they are hypopigmented. Scrapings show a mixture of clustered spherical yeasts and short mycelia. Under Wood's light the affected areas

fluoresce, and it is often apparent that the infection is more widespread than can be seen by visible light. Treatment Selenium sulphide 2.5% in a detergent base applied to affected areas and the scalp (a reservoir of yeasts), left on overnight and repeated a week later, usually clears the condition. Alternatives include topical imidazoles and oral itraconazole. 1 FURTHER READING IN SUPERFICIAL FUNGAL DISEASES Elewski B E. Hay R J, eds. 1999 Novel treatment strategies for superficial mycoses. J Am Acad Dermatol 40: Sl-42. Evans G V, Dodman B, Williamson D M, Brown G J, Bowen R G 1993 Comparison of terbinafine and clotrimazole in treating tinea pedis. Br Med J 307: 645-647.

VIRAL DISEASES

dysplasia verruciformis, predispose to squamous carcinoma. The hands, feet, face, around the knees, perianal and genital skin are the commonest sites for warts (Table 10.12). Because most warts resolve spontaneously, caution is needed in assessing therapy, and methods such as scalpel surgery and radiotherapy should be abandoned. For many non-genital warts, salicylic acid paints (or plasters for large plantar warts) are effective. Cryotherapy (p. 383) is uncomfortable but often more rapidly successful. Recently, intralesional bleomycin has proved effective. In selected cases curettage and minimal cautery may be needed. Genital and anal warts are frequently associated with other sexually transmitted diseases, requiring appropriate investigations. These lesions usually respond to liquid nitrogen cryotherapy or careful applications of podophyllin paint at weekly intervals, but this agent should be avoided during pregnancy because of the enhanced risk of absorption and fetal damage.

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Molluscum contagiosum Skin lesions are a common feature of many viral infections and may represent the direct consequences of virus replication (e.g. warts), the immune response to a virus, or interaction between the two. Only those where the skin or adjacent mucous membranes are the sole target are discussed here; the remainder, including herpes simplex and zoster, 2 are considered in Chapter 9.

Warts Warts arise because of hypertrophy of the prickle cell layer of the skin (or adjacent mucous membranes) induced by human papilloma virus. Warts are transmissible, inoculation being favoured by mild trauma. They are commoner in children and young adults, and are usually self-limiting and benign. However, some subtypes of virus (defined by DNA hybridization techniques), particularly those found in the genital tract and the rare condition epidermo-

Molluscum contagiosum (Fig. 10.16) is a contagious papular eruption caused by a DNA poxvirus. It occurs mainly in children but is also common in AIDS patients. The lesions are smooth, dome-shaped papules, often craterlike, with a central keratinous plug or depression. When multiple, they are typically in groups. Lesions are ultimately self-limiting. Direct microscopic examination of the cheesy contents or an entire curetted lesion reveals the characteristic eggshaped molluscum bodies. (These are epidermal cells filled with virus particles.) Electron microscopy can also be used. Single lesions can mimic benign or malignant epithelial tumours, e.g. keratoacanthoma or basal cell carcinoma. In young children it is often best to leave the lesions. Treatment is local destruction, e.g. with liquid nitrogen or by mildly traumatizing the papules and then painting with iodine.

TABLE 10.12 Viral warts Type of wart

Main site

Appearance

Common Plane (flat)

Hand Face and backs of hands Face and neck Scalp and neck Soles

Dome-shaped, papilliferous surface Flat-topped smooth papules (Fig. 10.15) Elongated Elongated with horny cap Circumscribed, often painful papules or nodules with altered surface pattern, sometimes with black dots Aggregation of numerous adjacent plantar warts Soft, velvety, vegetative papules and plaques

Filiform Digitate Plantar (verruca)

FIG. 10.15 Plane warts Multiple reddish-brown barely elevated lesions with a rough surface.

Mosaic plantar

Soles

Anogenital

Anal and genital regions

393

FIG. 10.17 Scabies burrows on wrists

FIG. 10.16 Domed umbilicated papules of molluscum contagiosum

Orf and milkers' nodules Orf is a poxviral disease of sheep, usually acquired directly from the perioral lesions that occur on lambs. Milkers' nodule is a similar condition acquired from infection of the teats of cows and ulcers in the mouths of calves. It is caused by a parapoxvirus. Several days after animal contact, a red papule appears and evolves into a 1-2 cm diameter smooth, bluish-red nodule, the centre of which may develop a crusted surface. There is often a whitish ring around the central crust with orf nodules 1 There may be lymphangitis and lymphadenopathy, and sometimes a rash on the limbs resembling erythema multiforme (p. 407). Resolution occurs in 3-4 weeks. Diagnosis is usually evident from the history but can be confirmed by electron microscopy. No treatment is required.

ARTHROPODS AND THE SKIN Numerous arthropods can inflict skin lesions on man, by the mechanisms listed below:

394

1

Fig. 10.10

4

Fig. 10.12

2

Fig. 10.11

3

MCQ10.4

• Mechanical trauma (e.g. horsefly, tungiasis) • Injection of toxins (e.g. some spiders, bees, wasps, ants) • Hypersensitivity (local and generalized) to injected materials (e.g. many arthropods, such as fleas, bedbugs); contact reactions (e.g. locusts); to an invading parasite (e.g. scabies); to retained mouth-parts, etc. (e.g. tick bite granulomas) • Secondary infection (e.g. many insect bites, scabies) • Transmission of disease (e.g. leishmaniasis, erythema chronicum migrans - caused by a spirochaete). Insect bite reactions should be suspected when there are grouped or linear arrays of itchy weals or papules. The lesions last longer than urticaria. Fleas and mites, often from domestic pets, mosquitoes, gnats, midges and bedbugs are frequent causes of this common problem. A careful history and examination of brushings from pets, their bedding and house dust can help identify the cause.

Scabies Scabies (Fig. 10.17) is an itchy dermatosis caused by the human mite Sarcoptes scabiei. Clinical features The female mite, just visible to the naked eye, makes the necessary journey from one human to another during close bodily contact and burrows into the horny layer, producing a serpiginous greyish elevation 1-10 mm long. Burrows are most commonly seen on the finger webs, wrists, elbows, around the nipples in women and on the male genitalia. In children the palms, soles and even the face may be colonized, and vesicles and pustules may be evident. In addition there is a widespread papular rash and extensive excoriation 0, probably the result of an allergic reaction to mite products. Generally there are only a few burrows at a time, but in so-called crusted or Norwegian scabies there are vast numbers, particularly on the hands. This mainly occurs in patients with learning difficulties, the immunosuppressed, the elderly and those who are unable to scratch.

With an initial attack there is a latent period of about 2 months before itching begins, but this period is reduced in subsequent episodes. The itching is often severe and tends to be worse at night. The distinctive burrows are usually overshadowed by widespread excoriations, eczematization and secondary infection.

The lesions following their bites often do not appear until well into the next day. They occur mainly on the face and upper limbs. The environment should be treated with an insecticide.

Diagnosis Mites can be extracted from burrows with a needle; somewhat easier is scraping the area after applying a drop of mineral oil or 30% potassium hydroxide and viewing the material microscopically for mites, eggs, faeces etc.

Lice are obligate human parasitic wingless insects. The itchy reactions are a result of sensitization. There are two species: Pediculus humanus, which occurs in two varieties - the head and the body louse - and Phthirus pubis, the pubic or crab louse.

Treatment The patient and all close contacts should be treated with a scabicide such as permethrin, lindane (gamma benzene hexachloride), malathion, or benzyl benzoate from the neck downwards. Properly applied, one dose is usually curative, but sometimes two applications 3 days apart are needed. Pruritus may continue for up to 2 weeks and can be helped by crotamiton (a less effective scabicide which also has antipruritic properties) or a topical steroid. 3

Other mites Dogs, cats, birds, grain and stored foodstuffs are sometimes sources of mites that can attack humans, producing itchy papules, often topped by tiny vesicles, and weals. Harvest mites, minute red creatures found in grass and other low vegetation, can produce similar and often very florid lesions. Diagnosis involves finding the offending mite, e.g. from brushings of pets.

Fleas Fleas include varieties that can burrow into skin (e.g. Tunga penetrans, found only in the tropics) and those that feed on the skin. In general the human flea is unusual, but occurs in overcrowded communities with poor hygiene. Bites from fleas living on pets, birds and occasionally wild animals, such as hedgehogs, are very common. The reaction to a flea bite is a hypersensitivity response. Individual lesions are like urticaria, but often have a haemorrhagic central punctum and last a week or two. They characteristically occur in groups, and often leave hyperpigmentation as they resolve. Troublesome itching can be treated with an oral antihistamine and secondary infection with an antibiotic. When the domestic pet is the source, the diagnosis can often be confirmed by examination of brushings from the animal. Flea faeces in this material stain damp white blotting paper red. Both the pet and the environment need appropriate treatment.

Bedbugs Bedbugs (Cimex lectularius) are nocturnal, wingless, bloodsucking insects that live in crevices in the walls, floor and furniture, and can best be seen in the middle of the night.

10

Lice

Head lice Head louse infection is very common in children, presenting as intense irritation, particularly at the back of the scalp. Secondary infection is frequent and may be mistakenly diagnosed as impetigo of the scalp. The insect is 3-4 mm long, but usually the eggs and egg cases (nits) are much more easily seen, firmly cemented to the hairs. Treatment is with malathion, a pyrethroid or carbaryl. Contacts should also be treated. Body lice The body louse is rare in developed countries, except in cases of self-neglect. There is widespread irritation, with papules and excoriation. The lice and their eggs are found on the clothing, particularly the seams, and are best treated by hot tumble drying. Pubic lice Pubic lice have legs somewhat like crabs' pincers, with which they are often found clinging to hairs. Secondary infection is common, and as these creatures are often acquired during sexual intercourse other venereal disease should be excluded. Treatment is with lindane (gamma benzene hexachloride), malathion or a pyrethroid.

PSORIASIS Psoriasis is a non-infective, usually chronic inflammatory skin disease with a number of clinical manifestations, the most common of which is red plaques covered by silvery scales (Fig. 10.18). 4 A distinctive arthritis may occur, and nails are often involved (Fig. 10.19). Genetic and environmental factors interact to account for the capricious natural history.

Aetiology Psoriasis occurs in about 2% of the population in Britain, but is less common in other countries, notably West Africa and Japan. The condition may present at any age, but onset is most common at puberty and the menopause. Additional triggering factors, of both onset and recurrence, are infection, especially streptococcal pharyngitis, which character-

395

Pathology and pathogenesis In the well-established psoriatic lesion there is epidermal thickening with increased mitoses, retention of nuclei in the horny layer (parakeratosis) accounting for the silvery scales, small collections of neutrophil polymorphs in the epidermis, tortuous dilated dermal capillaries and a dermal inflammatory infiltrate. Cell kinetic studies show that epidermal turnover occurs in 5-7 days, compared with the normal 30-45 days. Epidermal maturation is also abnormal, not just as a consequence of the rapid throughput. There is no comprehensive theory to account for the many abnormalities demonstrated in the epidermis, dermis, circulating granulocytes and lymphocytes, and the humoral immune system. CD4 helper lymphocytes in the dermis produce cytokines which initiate many of the inflammatory and proliferative events. From work in which psoriatic skin is explanted on to athymic nude mice it seems that the increased proliferation is intrinsic to the skin. It is likely that circulating factors determine the overall activity of psoriasis and maintain the inflammatory process in the plaques.

FIG. 10.18 Psoriasis Well-defined red plaque with silvery scales.

Clinical features The different patterns of psoriasis result from variations in expression of the disease (guttate, erythrodermic and pustular types) and modification of the features at certain sites, notably the scalp, flexures, palms and soles. The extent and duration are usually unpredictable, although some patterns are more likely to improve spontaneously, e.g. guttate psoriasis. Psoriasis means a condition (-iasis) of itching (psor-), but pruritus is not inevitable. 1 FIG. 10.19 Psoriatic arthritis Red swollen tender terminal interphalangeal joints with associated dystrophic nails.

istically provokes guttate psoriasis; trauma to the skin, generating new psoriatic lesions (Koebner's phenomenon, see below); and some drugs, notably lithium salts, systemic corticosteroids followed by their rapid withdrawal, and antimalarials. In some subjects UV radiation can initiate psoriasis on exposed skin. Rarely, hypocalcaemia provokes psoriasis. The importance of stress is disputed, but sudden psychological trauma can play a part in initiating the disease and causing relapse. The tendency to develop psoriasis is genetically determined but the mode of inheritance remains unclear. There is a close association with HLA-CW6 and HLA-DR7, the former conferring a 5-10-fold increased risk. HLA-B27 is seen in 70% of those patients with psoriasis and an ankylosing spondylitis pattern of spinal arthritis.

1 396

MCQ 10.5

2

Fig. 10.13

3

Fig. 10.14

Discoid or plaque psoriasis The well-defined, silvery-scaled red plaques may be found at any site, but the knees, elbows, extensor surfaces of limbs and the lower back are commonly affected. Scratching the scales reveals many tiny bleeding points. Flexural psoriasis Psoriasis of the axillae, groins and beneath the breasts is less readily recognized because the plaques are smooth, but usually remain more sharply defined than eczema. Lesions are typically symmetrical. Scalp psoriasis Scaling often becomes very thick, beneath which are telltale areas of well-defined erythema. 2 Psoriasis of palms and soles This may be more hyperkeratotic, without the silvery scale, but usually remains well defined. Guttate psoriasis There are numerous scaly papules and small plaques. 3 This type of psoriasis mainly occurs in children and adolescents. Erythrodermic psoriasis Total involvement of the skin can cause hypothermia and hypoproteinaemia (see also p. 410).

Pustular psoriasis Pustules occur when the neutrophil collections become clinically visible. The main varieties are a form localized to the palms and soles, in which yellow, white or greenish pustules (sterile) arise on erythematous scaly skin (Fig. 10.20), and a generalized type. In the latter the patient is ill, with fever and leukocytosis, and large areas of erythema develop myriad small sterile pustules which soon dry up and desquamate, to be followed by further waves of pustules. As with erythroderma, management entails rest, the prevention of hypothermia, and maintenance of fluid, electrolyte and protein balance, as well as control of the disease process. Localized pustular psoriasis of the palms and soles is probably genetically distinct, there being no association with HLA-CW6 or HLA-DR7, and often occurs without psoriasis elsewhere. Tar and dithranol are contraindicated in generalized pustular psoriasis, and generally unhelpful in palmoplantar pustular psoriasis. Psoriatic nail changes Common patterns are: • Multiple small pits, resembling a thimble (Fig. 10.21) • Onycholysis (separation of the nail), often with an adjacent zone of orange discoloration • Subungual (nailbed) keratosis • Thickening and distortion of nails. Nail changes are very common with psoriatic arthropathy involving the fingers.

FIG. 10.20 Pustular psoriasis of the soles Circumscribed areas of erythema, some scaling and pustules.

Psoriatic arthropathy Probably about 5% of psoriatics have a seronegative arthritis, although a much higher proportion have abnormalities detected by isotopic bone scans. Different patterns include:

10

• Distal arthritis - terminal interphalangeal joints of fingers and interphalangeal joints of toes • Simulation of rheumatoid arthritis, but more asymmetrical • Sacroiliitis and ankylosing spondylitis • Arthritis mutilans, involving multiple joints with marked bone resorption. Diagnosis and management are discussed on page 1151.

Management The choice of treatment will depend on many factors. These include the capabilities and lifestyle of the patient, as well as the type, location, extent and severity of the psoriasis. The options shown in Table 10.13 will not be appropriate for every patient, and are often used in combination. Some patients will prefer not to have any treatment. Nails do not respond well to topical therapy, but may improve with the rest of the psoriasis, especially when systemic treatments are used. Topical therapy Rest and bland applications are important in acutely inflamed psoriasis, erythrodermic and generalized pustular psoriasis. Many cases with discoid lesions respond well to tar and dithranol preparations, although, particularly with the latter, it is wise to begin with a weak preparation and gradually increase the potency to minimize irritation. Topical steroids are less likely to clear psoriasis completely, but with due attention to their potential hazards they are useful for areas that are readily irritated, such as the flexures, genitalia, ears and face; they are often more effective on the palms and soles. The most potent preparations are

FIG. 10.21 Psoriatic nail showing thimble-like pitting

397

CASE STUDY 10.1 A WIDESPREAD RASH IN A 35-YEAR-OLD WOMAN FOLLOWING AN UPPER RESPIRATORY TRACT INFECTION A 35-year-old married woman presented complaining of the sudden onset of a widespread rash, beginning 2 weeks after a severe sore throat for which she had received a course of penicillin. There was no previous history of skin disease but her mother and older sister both had psoriasis. On examination there were numerous well circumscribed, discrete red scaly plaques on the trunk, elbows and knees. There were also lesions in the scalp (Case Fig. 10.1.1).

Questions 1. What is the most likely diagnosis? 2. What other condition should be considered? 3. What treatment should be instituted?

Discussion The most likely diagnosis is guttate psoriasis. The sudden onset following a sore throat (probably streptococcal) is typical and the patient has a positive family history. Pityriasis rosea can also present in this way and can sometimes be difficult to distinguish, especially in the first week or two. However, lesions on the limbs and the scalp are rare in pityriasis rosea. The most effective treatment in this case would probably be the combined use of topical tar preparations and ultraviolet B (UVB) phototherapy, although some dermatologists would also use moderately potent topical steroids and/or vitamin D analogues (calcipotriol or tacalcitol), either as well as or instead of the tar. The phototherapy would normally be administered in a specialist facility

1

398

MCQ 10.6

twice weekly, initially for 6-8 weeks, before an assessment of the response was made. If the condition failed to settle satisfactorily, further measures might need to be considered. Questions 4. What therapies might be offered to this woman if firstline therapy fails? 5. What additional factors need to be considered in reaching the appropriate decision? Discussion It may be necessary to commence topical therapy with dithranol, an anthracene derivative which can eradicate psoriatic plaques completely. However, the treatment is messy, time-consuming and can, if mishandled, result in burns and staining of both skin and clothes. This woman was a busy executive with an international marketing company and was unable to accept the inconvenience dithranol would have caused. There is a case to be made for at least a short course of

CASE FIG. 10.1.1 Plaques of psoriasis

systemic therapy with acitretin (a retinoid), methotrexate or ciclosporin. It is important to discuss the implications of each of these drugs with the patient and her husband. They need to understand that acitretin is teratogenic. It may also cause hyperlipidaemia and a (usually mild) hepatitis. It is important to avoid pregnancy while on the drug and for 2 years after stopping. Methotrexate can, in exceptional circumstances, cause severe bone marrow suppression, but its main problem is hepatotoxicity if used over long periods. Ciclosporin is expensive and may cause renal and cardiovascular damage. In the circumstances this woman and her husband agreed that it was sensible, after all, to try to use dithranol at home under the supervision of a specialist nursing team from the hospital. Although progress was slow, the psoriasis reduced considerably in extent and the woman was able to manage her disease effectively thereafter with a combination of topical steroids and vitamin D analogues.

10

TABLE 10.13 Treatment choices in psoriasis Form

Site

First choice

Second choice

Third choice

Plaque

Face, flexures genitalia Scalp Trunk, Limbs: few plaques Trunk, limbs: many plaques

Topical steroid Tar gel or pomade Dithranol or calcipotriol Calcipotriol Dithranol ± UVB UVB Topical steroid Tar Dithranol

Mild tar or weak dithranol Dithranol or calcipotriol Tar PUVA

Topical steroid Topical steroid Systemic therapy, e.g. methotrexate cyclosporin

PUVA

Oral retinoid

Guttate

Calcipotriol ± UVB

UVB ± tar

Topical steroid

Erythrodermic with systemic complications

Oral retinoid

Methotrexate

Systemic steroid

Topical steroid Oral retinoid

PUVA Methotrexate

Oral retinoid Other systemic therapy

Palms and soles

Pustular psoriasis

Palms and soles Generalized

best avoided, except on the palms and soles, and even there they should be restricted to short courses. The vitamin D analogue calcipotriol is effective and provides an effective alternative to tar and dithranol. Ultraviolet (UV) radiation and photochemotherapy Ultraviolet B (p. 426) is used both alone, e.g. for guttate psoriasis, and together with other modalities. Photochemotherapy (also known as PUVA) is the combination of long-wave UVA and the photosensitizing drug psoralen, usually taken orally 2 hours previously. It is a powerful treatment for psoriasis, but prolonged use is likely to age the skin prematurely and to induce non-melanoma skin cancer. Photochemotherapy is valuable for extensive plaque psoriasis when topical therapy is poorly tolerated or has failed, and can be successful for erythrodermic and pustular forms. Systemic therapy For the most severe forms of psoriasis, antimitotic and immunosuppressant drugs are used. Methotrexate is effective and reasonably safe. In long-term use hepatic fibrosis can occur and liver biopsies are recommended every 1-2 years to identify this before it is irreversible. Alcohol should be avoided. Ciclosporin has recently been introduced for the treatment of cases where methotrexate is unsuitable. This drug is not antimitotic, and probably works by modulating the immune system. The main hazard is nephrotoxicity. Vitamin A derivatives (retinoids) with less toxicity than vitamin A itself have been found to be of value in pustular and erythrodermic psoriasis, and useful in combination with other treatments, e.g. photochemotherapy. Retinoids have a number of side-effects and, like methotrexate, are teratogenic, but they are not cytotoxic or immunosuppressant. They probably influence the disturbed maturation of the epidermis in psoriasis. 1

FURTHER READING ON PSORIASIS Greaves N W, Weinstein G D 1995 Treatment of psoriasis. N Engl J Med 332:581-588. Stern RS 1997 Psoriasis. Lancet 350:349-353. Workshop of the Research Unit of the Royal College of Physicians of London: Department of Dermatology, University of Glasgow, British Association of Dermatologists 1991 Guidelines for management of patients with psoriasis. Br Med J 303: 829-835.

ECZEMA AND DERMATITIS Eczema is a pattern of inflammation with many possible causes, rather than a disease. The different types are unified histopathologically by the presence of spongiosis in the epidermis. The term 'dermatitis' is often used to imply an eczema of external origin, but it should always be qualified, as in 'contact allergic dermatitis', as 'dermatitis' is used in many other contexts, e.g. dermatitis artefacta, dermatitis herpetiformis etc. Eczema is usually itchy and red; when the inflammation is intense, vesicles are seen and there is oozing from the surface (Fig. 10.22). If the process continues, scaling and thickening occur, and with rubbing and scratching lichenification (the development of leather-like plaques) is common. The earliest and most distinctive pathological change is spongiosis, the accumulation of oedema fluid within and between keratinocytes. Viewed in microscopic section, this produces an appearance somewhat like a sponge. In acute eczema the process extends to produce intraepidermal vesicles. In the dermis, and to a lesser extent the epidermis, there is an inflammatory infiltrate in which lymphocytes

399

contact allergen. The face is often affected, even when not directly exposed to a causative agent.

EXOGENOUS ECZEMA Irritant contact dermatitis When the skin changes are a direct result of exposure and allergic mechanisms are not involved, the rash is termed irritant contact dermatitis. Not all reactions to irritants are eczematous; for example, the agent may produce necrosis or urticaria. Because obvious irritants tend to be avoided, the main problems occur with those that require prolonged and repeated contact, e.g. detergents, alkalis, mineral oils and organic solvents. Atopic individuals are particularly susceptible, as are housewives, hairdressers and those in a number of industrial occupations. Even when a period of avoidance produces healing, chronic irritant dermatitis tends to recur readily with re-exposure.

Allergic contact dermatitis

FIG. 10.22 Eczema With intense inflammation there are vesicles and oozing. If the process continues, scaling and thickening occur.

are prominent. With time, both the epidermis and dermis become thickened. Aetiological factors in eczema include: • • • • • • •

400

Skin irritants Contact allergens Friction, low humidity, UV light Infections (bacterial, dermatophytes, yeasts) Atopic constitution Drugs and foods Local factors: venous stasis, ichthyosis.

Several factors may act in concert, particularly with eczema of the hand and lower leg, and not infrequently treatment is an inadvertent contributory factor. A careful history is essential in the evaluation of eczema. Several different clinical patterns of eczema and dermatitis (with eczematous features) are recognized. The basis for these patterns is well understood in some instances (e.g. contact allergic dermatitis) but obscure in others (e.g. discoid eczema). Because successful management depends on recognizing external factors that are contributing to the skin disease, it is helpful to classify according to whether the disease process is primarily exogenous or endogenous, although these distinctions are somewhat artificial. Whatever- the cause, while active, eczema tends to spread, often beyond any recognizable stimulus such as a

Allergic contact dermatitis is the response to a substance to which the individual has become sensitized. Most such substances are of low molecular weight and penetrate the skin to behave as haptens. After conjugation with a skin protein the complete antigen is taken up by Langerhans' cells, which migrate to regional lymph nodes and act as antigen-presenting cells in a T lymphocyte-mediated (type IV) immune response. All subsequent contact with the sensitizer results in an acute eczematous reaction. This type of response is uncommon in children, although contact urticaria is frequent in atopies (see below). Contact allergic dermatitis usually begins at the site of contact, but the clinical picture can at times be deceptive, e.g. nail varnish resin, which causes no trouble locally but gives rise to eczematous patches when it is transferred to the face and neck by the fingers. Many factors determine the acquisition of contact allergy. Some substances, e.g. epoxy resin and poison ivy, are inherently more likely to sensitize. Occlusion (e.g. a hand in a glove) and skin damage (e.g. from irritants) enhance penetration. It is possible that some individuals are more likely than others to be sensitized. The thick horny layer of the palms renders them less likely than the dorsa of the hands to be affected. Once initiated, repeated exposure tends to produce increasingly severe and widespread dermatitis, and sites far removed, such as the eyelids, can be involved. The allergic state usually persists for life. Some common sensitizers are listed in Table 10.14. Investigation: patch testing The allergic state is reproduced in miniature by the application of a non-irritating dose of a suspected chemical beneath an occluding disc or patch placed on the back for 48 hours. Because some allergens are ubiquitous, a

CASE STUDY 10.2 A 25-YEAR-OLD NURSE WITH AN ITCHY RASH ON HER HANDS A 25-year-old nurse developed an itchy rash that particularly involved her hands. She had been working on the labour ward for the previous 3 months. She reported to the hospital occupational health department one morning because of pain and swelling in her right hand. She had been feeling unwell, had been shivery, and had had aching muscles for the previous few hours. She had a past history of eczema in childhood and urticaria when given penicillin. She had bouts of sneezing when near furry animals. In her family history there was a sister with asthma. On examination she appeared unwell, had a temperature of 38.5°C, an erythematous, swollen, tender right hand, and both hands showed areas of erythematous thickening, fissuring and yellow crusts (Case Fig. 10.2.1). There were erythematous and excoriated patches and plaques on the chest and, back, and behind the knees. Questions 1. What is the most likely reason for the febrile illness and swollen right hand? 2. What investigations would be appropriate in this case? 3. What would be your immediate management? She has cellulitis secondary to a breach in the skin owing to hand eczema. The most likely cause is Bhaemolytic streptococcus group A, but Staphylococcus aureus, both organisms, or less probably some other bacteria, e.g. from her workplace, are also possible causes. Bacteriological confirmation is valuable, especially since she is systemically unwell; works in a hospital environment; and has a history very suggestive of allergy to penicillins. Useful investigations at the outset are swabs from crusted lesions, blood cultures, a full blood

count and serum antistreptolysin O titre (ASOT) and antideoxyribonuclease B (ADB). It was decided to admit her to hospital for parenteral therapy with i.v. cefuroxime. She tolerated this well and made a full recovery over the next 5 days. Investigations gave the following results: Hb 13.5 g/dL, WBC 23 x 10"/L, neutrophils 95%, ASOT 300, ADB >1200. Cultures from the skin showed Staph. aureus, sensitive to flucloxacillin. Blood cultures were negative. Note that she had a neutrophil leukocytosis, and of the two serological tests for evidence of acute streptococcal infection only the ADB was unequivocally positive. In general, ASOT is more commonly positive with pharyngeal infections. She was discharged and returned to work 1 week later. Shortly thereafter, she found that her hands became red and itchy again, but this time the eruption was over both hands and extended on to the wrists. She saw her GP, who prescribed betamethasone valerate cream (a potent topical corticosteroid) to use twice daily and an emollient for the dryness, but her hands did not improve. A referral

10

letter was sent to the local dermatologist but before she could be seen she had an episode of acute shortness of breath and collapsed while eating a salad in a restaurant. She was taken to the nearest A & E department and was found to be hypotensive, dyspnoeic, with grossly swollen lips and tongue, and with an extensive urticarial eruption. Anaphylaxis was diagnosed; she was treated with parenteral adrenaline (epinephrine), chlorphenamine (chlorpheniramine) and hydrocortisone, and made a rapid recovery.

Questions 4. What is the likely mechanism for the acute anaphylactic reaction? 5. How can it be investigated? Release of inflammatory mediators, especially histamine, from mast cells and basophils is the most common cause of acute anaphylaxis. In this case the release was probably IgE mediated. Other mechanisms include the direct action of some pharmaceutical agents (e.g. opiates) and circulating immune complexes.

CASE FIG. 10.2.1 Lymphoedema of the hands following recurrent eczema and infection

401

CASE STUDY 10.2 CONTINUED Investigations for IgE-mediated reactions include prick tests and in vitro methods such as the RAST (radioallergosorbent test). When the patient was evaluated by the dermatologist, the history revealed that she had had an acute swelling of the lips when blowing up balloons a few weeks earlier, and had also noted that her hands were becoming red and itchy immediately after she put rubber gloves on. Serum was sent for a RAST to latex proteins, and was strongly positive. As well as being relevant to her immediate reactions to rubber gloves and balloons, her hypersensitivity to latex proteins probably explains her episode of anaphylaxis in the restaurant: she had eaten avocado in the salad, and this is one of a number of plants which have proteins that cross-react with latex protein. Others include banana, chestnut and kiwi. She was also patch tested and had a positive reaction to sorbic acid (the preservative in her emollient cream). Discussion This case illustrates a number of problems that can occur in the atopic individual. Having had self-limiting eczema as an infant, the patient developed it again as an adult when her hands were subjected to repeated hand-washing with detergents and soaps in her work as a theatre nurse.

The skin in someone with atopic eczema commonly becomes colonized with Staph. aureus and sometimes Strep. pyogenes group A, and this led on to acute soft tissue infection (cellulitis). It is common for streptococcus not to be cultured from either the surface or the blood, and diagnosis only to be confirmed serologically. The interpretation here is that the cellulitis was due to B haemolytic streptococcus; the Staph. aureus was a superficial infection only. In a patient known to be allergic to penicillins there is some risk of cross-hypersensitivity with other antibiotics containing the (3lactam ring in their structure, but the risk was thought to be low because she had had urticaria without systemic symptoms many years ago. There is also a possibility that the causative organism would not be sensitive to a macrolide (e.g. erythromycin), which would otherwise be a reasonable choice. Hence the decision to admit her and give cefuroxime, a cephalosporin, albeit with a small risk of an allergic reaction. If she had been working on a medical ward there could well have been a significant risk of her being infected with a multiresistant Staph. aureus (MRSA), in which case i.v. vancomycin would have been the drug of choice. In a patient with continuing hand eczema, patch testing was the

selection of common sensitizers is tested as well as any chosen on the basis of the patient's history. A positive reaction does not prove the cause of a patient's rash, but does help confirm suspicions and suggest unsuspected materials. Positive reactions may be of past relevance only. Light-induced eczema Eczema on light-exposed skin may be due to:

1

402

Fig. 10.15

appropriate step to take to evaluate whether contact allergy (type IV hypersensitivity) was playing a part in addition to atopy and irritant exposure. She was tested for a large number of potential allergens, including those in her treatments. When it was found that she was allergic to the preservative in her emollient, this was changed to a soft white paraffin product with no preservatives, and all the areas where she had been applying the bland cream to dry skin improved. Type I allergy to the low molecular weight proteins in latex has become increasingly common over the past decade, especially in atopies, and is a significant hazard for nurses and doctors because of their frequent use of rubber gloves. Direct exposure of the allergenic material to internal surfaces (e.g. introduction of a rubber catheter) can be fatal. In this patient, whereas contact with rubber produced urticarial reactions, limited to the skin (her hands and lips), the ingestion of avocado led to acute anaphylaxis. With avoidance of allergens, use of a soap substitute, soft white paraffin as emollient and a mild corticosteroid ointment, the patient's hands recovered and she was able to return to work. She now uses vinyl gloves, rather than rubber ones, for hand protection.

• Photocontact allergy, e.g. sunscreen medicaments. The essential role of UV radiation is shown by patch testing with and without UVR • Photosensitive drug eruption, e.g. chlorpromazine, sulphonamide, thiazide • Exacerbation of existing eczema, e.g. atopic dermatitis. Phototoxic reactions, which resemble sunburn rather than eczema, can occur following contact with tar and its derivatives, some dyes and plants, and with drugs (p. 418). Sensitivity to airborne allergens can closely mimic light reactions, but areas normally spared from sun exposure, such as the skin beneath the ears, under the chin and

10

TABLE 10.14 Some common sensitizers Chemical

Source

Nickel Chromate Epoxy resin Paraphenylenediamine Rubber antioxidants Preservatives Lanolin Perfumes Topical drugs

Jewellery, watch bands, silver coins Wet cement, many engineering processes, leather Two-part glues Hair dyes Gloves, shoes Cosmetics and medicaments Cosmetics and medicaments Cosmetics and medicaments Neomycin, antihistamines, sulphonamides, some local anaesthetics Sticking plasters, newsprint

Colophony

around the eyes, are involved. Dermatomyositis may occasionally mimic a light-induced eruption.

ENDOGENOUS ECZEMA Atopic eczema/dermatitis Atopic eczema/dermatitis (Fig. 10.23) is closely associated with asthma, hay fever, urticaria and dry skin. There is usually a family history of one or more of these. The separate condition ichthyosis vulgaris (p. 405) is probably more common in atopic individuals than in the rest of the population. The skin readily becomes itchy in response to a number of allergic and non-allergic stimuli, and the pruritus may be disproportionate to the physical signs. High levels of circulating IgE antibodies are very common, as are multiple positive prick tests. The disorder is very common, most cases beginning in infancy, and at least 10% of the population are affected to some degree. There is often a fluctuating course, but most cases clear up by adulthood, the majority within the first 5 years of life. Aetiology There is much evidence for a genetic basis for the atopic state, although how this is translated into the various clinical manifestations is unknown. A number of immunological abnormalities have been described, including the overproduction of IgE, reduced numbers of suppressor/cytotoxic T lymphocytes, and cutaneous basophil hypersensitivity, e.g. to house dust mite antigen. Environmental factors are important determinants of fluctuations. These include ingested proteins (e.g. dairy products and eggs), and exposure to house dust mites, pollens and pet hair. Wool next to the skin frequently causes irritation. Extremes of climate often worsen the disease. Beyond a certain level of colonization, Staph. aureus may produce flares of erythema and pruritus.

FIG. 10.23 Atopic dermatitis in a young child: erythema, weeping and crusting

Clinical features Onset is often in the first 3 months of life. Itching is the major symptom and at times there may be little rash. In infancy the skin is often patchily dry and red, with episodes of vesiculation and crusting. By 1-2 years the elbow and knee flexures, wrists, hands and tops of the feet are typically involved. With prolonged rubbing and scratching, papules and then leathery plaques (lichenification) are seen. 1 At any stage secondary infection may occur, with superimposition of impetigo and follicular pustules. Urticaria from contact, e.g. with a pet or foods, is also common. Complications Eczema may be complicated by erythroderma (p. 409). Severely affected children are often growth retarded. Herpes simplex infection can be widespread (eczema herpeticum) and, particularly in the very young, may be disseminated to internal organs, with potentially fatal outcome. If eczema herpeticum is suspected, treatment with aciclovir (i.v. if the patient is unwell) should be commenced immediately. When eczema begins in infancy or early childhood the prognosis for recovery is generally good. Adults can be affected, especially when the skin is exposed to irritants, e.g. in nursing and hairdressing. Management The mainstays of management are the avoidance of irri-

403

SUMMARY 1 Classification of eczema Exogenous Irritant contact dermatitis Allegic contact dermatitis Light-induced dermatitis

Endogenous Atopic eczema/dermatitis Discoid (nummular) eczema Seborrhoeic eczema/dermatitis Pompholyx Asteatotic eczema Gravitational eczema

tants such as bubble bath, mild topical steroids, plentiful use of emollients when the skin is dry, antibiotics when necessary, tar preparations for the more chronic and less inflamed lesions, and a sedative antihistamine at night. Cotton clothes and the use of a soap substitute, e.g. emulsifying ointment or aqueous cream BP, are helpful. Current evidence suggests that children of atopic families should be breastfed, at least up to 3 months if possible. Subsequent supervised dietary manipulation may be helpful.

Discoid eczema Discoid (nummular) eczema consists of discrete rounded patches of eczema, usually symmetrically distributed, for which there is no apparent cause. The aetiology is unknown and treatment is symptomatic. A group 1 or 2 potency topical steroid is often needed, and infection, if present, should be treated with an antistaphylococcal antibiotic.

Seborrhoeic eczema/dermatitis Seborrhoeic eczema/dermatitis (Fig. 10.24) is distinctive in both appearance and location. The cause is unknown, but Pityrosporum yeasts play a part. There is usually no correlation with sebaceous activity, although it is a disorder of areas where sebaceous glands are plentiful. Severe seborrhoeic dermatitis is an early feature in about one-third of AIDS patients. There is less itching than with other eczemas. The lesions are yellowish-red, scaly away from flexures, and involve some or all of the following sites: scalp, eyelids, eyebrows, sides of nose, ears, axillae and groins, beneath the breasts, front of the chest, and upper back. The differential diagnosis will depend on the sites affected. In the scalp, psoriasis can be very similar. In the flexures, psoriasis, contact allergic dermatitis, dermatophyte infections and candidiasis may need to be excluded; the truncal form can resemble pityriasis rosea and pityriasis versicolor (the latter diagnosed from a scraping). Methyldopa can produce a seborrhoeic dermatitis-like drug eruption.

1 Fig.10.16 404

2

MCQ 10.7

FIG. 10.24 Nasolabial erythema and scaling of seborrhoeic dermatitis

The addition of sulphur, a mild tar, salicylic acid or an imidazole to a suitable topical steroid is often helpful. Shampoos containing ketoconazole, selenium sulphide or zinc pyrithione are useful for scalp involvement.

Pompholyx Pompholyx is an eruption of vesicles on the sides of fingers, palms and soles. Itching may be severe. The condition is usually episodic. Causes of pompholyx include the onset of warm weather; dermatitis or fungal infection of the feet (producing pompholyx of hands); ingestion of a contact allergen, e.g. nickel; and stress. Often no cause can be found. Treatment is symptomatic. If weeping is present, potassium permanganate soaks are helpful, followed by a group 1 or 2 potency topical steroid. Secondary infection is common and should be treated with a systemic antibiotic.

Asteatotic eczema Asteatotic eczema is a mildly inflammatory condition that occurs mainly in the elderly on the shins, as erythema with a crazy paving-like pattern of superficial fissuring and scaling. It may be a result of reduced epidermal lipids. Hypothyroidism, uraemia, dehydration, low humidity and overzealous cleansing may contribute. It often responds to less bathing and to emollients. A mild topical steroid ointment can be added if necessary.

Gravitational eczema 1

10

Eczema often occurs on the lower legs as a response to chronic venous hypertension, in association with haemosiderin staining, patchy atrophy, sclerosis, oedema, and perhaps ulceration. It is particularly common near the medial malleolus in patients with previous deep vein thrombosis, but may also be seen in relation to varicose veins and incompetent perforating veins (p. 429). Patches indistinguishable from those of discoid eczema may spread elsewhere. Important in management are improvement of the venous hypertension, e.g. with support hosiery, and the avoidance of potent topical steroids and potential sensitizers, such as neomycin, lanolin and preservatives. Symptomatic treatment of eczema Any causative and aggravating factors should be removed if at all possible. Acute weeping eczema can be soothed with wet compresses, e.g. aluminium acetate lotion BNF or 1:10000 potassium permanganate solution, followed by a topical steroid cream. In some cases, particularly contact allergy, when a cause has been recognized and dealt with, a short course of systemic steroids is justified. For less acute eczema, a topical steroid of the lowest effective potency is needed, often in a greasy base. If the surface is dry, additional applications of an emollient are helpful and reduce the likelihood of steroid overuse. For chronic lichenification, tar preparations (e.g. as impregnated bandages) are valuable. Secondary infection is usually best treated with a systemic antibiotic, e.g. flucloxacillin or erythromycin. 2

FURTHER READING ON ECZEMA AND DERMATITIS Brehler R et al 1997 Recent trends in the treatment of eczema. J Am Acad Dermatol 36:983-994 Charman C 1999 Clinical evidence: atopic eczema. Br Med J 318:1600-1604 Friedmann P S 1998 Allergy and the skin II - contact and atopic eczema. Br Med J 316:1226-1229 McHenry P M et al 1995 Management of atopic eczema. Joint Workshop of the British Association of Dermatologists and the Research Unit of the Royal College of Physicians. Br Med J 310:843-847

ICHTHYOSIS The term ichthyosis is used for a number of conditions in which there is either a disorder of keratinization or shedding of the horny layer, producing persistent, generalized scaly skin (Fig. 10.25). Most types of ichthyosis are inherited and present in infancy or childhood. Onset in adulthood can be associated with an underlying neoplasm (p. 423). Ichthyosis vulgaris is the only common type, occurring in about 1 per 300 of the population. It is inherited as an auto-

FIG. 10.25 Rough skin and scaling of ichthyosis

somal dominant trait and has distinctive histology: absence of the granular cell layer of the epidermis. Individuals have rough skin with white scales, maximal on the extensor surfaces and sparing the antecubital and popliteal fossae. There are often rough follicular papules (keratosis pilaris) on the upper arms and thighs. The physical signs are worse in winter. Avoidance of soap and regular use of emollients are helpful measures. Sex-linked recessive ichthyosis occurs in about 1 per 6000. Female carriers may show mild changes, but the fully developed condition, as seen in males, is more severe than ichthyosis vulgaris, with large brownish scales; the flexures are involved. The condition is characterized by steroid sulphatase deficiency. Acquired ichthyosis has a similar clinical pattern to ichthyosis vulgaris. As well as being associated with neoplasia, particularly Hodgkin's disease, it can occur in gross nutritional deficiency.

REACTION PATTERNS Despite the large number of named diseases, as an organ the skin has a limited range of reactions to noxious stimuli such as circulating immune complexes and infections. Some of these reaction patterns have sufficiently few common causes that their recognition can be helpful in arriving at a diagnosis. This may be particularly true when the patient has other symptoms, e.g. cough or malaise, for which there is no obvious cause.

405

SUMMARY 2 Reaction patterns • • • • • •

Urticaria and angioedema Erythema multiforme Erythema nodosum Pyoderma gangrenosum Cutaneous vasculitis Erythroderma

A single aetiological factor may produce one or more of the reaction patterns described below. For example, the hepatitis B virus may lead to urticaria if the effect on dermal blood vessels is fully reversible, but purpuric vasculitis if the damage is more profound. FIG. 10.26 Urticaria: arcuate weals

URTICARIA AND ANGIOEDEMA The characteristic lesion in urticaria is a weal (Fig. 10.26). This is caused by oedema in the dermis, so weals are raised and often pallid but surrounded by a zone of erythema. Urticaria is evanescent, usually lasting from minutes to a few hours (rarely more than 24 hours) and fades without trace. Itching may be severe. Lesions initially like urticaria may occur in vasculitis, arthropod bites and stings, and lupus erythematosus, but in these circumstances they are more long-lasting. If there is doubt, a skin biopsy can be helpful in distinguishing these conditions. Urticaria lasting more than 3 months is regarded as chronic, and in most cases no cause is found. Angioedema occurs in the subcutaneous tissues, particularly where they are rather loosely organized, such as in and around the mouth, around the eyes and on the scrotum. 1 The lesions are larger, less well defined and not necessarily itchy. Common causes of urticaria and angioedema are listed in Table 10.15. Many cases of chronic idiopathic urticaria are now recognized to be due to IgG autoantibodies directed against the high-affinity IgE receptor and, less commonly, IgE itself. The basis for urticaria and angioedema is vasodilatation and extravasation of fluid owing to release of mediators from mast cells and/or basophils. In some circumstances the mediators responsible can cause hypotension and bronchospasm, constituting anaphylactic shock (p. 97). Mechanisms include IgE and immune complex-mediated reactions, and direct effects of chemicals, e.g. toxins and drugs. Symptomatic treatment is with H1 antihistamines. Hereditary angioedema is a rare but potentially lifethreatening condition, in which non-pruritic swellings

TABLE 10.15 Common causes of urticaria and angioedema Drugs Penicillin, aspirin, X-ray contrast medium Foods Azo dyes, benzoate preservatives (chronic urticaria) Arthropod reactions Transfusion of blood products and foreign proteins

Plants Stinging nettles Systemic disease Hepatitis B, other virus infections systemic lupus erythematosus Contact urticaria Some foods and pet saliva on atopies Latex Inhalants Grass pollens, house dust

Physical stimuli Light pressure (dermographism), cold, light, increase in body temperature (cholinergic urticaria)

occur in the gastrointestinal and respiratory tracts as well as the skin and adjacent mucous membranes. A careful family history may suggest the diagnosis. There is either deficiency or an abnormality of the inhibitor of activated complement component Cl. The best laboratory investigation is the measurement of Cl esterase inhibitor by antigenie activity or functional assay. Also useful is the demonstration of low C4 and C2, the substrates of activated and unopposed Cl. Acute episodes may respond to Cl esterase inhibitor concentrate, and danazol can be used to suppress attacks. © FURTHER READING ON URTICARIA

406

1 Fig. 10.17 4 Fig. 10.19

2

MCQ 10.8

5

MCQ 10.9

0 Fig. 10.18

Kaplan A P 2002 Chronic ruticaria and angioedema New Engl J Med 346:175-179. Sabroe R A, Greaves M W 1997 The pathogenesis of chronic idiopathic urticaria. Arch Dermatol 133:1003-1008.

10

FIG. 10.27 Erythema multiforme: target lesions with central blisters

ERYTHEMA MULTIFORME AND STEVENS-JOHNSON SYNDROME The causes of erythema multiforme include: • • • • •

Herpes simplex Other infections, e.g. mycoplasma Drugs, e.g. sulphonamides Pregnancy Collagen vascular disease, e.g. SLE.

The distinctive features of erythema multiforme are the target lesion (Fig. 10.27), the distribution of the rash and the histology. It is an acute eruption that usually lasts about 3 weeks, maximally involving the hands and feet, forearms, 3 elbows and knees. Among a variety of erythematous lesions there are usually some target lesions. These have a purplish or blistering centre inside one or more red rings. The mucosae of the mouth, 4 genitalia and eyes may be involved (Stevens-Johnson syndrome, Fig. 10.28) with blistering and haemorrhage. Sometimes internal organs, e.g. the kidney and lungs, are affected. There is an interval of about a week between the stimulus and the eruption, but this is shorter with recurrences. The pathogenesis is not fully understood. When erythema multiforme is recurrent, the most common cause is herpes simplex. The condition is self-limiting but supportive care is needed, especially if there is eye and oral involvement. This will include oral toilet, analgesia, antibiotics, treatment of ocular complications and, in cases with widespread blistering, management as for burns on an intensive care unit.

FIG. 10.28 Stevens-Johnson syndrome Severe muco-cutaneous erythema multiforme due to mycoplasma infection. Note the conjunctivitis, haemorrhagic crusting on the lips and target lesions.

nodosum is often accompanied by fever, malaise and painful joints. Lesions disappear over 3-6 weeks, with the same colour changes as in a resolving bruise. It is mainly a condition of young adults. Most cases are probably due to circulating immune complexes lodging in or near the venules in the deep dermis and subcutaneous fat. Causes include: • • • • •

Sarcoidosis Streptococcal infection Ulcerative colitis and Crohn's disease Tuberculosis Other infections, e.g. yersinia, deep mycoses (where e.g. blastomycosis occurs commonly), Chlamydiapsittaci and lymphogranuloma venereum • Drugs (uncommon), e.g. oral contraceptives, sulphonamides • Leukaemia and Hodgkin's disease. 0 Similar but smaller nodules are seen in Behcet's disease (p. 1153). Erythema nodosum leprosum is clinically and histologically quite different (p. 327). The lesions of nodular vasculitis are more persistent and occur more on the calves. Bed rest is advisable at first, and a non-steroidal antiinflammatory drug may be helpful. Further management will depend on the cause.

ERYTHEMA NODOSUM The plaques and nodules of erythema nodosum (Fig. 10.29) are red, hot and tender. They typically occur over the shins but may be more widespread on the legs, on the outer aspect of the arms and sides of the neck. Erythema

PYODERMA GANGRENOSUM Pyoderma gangrenosum (Fig. 10.30) is an uncommon, noninfective ulcerating condition frequently associated with an

407

FIG. 10.30 Pyoderma gangrenosum: ulcer with purplish undermined edge

small lesions topical and intralesional corticosteroids can be effective; minocycline can be a valuable agent in milder cases.

CUTANEOUS VASCULITIS FIG. 10.29 Erythema nodosum Tender erythematous nodules over the shins in a young woman due to streptococcal pharyngitis.

underlying systemic disease. 1 The lower limbs and face are the most common sites, but any part of the body may be affected. The necrotic area often begins as a sterile pustule which breaks down and spreads, sometimes to form a huge ulcer, with a characteristic ragged, purplish overhanging edge. Lesions may be multiple. The pathogenesis is unclear, but many patients have evidence of a depressed immune system. Causes include: • • • • •

Ulcerative colitis Crohn's disease Rheumatoid arthritis Other forms of arthritis Leukaemia, lymphomas, monoclonal gammopathies and myeloma.

The differential diagnosis includes infective causes of ulceration (e.g. postoperative gangrene, p. 386) and vasculitic disorders (e.g. Wegener's granulomatosis). Cultures for aerobic and anaerobic bacteria and other organisms, and a biopsy, should be taken before treatment. Treatment is with high-dose corticosteroids, although for

1

408

4

Case 10.1 MCQ 10.10

2 5

Fig. 10.20 Fig. 10.22

0 Fig. 10.21

Palpable purpura is the hallmark of cutaneous vasculitis (Fig. 10.31) 2 but, depending on the type and degree of vessel wall damage, other lesions, not all of which are purpuric, may occur; these include livedo reticularis, weals, papules, pustules, infarcts and ulcers. Aetiological factors of cutaneous vasculitis include: • Bacteria, e.g. streptococci, gonococci, Mycobacterium tuberculosis (erythema induratum) and M. leprae (erythema nodosum leprosum) • Viruses, e.g. hepatitis B • Neoplasia, e.g. lymphoma • Drugs, e.g. sulphonamides,thiazides,captopril (see p. 418) • Food additives, e.g. tartrazine • Autoimmune diseases, e.g. lupus erythematosus, polyarteritis nodosa, scleroderma. The initial event is damage to the endothelium of the vessel. Both circulating and resident extravascular inflammatory cells are then activated to release mediators, some of which have destructive effects whereas others contribute to repair. The net result depends on many factors; these include the nature of the initial insult, the type and location of the vessels affected, and the adequacy of the collateral blood supply. One of the most common histological appearances is the accumulation of neutrophils, their breakdown products, and nuclear debris around damaged venules, an appearance termed leukocytoclastic vasculitis. Sometimes vasculitis occurs because there is inadequate clearance of a potential cause, such as circulating immune complexes, from the circulation, or there is a deficiency in repair mechanisms, e.g. removal of fibrin is

TABLE 10.16 Some multisystem vasculitides that may involve the skin Clinical patterns

Other organs commonly involved

Henoch-Schonlein purpura Polyarteritis nodosa

Joints, gut, kidney Kidneys, gut, cardiovascular system, nervous system, muscles and joints Eyes Kidneys and respiratory tract Gut and brain

Temporal arteritis Wegener's granulomatosis Malignant atrophic papulosis (Degos' disease) Lupus erythematosus

10

Widespread

are characterized by a leukocytoclastic vasculitis, and in many cases there is deposition of IgA around venules. There is no specific treatment, but some authorities use high-dose corticosteroids if there is severe renal disease. O

FIG. 10.31 Vasculitis: purpuric papules and nodules

too slow to maintain patency of affected vessels. A defect in the reticuloendothelial system may account for the occurrence of vasculitis in lymphomas, other malignancies and sarcoidosis. Sometimes the localization of vasculitic lesions can be explained by circumstances that slow blood flow, e.g. in the lower limbs and where skin is cooled by overlying fat. As well as attempting to find the cause, it is clinically important to know whether other organs are being affected, especially the brain, heart, kidneys, lungs and gut. There is no entirely satisfactory classification of multisystem vasculitis (see Ch. 22, p. 1181 for a further account of the vasculitides). Most multisystem vasculitides can involve the skin (Table 10.16).

Clinical features Henoch-Schonlein purpura Henoch-Schonlein purpura comprises arthralgia, abdominal pain and vasculitic rash, often with renal involvement (see p. 1076). Children are predominantly affected. A streptococcal sore throat and upper respiratory virus infections are the most common recognizable causes. The rash is mainly on the buttocks and extensor surfaces of the limbs. ©As well as purpura there are usually erythematous macules and papules, and urticarial weals. The lesions

Polyarteritis nodosa Polyarteritis nodosa, or PAN (see pp. 1076,1181), is a multisystem disorder in which there is necrotizing vasculitis of small and medium-sized arteries. 0 The distinctive feature in the skin is the occurrence of nodules along the course of subcutaneous arteries, best felt on the lower limb. In addition to nodules there are often purpuric papules, weals, or plaques of gangrene. Livedo reticularis, a net-like arrangement of bluish venules, is common. Malignant atrophic papulosis Malignant atrophic papulosis (Degos' disease) is a rare but very distinctive condition in which insignificant-looking red papules become slowly necrotic with a greyish-white central scale, and heal with porcelain-like white scars. Similar lesions occur internally, particularly in the intestine, and much of the high mortality is due to perforation or haemorrhage. The brain and kidney may also be affected. Rheumatoid disease Small purple or black spots around the nailfolds are very characteristic of rheumatoid disease (p. 1138), although they are also seen in other vasculitic diseases.

ERYTHRODERMA Erythroderma, or exfoliative dermatitis, is redness of all or nearly all the skin. There is usually some degree of scaling. Most cases of erythroderma evolve from more limited eczema or psoriasis. The principal causes include eczema; psoriasis; drugs, especially gold, allopurinol and sulphonamides (see p. 417); and lymphoma and leukaemia. The cause can usually be determined from the history and a skin biopsy, but in some cases no aetiology is found.

409

SUMMARY 3 Causes of erythroderma • • • • •

Eczema/dermatitis Psoriasis Drugs, e.g. gold, allopurinol Lymphoreticular neoplasia, e.g. mycosis fungoides Miscellaneous

The skin is red, hot to the touch and often oedematous; itching can be severe and scaling is variable. Patients feel uncomfortably cold and shiver. Erythroderma can have serious metabolic consequences, particularly in the elderly. The greatly increased blood flow through the skin, with loss of normal capacity for vasoconstriction, leads to hypothermia in a cold environment and can cause high-output cardiac failure. Blood flow to other organs can be greatly diminished. There is increased fluid loss from the skin surface, with compensatory thirst and oliguria. Anaemia is common, and in part is due to a state of malabsorption secondary to the skin disease (dermatogenic enteropathy). Serum albumin falls as a result of loss from shed skin scales and reduced synthesis. The skin is more prone to infection, and thrombophlebitis is common. Lymphadenopathy is usual. Systemic corticosteroids are needed for severe cases. Maintenance of fluid balance and body temperature is important and use of appropriate emollients can be helpful (p. 383). More specific treatment will depend on the underlying cause.

BLISTERING DISEASES Blisters are focal collections of free fluid in the skin. By convention small ones are called vesicles and larger ones bullae. They are the result of a defect or disturbance in the normal mechanisms that hold the components of the skin together. Extensive blistering produces a serious loss of normal skin function, and before effective treatment was available some of the bullous diseases had a high mortality. Many different pathological processes can result in the clinical appearance of a blister. The diagnosis may be obvious from the history, such as in an insect bite reaction, but often there is a differential diagnosis and investigations are necessary. Light microscopy of an early blister, preferably one less than 24 hours old (before re-epithelialization has begun), will provide useful evidence of the level of the split in the skin and sometimes details of the pathogenetic mechanism, e.g. spongiosis (Fig. 10.32). Electron

1

410

Fig. 10.23

2

MCQ 10.11

3

Fig. 10.24

A Sub-corneal: impetigo B Mid-epidermal: viral infections (e.g. herpes simplex, varicella zoster), eczema, friction blister C Supra-basal: pemphigus vulgaris D Basal lamina: pemphigoid, dermatitis herpetiformis E Sub-basal: porphyria F Variable: erythema multiforme, epidermolysis bullosa, blistering drug reactions G Variable: thermal burns (depends on severity of burn) FIG. 10.32 Examples of blistering diseases at different levels in the skin

microscopy allows a much more detailed analysis of blister formation and is particularly important in the accurate diagnosis of epidermolysis bullosa, a heterogeneous group of inherited blistering disorders. Immunological phenomena are central to some of the bullous diseases, particularly pemphigus, pemphigoid and dermatitis herpetiformis, and these are best demonstrated on a sample of unfixed skin from just beyond the edge of a blister (peribullous skin). Other tests that may be indicated include serum for antibodies (see below), bacteriological and viral studies on blister fluid, and, when appropriate, porphyrin estimations and patch testing.

Pemphigus vulgaris Pemphigus vulgaris (Fig. 10.33) is an uncommon, chronic intraepidermal blistering disease of unknown aetiology, characterized by the presence in affected skin and mucosa of an IgG antibody which localizes to the cell wall of keratinocytes (Fig. 10.34). A split forms within the epidermis. Aetiology and pathogenesis The disease is most common in middle age and in Ashkenazi Jews. The characteristic antibody is usually found in the bloodstream, and antibody titres correlate approximately with disease activity. Relapse is sometimes shown to be preceded by an increased titre. The pemphigus antibody probably brings about separation of keratinocytes by

10

FIG. 10.33 Erosions due to pemphigus vulgaris

activating proteinases. Occasionally pemphigus is associated with other immunological diseases, e.g. thymoma, myasthenia gravis and SLE. Clinical features Pemphigus often begins in the mouth and sometimes other mucous membranes, with non-healing erosions. Blisters appear sooner or later on previously normal-looking skin, and when the disease is active sideways pressure with a finger on unblistered skin can produce new blisters (Nikolsky sign). Increasing numbers of flaccid blisters appear and, when they burst, leave erosions. The resultant problems of infections and fluid loss are similar to the consequences of extensive burns. 1 2 Diagnosis The diagnosis is made from characteristic histology, showing a suprabasal split and free-floating keratinocytes (acantholysis). 3 Immunohistochemical techniques show that the keratinocytes are coated with IgG. In all but localized or treated disease the pemphigus antibody can be demonstrated in the serum. Treatment Treatment is with high doses of corticosteroids (about 80mg prednisolone daily), together with an immunosuppressant such as azathioprine, with subsequent gradual reduction of the steroid. Gold salts have also been used with success, but toxicity is a problem. Even with treatment pemphigus remains a serious disorder, up to 25% of patients dying from the disease or the consequences of treatment. Most patients need maintenance therapy for lengthy periods, although in some a true remission occurs.

FIG. 10.34 The lesions of pemphigus vulgaris A, pemphigoid B and dermatitis herpetiformis C (IF = immunofluorescence).

Bullous pemphigoid Bullous pemphigoid (Fig. 10.28) is a fairly common subepidermal blistering disease characterized by an antibody that localizes to the lamina lucida of the basement membrane (Fig. 10.35). Pathology In pemphigoid the complement system is activated, and C3a and C5a attract and activate eosinophils. Eosinophil products and mast cell mediators contribute to the split that occurs in the basement membrane and the clinically evident inflammatory reaction. Clinical features Pemphigoid is mainly a disease of the elderly. It is usually preceded by an erythematous itchy rash, which can be mistaken for urticaria or eczema. It may be localized for some weeks before becoming generalized. The blisters are tense, clear or bloodstained, and often remain intact for several days. Unlike pemphigus, pemphigoid does not usually involve the mucous membranes. When blisters do

411

RECENT ADVANCES IN UNDERSTANDING BLISTERS AT THE MOLECULAR LEVEL The structural integrity of cells is greatly dependent on the three-dimensional network of intermediate filaments within them, and defects in these filaments can result in mechanical weakness. The keratins are a family of intermediate filament proteins maximally expressed in the keratinocytes, and contribute greatly to the strength of the skin. Some forms of epidermolysis bullosa, a group of mostly inherited blistering diseases, have now been attributed to mutations in keratin genes, and the split in the epidermis occurs at the site where the particular keratin is maximally produced. The molecular genetic basis for the most severe types of epidermolysis bullosa, EB letalis and recessive dystrophic EB, has also been discovered recently. EBL is usually due to a defect in the basement membrane protein laminin 5, and RDEB is due to mutations in the gene coding for collagen type 7. In some families it is now possible to make a prenatal diagnosis from a firsttrimester chorionic villus sample. The molecular basis for the immunobullous diseases is now better understood. In pemphigus vulgaris the antigen is desmoglein 3, a transmembrane component of the specialized keratinocyte attachment zones, the desmosomes. In pemphigus foliaceus the antigen is desmoglein 1. In bullous pemphigoid the target antigen is either a 230 or 180 kDa protein in the basement membrane zone.

FURTHER READING Huilgol S C, Bhogal B S, Black M M 1995 Immunofluorescence of the immunobullous disorders. Eur J Dermatol 5:186-195. Mellerio J E 1999 Molecular pathology of the cutaneous basement membrane zone. Clin Exp Dermatol 24:25-32.

break, the skin usually heals and the prognosis is better than that of pemphigus. There is a localized variant of pemphigoid, involving the mucous membranes, in which scarring occurs. Treatment Treatment of pemphigoid is with prednisolone and azathioprine to facilitate steroid withdrawal.

Dermatitis herpetiformis Dermatitis herpetiformis is an uncommon, chronic, intensely itchy disorder in which subepidermal blistering usually occurs.

1 412

MCQ 10.12

2

Fig. 10.25

FIG. 10.35 The blisters of bullous pemphigoid are tense, clear or bloodstained, and often remain intact for several days

Aetiology and pathogenesis There is a close association with HLA-B8 and DRW3, gluten-sensitive enteropathy, and deposition of IgA in the dermal papillae throughout the skin. The enteropathy may not be symptomatic, but it is likely that absorbed products derived from gluten are important in the pathogenesis of the skin lesions. Abnormal immunity in patients with dermatitis herpetiformis is suggested by an increased incidence of organ-specific autoimmune disease, and a few patients (as with coeliac disease) develop small bowel lymphoma. The skin lesions are a result of activation of dense clusters of neutrophils in the dermal papillae, producing damage and then fluid accumulation. Clinical features Dermatitis herpetiformis usually begins in young adults, but can begin at any age and can persist indefinitely. The initial lesions are very itchy grouped weals or papules, on which arise small blisters (Fig. 10.36). Extensor surfaces are the characteristic sites, especially the elbows, knees, shoulders, buttocks and scalp. Oral lesions are sometimes seen. 1 Diagnosis The diagnosis is best made from finding typical histology in an early lesion and IgA deposition in unaffected skin. (In the lesions the IgA can disappear as a result of the inflammatory infiltrate.) A jejunal biopsy usually shows

10

FIG. 10.37 Pityriasis rosea Pink plaques with characteristic scaling centrally.

suggests an infective cause, and a viral aetiology is likely but unproven.

FIG. 10.36 Dermatitis herpetiformis: itchy papules and vesicles

subtotal villous atrophy. Potassium iodide, both systemically and topically, provokes dermatitis herpetiformis and has occasionally been used as a diagnostic test. Treatment Dapsone has a dramatic beneficial effect in this condition, probably by modulating the neutrophil myeloperoxidase enzyme system, and/or the alternative pathway of complement activation. Haemolytic anaemia can occur, in which case sulphamethoxypyridazine is an alternative. A glutenfree diet is helpful in most patients and may reduce the likelihood of intestinal lymphoma.

Clinical features The first lesion to appear, known as the herald patch, is red, circumscribed, slightly scaly and larger than those that will follow about 10 days later. The generalized eruption is maximal on the trunk and proximal aspects of the limbs, and usually includes distinctive ovoid patches (Fig. 10.37) whose long axes are parallel to the major skin creases. 2 This produces a pattern somewhat like a Christmas tree on the back. The pink borders of these lesions are separated from the slightly brown centres by collarettes of scale. There is usually an admixture of smaller pink papules. Itching may occur, and occasionally there is malaise and lymphadenopathy. The rash usually lasts 4-6 weeks. Recurrences are very unusual. Differential diagnosis There are no diagnostic tests. Conditions that may resemble pityriasis rosea include drug eruption, seborrhoeic dermatitis, guttate psoriasis, tinea corporis and secondary syphilis. Treatment A mild topical steroid may be helpful.

FURTHER READING ON BULLOUS DISEASES

Lichen planus

Nausari H C, Anhalt G J 1999 Pemphigus and bullous pemphigoid. Lancet 354:667-671.

Lichen planus (Fig. 10.38) is a fairly common disease that may affect the skin, hair, nails and mucous membranes. The histology is distinctive and shows damage to the basal epidermal cells, with a dense band of lymphocytic infiltrate immediately beneath. There are close similarities to the skin changes seen in graft-versus-host disease and some drug reactions (p. 418).

MISCELLANEOUS DISORDERS OF UNKNOWN CAUSE Pityriasis rosea Pityriasis rosea, a common self-limiting disorder, occurs mainly in children and young adults. Clustering of cases

Clinical features The skin lesions are usually very itchy, and typically form purplish, polygonal, shiny, flat-topped papules. They are usually found on the flexor aspect of the wrists, the lower

413

FIG. 10.38 The lesions of lichen planus typically form purplish, polygonal, shiny, flat-topped papules

back and the shins. Individual lesions often show distinctive fine white lacy patterning (Wickham's striae). Larger, more warty plaques are sometimes found on the lower legs. Induction of new lesions by injury to the skin (Koebner's phenomenon) is often seen. In the mouth lichen planus is seen mainly as a network of white lines on the buccal mucosa and white patches on the tongue, 1 but occasionally can cause chronic ulceration. The scalp may be involved, producing patches of inflammation from which hair fall is usually permanent. The nails can also be affected, usually with longitudinal areas of thinning; in some cases nails also can be permanently lost. Lichen planus often lasts a year or more, and to some extent it is steroid responsive. Postinflammatory hyperpigmentation is common. Treatment Topical steroids may help the pruritus. For widespread symptomatic lichen planus a course of prednisolone, 2030 mg daily for 4-6 weeks, then tapering, can shorten the course of the disease.

Granuloma annulare There are two forms of granuloma annulare, localized (Fig. 10.39) and generalized; as a rule both are asymptomatic. Histologically there is palisading granuloma formation around focal areas of dermal necrosis. Localized granuloma annulare presents as rings of smooth firm papules. The backs of the hands and the tops of the feet are common sites. The commonest misdiagnoses are warts and fungal infection, in which epidermal changes are prominent, in contrast to the smooth surface of granuloma annulare.

414

1

Fig. 10.26

2

Fig. 10.28

2

Fig. 10.27

3

MCQ 10.13

FIG. 10.39 Granuloma annulare, localized form Note the ring-shaped arrangement of dermal papules.

In generalized granuloma annulare the papules are much more widespread and not necessarily in ring-shaped configurations. 2 This is often associated with diabetes mellitus. Diagnosis is confirmed by biopsy. Treatment A potent corticosteroid, topically or by injection, can be used for symptomatic lesions, but granuloma annulare is self-limiting and most cases need no treatment.

Necrobiosis lipoidica This condition (Fig. 10.40) occurs in about 3 per 1000 diabetics, and more than half of patients with necrobiosis lipoidica are overtly diabetic (see Ch. 19). The pathology is similar to that of granuloma annulare but with more pronounced dermal necrosis. The most common site is the shin. The lesion begins as a purplish plaque which gradually enlarges and becomes atrophic, with yellowish areas centrally. Ulceration is quite common. The condition is chronic, and when there is associated diabetes careful control of blood glucose has no effect on the progress of the skin lesions. Treatment The active advancing edge may be responsive to topical or intralesional corticosteroid. Older lesions can sometimes be disguised by cosmetic camouflage.

Sarcoidosis The skin can be invaded in sarcoidosis (Fig. 10.41). Sarcoidosis is discussed on page 682.

10

FIG. 10.40 Necrobiosis lipoidica Subcutaneous vein visible due to central atrophy, bordered by dermal inflammation.

Lichen sclerosus Lichen sclerosus is a distinctive inflammatory condition in which lesions are usually white. The commonest site is the anogenital skin. The cause is unknown. Clinical features Most patients are female, and present either in middle or later life or, less commonly, before puberty. Whereas patients in the older age group tend to have a more protracted course, in prepubertal girls the disease may resolve spontaneously at or around puberty. Usually the vulva is affected, often together with the perianal skin, giving a figure-of-eight appearance. The initial lesion is a white papule; lesions tend to coalesce, and involved skin often becomes wrinkled and atrophic. In the vulva, purpura is common and resorption of the labia may occur. Pruritus is very common. Scratching will often produce excoriations and erythema, which can mask the characteristic whiteness. Dysuria, dyspareunia and, in children, constipation are complications. In the male, involvement of the foreskin and glans can lead to balanitis, phimosis and meatal stricture. Squamous carcinoma is a risk in both sexes. Extragenital lesions occur in a minority. There is an increased likelihood of organ-specific autoimmune diseases. Differential diagnosis Vitiligo can involve the genital skin but does not cause pruritus, and apart from the pallor the skin is otherwise normal. When the pallor is not evident, eczematous conditions, intraepidermal neoplasia and lichen planus may need to be excluded. A biopsy is usually diagnostic.

FIG. 10.41 Sarcoidosis Note the shiny brownish-red indurated swelling of the ala and the two hyperpigmented dermal nodules on the left cheek.

Treatment A superpotent topical corticosteroid twice daily for several weeks initially, and then for shorter periods as necessary, can reverse clinical and histological manifestations in the genital area. Circumcision is often indicated for phimosis. Long-term follow-up is worthwhile in view of the risk of carcinoma. ©

SKIN CHANGES (N DIABETES There are a number of cutaneous problems that occur in diabetics, one of the most common being recurrent infections. Mucosal candidal infections may occur, 4 as may recurrent staphylococcal boils (p. 387). Indeed, in developed societies, the carbuncle (p. 387) is only seen with any frequency in diabetics. Injection sites may become infected, and occasionally deep abscesses may form. Patients with sensory neuropathy may fail to notice repetitive trauma (usually from footwear). This predisposes to ulceration, commonly on the sole (p. 1016). Necrobiosis lipoidica (Fig. 10.33) and granuloma annulare (Fig. 10.32) have histological features in common, and both occur in diabetics (see above). The term 'diabetic dermopathy' refers to small, duskybrown, scar-like lesions that often appear on the shins in diabetics. The patients usually have microangiopathy.

415

TABLE 10.17 Pathogenesis of drug eruptions - some examples

Mechanism Direct effects Immunological IgE-mediated Immune complex Effector pathway stimulation Side-effect Overdosage Cumulative toxicity FIG. 10.42 Xanthelasma Creamy yellow dermal lipid deposits in a diabetic with hyperlipidaemia.

Indirect effects Drug interaction Metabolic effects Ecological disturbance

'Diabetic sclerosis' or 'cheiroarthropathy' occurs in at least 30% of juvenile-onset insulin-dependent diabetics. The fingers and toes become stiffened and sclerodermatous. The patient is unable to straighten the fingers completely, and cannot place them flat on a table. A rarer condition is scleroedema, in which the skin of the neck and upper back suddenly becomes stiff and thickened. These changes gradually spread on to the face, trunk and upper arms. Rarely, diabetics develop distinctive non-inflammatory blisters on the extremities. Hyperlipidaemia is a common complication of diabetes, and lipid deposits in the skin may occur in the form of eruptive xanthomata, most commonly on the buttocks and extensor surfaces. Palpebral xanthelasmata may also be seen in diabetics (Fig. 10.42). Injection-site lipoatrophy and lipohypertrophy are discussed on page 992. Rarely, glucose intolerance and diabetes are part of a constellation of changes, including generalized fat reduction (lipodystrophy) and acanthosis nigricans. Such patients often have marked insulin resistance. There is an association between vitiligo and maturity-onset as well as insulin-dependent diabetes.

DRUG ERUPTIONS

416

Drug eruptions are a frequent occurrence in hospital practice and can produce skin changes in many ways (Table 10.17). Some of these, such as the predisposition to candidal infection by a broad-spectrum antibiotic, are not direct effects of drugs on the skin, but are none the less a consequence of drug exposure. Often the exact mechanism of a drug eruption is unknown. Some drugs - such as antibiotics, thiazides and sulphonamides, gold, allopurinol, phenylbutazone and other non-steroidal anti-inflammatories - are relatively

Exacerbation of existing disease

Drug

Clinical pattern

Penicillin Sulphonamides Acetyl salicylic acid

Urticaria Vasculitis Urticaria

Cytotoxic drugs Anticoagulants Corticosteroids

Alopecia Purpura Striae

Aspirin-displacing warfarin Isoniazid Broad-spectrum antibiotics Hydralazine

Purpura

Lithium

Pellagra Candidiasis Lupus erythematosus Psoriasis

SUMMARY 4 Skin changes in diabetes mellitus • Cutaneous infections

• • • • • • • • •

Neuropathic ulcers Necrobiosis lipoidica (diabeticorum) Disseminated granuloma annulare Diabetic 'dermopathy' Diabetic sclerosis (cheiroarthropathy) Scleroedema adultorum (of Buschke) Bullae (bullosis diabeticorum) Xanthomata and xanthelasmata Effects of insulin injections

- candidiasis - staphylococcal infections - injection site infection

lipoatrophy lipohypertrophy (Insulin tumours') infections and abscesses

• Generalized lipodystrophy (lipoatrophy not due to insulin injection)* • Acanthosis nigricans* • Vitiligo * When these cutaneous signs accompany diabetes, there is usually gross insulin resistance

common causes of rashes, and others very rare, but in all patients who develop a rash the drug history is of great importance. Not only prescribed drugs, but also medicines and tablets bought over the counter, must be considered.

TYPES OF DRUG ERUPTION Urticaria The mechanisms whereby a drug can cause urticaria include IgE-mediated immediate hypersensitivity, immune complex-mediated generation of activated complement components (serum sickness), a direct action on mast cells causing them to release histamine, and modulation of arachidonic acid metabolism. The drugs commonly implicated in urticaria are: • Penicillin and related antibiotics • X-ray contrast media • Enzymes • Blood products

• Opiates • Non-steroidal antiinflammatory drugs • Pollen vaccines • Iodides.

Angioedema and anaphylaxis may accompany urticaria, particularly when the drug has been injected, and can be life-threatening. Urticaria usually begins within minutes or hours of the drug being given, but when it is immune complex-related it occurs several days after the challenge and is often associated with fever, lymphadenopathy, joint symptoms and haematuria as a result of renal damage.

Ampicillin, amoxicillin and derivatives, e.g. talampicillin, are common causes, especially when the patient has infectious mononucleosis or lymphatic leukaemia, or is also taking allopurinol, and can begin up to a few days after the antibiotic has been stopped. The common causes of morbilliform (exanthematic) drug eruptions are: • • • • • •

Allopurinol Antituberculous drugs Captopril Carbamazepine Gold salts H2 antihistamines

• • • • • •

10

Penicillamine Penicillins Phenothiazines Phenylbutazone Sulphonamides Thiazides.

Erythroderma When caused by a drug, erythroderma, or exfoliative dermatitis (p. 409), tends to begin several weeks after the drug has been started. Important causes of drug-induced erythroderma are: • • • • • •

Allopurinol Carbamazepine Phenytoin Isoniazid Lithium Gold salts

• • • • • •

Chloroquine Barbiturates p-aminosalicylic acid Captopril Sulphonamides Methyldopa.

Morbilliform eruption A widespread, symmetrical, blotchy, maculopapular erythematous rash (Fig. 10.43) is probably the commonest drug eruption. There is often a mild fever, but serious consequences are uncommon. The mechanism is usually obscure but does involve delayed hypersensitivity in some cases, especially when the onset is within a few days of the drug being started. Morbilliform eruptions usually begin within a week of the onset of the drug, and may progress to erythroderma if the drug is continued.

Erythema multiforme Erythema multiforme (p. 407) is a reaction distinguished by target lesions. Most cases are not due to drugs. The commonest drugs to cause erythema multiforme are: • • • •

Sulphonamides Phenytoin Phenylbutazone Barbiturates

• • • •

Penicillins Carbamazepine Rifampicin Gold salts.

Toxic epidermal necrolysis

FIG. 10.43 Morbilliform drug eruption Maculopapular erythema brought on by co-trimoxazole.

Toxic epidermal necrolysis is a rare drug reaction which has a high mortality. There is often a brief prodrome of malaise and fever, followed by widespread, tender erythematous areas which then blister. Large sheets of epidermis readily rub off with light pressure, to leave painful denuded dermis. Mucous membranes as well as skin may be involved. Fluid imbalance, septicaemia and pneumonia are the most common problems. Differentiation from staphylococcal scalded skin syndrome (p. 385) can be made histologically on a blister roof because in toxic epidermal necrolysis the roof consists of the whole epidermis. Butazones, Sulphonamides, allopurinol, gold salts and phenytoin are examples of drugs that can cause the syndrome, which can also be due to infections, graft-versus-host disease and lymphoma. Management is similar to that of widespread burns, with treatment of fluid and protein loss and of infection.

417

Allopurinol Thiazides Phenytoin Thiouracil Non-steroidal antiinflammatory drugs

Photosensitivity The most common photosensitivity drug reaction resembles sunburn and is usually phototoxic, i.e. does not involve immunological mechanisms. Occasionally drugs produce photoallergic reactions which may look like eczema on light-exposed skin. Drugs which can induce phototoxic and photo-allergic reactions include: Phenothiazines Thiazides Sulphonamides Tetracyclines Sulphonylureas

• • • • •

Nalidixic acid (bullous) Amiodarone Azapropazone Protriptyline Psoralens.

Drugs can also induce photosensitive diseases, e.g. procainamide can induce lupus erythematosus, and isoniazid pellagra.

Fixed drug eruption The characteristic feature of a fixed drug eruption is that inflammation occurs in exactly the same place or few places each time the drug is taken. The reaction is usually a round red patch, which may blister (Fig. 10.44), and after the inflammation has subsided there is often prolonged hyperpigmentation. The causes change with variations in drug use, but a recent survey in the UK identified several common offenders - paracetamol, non-steroidal anti-inflammatory drugs, fluconazole, terbinafine, sulfasalazine, tetracylines, trimethoprin, diltiazem and proton pump inhibitors.

• • • •

Sulphonamides Hydralazine Quinidine Captopril.

Erythema nodosum Drugs are rarely responsible for erythema nodosum, and other causes should be sought (p. 407). Oral contraceptives and Sulphonamides are the drugs most likely to be involved.

Pigmentation changes induced by drugs Colour change (Table 10.18) can be produced by deposition of the drug in the skin and mucous membranes, stimulation of melanin production and alteration of the distribution of pigment so as to make it more apparent, as in postinflammatory hyperpigmentation (p. 427). The hyperpigmentation after fixed drug eruption may be the presenting feature. In some situations the pigmentation is only evident in light-exposed skin. In many examples of drug-related pigment change the mechanism is unknown.

Lichenoid drug eruption

Vdsculitis

The rash in lichenoid drug eruption is similar to that of lichen planus (p. 413). It usually begins weeks to months after the drug is started. As in idiopathic lichen planus, hyperpigmentation is common. Important causes of lichenoid drug eruptions are:

Drug-induced vasculitis (p. 408), usually in the form of palpable purpura, and often with urticarial and blistering lesions, can be accompanied by similar lesions in other organs and may be a serious illness. The commonest drugs to cause allergic vasculitis are:

• • • • •

Gold salts Antimalarials Thiazides Phenothiazines Methyldopa

• • • •

Furosemide (frusemide) p-Blockers Penicillamine Chlorpropamide.

Drug-induced lupus erythematosus

418

FIG. 10.44 Fixed drug eruption: dusky erythema with central blister

Drug-induced lupus erythematosus has some differences from the naturally occurring condition (p. 1172). It is likely that affected individuals have a genetic predisposition. This has been best documented in association with hydralazine and procainamide. With hydralazine the disorder is broadly dose-related, being seen in 5% of those on 100 mg daily, in 10% of those on 200 mg daily, but not in patients on 50 mg daily. Other common causes include penicillamine, phenytoin, methyldopa, B-blockers, sulfasalazine and oral contraceptives. In most cases druginduced lupus erythematosus occurs after the drug has been taken for at least a few months. On discontinuation, the disease resolves in most cases, but can persist for years. The condition is relatively less common in black people and more common in the elderly; renal and central nervous system disease are less likely to occur than in idiopathic

TABLE 10.18 Pigmentation caused by drugs

TABLE 10.19 Eczertia induced by topical drugs

Patterns

Eliciting drug

Source of topical exposure

Antibiotics, e.g. penicillin, streptomycin Antihistamines Aminophylline

Contents of medical and veterinary ampoules

Drug

Brown Similar to Addison's disease Similar to chloasma Light-exposed areas

Generalized Generalized, with patchy pigmentation Blue-grey Light-exposed areas

Generalized, maximal on light-exposed areas

Shins, nails and palate (and sometimes light-exposed areas) Yellow Generalized

Red Generalized

ACTH Phenytoin Oral contraceptives Phenothiazines Psoralens Cytotoxics Cytotoxics e.g. busulfan Pyrimethamine Arsenic

Minocycline Amiodarone Phenothiazines Gold Silver Bismuth Antimalarials

Mepacrine

Clofazimine Methysergide

lupus erythematosus. Antihistone antibodies are characteristic, and antinative DNA antibodies are not found. Complement levels remain normal.

Purpura When caused by a drug, purpura is usually a result of thrombocytopenia, vascular damage or both. Mechanisms include both toxic and allergic effects.

Pruritus Itching without a rash is considered on page 433. Drugs can cause generalized pruritus and the most common causes are: • Opiates • CNS stimulants • Antidepressants

• Oral contraceptives • Hepatotoxic drugs • Chloroquine.

For many drugs the mechanism is unknown, but some produce intrahepatic cholestasis.

Acne and acneform eruption In true acne there are comedones, papules and pustules in

10

In antipruritic creams, e.g. mepyramine Cross-reaction with ethylenediamine in Tri-adcortyl cream

a characteristic distribution (p. 431). Drugs exerting an androgenic stimulus, such as testosterone and some progestogens, can exacerbate or induce acne. An acne-like eruption, in which there are follicular lesions but in which the morphology or the distribution differs from true acne, is seen with a number of drugs, including corticosteroids and ACTH, halogens, antiepileptic drugs, isoniazid and lithium salts.

Alopecia Partial or complete hair loss is very common and appears early with cytotoxic drugs, but can occur, rarely and late, with other drugs, e.g.: • Cytotoxic agents (especially cyclophosphamide and anthracyclines) • Retinoids

• • • • •

Anticoagulants Oral contraceptives Antithyroid drugs Phenytoin Valproate.

Hypertrichosis Corticosteroids and androgenic steroids can produce hirsutism, but some drugs can induce increased hair growth on areas not dependent on a sex hormone stimulus. Minoxidil, ciclosporin, diazoxide, phenytoin and penicillamine are the main causes.

Eczema If sensitized via the skin to a 'drug' and then 'challenged' by an internal route, the patient can develop an often widespread eczematous eruption. Examples are given in Table 10.19.

Vesicular and bullous drug eruptions Blistering can occur in several different types of drug eruption already described, e.g. fixed eruption, erythema multiforme, photosensitivity and vasculitis. Bullae are common at sites subjected to prolonged pressure in drug-induced coma. Porphyria (p. 1026) can be precipitated by drugs, as occasionally can pemphigus (e.g. rifampicin) and acquired epidermolysis bullosa (e.g. furosemide [frusemide]).

419

INVESTIGATION AND TREATMENT OF DRUG REACTION The evaluation of a possible drug reaction should include the following: • A careful assessment of the risk to the patient, from the rash itself and from the involvement of other organs, e.g. kidneys and brain in a vasculitis; an assessment of the airway and maintenance of adequate circulation in urticaria/anaphylaxis. • A full drug history, including all current and recently completed treatments (tablets, mixtures, injections, suppositories etc.) and their timing in relation to the onset of the rash. Some drugs can cause a rash several days after they were last given, e.g. ampicillin, gold and depot preparations. • Past drug history and associated rashes. • Other possible explanations for the rash, e.g. a virus infection. • Consideration of which drugs can be stopped. Nonessential drugs should be stopped and essential drugs changed to structurally different ones if possible. • Laboratory investigations. Except for the investigation of drug-induced blood dyscrasias, these are disappointing. Blood eosinophilia, if present, is supportive of drug eruption. • A skin biopsy may help in some cases. • Treatment. The most immediately serious drug reaction is anaphylaxis. Emergency treatment is with 1:1000 adrenaline, 1 mL i.m., or slowly i.v. if the patient is moribund. Parenteral antihistamine and hydrocortisone are also given, and if necessary the patient is intubated and managed on ICU.

and vasculitis will require treatment with systemic corticosteroids. FURTHER READING ON DRUG ERUPTIONS Breathnach S M, Hintner H 1992 Adverse drug reactions and the skin. Oxford: Blackwell Scientific.

INTERNAL MALIGNANCY AND THE SKIN Skin abnormalities may be the first indicator of a systemic malignancy (Table 10.20). The cause of many other skin disorders associated with malignancy is unknown. Some are: • Generalized pruritus without a primary rash (p. 433). • Dermatomyositis, adult onset 1(p- 1180). • Acanthosis nigricans (Fig. 10.45). The skin becomes hyperpigmented and warty but feels soft. Body folds, e.g. axillae, are affected. There are other causes, such as obesity, some drugs and some inherited syndromes, but onset in a lean adult is highly likely to be associated with an adenocarcinoma or lymphoma. • Acquired hypertrichosis lanuginosa. This is a rare condition but one that has a strong association with malignancy, especially Hodgkin's disease. The patient

Depending on severity, some patients with erythroderma, bullous erythema multiforme, toxic epidermal necrolysis TABLE 10.20 Skin manifestations of malignancy Direct involvement e.g. Direct spread from breast carcinoma; plaques and nodules from lymphoma Genetic predisposition e.g. Multiple cysts and benign skin tumours occurring with colonic carcinoma with autosomal dominant inheritance (Gardner's syndrome) Carcinogen (also causing skin disease) e.g. Vinyl chloride skin eruption and angiosarcoma of the liver following exposure to vinyl chloride monomer (used in plastic manufacture) Metabolic products of tumour e.g. Flushing due to malignant carcinoid; migratory necrolytic erythema with glucagonoma - partly due to essential amino acid deficiencies induced by metabolic abnormality

420

1

Fig. 10.29

2

Fig. 10.30

3

Fig. 10.31

4

Figs 10.32,10.33

FIG. 10.45 Hyperpigmentation and velvety thickening due to acanthosis nigricans

•

• •

•

develops blond downy hair over the whole face and then elsewhere. Erythema gyratum repens. Here the skin develops irregular wavy bands of erythema, the overall appearance resembling wood grain. Nearly all cases have an associated malignancy. Acquired ichthyosis. The unexplained occurrence of dry, scaly but non-inflamed skin is often associated with lymphoma (p. 405). Pachydermoperiostosis with finger clubbing. The skin becomes thickened, with extra folds; the hands, elbows, knees and tongue enlarge and there may be painful periosteal new bone formation (see hypertrophic pulmonary osteoarthropathy, p. 619). These changes are associated with bronchial carcinoma. Pancreatic panniculitis. Tender red nodules of distinctive histology, owing to the effect on subcutaneous fat of circulating lipases from the pancreas, indicate either malignancy or inflammation in that organ. There is often arthritis and eosinophilia.

NAEVI AND TUMOURS OF THE SKIN Most primary tumours are either clearly benign or malignant, but occasionally some benign lesions evolve into malignant patterns of behaviour and are termed premalignant. Some of the known causes are listed in Table 10.22 (p. 424). A naevus is a circumscribed developmental defect, and the term has a similar meaning to hamartoma. Naevi are often, but not necessarily, evident at birth. There may be more than one cell type involved in the process. Each of the cell types in the skin can proliferate to produce a tumour, and the exact diagnosis usually rests with the pathologist. Many benign tumours and naevi are of little more than cosmetic importance, but in some instances they are pointers towards a genetic syndrome or multisystem disorder. Malignant skin tumours can be fatal, and often come to attention during a routine medical examination. Malignant metastases in the skin can occasionally be the presenting feature of a cancer elsewhere, and the histology can provide a valuable indication of the organ of origin.

The blue naevus is a slate-coloured lesion composed of a localized proliferation of melanocytes in the dermis which never reached the epidermis during development. Malignant melanoma (p. 424) may arise from a seemingly benign melanocytic naevus, but this is rare except from giant congenital pigmented naevi.

10

Vascular naevi There are several types of vascular naevi, some of which resolve in infancy or childhood (e.g. the salmon patch and strawberry naevus). The port wine stain is an area of permanent vascular dilatation, often on the face, where it may produce a disfiguring purplish discoloration. When the area affected is in the distribution of the ophthalmic division of the trigeminal nerve, there may be an associated vascular anomaly in the brain or meninges which can cause epilepsy, hemiplegia or retardation (Sturge-Weber syndrome), and various ocular abnormalities, especially glaucoma, can occur. The skin change can be successfully treated with the dye laser. Epithelial naevi Developmental malformations involving epidermal keratinocytes affect at least 1 in 1000 live births. They are usually circumscribed verrucous plaques which are often linear on the limbs, but may assume quite bizarre, whorled configurations, especially on the trunk. Occasionally lesions may be widespread. Such multiple lesions may be associated with developmental defects in the CNS and skeleton.

Naevi and multisystem disease

Naevi

Tuberous sclerosis Tuberous sclerosis is an autosomal dominantly inherited disorder in which mental deficiency is associated with an abnormality of many other organs. The first skin lesions to appear, often in early infancy, are the 'ash leaf macules. These well circumscribed, often irregularly shaped pale patches are best seen with Wood's light. From later childhood onwards, one or more of the following may appear: red angiofibromatous papules on the face (misnamed adenoma sebaceum), 2 thickened plaques on the trunk (shagreen patches) and periungual fibromas 3 (smooth nodules beside the nails). The skin lesions can be important in recognizing carriers of the gene.

Pigmented naevi Pigmented (melanocytic) naevi, or common moles, are occasionally evident at birth, but more commonly appear in childhood or adolescence. The naevus is initially brown, with clusters of proliferating melanocytes at the base of the epidermis. Melanocytic naevi that develop after birth are usually symmetrical in shape and colour and rarely grow to more than 1cm in diameter. In time the cells migrate into the dermis, and the lesion often becomes a fleshcoloured nodule.

Von Recklinghausen's disease (neurofibromatosis) The many features of von Recklinghausen's disease, or neurofibromatosis (Fig. 10.46), an autosomal dominantly inherited condition, include acoustic neuroma, glioma, spinal deformities and phaeochromocytoma. The skin shows multiple pale brown patches (cafe au lait macules}, especially in the axillae (a pathognomonic sign), and soft nodules (neurofibromas) 4 composed of nerve sheath cells.

421

FIG. 10.46 Neurofibromatosis is associated with localized areas of hyperpigmentation

Benign tumours and cysts The growth of these is usually slow, does not destroy normal tissues and is eventually self-limiting. The lesion produced is generally symmetrical in shape. Seborrhoeic warts are one of the commonest skin abnormalities, occurring with increasing frequency with advancing years. The lesions vary in colour from pale brown to very dark brown/black, and usually look as though they have been 'stuck on'. The surface is irregular and rather greasy to the touch. The simplest treatment is freezing with liquid nitrogen, although this is only necessary if the lesion is causing symptoms. Dermatofibromas (histiocytomas) normally present as firm papules, 0.5-1 cm in diameter (although occasionally they are significantly larger). The lesion moves easily within the skin and is never fixed to deeper tissues. If the diagnosis is certain dermatofibromas can safely be left, but excision is the treatment of choice if this is deemed necessary. Pyogenic granulomas grow rapidly, often following tauma and often on a digit. They are more common in children and young adults, but may be seen at any age.

1

422

Fig. 10.34

The surface is red, friable, and bleeds easily, consisting as it does of vascular proliferative tissue. In most instances a thin epithelium eventually extends to cover the raw surface, and lesions may involute spontaneously. It is more practical, however, to remove the whole lesion by curettage or by excision; the tissue should always be sent for histopathology. Smaller tumours may respond to cryotherapy. Skin tags develop in clusters around the neck, axillae and groins, more commonly in the obese (although there appears to be an inherited tendency in some families). Occasionally there may be a background of mild acanthosis nigricans (see p. 420). Lesions catch on clothing and jewellery and can be removed easily with a pair of scissors or by diathermy. Lipomas may be solitary or multiple, a tendency to numerous lipomas being inherited as an autosomal dominant trait in some families. They feel soft, subcutaneous and, as they enlarge, lobulated. Some lesions are mildly painful when knocked. There is no satisfactory therapy other than formal excision. Kemtoacanthomas are rapidly growing and, by definition, self-limiting tumours with a histopathology that may be difficult to distinguish from a well-differentiated squamous cell carcinoma. They arise most commonly on the head and neck, the hand and forearm and on sun-damaged skin in general. The normal course of events is for the lesion to grow rapidly over 4-6 weeks, reaching a maximum of about 2-3 cm in diameter. Growth then ceases, and a period of quiescence is followed by equally rapid shrinkage and disappearance. There is often a small pit left in the skin. The lesions are highly characteristic in shape, annular with a central keratin plug, 1 but these feaures are shared by some invasive squamous cell carcinomas (see below) and complete removal is recommended unless the patient is very old and frail. Epithelioid cysts and pilar cysts are both frequently called 'sebaceous cysts' by the terminologically inexact. Both consist of spheres of epithelium producing keratinous material internally. This results in a smooth, round swelling which moves easily over deeper structures in most instances. Occasionally inflammation and subsequent scarring leads to a tethered feel. Epithelioid cysts may occur anywhere, but are most common on the face, neck and trunk. They frequently follow in the wake of severe acne and there may be a small punctum on the surface. Pilar cysts are essentially a malformation of hair root sheath and are normally found on the scalp. There is often a positive family history. Another common keratinizing cyst is the milium, which are usually multiple (milia). They may arise in scars or other areas of trauma, but are most commonly found on the face, either in clusters around the eyes or more widely scattered, when they may be associated with signs of chronic sun damage. Keloid. A keloid is an excessive growth of connective tissue after an injury (including surgery or infection). Unlike a hypertrophic scar, it tends to grow beyond the limits of the initial trauma and can occur spontaneously.

Keloids are very long lasting. They are firm, smooth, rounded, protuberant swellings, often itchy and sensitive. In whites they tend to be purplish, and in dark-skinned patients they are often hyperpigmented. They are common in black races and at certain sites, e.g. the sternum, shoulders, upper back and the beard area. Treatments include injections of corticosteroid, compression and applications of silicone sheeting.

sites. In some cases there is an association with internal malignancy. Bowen's disease presents as a slow-growing, well-defined, red scaly or crusted patch. It is often solitary, although it can be multiple. The major differential diagnosis is psoriasis. Small lesions can be treated as for actinic keratosis, but for larger lesions excision is preferable.

10

Malignant and premalignant tumours Precursors to squamous carcinoma Actinic keratosis Actinic (solar) keratosis is a lesion that arises on skin chronically damaged by the harmful effects of UV radiation, in particular UVB (p. 426). The face (Fig. 10.47), bald scalp, backs of hands and forearms are common sites. Actinic keratoses are often multiple; they are more likely in the blue-eyed, fair or red-haired, and rare in darkskinned people. The individual lesion usually presents as a papule or plaque of hard, often brownish keratin. Transformation to squamous carcinoma is uncommon. Actinic keratoses can be treated by a number of modalities, e.g. cryotherapy, curettage and 5-fluorouracil cream. Bowen's disease Bowen's disease can be a consequence of previous ingestion of inorganic arsenic, usually given as a tonic many years ago. It is more common on covered than on exposed

FIG. 10.47 Solar keratosis A focal area of hard keratin accumulation with a zone of underlying erythema on sun-damaged skin.

Squamous carcinoma More than in other skin malignancies, there is likely to be an identifiable cause (Table 10.21) for squamous carcinoma (Fig. 10.48). The tumour often arises from a premalignant condition and is distinguished clinically by induration of the base and surrounding normal tissues. With growth, ulceration usually occurs. Squamous carcinoma is more liable to metastasize to regional lymph nodes than is basal carcinoma, and distant metastases can occur. Diagnosis is by biopsy. Keratoacanthoma (see Table 10.21) can be difficult to distinguish both clinically and histologically from squamous cell carcinoma. Treatment will usually be by surgical excision, although in some circumstances radiotherapy may be preferable. Basal cell carcinoma Basal cell carcinoma (BCC), or rodent ulcer (Fig. 10.49), arises from cells that resemble the basal layer of the epidermis, and may have its origin from skin appendage epithelium. It is the commonest malignant skin tumour in white skin, and although sunlight exposure is clearly a major aetiological factor, unlike squamous cell carcinoma it is not often seen on the backs of the hands. The face is the commonest site, although when there has been exposure to a systemic carcinogen, such as inorganic arsenic, BCC can be multiple and widespread.

FIG. 10.48 Squamous carcinoma is characterized by induration of the base of the tumour and eventual ulceration

423

TABLE 10.21 Factors predisposing to primary skin malignancy • • • • • • • •

Ultraviolet radiation X-rays Chemicals, e.g. hydrocarbons in mineral oil, inorganic arsenic Immunosuppression Genetic, e.g. xeroderma pigmentosum Scars, e.g. old burn scar Long-standing skin disease, e.g. lupus vulgaris, chronic leg ulcer Some human papilloma viruses (rare)

TABLE 10.22 The rising tide of melanoma USA lifetime risk (to age 75) 1935

1:1500

1991

1:105

2000

1:75

Melanoma is: • the commonest cancer in young adults aged 25-29 • the commonest cancer in males aged 30-34 • the second commonest cancer (to breast) in females aged 30-34

FIG. 10.50 Superficial spreading melanoma usually grows with an irregular edge and variable pigmentation

FIG. 10.49 Basal cell carcinoma is often translucent, with overlying telangiectatic vessels

The tumour is usually slow-growing, evolving from a translucent papule. Various growth patterns may occur, e.g. superficial spreading, nodular, infiltrative and sclerosing. Most nodular and infiltrative tumours ulcerate. Except for the sclerosing variety, BCC tends to retain a translucent raised margin as it extends into surrounding tissues. Telangiectatic vessels are often visible on the surface and

424

Fig. 10.36

1

Fig. 10.35

2

4

Fig. 10.37

0 Fig. 10.38

7

Fig. 10.39

3

Case 10.2

6 MCQ 10.14

may bleed on contact. 1 In some tumours there is an admixture of melanocytes, and the resultant lesion can simulate malignant melanoma. Local destruction can be extreme, 2 and very rarely BCC metastasizes. Treatment is usually by excision, radiotherapy, curettage or cryotherapy. Malignant melanoma Malignant melanoma (Fig. 10.50) usually arises either from previously normal-looking skin, 3 4 or from a benign melanocytic naevus. It may also arise from a naevus in a nailbed, in a mucous membrane or from the choroid or the iris. At present there is a rapidly rising incidence among white people (Table 10.22) and, aetiologically, short bursts of sun exposure, as during a hot, sunny holiday, may be important. There is not the same association with chronic sun damage as with squamous cell carcinoma, and to a lesser extent BCC. Conditions that can give rise to melanoma are lentigo maligna (Hutchinson's freckle) and dysplastic naevus. Lentigo maligna evolves as a flat, brown, variably pigmented patch, which slowly spreads on markedly sun-damaged skin. 5 Dysplastic naevi are

unusual-looking, often larger than average, with a distinctive histology; they are sporadic or inherited as an autosomal dominant characteristic, and may be a precursor to melanoma. Melanoma is often suspected when an enlarging pigmented lesion has one or more of the following: irregular notched border; irregular pigmentation, often with red and white as well as brown/black areas; itching or prickling sensation; inflammatory halo; ulceration and bleeding. The malignant cells spread laterally, in and just beneath the epidermis, and inwards. The prognosis depends on the depth of invasion, being excellent for completely excised, very superficial tumours. Metastasis occurs both to regional lymph nodes and distantly. ©

plaques and tumours appear (Fig. 10.51). Itching usually occurs. Erythroderma (p. 409) can develop, and if there are circulating neoplastic T cells this constitutes Sezary's syndrome. Lymphadenopathy and visceral involvement occur late and indicate a poor prognosis.

10

Metastatic malignancy Nodules, often ulcerating, may occur with many visceral malignancies. Paget's disease of the nipple The epidermis of the nipple becomes invaded by malignant cells arising from an underlying intraduct carcinoma of the breast tissue. The lesion is red, crusted and well defined, like Bowen's disease.

Lymphoma and leukaemia in the skin B-cell lymphoma, Hodgkin's disease and leukaemia may occasionally metastasize to the skin, or rarely present with cutaneous nodules. The skin is usually involved rather late in the course of the disease. The diagnosis is made from biopsy and other characteristic features of these diseases. T lymphocytes have an affinity for the epidermis and its appendages, and therefore T-cell neoplasia often involves the skin from the outset and may appear to be localized to the skin in some cases. Mycosis fungoides is the best-characterized T-cell cutaneous neoplasm. There is often a long phase of poikilodermatous patches (poikiloderma is a combination of erythema, atrophy and reticulate pigmentation) before

Kaposi's sarcoma Kaposi's sarcoma (Fig. 10.52) probably has a viral aetiology - humanherpesvirus 8. The lesions of this multicentric vascular neoplasm are usually purplish patches, plaques or nodules. Leakage of blood readily produces purpura and brown staining of the skin. The lymphatics can be affected, producing lymphoedema. Initially the lesions may be insignificant-looking, flat, reddish-brown or purple patches. ©A distinctive feature of AIDS-related Kaposi's sarcoma (p. 449) is a tendency for ovoid lesions to orientate along major skin creases, which on the trunk resembles the arrangement seen in pityriasis rosea.

FIG. 10.51 Mycosis fungoides This patient has numerous infiltrated plaques of T cell lymphoma in the skin.

FIG. 10.52 Kaposi's sarcoma in an AIDS patient There are multiple purple plaques and nodules.

425

Treatment, when indicated, is radiotherapy for localized lesions and, in some cases, cytotoxic chemotherapy for extensive disease. Primary sarcomas Malignant tumours arising from the various mesenchymal elements in the skin are all rare and present as enlarging masses.

AIDS AND THE SKIN

TABLE 10.23 Skin and oral lesions in AIDS Seborrhoic dermatitis (early feature in 30%) Itchy folliculitis (Fig. 10.53) Kaposi's sarcoma Infections Molluscum contagiosum Perianal warts Superficial fungal infection Herpes zoster and simplex Atypical mycobacteria

Severe drug eruptions Exacerbation of psoriasis Vasculitis Diffuse alopecia Dry skin (late) Oral hairy leukoplakia (see Fig. 11.9) Oral candidiasis Oral Kaposi's sarcoma

Skin and oral lesions are common features in patients with symptomatic HIV infection (Table 10.23). TABLE 10.24 Electromagnetic spectrum

SUNLIGHT AND THE SKIN For descriptive purposes, the continuum of electromagnetic radiation emitted by the sun is divided into segments according to wavelength (Table 10.24). Of the energy reaching the earth's surface, 99% is ultraviolet through to middle infrared. The shorter wavelengths of ultraviolet are filtered out by ozone in the stratosphere and by the atmosphere. The response of skin to solar radiation depends on the wavelength and on natural defences, the most important being melanin deposition. Ultraviolet B (UVB) is responsible for acute sunburn and the chronic changes of sun exposure: atrophy, dryness, blotchy pigmentation and wrinkling, solar keratoses and many skin cancers. The consequences of failure to repair damage inflicted on cellular DNA by UVB are seen in the rare autosomal recessively inherited condition xeroderma pigmentosum, in which sun-exposed skin becomes prematurely aged and skin cancers can appear in childhood. UVA has a much less obvious effect on normal skin, but is often responsible for photosensitive drug reactions and polymorphic light eruption. A clinical clue that UVA is playing a part is the provocation of a sun-related skin disorder behind window glass, as this filters out UVB. The action spectrum, i.e. the determination of exactly which wavelengths are responsible for a photosensitivity disorder, is known for only a few diseases. Visible light does not produce reactions on normal skin, but is responsible for photosensitivity in some diseases, notably the porphyrias, where the maximal reactivity is around 400 nm. Although most of the consequences of solar radiation on the skin appear harmful, one benefit is the synthesis of vitamin D3. UV radiation is essential to break the steroid

Type

Wavelength

Gamma Vacuum UV Ultraviolet C (UVC) Ultraviolet B (UVB) Ultraviolet A (UVA) Visible light Near infrared Middle infrared Far infrared Microwaves and radiowaves

0.1-100A 10-200 nm 200-290 nm 290-320 nm 320-400 nm 400-760 nm 0.74-1.5 um 1.5-5.6 um 5.6-1000 um >1mm

B ring and convert 7-dihydrocholesterol to previtamin D3, which then isomerizes spontaneously to vitamin D3. The immune system in the skin is modified by UV exposure, which may be important in the development of skin cancer.

Polymorphic light eruption Polymorphic light eruption is a common disorder that occurs mainly in females. Usually in spring, a day or so after sun exposure, itchy red papules, plaques and sometimes vesicles appear on sun-exposed sites. The condition gradually settles with continued sun exposure.

Drug photosensitivity It is usually not known whether allergic or toxic mechanisms are involved in drug photosensitivity. The drugs commonly responsible are given on page 418.

Phytophotodermatitis 1 426

1

Fig. 10.40

4

MCQ 10.15

2

Fig. 10.41

0 Fig. 10.42

Psoralens, a group of chemicals found in many plants, can be activated by UVA to produce inflammation and hyperpigmentation; 8-methoxypsoralen with UVA is used

TABLE 10.25 Causes of widespread hyperpigmentation Condition

Cause

Hypoadrenalism Cushing's syndrome

ACTH excess

Renal failure

Vitamin B12 deficiency

MSH Carotenoids Melanin Haemosiderin Melanin

Any debilitating diseasf disease

Melanin

Drugs

Melanin and sometimes the drug Keratin

Haemochromatosis

FIG. 10.53 Itchy folliculitis Excoriated follicular papules in a patient with AIDS.

therapeutically as PUVA (p. 418). Contact with a plant containing a psoralen (e.g. common rue, giant hogweed), together with sun exposure, produces erythema, often blistering, and then considerable hyperpigmentation.

Photoallergic contact dermatitis A number of cosmetics and even sunscreens contain chemicals which are activated by UV and, in combination with skin constituents, generate photoallergy. Investigation is by patch testing using two sets of patches, one of which is exposed to UV after a period of contact with the skin. Photocontact allergy produces positive results only in the set that has been irradiated. In some patients the state of photosensitivity persists long after the allergen has been withdrawn.

Metabolic disorders with light sensitivity Skin sensitivity to sunlight may occur in porphyrias (except the acute intermittent variety 2)> pellagra, carcinoid syndrome 3 and Hartnup disease.

Disorders aggravated by sunlight Many skin diseases may be worsened or triggered by sunlight. Common examples are lupus erythematosus and recurrent facial herpes simplex. Careful use of sunscreens can be helpful. 4

Acanthosis nigricans

10

Pattern Maximal in flexures, creases of palms and soles, sites of friction and pressure, and buccal mucous membranes Diffuse, maximal on hand and face Exposed skin and flexures Widespread, accentuated over knuckles Hypomelanosis of hair Generalized or Addisonian See p. 419, Table 10.18 Flexures, sides of the neck

the melanocytes and distributed in cellular organelles called melanosomes via cell processes (dendrites) to the keratinocytes of the skin and hair. All races have the same number of melanocytes - about 1 per 10 basal keratinocytes - the differences in skin colour being due to the amount of melanin formation in the melanosomes (maximal in dark races) and the way these are dispersed (singly in black people; in membrane-bound packages in white people). Apart from genetic factors, melanin production is stimulated by UV radiation and certain hormones, e.g. melanocyte-stimulating hormones (MSH), the chemically related ACTH, and female sex hormones. Hyperpigmentation is a common sequel to many inflammatory skin diseases, especially those in which the lower epidermis is damaged. There is both stimulation of melanogenesis and passage of melanin into dermal macrophages. Sometimes hyperpigmentation is due to substances other than melanin, e.g. haemosiderin (brownish-red) and drugs, e.g. amiodarone (grey). Many conditions associated with localized areas of hyperpigmentation are described elsewhere. These include neurofibromatosis (Fig. 10.38), xeroderma pigmentosum and Peutz-Jeghers disease. In practice the commonest are freckles, benign melanocytic naevi and postinflammatory hyperpigmentation. The causes of generalized or extensive hyperpigmentation are given in Table 10.25.

PIGMENTATION LOSS OF PIGMENT Normal skin colour is determined by haemoglobin, both oxygenated (red) and reduced (blue),carotenoids (yellow) and melanin (brown). Melanin is a polymer, synthesized from tyrosine in

Complete or partial loss of melanin pigment can have many causes. It is helpful to consider localized and generalized loss of pigment separately (Table 10.26).

427

TABLE 10.26 Localized and generalized pigment loss Condition

Causes

Clinical features

Localized hypopigmentation Vitiligo Loss of melanocytes

Pityriasis versicolor

Toxic effect on melanocytes

Well-defined white patches, often with hyperpigmentation of the bordering skin Personal or family history of organ-specific autoimmune disease common Slightly scaly macules mainly on the trunk, paler after sun exposure

Postinflammatory

(i)

(ii)

Faulty melanin transfer to keratinocytes Loss of melanocytes

Tuberous sclerosis 1 Poorly developed melanosomes Leprosy Decreased melanocytic activity Generalized pigment loss Albinism Faulty production of melanin in skin, hair and eyes Phenylketonuria Competitive inhibition of tyrosinase by phenylalanine ACTH and MSH Hypopituitarism deficiency

Pale patches with or after inflammation, e.g. eczema e.g. scarring after lupus erythematosus Leaf-shaped, pale macules and fibromas Pale patches are anaesthetic FIG. 10.54 Vitiligo shows sharply outlined areas of pigment loss Pale skin and hair, pink irises Pale skin with mental deficiency Associated endocrine deficiencies

Vitiligo Vitiligo (Fig. 10.54) is an acquired disorder in which melanocytes are lost from the basal layer of the epidermis. It occurs in about 0.4% of the population. A genetic basis is likely, as about 40% have a family history. In the individuals and their families there is an increased frequency of organ-specific autoimmune diseases, e.g. hypo- and hyperthyroidism. The precise pathogenesis is unknown. Clinical features Vitiligo has often begun by the age of 20. It is characterized by sharply defined areas of pigment loss, sometimes with mild hyperpigmentation of the adjacent normal skin. 0 The texture is normal and there is no scaling. In paleskinned individuals their first awareness may be sunburn in the depigmented skin. Any site can be affected and symmetrical involvement is common. Occasionally vitiligo

428

1

Figs 10.30, 10.31

3

MCQ10.16

0 Fig. 10.43

follows a dermatomal pattern. The face, axillae, groins, backs of hands, knees and elbows, and the genitalia are common sites. The condition is usually progressive, but repigmentation can occur spontaneously. 3 Diagnosis Diagnosis is usually straightforward. By Wood's light (p. 382) pityriasis versicolor (which is scaly) fluoresces yellow, and vitiligo is more strikingly white than the other causes of hypopigmentation (Table 10.27). The pale macules of leprosy are hypoanaesthetic. Treatment No treatment is entirely satisfactory. Cosmetic camouflage is helpful in a few. Sunscreens should be used on exposed areas to prevent burning and chronic sun damage, and in the pale-skinned this measure can improve the appearance by reducing tanning of the surrounding normal skin. Other measures used include psoralens and UVA (see PUVA treatment of psoriasis, p. 399) and the short-term application of potent topical corticosteroids.

PRESSURE SORES A pressure sore (bed sore, decubitus ulcer) is the consequence of sustained pressure to the tissues and is usually seen over a bony prominence, such as the ischial tuberosity, greater trochanter and elbow. The normal response to sustained pressure is movement to relieve that pressure. If

TABLE 10,27 Pathogenesis of pressure sores

TARLE 10,28 Causes of leg ulceration

Major factors Prolonged immobility e.g. Paraplegia Arthritis Operations and intensive care Plaster casts Apathy Loss of sensory stimuli e.g. Coma Multiple sclerosis Vascular disease e.g. Atherosclerosis

Cause

Example

Venous hypertension Arterial diseases Vasculitis Pyoderma gangrenosum Trauma Infections

Venous thrombosis Atherosclerosis, diabetes mellitus Rheumatoid disease, Wegener's granulomatosis See p. 407 Mechanical injury, burns, bites Ecthyma, tuberculosis, syphilis, deep fungal infection Leprosy, diabetes mellitus Disseminated intravascular coagulation, platelet disorders, sickle cell anaemia and spherocytosis, polycythaemia Cryoglobulinaemia Radiodermatitis Cutaneous carcinomas, Kaposi's sarcoma

Contributory factors Anaemia Hypoproteinaemia Severe weight loss

Neuropathy Blood disorders Plasma protein disorders Scarring disorders Neoplasia

discomfort is not felt or movement is not possible, then ischaemia is likely to occur. Friction (lateral pressure) exacerbates the tissue damage. Because fat and muscle are more susceptible, subcutaneous necrosis may be much greater than the surface changes suggest. Factors responsible for pressure sores are listed in Table 10.27. The earliest clinical sign is redness on an area subjected to pressure, the erythema not fading within 30 minutes. Action at this stage may prevent further damage. Progressive damage is manifested by blistering, ulceration and the formation of slough.

Management For any patient at risk, prevention is the chief aim. Frequent changes of position - with care not to exert friction by dragging the skin, and careful choice of the surface on which the patient is lying or sitting - are crucial. For the established pressure sore, these measures are equally important. In addition, anaemia and malnutrition should be corrected, slough should be removed and the sore kept scrupulously clean. In some cases excision of the entire necrotic area, with closure or grafting, should be considered.

10

VENOUS LEG ULCERATION Venous leg ulceration is also known as stasis or gravitational ulceration. The skin changes are due to the consequences of raised pressure in the venous system.

Aetiology and pathogenesis In most cases venous return is compromised by previous deep vein thrombosis. In a few cases ulceration is associated with varicosity of the superficial veins, or with defective communicating veins. Pressure in the venous system is raised because the valves are absent or destroyed, and this increased pressure is transmitted back to the capillary bed in the skin. There is extravascular deposition of fibrin, followed by fibrosis, and these changes are thought to impair transfer of oxygen and nutrients to the skin. It is also likely that venous distension produces reflex arteriolar constriction. This phenomenon occurs in normal individuals when standing still, and in them is promptly relieved by exercise, but this relief does not occur in those with persistently raised venous pressure. Patients who develop leg ulcers may also have decreased ability to lyse the fibrin, and this may contribute to the pathogenesis.

LEG ULCERATION

Clinical features Ulceration of the lower leg can have many causes, some of which are shown in Table 10.28. In the developed world most cases of leg ulceration are wholly or partly due to disorders of the venous system, but arterial insufficiency often coexists and may be the major factor in many patients. In the tropics, infective causes are much more important. Particularly in the elderly there can be multiple aetiological factors.

Venous ulceration is most common in middle-aged and elderly women. 'Interestingly, leg ulcers occur frequently and early in Klinefelter's syndrome (p. 68). Venous ulcers are usually preceded by varying combinations of oedema, prominent venules around the ankle, brown discoloration due to extravasation of red blood cells, eczema (p. 405), fibrotic thickening of the dermis and subcutaneous fat, and white plaques stippled with telang-

429

tional deficiency, anaemia, diabetes, obesity, hypertension, cardiac and renal disease, myxoedema, and any disease causing immobility. It is most important to assess the arterial system in the legs, as the compression that is valuable for venous insufficiency can be harmful if there is a poor arterial inflow. A simple Doppler device should be used, and if the ratio of inflow pressure in the ankle or foot to that in the arm is less than 0.8, compression should not be used without a vascular surgical assessment. Raised venous pressure can be counteracted by elevation of the legs at night and for periods during the day, and by careful use of compression bandages combined with exercise. If the ulcer is due to incompetent superficial or communicating veins rather than to deep vein thrombosis, surgical treatment may be indicated. Numerous treatments are available for the ulcer itself, and in most circumstances materials that do not contain potential sensitizers and maintain a moist surface should be used. Desloughing is often best achieved with a hydrocolloid dressing. Cellulitis requires systemic antibiotics. When venous ulceration has healed, the patient should continue to exercise and maintain compression with suitable stockings indefinitely. FIG. 10.55 Venous hypertension Ankle showing changes of venous hypertension: dilated veins, haemosiderin staining and atrophie blanche.

iectases (atrophie blanche) (Fig. 10.55). These signs occur most commonly near the medial malleolus, 1 but may be seen also on the lateral aspect of the ankle and over communicating veins. Another characteristic site is over the dorsum of the foot near the base of the toes. Ulceration may occur spontaneously or after trauma, which is often trivial. 2 Unlike ulceration due to arterial disease or vasculitis, venous ulcers are often painless. The base of the ulcer usually shows red granulation tissue and the edge is oedematous. The ulcer may be complicated by infection; cellulitis, usually due to Staph. aureus and/or Strep. pyogenes, can develop rapidly. Another common complication is contact allergic dermatitis due to medicaments applied to the ulcer, e.g. antibiotics and antiseptics (p. 400). In time the fibrotic process causes lymphoedema, and loss of movement at the ankle joint often occurs. Rarely, squamous and basal cell carcinoma can develop in chronic venous leg ulcers.

Management Patients with venous leg ulcers often have other disorders, correction of which facilitates healing. These include nutri-

1

430

Fig. 10.44

2

Case 10.3

3

Fig. 10.45

ARTERIAL ULCERATION When the arteriolar supply to a region of skin is insufficient or interrupted necrosis occurs, with resultant ulceration. The more profound process of gangrene is discussed on page 603. In general, vascular occlusion can occur because of changes outside the vessel wall, within the wall itself (as in atherosclerosis and vasculitis), and as a result of changes in the blood (as in cryoglobulinaemia and platelet thrombi). The symptoms and signs will be determined by the size of the ischaemic area and the speed with which the process occurs. The most common cause of arterial ulceration is atheromatous disease of the aorta and its tributaries.

Clinical features of ulceration due to atherosclerosis Arterial ulcers tend to be painful, sometimes severely so. There may be coldness, and pallor exaggerated by elevation of the limb, but cyanosis and blotchy erythema are also seen. Chronic ischaemia results in dryness and atrophy of the skin, loss of hair, and thickened, distorted nails. Intermittent claudication may be present (p. 602). Common sites for arterial ulceration due to atherosclerosis are the front or lateral aspect of the ankle, 3 and the toes. The ulcer tends to be well demarcated, with a grey sloughcovered base, which may expose deeper structures such as tendons. The management of arterial ulceration is usually the province of the vascular surgeon.

10

ACNE VULGARIS Acne vulgaris primarily involves the pilosebaceous follicles, i.e. the sebaceous glands, ducts, and the distal part of the hair follicles into which they open. The lesions include keratinous plugs in the ducts (comedones), inflammatory papules, pustules, nodules, cysts and scars.

Pathogenesis The best-defined factors determining the occurrence of acne vulgaris are androgenic stimulation of the sebaceous glands and the commensal anaerobic bacterium Propionibacterium acnes, which heavily colonizes active pilosebaceous follicles. Although the onset of acne around puberty is explained by the increased output of androgens at that time, it is much less clear why the disease becomes quiescent without any measurable change in the hormonal milieu or numbers of propionibacteria. The basis for the disorder of keratinization in the sebaceous ducts which produces the comedones is uncertain. Inflammatory lesions are mainly derived from closed comedones (see below). Possible mediators of inflammation include free fatty acids, bacterial cell wall components and enzymes, and the patient's complement system. The pus in acne lesions is sterile and a consequence of inflammation, which is often so severe that scarring results.

Clinical features Acne can occur in infants, but is usually mild and due to the influence of transplacental hormonal stimulus. In older children acne often represents the beginnings of puberty, but may not occur until the mid-teens or beyond. The areas affected are those with maximal numbers of pilosebaceous follicles: the face, upper trunk and shoulders. Comedones are either open (blackheads) or closed (small whitish papules). The inflammatory lesions are erythematous, varying from papules through pustules to nodules and large collections of pus (wrongly) called cysts (Fig. 10.56). The more destructive lesions heal with scarring, which is usually pitted but is hypertrophic or keloidal in those so predisposed. The course of acne can be erratic and there are often premenstrual exacerbations. Lesions resembling acne can be provoked by halogenated hydrocarbons, mineral oils, tars, greasy cosmetics, and drugs (p. 419).

Management Acne can have serious psychological effects and should not be ignored on the basis that it will get better sooner or later. Mild cases often respond to topical agents alone, e.g. benzoyl peroxide 2.5-10% gel, or topical retinoic acid. The latter is more irritant, but often more effective when comedones are the predominant feature. If there is insufficient

FIG. 10.56 Acne Note the papules, pustules, cysts and nodules.

response after a few weeks' treatment, or if the acne is of moderate severity, an oral antibiotic should be used in addition (or instead, if topical therapy proves too irritant). Tetracyclines and erythromycin are equally effective, usually in a dose of 0.5 g twice daily for several months. Topical antibiotics, e.g. 1 % clindamycin, can also be effective. For females with moderate acne, hormonal modulation with the antiandrogen cyproterone acetate may be more effective. This drug must be given with an oestrogen in the form of a low-dose oral contraceptive pill. Patients with severe and destructive acne usually need treatment with oral isotretinoin. This vitamin A analogue is highly effective but has a number of adverse effects, notably teratogenicity, and in the UK is restricted to hospital use. Other measures sometimes used include intralesional corticosteroids for inflammatory nodules and cysts, and dermabrasion, a surgical technique to improve scarring.

HYPERHIDROSIS Excessive sweating can be a feature of several systemic illnesses, or an isolated complaint.

Generalized hyperhidrosis Sweating from much of the body surface is a feature of many febrile illnesses and may be the presenting symptom (e.g. of tuberculosis and malaria). Other diseases

431

associated with a similar pattern of widespread sweating include lymphoma, hyperthyroidism, hypoglycaemia, phaeochromocytoma, the menopause, diabetic autonomic neuropathy and acromegaly. Drugs that may cause sweating include alcohol (commonly) and fluoxetine (rarely).

Palmoplantar and axillary hyperhidrosis Emotional stress and mental activity typically produce excessive sweating to varying degrees from the palms, soles and armpits. Other areas that may be involved include the face and groin. This pattern of hyperhidrosis is common, not associated with underlying disease, but can cause significant disability.

Asymmetrical hyperhidrosis This can be caused by a variety of neurological lesions, from the brain downwards. A particular example is sweating on one side of the face associated with eating (gustatory hyperhidrosis). This often occurs after an injury that results in loss of the normal nerve supply to the parotid gland, the regenerating fibres instead supplying the sweat glands.

Treatment

and sinus tracts. The areas affected are the axillae, anogenital area and breasts. Tender inflammatory nodules, which discharge pus, are seen and blackheads are often present early on. Because bacteria play a perpetuating role in this disorder, courses of antibiotics (if possible governed by sensitivity testing) are helpful but not curative. Incision, marsupialization and even wide excision may be needed in chronic cases. Hormonal modulation, e.g. with antiandrogens in females, may have a role in treatment, and isotretinoin may help in some cases.

ROSACEA Rosacea is a common condition of the middle-aged and elderly, in which there are varying combinations of redness of the face with telangiectasia, papules and sterile pustules (Fig. 10.57). 1The facial erythema is often easily exacerbated by spicy foods, alcohol and emotional upset; chronic UV exposure may have an aetiological role. Unlike acne there are no comedones and no elevation of sebum excretion rate. Common associations are eye disorders (e.g. conjunctivitis and keratitis), facial lymphoedema and rhinophyma, a hypertrophy of the nasal skin and its appendages. Despite the cause remaining unknown, treatment with oral oxytetracycline (erythromycin is an

Axillary hyperhidrosis can sometimes be helped by 20% aluminium chloride in alcohol applied at bedtime. Palmar and plantar hyperhidrosis are usually better treated with iontophoresis, either using water alone or with the anticholinergic drug glycopyrronium bromide in solution. This treatment utilizes DC electricity to drive ions into the skin. Psychological methods and even psychotropic drugs are useful in some patients in whom anxiety is a prominent trigger. Transthoracic endoscopic sympathectomy can be very effective in selected patients with palmar hyperhidrosis. Recently, success has been claimed for localized injections of botulinum toxin.

HIDRADENITIS SUPPURATIVA Hidradenitis suppurativa is a chronic suppurative, inflammatory and scarring condition of blocked apocrine glands. There may be a genetic basis for this disorder, which has some similarity to acne vulgaris and may be associated with it. Following keratinous plugging of the apocrine glands there is bacterial infection, subsequent gland rupture, damage to surrounding tissues, and healing with scarring

1

432

Fig. 10.46

FIG. 10.57 Rosacea Rosacea is characterized by erythema, papules and pustules but there are no comedones. 1

TABLE 10.29 Systemic causes of generalized pruritus

TABLE 10.30 Causes of prurifus ani

Hepatic disease Obstructive biliary disease Pregnancy: oestrogen-induced cholestasis

Anorectal disease Fissure Haemorrhoids Rectal carcinoma Faecal soiling Skin disease Psoriasis Atopic dermatitis Irritant and allergic contact dermatitis (especially medicaments)

Endocrine disease Hyper- and hypothyroidism Diabetes mellitus (rare) Renal Chronic renal failure Parasitic Trichinosis Onchocerclasis Malignancy Hodgkin's disease Leukaemia and lymphoma Polycythaemia rubra vera Other neoplasms

Haematological Iron deficiency Polycythaemia rubra vera Drugs Opiates Subclinical drug sensitivity Psychiatric Neurosis Psychosis, e.g. delusion of parasitosis

alternative) is effectively suppressive in most cases. Topical metronidazole is also helpful. It is usually helpful to minimize the effects of sun exposure. Rosacea is slowly worsened by the use of topical steroids on the face, and a similar condition, perioral dermatitis, can be initiated by the more potent topical steroid preparations.

PRURITUS Pruritus, or itching, is the distinctive sensation whose outward manifestation is the act of scratching. Except for the role of histamine in some disorders, and bile salts in obstructive liver disease, we know disappointingly little about the mechanisms of this common symptom. When severe, pruritus can surpass pain in the distress it can cause. Many skin diseases can be itchy, and some, such as scabies, dermatitis herpetiformis, lichen planus and urticaria, severely so. Dry skin of whatever cause tends to be itchy, and this is a particularly common problem in the elderly and one of the reasons for pruritus in the atopic individual. Occasionally an external cause (such as fibreglass or scabies) can produce widespread pruritus with little to see. Itching can occur without any primary rash, the skin changes, if any, being those caused by rubbing and scratching. Generalized pruritus may be a pointer to systemic disease (Table 10.29). Wherever possible, the underlying cause of generalized pruritus should be treated. When symptomatic measures are called for the use of emollients can be helpful, probably because dry skin has a lower threshold for pruritus. Oral HI antagonists can provide some relief, particularly when sedative antihistamines are used. Uraemic pruritus

10 Infection Candidiasis Infestation Threadworms Psychogenic Anxiety Depression Unknown

TABLE 10.31 Causes of pruritus vulvae Diseases special to vulvaf skin Lichen sclerosus et atrophicus Leukoplakia Carcinoma Skin disease Psoriasis Atopic dermatitis Irritant and allergic contact dermatitis (especially medicaments)

Infection Candidiasis Trichomonas Infestation Pediculosis Psychogenic Anxiety Depression Unknown

can be helped by UVB. Pruritus due to cholestatic liver disease often responds to cholestyramine or colestipol. The itch in polycythaemia rubra vera may respond to antiserotonin agents, cyproheptadine or pizotifen. Localized pruritus without primary signs of skin disease is common in the perianal (Table 10.30) and vulval areas (Table 10.31). Sometimes there is a psychological basis for this.

ALOPECIA The evaluation of alopecia, or hair loss, takes account of the distribution, any abnormalities of the hair shafts, and the scalp.

Androgenic alopecia (common baldness) The prerequisites for this very common condition are an inherited tendency; some degree of ageing; and postpubertal androgen levels. The longer, coarser, pigmented terminal hairs on the scalp are progressively replaced by small, fine vellus hairs. In males there is recession of the anterior hairline and thinning over the crown, and ulti-

433

mately terminal hair may only be present at the back and sides of the scalp. In an endocrinologically normal female there is thinning over the top of the scalp, but baldness to the extent seen in males is uncommon, except in the elderly, and if present warrants careful evaluation. Treatment In a few, with a short history of hair loss, topical minoxidil can induce modest regrowth of hair, but even with sustained application the hair usually falls out eventually, and the treatment is expensive. Some resort to hair transplantation.

Diffuse alopecia Diffuse alopecia is a decrease in hair density over the whole scalp without changes in the skin or hair morphology. In some instances, e.g. a febrile illness, childbirth and severe emotional upset, the causative factor synchronizes a proportion of the follicles so that hairs are shed 2-3 months later, a phenomenon called telogen effluvium. Regrowth usually takes place in about 6 months. Normal hair growth requires a adequate nutrition, and diffuse alopecia accompanies malnutrition and wasting conditions. Iron deficiency, even in the absence of anaemia, has been associated with hair loss. Dry and progressively sparse hair is a feature of hypothyroidism. Many drugs (p. 419) can produce diffuse alopecia, sometimes (as with cytotoxic agents) within days of administration, or after several weeks (as with anticoagulants, antithyroid drugs and the retinoids). Stopping the oral contraceptive has been associated with mild hair loss, similar to the effect of childbirth.

Alopecia areata Alopecia areata (Fig. 10.58) is a common condition in which there is loss of hair in patches, typically with no skin changes. Hair on the face and body as well as the scalp may be affected. A distinctive feature is the presence of shortened hairs which taper markedly where they emerge from the scalp (exclamation-mark hairs). White hairs tend to be spared the process causing the loss. Alopecia areata is usually reversible, and when hair grows back it is often initially white. When the entire scalp becomes affected the condition is called alopecia totalis, and if all the body hair is lost as well the term alopecia universalis is applied. Regrowth usually occurs, but is less likely with these more severe forms. Nails may show a distinctive pattern of pitting and ridging. 1 There is sometimes an association with one or more organ-specific autoimmune diseases in the patient or family, such as vitiligo. The cause of alopecia areata is not known. Topical and intradermal corticosteroids can be helpful in selected cases. Treatment by induced contact allergic dermatitis, e.g. to diphencyprone, can be useful.

Inflammatory alopecia Fungal (p. 389) and bacterial infection can cause patchy hair loss with varying degrees of erythema, oedema and pustules. Lichen planus (p. 413) and lupus erythematosus (p. 1172) may affect the scalp, and characteristically produce atrophy. Occasionally metastatic neoplasia presents as inflammatory alopecia.

Traumatic alopecia Hair can be damaged by chemicals, e.g. those used in permanent waving, and physical trauma such as twisting between the fingers and pulling.

HIRSUTISM AND HYPERTRICHOSIS

FIG. 10.58 Alopecia areata A distinctive feature of alopecia areata is the presence of shortened 'exclamation mark' hairs which taper markedly where they emerge from the scalp.

Hair growth can be excessive by being coarser, longer and/or more profuse than is normal for age, sex and race at any particular body site. The term hirsutism is used to describe excessive hair growth in females on those areas where secondary sexual hair occurs in males, i.e. the upper lip, beard area, chest, around the nipples, upper back, lower abdomen etc. Hypertrichosis designates other patterns of excessive hair growth. Both hirsutism and hypertrichosis can have a familial basis and are commoner in certain races.

Hirsutism 1

434

Fig. 10.47

2

Fig. 10.48

When hirsutism occurs together with other symptoms and signs suggestive of an underlying endocrine cause, such as menstrual irregularities, infertility and virilization (clitoromegaly, deepening of the voice and male pattern baldness),

10

TABLE 10.32 Endocrine causes of hirsutism Ovarian Adrenal Pituitary Exogenous

Polycystic ovaries Virilizing tumours Congenital adrenal hyperplasia Adenoma and carcinoma Cushing's syndrome Acromegaly Corticosteroids, androgens, progestogens

appropriate investigations should be carried out. Table 10.32 lists some endocrine causes. In most cases hirsutism is an isolated finding, probably caused by an increased sensitivity of hair follicles to normal levels of circulating androgens, and in the absence of other symptoms investigation is unnecessary.

Hypertrichosis There is no known underlying cause for hypertrichosis. It can occur as an isolated event, e.g. over the lower spinal column in spina bifida occulta, in association with melanocytic naevi, and in areas of chronic inflammation; or as a more generalized phenomenon, e.g. in malnutrition, some porphyrias, and with certain drugs, notably ciclosporin and minoxidil.

Treatment When there is an underlying endocrine cause of hirsutism, treatment of this may help. For idiopathic hirsutism, treatment should be tailored to the needs of the individual. For mild cases counselling alone may be sufficient. Excessive hair can be removed by depilatory creams, waxing or shaving. Follicles can be destroyed by electrolysis or certain types of laser therapy. For some patients the antiandrogen cyproterone acetate (given together with ethinyl oestradiol to maintain a normal menstrual cycle) can gradually reverse hirsutism, but the effect only lasts as long as the treatment.

NAILS AND DISEASE The nail is a specialized sheet of keratin largely produced by an invagination of the epidermis called the matrix, which is located beneath the posterior nailfold and extends beneath the nailplate as the lunule (halfmoon). Disorders of the nails may result from local causes such as psoriasis, fungal infection and lesions beneath the nail (e.g. melanoma), or reflect a systemic disorder (see below).

Clubbing Normally the angle between the nail and the posterior nail-

FIG. 10.59 Koilonychia The nail plates are thinned and spoon-shaped depressions.

fold is less than 180°. In clubbing this angle increases, often becoming more than 180°. The causes are discussed on page 619.

Koilonychia Koilonychia is flattening or even depression of the normal slight convexity of the nail, and is usually due to iron deficiency (Fig. 10.59).

Beau's lines Beau's lines are transverse grooves in all the nails, reflecting a transient reduction in nail growth due to a severe illness. They may also occur after childbirth.

Yellow nail syndrome In yellow nail syndrome the nails become yellow, thickened and excessively curved, and virtually stop growing. 2 Cuticular attachment is lost and there is usually some separation of nail from nailbed. The nail changes are associated with lymphoedema, bronchiectasis and pleural effusions. It is more common to find yellow nails in circumstances such as psoriasis and dermatophyte fungal infection, these conditions being recognized by the associated skin changes and mycological investigations. Splinter haemorrhages Splinter haemorrhages are usually longitudinal or dotshaped areas of haemorrhage beneath the nails (Fig. 10.60). Most are the result of minor trauma, are painless, and appear beneath the distal third of the nail. Psoriasis and fungal infection of the nails may be associated with similar distal splinters. Painful and proximal splinter haemorrhages are much more likely to be associated with medical causes, of which the best established are subacute bacterial endocarditis, trichinosis, chronic mountain sickness and indwelling radial arterial catheters.

435

Dermatitis artefacta Dermatitis artefacta is mainly seen in females. The lesions are self-inflicted but this is denied, and they may indeed be produced subconsciously. They are often bizarre in appearance, resistant to therapy (except occlusive dressings, in which case lesions may appear at new sites), and often regarded with indifference. The patients tend to be immature or insecure, but the motivation behind dermatitis artefacta is often difficult to elucidate and the condition can be protracted. Self-inflicted damage is also seen in psychotics and the Lesch-Nyhan syndrome, a rare X-linked inherited disorder of purine metabolism associated with mental retardation and spasticity.

Delusions of infestation

FIG. 10.60 Splinter haemorrhages Elongated deposits of blood beneath the nail plate.

Paronychia Paronychia is a painful swelling of the posterior nailfold. When acute, staphylococcal infection is likely. A more gradual onset and chronic course is usually associated with Candida albicans. 1 Women are especially prone to chronic paronychia. Common predisposing factors are occupations in which the hands are frequently wet, diabetes mellitus and poor peripheral circulation.

This is the conviction that there are parasites on or in the skin, often supported by offerings of excoriated skin fragments. Such a delusion may be one element in a broader presentation of psychosis, including that due to organic disorders such as vitamin B12 deficiency, but can present in an isolated form (monosymptomatic delusional hypochondriasis). It is of course essential to exclude infestation such as scabies and pests in the home. The monodelusional state often responds well to the psychotropic drug pimozide.

Dermatological non-disease The term 'dermatological non-disease' describes a disproportionate anxiety about minor and often physiological skin changes. Such patients are difficult to manage, but can be seriously disturbed and at risk of suicide.

PSYCHOLOGICAL CAUSES OF SKIN

DISEASE

GENODERMATOSES

Many bona fide skin diseases, such as eczema and psoriasis, may worsen or be precipitated during periods of psychological stress. Similarly, anxiety and depression commonly accompany distressing skin disease, and can often be ameliorated by explanation, reassurance and encouragement. There is a direct psychological cause with dermatitis artefacta, many cases of delusions of infestation, and psychogenic pruritus. A diagnosis of psychogenic pruritus rests on exclusion of an organic cause as well as association with other psychoneurotic symptoms and signs.

1

436

Fig. 10.49

The skin is affected in a number of genetically determined syndromes, some of which are covered in this chapter or, because they most frequently present with the systemic manifestations, elsewhere in this book. However, there are some important disorders that often present with cutaneous features that should be discussed briefly here. Darier's disease is an autosomal dominant condition in which clusters of warty papules are seen on the face, neck and trunk, in association with abnormal nails (classically linear streaks and 'v'-notching) and palmar pits. The term palmoplantar keratoderma is used to describe diffuse or patchy thickening of the palms and soles. There are many variants, some of which are simply a nuisance and affect only the hands and feet. In some, however, there may be associated abnormalities, e.g. mental retardation and carcinoma of the oesophagus. Ehlers-Danlos syndrome is a name given to a group of disorders in which there are

10

TABLE 10.33 Syndromes associated with cancers Syndrome

Features

Cowden's syndrome Gardner's syndrome Rothmund-Thomson syndrome Xeroderma pigmentosum Xeroderma pigmentosum variant Bloom's syndrome Howel-Evans syndrome Muir-Torre syndrome Peutz-Jeghers syndrome

Multiple trichilemmomas; fibromas of the lips; acral keratoses; carcinoma of breast, pancreas, thyroid Multiple epidermoid cysts; intestinal polyposis Poikiloderma; photosensitivity; short stature; skin and soft tissue cancers (e.g. osteosarcoma) Early-onset photosensitivity; excessive freckling; multiple skin cancers; some variants also develop internal cancers and CNS defects Similar, but less severe changes; later onset Growth retardation; pigmentary anomalies; leukaemia Palmoplantar keratoderma with carcinoma of the oesophagus Sebaceous gland carcinomas; colonic carcinomas Intestinal polyps occasionally undergo malignant transformation

FIG. 10.61 Hereditary haemorrhagic telangiecstasia Papular telangiectases on the forehead. Unlike many spider naevi, these lesions do not fill from the centre when emptied by pressure.

abnormalities of connective tissue (see also p. 71). Some forms are mild, consisting largely of hyperextensible joints and rather lax, friable skin. Others, however, are associated with major vascular problems, including arterial rupture. Pseudoxanthoma elasticum (see also p. 71) is a condition in which the skin of the neck, the elbow folds and occasionally other sites, gradually becomes more and more papular. The final appearance is said to look like the skin of a plucked chicken. The condition may be entirely benign, but in some pedigrees the connective tissue defects lead to 'angioid' streaks in the retina, blood vessel rupture and mitral valve prolapse. Hereditary haemorrhagic telangiectasia presents with multiple telangiectases on the face (Fig. 10.61), especially the lips. There are often lesions in the respiratory and gastrointestinal tracts as well, which may bleed. The skin is affected in a number of inherited immunodeficiency syndromes, either with multiple infections (e.g. in agammaglobulinaemia and severe combined immune deficiency) or with more direct cutaneous changes (e.g. eczema in Wiskott-Aldrich syndrome or the telangiectases of ataxia telangiectatica). There are also a number of syndromes associated with cancers which have significant cutaneous features. Some of these are listed in Table 10.33.

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the western world male homosexuals are more likely to contract hepatitis B, syphilis and HIV infection than are their heterosexual counterparts. However, the incidence of newly acquired syphilis and gonorrhoea in homosexual men fell as trends in sexual behaviour changed in the 1980s. The basis of any STD service is the control of sexually transmitted infections. There are basic requirements:

Genitpironary

Disease I G Williams

Sexually transmitted diseases 439

Acquired immune deficiency syndrome (AIDS) 439

HIV neurological disease 448 Sexually transmitted infections 456

SEXUALLY TRANSMITTED DISEASES Sexually transmitted diseases (STDs) are caused by infections transferred through sexual contact. Our appreciation of the range of agents capable of being transmitted sexually has increased.

Epidemiology The prevalence and incidence of sexually transmitted infections vary in different parts of the world. This is due to variations both in the diseases found and in the methods of reporting such infections. The type of sexual behaviour and the sexual orientation of the person involved also influence the transmission of the infectious agents. This is clearly demonstrated by the fall in incidence of syphilis and gonorrhoea after the introduction of penicillin (Figs 11.la, 11.1b), the rise in incidence in the 1960s due to an increase in the number of people's sexual partners, followed by a substantial fall in the 1980s, when the AIDS epidemic resulted in a change in sexual behaviour in homosexual men. Figure 11.2 shows the most commonly found STDs treated at genitourinary medicine clinics. This is an underestimate of the problem. Morbidity associated with STD is more common in women and the agents responsible are more difficult to identify. Reported STDs are observed mostly in the 20-24-yearold age group, followed by 25-29 and 15-19-year-olds. In

• The patient needs ready access to a specialist centre for accurate diagnosis and treatment of any infection. Attendance needs to be voluntary. Treating the index case only partly helps in controlling an infection, and therefore sexual partners need to be identified and treated. • Patients are much more likely to cooperate in these matters if they are assured of absolute confidentiality. The STD service is the most confidential are in the health service, and details are generally only released with the patient's consent. • Education about STDs, both for an individual and as part of general health education, is important in helping to control the spread of infection. • The clinics keep a record of the number of patients seen with each infection, and these figures form part of a detailed national epidemiology report.

ACQUIRED IMMUNE DEFICIENCY SYNDROME (AIDS) Definition The first recognized cases of the acquired immune deficiency syndrome (AIDS) occurred in the summer of 1981 in America. Reports began to appear of Pneumocystis carinii pneumonia and Kaposi's sarcoma in young men, who, it was subsequently realized, were both homosexual and immunocompromised. Even though the condition became known early on as AIDS, its cause and modes of transmission were not immediately obvious. The virus now known to cause AIDS, the human immunodeficiency virus (HIV), was discovered in 1983. The definition of AIDS has changed over the years as a result of increasing appreciation of the wide spectrum of clinical manifestations of infection with HIV. Currently AIDS is defined as an illness characterized by one or more indicator diseases (Table 11.1). In the absence of another cause of immune deficiency, and without laboratory evidence of HIV infection (if the patient has not been tested or the results are inconclusive), certain diseases, when definitely diagnosed, are indicative of AIDS. Regardless of the presence of other causes of immune deficiency, if there is laboratory evidence of HIV infection, other indicator diseases that require a definitive (or in some cases only a presumptive) diagnosis also constitute a diagnosis of AIDS.

439

TABLE 11.1 AIDS indicator diseases

FIG. 11.1 Incidence in England and Wales of A gonorrhoea 1918-1990, B infectious and early latent syphilis 1931-1998

Recurrent/multiple bacterial infections - child aged under 13 Candidiasis - pulmonary *Candidiasis - oesophageal Cervical carcinoma - invasive Coccidioidomycosis - disseminated Cryptococcosis - extrapulmonary Cryptosporidiosis - with diarrhoea persisting for more than one month *Cytomegaiovirus retinitis Cytomegalovirus disease - not in liver, spleen or nodes HIV encephalopathy Herpes simplex virus (HSV) infection - mucocutaneous ulceration lasting for more than one month or pulmonary, oesophageal infection Histoplasmosis - disseminated Isosporiasis - with diarrhoea persisting for more than one month *Kaposi's sarcoma tymphoid interstitial pneumonia - child aged under 13 Non-Hodgkin's lymphoma - Burkitt's or immunoblastic Primary cerebral lymphoma *Disseminated mycobacteriosis, e.g. Mycobacterium avium *Mycobacterial tuberculosis - extrapulmonary, pulmonary * Pneumocystis carinii pneumonia *Recurrent pneumonia within a 12-month period Progressive multifocal leucoencephalopathy Salmonella septicaemia - recurrent *Cerebral toxoplasmosis Wasting syndrome due to HIV * These diseases may be diagnosed presumptively if laboratory evidence of HIV exists.

Disease Genital warts Non-specific genital infection Chlamydia infection Genital herpes Gonorrhoea Trichomonas Syphilis FIG. 11.2 Number of cases of sexually transmitted disease seen in STD clinics in England and Wales, 1998 (excluding HIV)

440

In 1993 the Centers for Disease Control in the USA extended the definition of AIDS to include all persons who are severely immunosuppressed (a CD4 count <200 x 106/L), irrespective of the presence or absence of an indicator disease (Table 11.2). For surveillance purposes this definition has not been accepted within the UK and Europe, where AIDS continues to be a clinical diagnosis defined by one or more of the indicator diseases.

Epidemiology Transmission

HIV has been isolated from semen, cervical secretions, lymphocytes, cell-free plasma, cerebrospinal fluid, tears, saliva, urine and breast milk. This does not mean, however, that these fluids all transmit infection, as the concentration of virus in them varies considerably. Semen, blood, and possibly cervical secretions are particularly infectious. The commonest mode of transmission of the virus throughout the world is by sexual intercourse: whether this is anal or vaginal is unimportant. Other methods of transmission are through the receipt of infected blood or blood products and donated organs and semen. Transmission also occurs through the sharing or reuse of contaminated needles by injecting drug users or for therapeutic procedures, and from mother to child. Transmission from mother to child occurs in utero, at birth (intrapartum) and through breast milk. There is no well documented evidence that the virus is spread by saliva. It is not spread by casual or social contact. Health-care workers can, however, be infected through

TABLE 11.2 Centers for Disease Control (CDC) revised classification system for HIV infection (1993)

New HIV infections in 1999

Clinical categories

A Asymptomatic, acute (primary) HIV or PGL

B Symptomatic, not (A) or (C) conditions

C AIDSindicator conditions

1. >500x10 /L

A1

B1

2. 200-499 x10 6 /L

A2

B2

3. <200x10 6 /L

A3

B3

C1 C2 C3

CD4+Tcell categories 6

TABLE 11.3 Global summary of the HIV/AIDS epidemic during December 1999 (WHO/UNAIDS)

PGL = persistent generalized lymphadenopathy.

Adults (women Children <15 years TOTAL

People living with HIV/AIDS

Adults (Women Children <15 years TOTAL

11

5 million 2.3 million) 570000 5.6 million 32.4 million 14.8 million) 1.2 million 33.6 million

Deaths due to HIV/AIDS, 1999

2.6 million

Cumulative number of deaths due to AIDS/HIV

16.3 million

needle-stick injuries and by skin and mucosal exposure to infected blood or body fluids. Finally, there is no evidence that the virus is spread by mosquitoes, lice, bedbugs, in swimming pools, or by sharing cups, eating and cooking utensils, toilets or air space with an infected individual. In other words, HIV and AIDS are not contagious.

Size of the problem Worldwide The WHO and UNAIDS estimate that by the end of 1999, 32.4 million adults and 1.2 million children worldwide will be living with HIV, and that cumulatively since the start of the epidemic, 16.3 million people will have died from HIV/AIDS (Table 11.3). The largest burden of infection has fallen on the developing world, particularly subSaharan Africa, which has close to 70% of the global total for HIV-infected people but is home to just 10% of the world (Fig. 11.3). In adults aged between 15 and 49 years it is estimated that the prevalence of those living with HIV/AIDS in 1999 was 8% in sub-Saharan Africa, compared to 0.56% in North America and 0.25% in western Europe. Recent studies have shown that although in the developing world HIV is transmitted predominantly by heterosexual intercourse, the female-to-male ratio of infected persons in sub-Saharan Africa is 1.2:1. There are several factors that might account for this, including the greater efficiency of male-to-female HIV transmission through sex, and the younger age at first sexual contact for women. Elsewhere in the world, estimated new infections continue to increase markedly in south and southeast Asia, including India, although preventative programmes in Thailand are beginning to be effective. Eastern Europe and central Asia, constituting Russia and the other former states of the USSR, also saw a marked increase in the estimated reported number of HIV-infected people, rising by one-third, and largely driven by transmission through injecting drug use. United Kingdom and United States By December 1999, 724636 cases of AIDS in adults had

FIG. 11.3 Adults and children estimated to be living with HIV/AIDS as of December 1999 (WHO/UNAIDS)

been reported in the United States, and in the United Kingdom the total was 16457. These figures are thought to be reasonably accurate and complete. Both countries have seen a significant decrease in the number of new cases of AIDS reported, a result of clinically effective antiretroviral therapy; however, new infections with HIV continue to occur and the prevalent population of people living with AIDS/HIV is rising. In North America and the UK the first wave of the epidemic occurred in homosexual men. Although new infections among men who have sex with men still arise, this group now accounts for less than 50% of those newly diagnosed with HIV infection per year in both countries. In the USA an increasing proportion are among injecting drug users who share needles or equipment, and in the UK among heterosexuals (Fig. 11.4). The latter is driven largely by an imported epidemic from subSaharan Africa, with only small numbers having acquired the infection through heterosexual contact within the UK. In the USA, 16% of AIDS cases have occurred in women, although the commonest route of transmission among such women is injecting drug use (42%). The next most common is heterosexual contact (40%).

441

FIG. 11.4 A changing epidemic: cases of HIV infection by exposure category diagnosed in the UK 1989-1999

THE HUMAN IMMUNODEFICIENCY VIRUS The human immunodeficiency virus type 1 (HIV 1) was first isolated in 1983 at the Pasteur Institute, Paris. It has a cylindrical core surrounded by a bilayered lipid envelope acquired as the new virion buds from its host cell. Implanted into this envelope are viral glycoproteins (Gp41 and 120 - Fig. 11.5) carrying receptor sites for the CD4 antigen expressed on the surface of host cells. Only cells bearing this antigen are susceptible to infection. The inner core of the virus is made up of the capsid protein P24 encasing two strands of viral RNA and viral enzyme molecules. The nucleic acid of HIV 1 has been cloned and sequenced. It has a basic gene structure common to retroviruses but is very different from the other human retroviruses, human T-lymphotrophic viruses 1 and 2. A second human immunodeficiency virus (HIV 2) was isolated in 1986 and has similar biological properties to HIV 1, but is limited to west Africa or countries with links to that area. On entry to the infected cell the viral reverse transcriptase enzyme (hence retrovirus) makes a DNA copy (proviral DNA) of the RNA genome (Fig. 11.6). The pro viral DNA is able to integrate into the host cell DNA. Latent or non-productive or productive viral replication may occur. During productive replication RNA transcripts are made from the proviral DNA, and complete virus particles

1

442

MCQ 11.1

FIG. 11.5 Schematic representation of the Human Immunodeficiency Virus

are assembled and released from infected cells by characteristic budding. The virus has three main genes: • 'Pol', which encodes for the three viral enzymes: reverse transcriptase, integrase and protease; • 'env' which encodes for the envelope glycoproteins; • 'gag', which encodes for core proteins. In addition, there are accessory genes which encode for regulatory proteins that control HIV replication within the target cell. 1

IMMUNOLOGY OF AIDS In the weeks following infection there is a sharp increase in plasma viral load, widespread dissemination of the virus, and occasionally clinically an acute seroconversion illness. An immune response to HIV develops, followed by a fall in detectable plasma viraemia. Although a period of prolonged clinical latency then ensues, viral replication continues within lymphoid tissue, together with a gradual fall in the number of circulating CD4 T cells in the peripheral blood. Destruction of lymphocytes bearing the T4 or CD4 differentiation antigen and loss of specific T-helper cell function seems to be the primary abnormality of immune dysfunction. The CD4 molecule, however, is also displayed

TABLE 11.4 Immunological abnormalities In HIV infection

11

Lymphopenia: CD4 T lymphocyte (naive and memory) cytotoxic responses: cell-mediated T cells (CD8) natural killer cells T-cell antigen repertoire 4 proliferative responses (mitogens, antigens) decrease skin allergy to common recall antigens e.g. Candida, PPD, tetanus immunoglobulins: polycolonal B-cell activation decreased de novo antibody response cytokine e.g. TNF-a, interleukins

FIG. 11.6 HIV replication cycle The main targets for antiretroviral treatments are inhibition of the viral enzymes: 1. Fusion of virus with CD4 receptor molecule; 2. Reverse transcriptase, which facilitates the transcription of viral RNA to a DNA copy; 3. Protease, which is necessary for cleavage of pre-cursor viral structure proteins after budding of HIV virion.

at lower density on other cells, such as monocytes, macrophages and some B lymphocytes, some of which may act as reservoirs of HIV infection. The CD4 lymphocyte has a pivotal role in the immune response (interacting with macrophages, other T cells, B cells and natural killer cells, either by direct contact or via the influence of lymphokines such as y-interferon and interleukin 2, see Ch. 4). The other immunological abnormalities seem to be largely secondary to the disorder of CD4 lymphocytes (Table 11.4). In vitro, HIV produces a cytopathic effect in susceptible cell lines, multinucleate giant cells (syncytia) form and cell death occurs. The mechanism(s) by which it produces immune dysfunction in vivo are not yet fully understood, but may include a direct cytopathic effect of HIV on the CD4 lymphocyte, HIV-specific cellular immune responses directed towards infected cells, and the triggering of programmed cell death (apoptosis) by viral proteins. Different factors, both viral and host determined, are likely to influence the rate of disease progression. A small number of HIV-infected persons, however, show little evidence of immunosuppression many years after acute infection (long-term non-progressors). It is thought that the breadth of the immune response to the different HIV anti-

gens at the time of primary infection is pivotal in determining disease progression. In most infected persons there is a rapid loss of specific T-helper cell and CTL responses to multiple HIV antigens during primary infection, which do not recover during chronic established infection. In persons where these specific immune responses are preserved, plasma HIV RNA levels are low, viral replication is contained and clinical disease progression slow. A better understanding of these specific protective immune responses may lead to a more complete knowledge of the immunopathogenesis of AIDS and the possible development of a protective vaccine.

NATURAL HISTORY Acute infection with HIV may be accompanied by a transient non-specific illness similar to glandular fever; it includes fever, malaise, myalgia, lymphadenopathy, pharyngitis and a rash. A transient aseptic meningoencephalitis may also occur. Most acute infections, however, are subclinical. The acute infection is accompanied by the development of antibodies to the core and surface proteins, usually in 2-6 weeks, although delayed seroconversions have been observed. Antibodies are usually detected by enzyme-linked immunoassays, and their presence can be confirmed by immunofluorescence or Western blot. Molecular techniques (PCR) have been developed to measure quantitative levels of plasma viral RNA and cellular viral DNA. High levels of plasma viraemia are detectable at times of seroconversion and before the appearance of antibodies. Diagnosis of acute primary infection can be confirmed by a positive PCR test for proviral DNA (or viral RNA using assays of high specificity) together with either a negative antibody test or the presence of an evolving antibody response. Following acute infection plasma levels rapidly decline and a chronic infection ensues (Fig. 11.7) which is asymptomatic in the early stages. Physical examination may show no abnormality, but about one-third of patients have persistent generalized lymphadenopathy (PGL). This is defined as lymph nodes of 1 cm or more in diameter in

443

FIG. 11.8 Oral candidiasis in the patient with symptomatic HIV infection The figure shows scattered white plaques with underlying erythema on the soft palate. FIG. 11.7 Progressive depletion of CD4 T cells in AIDS Plasma viraemia in peripheral blood, CD4 levels following primary infection with HIV. Once the CD4 count falls below a certain level the risk of major opportunistic infections increases substantially (adapted from Pantaleo G, Graziosi C, Fauci AS. New Eng J Med 1993 328: 327-334).

two or more non-contiguous extrainguinal sites, which cannot be explained by any other infection or condition. The commonest sites of lymphadenopathy are the cervical and axillary lymph nodes; it is unusual in the hilar lymph nodes. Biopsy usually shows a benign profuse follicular hyperplasia. At some time after the initial infection non-specific constitutional symptoms develop. These may be intermittent or persistent, and include fevers, night sweats, diarrhoea and weight loss. Patients may also be affected by several 'minor' opportunistic infections or conditions that tend to affect the mucous membranes and skin, such as oral candidiasis (Fig. 11.8), oral hairy leukoplakia (Fig. 11.9), herpes zoster, recurrent oral or anogenital herpes simplex, and other skin conditions such as seborrhoeic dermatitis, folliculitis, impetigo and tinea infections. This collection of symptoms and signs, which are often a prodrome to the development of major opportunistic infections or tumours, is referred to as symptomatic non-AIDS (Table 11.5). Without treatment with antiretroviral therapy, about 75% of HIV-infected people developed symptomatic disease (either AIDS or non-AIDS) and 45-50% develop AIDS in 9-10 years from primary infection. Retrospective testing of stored blood samples from early prospective

FIG. 11.9 Oral hairy leukoplakia in a patient with symptomatic HIV infection The figure shows a corrugated white patch on the lateral border of the tongue.

cohort studies have shown that levels of plasma viral load, combined with the absolute CD4 count, are highly predictive of the risk of clinical progression (Fig. 11.10). Infected persons with low plasma viral load levels following primary infection, presumably reflecting a better-preserved specific immune response to HIV, have a much lower risk of clinical progression than those with substantially higher plasma viral load. 12

OPPORTUNISTIC INFECTIONS

1

444

Case 11.1

2

MCQ 11.2

The incidence of opportunistic infections in populations of HIV-infected persons has fallen significantly in the developed world over the last few years with the widespread use of more effective antiretroviral therapies and better predictive monitoring of the risk of clinical progression in

11

TABLE 11.5 Common complications of symptomatic HIV disease Early

CD4 count 100-500 x106/L *Constitutional symptoms (fever, diarrhoea, weight loss) *Herpes zoster *0ral hairy leucoplakia *0ral Candida *Skin problems

Late

CD4 count 200-50 x10 6 /L Recurrent bacterial pneumonia Pulmonary tuberculosis Pneumocystis carinii pneumonia Oesophageal Candida Kaposi's sarcoma Cryptosporidial-microsporidial diarrhoea Cryptococcal meningitis Cerebral toxoplasmosis *HIV peripheral neuropathy

Advanced

C D4 count <50x10 6 /L CMV diseases: retinitis, colitis, polyradiculopathy, encephalitis Disseminated MAI infection Severe wasting syndrome AIDS-related dementia Lymphoma

FIG. 11.10 Risk of progression to AIDS at 3 years by CD4 count and plasma viral load (adapted from Mellers JW, Munoz A, Giorgi JB et al. Ann of Intern Med 1997 126: 946-954).

Progressive multifocal leucoencephalopathy * Symptomatic non-AIDS.

Pulmonary complications an individual. Opportunistic infections, however, remain common in the developing world, and in those who are newly diagnosed in late-stage disease or who decline antiretroviral therapy or who have experienced multiple treatment failures. The organisms responsible for the opportunistic infections that occur in patients with AIDS are unusual pathogens. Most of the infections are due to reactivation of latent organisms in the host or, in some cases, to ubiquitous organisms to which we are continually exposed. The infections are often difficult to diagnose because conventional serological tests are unhelpful, and treatment often suppresses rather than eradicates the organisms. If patients are able to respond to effective antiretroviral combinations, then immune reconstitution can occur and relapse of opportunistic infections is uncommon. In the absence of effective antiretroviral therapy severe immune deficiency persists, and relapse of opportunistic infections is common and continuous treatment with prophylactic drugs may be necessary. Three main organ systems are affected: the respiratory system, the gastrointestinal tract and the central nervous system. In addition, patients may present with a history of night sweets, chronic ill health, fevers or weight loss.

Pneumocystis carinii pneumonia (PCP) is one of the commonest life-threatening opportunistic infections in patients who progress from symptom-free infection to AIDS. The presentation is subacute, and malaise, fatigue, weight loss and shortness of breath often develop over several weeks. Typical retrosternal or subcostal chest discomfort, associated with increasing shortness of breath, a dry cough and fever, finally cause the patient to seek help. The chest X-ray at presentation may be normal or show bilateral fine infiltrates, which are typically perihilar (Fig. 11.11). The arterial oxygen tension is usually depressed, and the carbon monoxide transfer factor, when available, is low. A fall in oxygen saturation levels from normal at rest to below normal on exercise is a useful sign of early infection. The diagnosis is confirmed by cytological examination of induced sputum or of bronchoalveolar lavage (BAL) from fibreoptic bronchoscopy. First-line treatment is high-dose co-trimoxazole for 18-21 days, but intolerance may be a problem owing to nausea, rash and bone marrow suppression. Pyogenic bacterial causes of pneumonia should always be considered, particularly as its presentation may be atypical. The radiological appearances may include diffuse infiltrates as well as the more typical focal or lobar patterns. Bronchoscopy is frequently helpful to differentiate

445

Gastrointestinal and hepatic complications Oral and oesophageal complications Oral candidiasis occurs frequently (see Fig. 11.8). Oesophageal candidiasis is the commonest cause of dysphagia or retrosternal discomfort and may frequently be the first AIDS-defining illness (Fig. 11.12). Oral candidiasis alone does not fulfil the criteria for AIDS. Oesophageal infection is best shown by culture or biopsy at endoscopy, although plaques of Candida albicans can often be seen during a barium swallow. Ulceration may be focal or diffuse. Cytomegalovirus and herpes simplex virus may both cause a similar pattern of ulceration in the oesophagus (and also may affect the stomach and duodenum), and should always be considered if oesophageal symptoms do not resolve on treatment with systemic antifungal agents.

FIG. 11.11 Chest radiograph of Pneumocystis carinii pneumonia, showing bilateral interstitial shadowing

between PCP, pyogenic bacteria and other infections, particularly in patients with an atypical presentation or who fail to respond to treatment. Cryptococcal pneumonia may occur in patients with cryptococcal meningitis and disseminated infection. Cytomegalovirus may be seen in BAL specimens, but appears not to be a major cause of pneumonia. 1 Infection with Mycobacterium tuberculosis occurs and, since 1993, has constituted a diagnosis of AIDS (see Case study Fig 11.1.1, p. 454). The downward trend of reported cases of tuberculosis in the United States has slowed at the same rate as the HIV epidemic has grown. Pulmonary tuberculosis can occur at different stages of immunosuppression, but tends to appear earlier in HIV disease than the atypical mycobacterial infections that complicate severe immunosuppression of advanced AIDS. In subSaharan Africa tuberculosis, both extrapulmonary and pulmonary, is a major cause of morbidity and death in HIV-infected persons. 2

Diarrhoea, malabsorption and weight loss Diarrhoea is a common symptom in patients with chronic HIV infection, with or without other manifestations of AIDS. In the majority of cases a pathogen is found, although an enteropathy with malabsorption may occur secondary to HIV infection. Cryptosporidium, a coccidian protozoal parasite, is probably the commonest pathogen isolated from patients with AIDS who have diarrhoea. It is the commonest of the protozoal causes of diarrhoea, which also include Isospora belli and microsporidia. In immunocompetent human

SUMMARY 1 Pulmonary infiltrates in HIV disease 1. Differential diagnosis Infective:

• Pneumocystis carinii pneumonia • Bacterial infection:

•

• • •

Streptococcus pneumoniae Haemoph/lus influenzae Pseudomonas aeruginosa Mycobacterial: M. tuberculosis Atypical mycobacteria M. avium-intracellulare M. kansasii M. xenopi Cryptococcus neoformans Toxoplasma gondii Cytomegalovirus

Non-infective: • Kaposi's sarcoma • non-Hodgkin's lymphoma • non-specific interstitial pneumonitis 2. Investigation

1

446

Fig. 11.1

2

MCQ 11.3

3

Fig. 11.2

Arterial blood gases or oximetry Sputum examination: Smear for acid-fast bacilli, Culture Fibre-optic bronchoscopy and broncho-alveolar lavage CT scanning, Nuclear medicine scanning Open lung biopsy

More recently, with improved diagnostic techniques, microsporidium, a small obligate intracellular protozoa, has been increasingly identified as a possible cause of diarrhoea and weight loss in patients with AIDS where no other pathogen had previously been found. Cytomegalovirus and herpes simplex virus can cause focal or diffuse ulceration of the gut, from the mouth to the anus. Herpes simplex virus most commonly causes mucocutaneous lesions at the upper and the lower ends of the gastrointestinal tract, whereas cytomegalovirus most frequently causes a colitis or oesophageal ulceration. Atypical mycobacteria of the avium intracellular complex are ubiquitous organisms that have little virulence for the immunocompetent host. Disseminated infection with Mycobacterium avium-intracellulare (MAI) of several organs occurs in patients with AIDS. Gastrointestinal infection may be associated with fever, weight loss, abdominal pain, diarrhoea and malabsorption. Diagnosis can be made by acid-fast staining of the stool or biopsy material, or both, or culture of blood or tissue. Shedding of atypical mycobacteria in stools alone does not indicate disseminated disease, but may often precede the presenting symptoms of disseminated infection. These are typically high fevers, anaemia and weight loss. 0 The diagnosis is most frequently confirmed on blood cultures or bone marrow examination. Mycobacterium tuberculosis infection of the bowel does occur, but is less common. Campylobacter and Salmonella species infections may cause diarrhoea, but the latter more commonly presents as a fever of unknown origin with bacteraemia.

FIG. 11.12 Barium swallow of oesophageal candidiasis The figure shows extensive oesophageal ulceration.

hosts cryptosporidium produces a transient diarrhoeal illness. In people infected with HIV it can cause transient, intermittent or persistent diarrhoea, ranging from loose stools to watery diarrhoea, colic, and severe fluid and electrolyte loss. Oocysts can be found in stools. If direct smears of unconcentrated faecal samples stained with iodine or modified acid-fast stains fail to show the oocysts the samples should be concentrated. The diagnosis should not be discounted without examining multiple specimens.

Hepatitis and cholestasis At all stages of HIV infection the commonest causes of acute hepatitis, both symptomatic and asymptomatic, are either drug toxicity or coinfection with viral hepatitis B or C. Treatment with many of the current antiretroviral agents is associated with a risk of drug-induced hepatitis, e.g. the nucleoside analogue stavudine, the non-nucleoside reverse transcriptase inhibitor nevirapine (usually in association with a rash and fever) and the protease inhibitor ritonavir. Severe acute hepatitis with liver failure secondary to hepatitic steatosis (in which the liver cells are filled with small fat droplets) is a rare complication of treatment with the reverse transcriptase inhibitors. Drugs used to treat specific acute opportunistic infections may also be implicated, and include the antimycobacterial agents, systemic azoles and high-dose co-trimoxazole. When multiple drugs are being taken then drug-induced hepatitis must always be considered. Acute primary infection with viral hepatitis A, B or C should be considered. Chronic infection with viral hepatitis B and C is more common among homosexual men and injecting drug users. In those coinfected with HIV there is a higher likelihood of progression to more severe chronic liver disease and cirrhosis. In patients with AIDS specific opportunistic infections

11

447

can cause hepatitis, which may present as fever, abdominal pain and hepatomegaly. If an ultrasound does not show dilated intra- or extrahepatitic bile ducts, suggesting obstruction, needle biopsy often shows granuloma hepatitis, usually caused by atypical mycobacteria rather than M. tuberculosis. The herpes viruses may also occasionally cause hepatitis as part of a disseminated infection. Acalculous cholecystitis and cholangitis show an endoscopic retrograde cholangiographic picture similar to that of primary sclerosing cholangitis, with strictures and dilatation of the biliary tree. Cryptosporidium and cytomegalovirus have been isolated and are implicated as a cause of this syndrome (Fig. 11.13).

tomatic disease. At necropsy up to 90% of patients dying of AIDS have chronic subcortical encephalitis, characterized by infected macrophages and microglial cells that fuse to form multinucleate giant cells. There is also patchy demyelination and astrogliosis.

Neurological complications Cerebral toxoplasmosis is the commonest cause of intracranial mass lesions and usually presents with focal symptoms and signs (Fig. 11.14). The main differential diagnosis is primary intracerebral lymphoma. Cytomegalovirus commonly causes a retinitis (Fig. 11.15) and presents with blurring and/or partial loss of vision. It may eventually lead to blindness. CMV may also cause a polyradiculoneuropathy or encephalitis, which is more rapid in onset and progression than HIV encephalitis alone. Differentiation may be helped by the detection of cytomegalovirus DNA by polymerase chain reaction (PCR) in the cerebrospinal fluid. Meningitis due to Cryptococcus neoformans should always be considered in patients with advanced disease presenting with headache and fever, although symptoms may be more non-specific. Infection with the papovavirus JC is responsible for progressive multifocal leukoencephalopathy (PML), a form of demyelination which causes progressive neurological impairment such as hemiparesis, with or without aphasia. 1 The majority of persons who develop PML have a positive PCR test for JC virus in their cerebral spinal fluid.

FIG. 11.13 ERCP of HIV associated sclerosing cholangitis The figure shows dilation of the common bile duct and dilation and stricture of the hepatiticbilarytree.

HIV NEUROLOGICAL DISEASE Apart from opportunistic infections, chronic HIV infection is associated with several syndromes that affect the nervous system, in addition to the transient meningoencephalitis, myelopathy and peripheral neuropathy of acute infection. These neurological diseases are due to the direct or indirect effects of HIV and not to opportunistic infection. AIDS-related dementia (HIV encephalopathy) has been estimated to occur in 10-40% of patients with symp-

448

1

Case 11.2

4

MCQ 11.4

2 Fig. 11.3 5 Fig. 11.5

0 Fig. 11.4 FIG. 11.14 CT brain scan of cerebral toxoplasmosis The figure shows multiple ring enhancing lesions with oedema.

11

FIG. 11.15 Cytomegalovirus retinitis in a patient with AIDS The figure shows extensive areas of white granular retinal necrosis and haemorrhage. ©

The clinical features are characterized by cognitive and behavioural changes that include memory loss, apathy and impaired concentration and attention. Neurological examination may show hyperreflexia, hypertonia and frontal lobe signs. CT or MRI often show cerebral atrophy © and non-specific changes in the white matter. The cerebrospinal fluid findings are non-specific. Opportunistic infections, intracranial mass lesions, metabolic encephalopathy and neurosyphilis should be excluded. Treatment with antiretroviral therapies may improve symptoms in those with early cognitive impairment, but probably have little impact on those with severe AIDS dementia other than to reduce their risk of subsequent opportunistic infections. HIV infection is also implicated in vacuolar myelopathy, affecting primarily the posterior and lateral spinal cord, an aseptic meningitis and the following neuropathies: axonal sensory, chronic inflammatory demyelinating and mononeuropathies. 45

FIG. 11.16 Cutaneous lesions of kaposi sarcoma in AIDS, appearing as purple raised plaques or nodules on the skin surface

TUMOURS Kaposi's sarcoma Kaposi's sarcoma (KS) is a presenting feature in 16% of patients, though the incidence has fallen over recent years. It is commoner in homosexual men than in the other groups at risk. The Kaposi's sarcoma of AIDS differs from classic Kaposi's sarcoma in that widespread skin (Fig. 11.16), mucous membrane (particularly the oral cavity and palate), visceral and lymph node disease occurs. Visceral, particularly gastrointestinal, lesions are present in as many as half of all patients at presentation. Nodules of Kaposi's sarcoma also occur in the lungs. Chest X-ray appearances vary from confluent irregular masses to interstitial nodularity and are better illustrated on a CT scan of the thorax (Fig. 11.17). CT of the thorax

FIG. 11.17 CT scan of pulmonary kaposis sarcoma The figure shows irregular masses and nodules in the lung parenchyma.

may be useful in differential diagnosis. At bronchoscopy, endobronchial lesions may be seen. Kaposi's sarcoma consists of spindle-shaped cells arranged in nodules and broad bands, and contains vascular slits filled with extravasated

449

erythrocytes. The diagnosis of Kaposi's sarcoma in very early skin lesions may be extremely difficult, as little more may be seen than a few irregular dilated vascular channels in the mid dermis and a mild inflammatory cell infiltrate. A herpes virus, kaposi sarcoma-associated herpes virus 8 (KSHV8), has been identified in kaposi sarcoma lesions of all forms, including both classic and AIDS associated. The incidence of positive serology to KSHV8 in different HIVinfected patient populations reflects the incidence of KS in these patient groups. The presence of KSHV8 in blood is predictive of the subsequent risk of developing KS. These observations suggest a causal role for KSHV8 in the development of KS.

Non-Hodgkin's lymphoma As in other chronically immunosuppressed patients, there is a greatly increased risk of non-Hodgkin's lymphoma. Although the tumour typically affects lymph nodes, extranodal disease is common and affects the central nervous system, bone marrow and gastrointestinal tract. The diagnosis should also be considered in patients with weight loss, constitutional symptoms and anaemia. These are B-cell lymphomas of high or intermediate grade. Response to cytotoxic drugs occurs, but treatment is difficult and usually unsuccessful because of profound immune suppression. In addition to secondary involvement of the CNS a proportion of AIDS associated Non-Hodgkin's lymphoma presents as primary CNS lymphoma; tumours which are intracranial parenchyma lesions limited to the CNS. Patients usually present with single large mass lesions in the brain (Fig. 11.18). 1

Other tumours Squamous carcinomas of the mouth and anorectum occur in homosexual men with antibodies to HIV. Human papillomavirus may play a part. There is a higher proportion of cervical intraepithelial neoplasia (CIN) in HIV infected women and a higher rate of progression from lower to high grade CIN.

TREATMENT AntiretroviraIs Acute primary infection Treatment with antiretroviral agents should be considered in patients with acute primary HIV infection.

1 Fig. 11.6 450

FIG. 11.18 CT brain scan of primary cerebral lymphoma The figure shows a large single ring enhancing lesion with mid-line shift.

There is, however, no substantial evidence that antiretroviral therapy started at this stage results in greater longterm clinical benefit than if treatment is initiated during established chronic infection. However, the initiation of therapy within a few weeks of infection can result in immunological benefit, with preservation of specific Thelper cell responses to HIV, higher T-helper (CD4) cell counts and better HIV-specific cytotoxic T-lymphocyte responses. Although these preliminary immunological observations are impressive, their relative importance in the long-term treatment of HIV infection is not known. It is also uncertain whether the treatment initiated during primary infection should be continued long term or can be stopped after 1-2 years, with preservation of immunological benefit. Trials are under way to evaluate this treatment strategy. Until further evidence is available the decision to start antiretroviral therapy at this stage is a balance between preserving immune responses and the possible risk of drug toxicity, therapy failure, and the lack of evidence of long-term clinical benefit. Chronic adult infection The treatment of HIV infection has improved markedly over the last few years, and has resulted in decreases in the incidence of opportunistic infections and an improvement in survival. The results of large randomized clinical trials in the mid-1990s established a strong relationship between falls in plasma viral load occurring on therapy and clinical benefit in the short to medium term. It is now accepted that the objective of therapy is to sustain the suppression of viral load to levels that are preferably below the limits of

detection with the currently available ultrasensitive assays (less than 50 copies per mL). The suppression of viral replication results in sustained increases in CD4 cell counts (both memory and naive T cells), increases in the T-cell antigen repertoire, and re-establishment of T-cell responses to various antigens (e.g. CMV, mycobacteria). Failure to suppress plasma viral load optimally is associated with subsequent rebound of the viral load, the emergence of viral isolates with reduced drug sensitivity and subsequent falls in CD4 cell counts, and continued damage to the immune system. Currently there are three classes of antiretroviral drug available. These are nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs) and the protease inhibitors (PIs). The NRTIs are direct competitive inhibitors of the viral enzyme reverse transcriptase. NNRTIs are indirect inhibitors that bind to a site distant to the active site of the enzyme. The protease inhibitors inhibit the viral enzyme protease, which is responsible for the post-translational cleavage of precursor structural core proteins following budding of the HIV virion (see Fig. 11.6). Clinical trials have shown that a combination of three or more antiretroviral drugs results in greater and more sustained falls in plasma viral load, and increases the CD4 count more than with mono or dual therapy. It is currently usual standard clinical practice to combine two NRTIs with either one NNRTI or one or two PIs (Table 11.6). Comparative trials have shown that a triple combination containing either a PI or an NNRTI have similar antiviral efficacy at 12-18 months. Although there is more substantial trial evidence of the clinical benefit of PIs, it is generally accepted that NNRTI-containing regimens will result in similar clinical benefit, in view of their similar effects on viral load and CD4 count. It remains unclear, however, which regimen is the better for patients who have never received treatment. Recent trials have also demonstrated that combinations of 3 NRTIs as initial therapy to have similar efficacy to certain combinations to 2 NRTIs + either 1 NNRTI or 1 PI. It is also not yet clear which regimen should be used in patients who have experienced one or two failures of therapy. Trials are under way to assess different treatment strategies in each of these situations. There is no evidence from randomized clinical trials that helps to decide with the current therapies when, in the natural history of HIV infection, to initiate therapy. Treatment guidelines (Table 11.7) have used surrogate (laboratory-based) data from prospective studies of the natural history of the disease to guide the time to start therapy. These data have been added to the current knowledge of the effectiveness and tolerability of current combination treatments and the willingness of an infected person to start therapy. Most patients will start therapy once their CD4 count is 350 x 106/L or below, but national guidelines vary and so do the motivation and willingness of individual patients. A significant proportion of patients present and are

11

TABLE 11.6 Antiretroviral regimens (2001) 1. 2 NRTIs plus either: 1 NNRTI or 1PI or

2 PIs 2. 3 NRTIs

e.g. zidovudine or stavudine + lamivudine or didanosine e.g. nevirapine or efavirenz e.g. nelfinavir or lopinavir/r e.g. saquinavir + ritonavir zidovudine, lamivudine, abacavir

Recommended antiretroviral regimens for the initial treatment of established chronic infection in adults (2001) NRTis, nucleoside reverse transcriptase inhibitors NNRTIs, nonnucleoside reverse transcriptase inhibitors PIs, protease inhibitors.

TABLE 11.7 Treatment guidelines for starting antiretroviral therapy adults (2001) Disease stage

BHIVA(1)

US DHHS (2)

Symptomatic Asymptomatic (i) CD4<200x10 6 /L (ii) CD4 200-350 x106/L

Treat

Treat

Treat Consider treatment depending upon VL, rate of CD4 count decline symptoms and patient wishes Definitely

Treat Treatment should be generally offered

(ii) CD>350x10 6 /L

Defer or consider treatment if high VL

(1) BHIVA, British HIV Association Guidelines (Oct 2001). (2) USDHHS, United States Department of Health and Human Services (Feb 2001). VL, viral load. Treatment guidelines are constantly reviewed and updated.

diagnosed in latent disease when symptomatic and have CD4 counts of <200 x 106/L. Even in patients who are newly diagnosed at a late stage of disease, starting antiretroviral therapy can result in substantial increases in CD4 count and sustained clinical benefit. Although clinically effective, current antiretroviral drugs are not ideal. In patients not previously treated with antiretroviral drugs only 50-60% will sustain falls in plasma viral load to undetectable levels, as measured by the current ultrasensitive assays at 1 year of therapy. Poor tolerability and side-effects account for a high proportion of therapeutic failures, together with poor adherence and limited antiviral potency. Excellent compliance with combination therapies is a major determinant of therapeutic success. Every effort should be made, in both choice of

451

TABLE 11.8 Treatment guidelines for major opportunistic infections Infection

Drug

Dose

Duration 14-21 days 6 weeks

Pneumocystis carinii pneumonia

Trimethoprim/sulfamethoxazole

15-20/75-100 mg/kg/day (divided doses)

Cerebral toxoplasmosis

Pyrimethamine + sulfadoxine orclindamycin

Cytomegalovirus retinitis

Ganciclovir cidofovir

200 mg on first day then 50mg o.d. 4-6 g daily 600mg q.d.s. 10mg/kg/day/i.v. 5mg/kg/weekly/i.v.

Cryptococcal meningitis

(i) (ii)

Amphotericin B ± flucytosine or fluconazole

Disseminated MAI

Clarithromycin + ethambutol + rifabutin

Oesophageal candidiasis

Ketoconazole Fluconazole

0.5-1.0mg/kg/day/i.v. 75-100 mg/kg/day 600-800 mg/day 500mg-1gb.d. 15 mg/kg/day 400-600 mg/day 200-400 mg/day 50-100 mg/day

2 weeks 6 weeks

Indefinite

7-14 days

Following treatment course all major opportunistic infections require maintenance treatment regimens at adjusted doses. With effective antiretroviral therapy CD4 counts increase and secondary prophylaxis and treatment for MAI infection may be discontinued.

therapies and clinical and psychological support, to aid adherence to treatment. The emergence of viral isolates which are resistant to antiretroviral drugs is common in patients experiencing therapy failure. Phenotype and genotype assays have recently become available, and initial studies have demonstrated better virological outcome from their use in guiding the choice of new antiretroviral regimens in patients who are experiencing treatment failure. Recently long-term toxicities with antiretrovirals have been increasingly recognized, with patients experiencing metabolic toxicity (e.g. diabetes, hyperlipidaemia and lactic acidosis) and fat redistribution syndromes (lipodystrophy). The pathogenesis for some of these toxicities, particularly lipodystrophy, is not fully understood. Several predisposing factors seem to be involved, including specific actions of antiretroviral drugs, the previous treatment history and age of the patient. Antiretroviral agents with new sites of action are being developed. The binding of HIV to the CD4 molecule on the cell surface has long been a potential target for therapy. Recently, fusion inhibitors have been developed (T20) which bind to the HIV transmembrane protein GP41, preventing the conformational changes necessary for viral entry into the cell. Initial trials of T20 in patients who have experienced multiple therapy failures have shown good

452

1

MCQ 11.5

2

Case 11.3

3

Case 11.4

4

Case 11.5

antiviral response in the short term, suggesting that this new class of drugs maybe beneficial clinically. Another approach is through chemokine receptors, which act as coreceptors for HIV binding and determine the susceptibility of the target cell to infection by different HIV strains. New drugs are being developed which block chemokine receptor binding. 12

Opportunistic infections In the developed world, treatment of major opportunistic infections associated with HIV infection is usually effective. Mortality remains highest in those who present late with previously undiagnosed HIV infection, and treatment is frequently associated with a high incidence of drug sideeffects which limit tolerability. Treatment guidelines for the major opportunistic infections are outlined in Table 11.8. Alternative regimens for the treatment of Pneumocystis carinii pneumonia in those intolerant to high-dose co-trimoxazole are combinations of clindamycin and primaquine, or intravenous pentamidine and atovaquone. Steroid therapy is indicated in those who present with severe hypoxia (Pao2 < 9.3kPa), as this has

SUMMARY 2 AIDS prevention strategies • Control of generally sexually transmitted infections • Promoting safe sex behaviour in people with known HIV infection and those not infected or of unknown status • Promoting early diagnosis of HIV infection in those at risk • Ensuring good and equal access to HIV treatment services

been shown to improve clinical outcome and response. Although Pneumocystis resistance to co-trimoxazole has been demonstrated, poor clinical response to treatment is usually associated with late presentation or coinfection with bacterial or viral pathogens. Either intravenous ganciclovir or cidofovir is effective for the treatment of a first episode of CMV retinitis or other CMV end-organ disease, such as colitis or oesophageal ulceration. Although the dose scheduling is convenient, renal toxicity with cidofovir is common and frequent laboratory monitoring for toxicity is mandatory. With the initiation of effective antiretroviral therapy, relapse of CMV retinitis is uncommon. In those who do experience relapse, switching anti-CMV agents to combinations of foscarnet and ganciclovir or ganciclovir ocular implants maybe effective. For patients who present with a single or multiple intracerebral space-occupying lesion where toxoplasmosis is a probable diagnosis, the use of steroids should be avoided if possible because the interval MRI brain scan at 2 weeks, to determine an antitoxoplasmosis treatment response, may be difficult to interpret as a result of the effect of steroids on cerebral odema. In those not responding, a diagnosis of primary CNS lymphoma should be considered, particularly if it is a single lesion or there is supporting evidence from a gallium scan. The appearances on an MRI brain scan unfortunately do not aid differentiation. Gastrointestinal infection with cryptosporidium usually results in a self-limiting illness in patients with less advanced immunosuppression. However, in those with severe immunosuppression (CD4 count < 200) chronic infection can result in frequent diarrhoea, severe weight loss, nausea, vomiting, and salt and water depletion. Treatment with specific anticryptosporidial agents is disappointing. Initiation with antiretroviral combination regimens has, however, been shown to be effective as an effect of the improvement in the immune system. It is important for any patient presenting with a major opportunistic infection to be started on an effective antiretroviral combination regimen. Immune reconstitution on antiretroviral therapy will substantially reduce the risk of relapse and of additional opportunistic infections, and may allow the discontinuation of secondary prophylaxis. Effective immune reconstitution with antiretrovirals can also result in disease as T-lymphocyte responses to different antigens are regained. In patients with advanced immune deficiency (CD4 < 100 x 106/L) started on effective antiretroviral therapy, clinically apparent CMV and mycobacterial disease have been reported in the first few months of therapy. This is a result of the immune system mounting effective responses to previously silent infections. It is routine practice for primary prophylaxis against certain opportunistic infections to be started once the CD4 count falls to below 200 x 106/L, irrespective of whether the patient is on an antiretroviral regimen or not. Approxi-

mately one in five persons not on antiretroviral therapy will develop Pneumocystis carinii pneumonia within 1 year of their CD4 count falling to below 200 x 106/L. Primary prophylaxis with cotrimoxazole 960 mg once daily or an alternative regimen (e.g. dapsone 100 mg once daily) reduces this risk to a few per cent. In patients with a CD4 count less than 100 x 106/L and positive serology to toxoplasmosis, once-daily cotrimoxazole is also effective prophylaxis against cerebral toxoplasmosis. Dapsone 100 mg once daily and pyrimethamine 25 mg three times per week is an alternative in patients intolerant of co-trimoxazole. In patients with CD4 counts less than 50 x 106/L prophylaxis with azithromycin 1200 mg once weekly against disseminated Mycobacterium avium intracellulare infection should be considered. Alternative regimens are clarithromycin 500 mg twice daily, or weekly azithromycin plus rifabutin 300 mg daily. Chemoprophylaxis against mycobacterial tuberculosis may also be considered, particularly in those with a high background risk of exposure, but active disease needs to be excluded first, as this requires combination treatment. National guidelines differ, and prophylaxis may not be appropriate in populations with either very high or very low prevalence rates of clinical tuberculosis. Both secondary and primary prophylaxis to most opportunistic infections may be safely discontinued when the CD4 count on antiretroviral therapy has risen persistently to above 200 x 106/L, or even above 100 x 106/L for some opportunistic infections such as CMV disease. Prevention of environmental exposure to certain opportunistic infections may be possible, particularly to cyptosporidium and toxoplasmosis. Outbreaks of cryptosporidial diarrhoea from public water supplies can occur. Patients with severe immune deficiency should be advised to boil their water or use bottled water where the risk of contamination at source may be less than with public supplies. HIV-infected persons who lack IgG antibody response to toxoplasmosis should be counselled about the various sources of toxoplasma infection, and particularly should be advised not to eat raw or undercooked meat. 3 34

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STRATEGY FOR CONTROL OF HIV AND AIDS Both HIV infection and other traditional sexually transmitted diseases (STDs) share similar risk factors in relation to their spread, but in addition they can potentate each other. Both of these facts need to be understood if effective control programmes are to be developed. The presence of an STD, particularly genital ulcers, can enhance both the acquisition and transmission of HIV by increased shedding of the virus within and from the genital tract. Several studies have shown that the risk of acquiring HIV in the presence of an ulcerative or non-ulcerative STD is increased 2-6-fold. The shared risk factors for the acquisi-

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CASE STUDY 11.1 ACUTE DIARRHOEA IN HIV INFECTION A 45-year-old homosexual man presented with a 6-week history of liquid diarrhoea (5-6 times daily), weight loss of 6 kg, episodic abdominal pain and, more recently, nausea and anorexia. He had no recent travel history and no previous history of chronic diarrhoea. He had not noticed blood in his stool, or fever. He was not taking any medication and had no other history. He was a non-smoker and drank 15 units of alcohol per week. He had been found to be HIV antibody positive 6 years ago, but had not attended for regular monitoring and follow-up. On examination he was afebrile, he appeared wasted, had pseudomembranous oral Candida in his mouth and seborrhoeic dermatitis on his face. His abdomen was mildly distended with active bowel sounds, but was otherwise soft and nontender. His CD4 count on this occasion was 110 x 106/L, with a plasma HIV RNA level of 75000 copies per mL. Questions 1. What is the differential diagnosis? 2. How would you manage this patient? Discussion This man presents with chronic diarrhoea, abdominal pain and weight loss. He is known to be HIV antibody positive, and recent tests show that he is severely immunosuppressed, with a CD4 T-cell count of 110 x 106/L. On examination he has oral Candida and seborrhoeic dermatitis - both indicators of clinical progression to symptomatic HIV disease.

454

It is important to exclude an infective cause for his diarrhoea. Several stool samples should be sent for both bacterial culture and microscopy for ova cysts and parasites. (If the patient had taken antibiotics recently then diarrhoea due to Clostridium difficile toxin would also be considered). If repeat stool samples are found to be negative for pathogens, colonoscopy and duodenoscopy with biopsy of the bowel mucosa should be undertaken. If no pathogens are identified then a diagnosis of wasting syndrome secondary to HIV enteropathy can be made by exclusion. Patients with HIV enteropathy have partial villous atrophy of the small bowel mucosa. Gastrointestinal infection with cryptosporidium is frequently responsible for weight loss and persistent diarrhoea in HIV-positive patients with severe immunosuppression. Cryptosporidial infection (Case Fig. 11.1.1) causing diarrhoea for more than 1 month is an AIDS-defining illness. Both the large and the small bowel may

become infected. The small bowel involvement is associated with persistent nausea and recurrent vomiting. Prior to effective antiretroviral treatment gastrointestinal cryptosporidiosis in patients with CD4 counts less than 200 x 106/L was difficult to treat, and severe disease was associated with high morbidity and occasional mortality. There is uncontrolled evidence that a 4-week course of paramomycin may be helpful, but symptom control with antidiarrhoeal drugs was previously the mainstay of treatment. Today, with the availability of effective antiretroviral treatment, this man should be started on a triple combination regimen and given symptom control for his nausea and diarrhoea as required. Subsequent immune reconstitution on therapy should result in clearance of the cryptosporidium and resolution of the diarrhoea. HIV-infected persons with CD4 counts less than 200 should be advised to boil their water as a prophylactic measure against cryptosporidial infection.

CASE Fig. 11.1.1 Cryptosporidial infection of the small bowel

tion of HIV and other STDs, and the interaction between them, has led to the setting up of integrated control programmes in the hope of reducing STDs and slowing the spread of HIV. This strategy was reinforced by the results

of one study in Africa which showed a significant reduction of HIV transmission rates with the provision of STD treatment services. Control of HIV has two elements, primary and sec-

ondary. Primary prevention is aimed at stopping infection occurring in the first place. This is achieved through health education and programmes to market and encourage the use of condoms. In the UK, initial health education campaigns resulted in homosexual men, in particular, adopting safe sex practices. However, such changes are not always easy to sustain, and repeated reinforcement and monitoring is required. Secondary prevention is aimed at promoting health-care seeking behaviour, so that those who could be infected recognize this, regardless of symptoms, and as a result come forward for HIV testing and care if required. This is particularly important, as primary prophylaxis can be offered for PCP, and combination antiviral therapy can have an effect on morbidity and mortality. Everyone is potentially at risk of infection: even though the prevalence among those without recognized risk factors is currently low, it requires sexual contact with only one infected person for transmission to occur. Those who are HIV seronegative and in a mutually monogamous relationship have nothing to fear. The sensible message to everyone else must be: to reduce your risk, reduce your number of sexual partners, know about your partner's previous sexual and drug use history, and use a condom. Condoms may not provide total protection, but they will help considerably if used properly and every time. Preventing the transmission of HIV among injecting drug users must rely on stopping the sharing of needles and other paraphernalia that go with injecting drugs (syringes, mixing bowls, spoons etc.), as well as advising on safer sex practices. Users need to be advised of the risk of sharing; this applies to any form of injection, whether intravenous, intramuscular or subcutaneous. Equally important is advice on the risk of transmitting or acquiring the virus sexually, as well as the potential risk of both male and female prostitution, as this may be used to finance a drug habit. For any individual the best primary prevention is to stop using drugs, but if this is unrealistic at the time, the next option is to stop injecting and switch to sniffing, smoking or swallowing drugs. In the realization that people still continue to inject, a large number of needle exchange programmes have been set up throughout the UK, and are currently thought to be useful in cutting down the sharing of needles. Vertical transmission from mother to child is uncommon in the UK. The risk of an HIV-positive pregnant woman transmitting HIV to her unborn child is thought to be about 13% in developed countries, but up to 30% in the developing world. Intrapartum transmission accounts for the majority of cases of vertical transmission. Factors associated with a higher risk include prematurity, the use of instrumentation during birth, maternal diagnosis of AIDS, maternal viral load levels and breastfeeding. Seropositive women, or women who are considering parenthood, need to be counselled about the risk of pregnancy, to both the mother and her unborn child. A seropositive woman who becomes pregnant can obviously be offered termination, but treatment interventions substantially reduce the risk of perinatal transmission and therefore many wish to go to term.

Early clinical trials showed that zidovudine monotherapy given to mothers from the second trimester up to and including the intrapartum period, together with 6 weeks of zidovudine therapy given to the infant, results in an approximately 70% reduction in transmission rates. Subsequent studies have shown a relationship between the level of maternal plasma viral load on treatment at birth and the risk of transmission. In the developed world it is now common practice to initiate triple combination antiretroviral therapy to achieve and sustain maximum suppression of maternal plasma viral load levels during pregnancy and through the intrapartum period. The avoidance of breastfeeding is essential to sustain this reduction in risk. The implementation of these measures, however, is only possible if both the mother and her physician are aware that she is seropositive during pregnancy. HIV antibody testing should routinely be offered to all pregnant women, irrespective of the perception of risk. In the developing world vertical transmission is a major problem and complex triple combination therapies are too costly. Recent studies have investigated simpler and shorter-course treatments. A single dose of the nonnucleoside reverse transcriptase inhibitor nevirapine, given to the mother at the onset of labour and to the infant aged 48 hours, has been shown to reduce perinatal transmission by approximately 50%, compared to a short course of zidovudine given to the mother during labour and postnatally to the infant for 7 days. Peripartum therapeutic intervention will have no effect on intrauterine transmission. The reduction in transmission rates in infants at 6 weeks is likely to be lost in a breastfeeding population at 2 years, as a result of continued postnatal transmission. The widescale implementation of an effective therapeutic intervention to prevent perinatal transmission in the developing world is a challenge that remains to be met. The risk of occupational transmission of HIV as a result of needle-stick injuries has been estimated to be 0.3%. Although there is no substantial evidence of clinical efficacy, and based largely on biological rationale, it is recommended that health-care professionals who sustain a significant exposure to a bodily fluid from an HIV-infected person should take a triple combination regimen as postexposure prophylaxis for 4 weeks after the incident. Prophylaxis should be started as soon as possible after the incidence, preferably within 1-2 hours. The relative benefit of such a regimen remains uncertain. Postexposure prophylaxis has also been considered after sexual exposure, but in the absence of any data to support a relative benefit no specific guidelines have been recommended.

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FURTHER READING Adler M W (ed) ABC of AIDS, 5th edn. London: BMJ Publishing, 2001. British HIV Association (BHIVA) Guidelines for the treatment of HIV infection. HIV infected adults with antiretroviral therapy. HIV Medicine 2001.

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Granziosi C et al. Immunopathogenesis of HIV infection. AIDS Res Hum Retroviruses 1998; 14(Suppl 2):5135-5142.

SEXUALLY TRANSMITTED INFECTIONS GENITAL HERPES INFECTION The biology of herpes simplex infection and herpes labialis is dealt with in detail in Chapter 9 (p. 286). Genital herpes simplex virus infection is the commonest ulcerative STI in England and Wales and reported cases have increased severalfold over the last 20 years, particularly in females aged 16-24 years.

FIG. 11.19 A clinical episode of genital herpes affecting the penis The figure shows multiple small shallow ulcers around the foreskin.

Primary genital infection HSV 2 is largely associated with genital infection. Primary genital infection, or the first clinical episode, is most common in young, sexually active adults, and the risk of infection is proportional to the number of sexual partners. After an incubation period of 2-7 days, clusters of vesicles with surrounding erythema appear at the site of virus entry, on the glans or penile shaft in men, or on the vulva and vaginal mucosa in women. Homosexual men may develop rectal and perianal lesions. The lesions are usually painful and there may be systemic illness, with headache, myalgia, fever and local lymphadenopathy. Occasionally paraesthesia may develop in areas supplied by infected nerves, and there may be associated urinary retention or constipation. Skin and mucosal lesions resolve over 2-3 weeks. Virus may be shed from the lesions for up to 12 days. Infection of neonates is discussed on page 286.

Recurrent genital herpes Recurrent clinical episodes cause lesions similar to, but milder than, those of the primary episode (Fig. 11.19), with more localized lesions occasionally accompanied by shooting pains in the buttocks or legs. Recurrent episodes are associated with less pain and are shorter in duration. Systemic manifestations are rare. Often patients notice prodromal symptoms of local paraesthesia 24-48 hours before lesions appear. The rate of recurrence is variable, although the majority of patients experience a recurrence within 12 months of the first clinical episode. Asymptomatic secretion of virus can occur in the mouth or in the vagina, but this is rarely a source of transmission.

1 456

MCQ 11.6

2

Case 11.6

Management of genital herpes First clinical episodes of genital herpes, when severe, are usually treated with 5 days of oral aciclovir (200 mg five times daily), with analgesics and saline baths. For recurrences, local hygiene is usually all that is required. If episodes are frequent and severe suppressive aciclovir therapy may be necessary. Counselling on the management of recurrences and the prevention of transmission is required.

MOLLUSCUM CONTAGIOSUM Molluscum contagiosum is an infection of the skin caused by a poxvirus. The incubation period is variable but is usually around 14 days. A typical lesion is a smooth, firm papule, with the vertex being umbilicated and containing a waxy substance. Lesions commonly appear on the genitalia, suprapubic area and inner thighs, but can appear anywhere on the skin surface. They appear to be more common in people who are HIV positive, when the face, including the eyelids, may be involved. Spontaneous regression may occur. Therapies include curettage and liquid cryotherapy, or the application of phenol after disruption of the lesions.

GENITAL WARTS Warts are caused by a small DNA virus (papillomavirus) belonging to the papovavirus group. Anogenital warts are sexually transmitted (p. 393) and are regarded as important in view of increasing evidence associating them with cervical cancer.

have increased significantly over the last few years, the highest among 16-19-year-old females.

11

Clinical features Men usually have urethral discharge and dysuria about 10 days after exposure to infection. In women the infection is usually silent, but may present with an abnormal vaginal discharge or with symptoms of pelvic inflammatory disease. If uncomplicated rectal infection occurs there may be anal discharge, perianal dampness, irritation and tenesmus. Complications are more common in women than in men. In women they include bartholinitis, salpingitis and perihepatitis. In men the complications include epididymo-orchitis, prostatitis and sexually acquired reactive arthropathy (Reiter's syndrome, p. 1151). FIG. 11.20 Genital warts involving the vulva and perineum

In men warts can appear on any part of the genitalia, but especially the frenulum, the coronal sulcus and the inner surface of the foreskin. They are called condylomata acuminata. They may be found in the male urethra and appear as bright red lumps at the meatus. In women the vulva and cervix can be involved (Fig. 11.20), as can the perineal area in both sexes. Cervical condylomata may be flat and identifiable only by colposcopy. They may be associated with cervical dyskeratosis and koilocytosis.

Management Local application of cytotoxic agents such as podophyllin, or of destructive agents or methods such as trichloracetic acid, cautery, diathermy or cryosurgery, is still the main therapeutic approach. Ablation of cervical warts by laser therapy is effective. Sexual partners should be contact traced and treated. Women diagnosed with genital warts, and the female partners of men with genital warts, should also have cervical cytology.

CHLAMYDIA TRACHOMATIS Genital infection Chlamydia trachomatis is an obligatory intracellular parasite whose replication results in the death of the infected cell. During its lifecycle the infectious particle changes to an actively dividing form, which later reorganizes into the infectious form that is released on cell lysis. Non-specific genital infection (NSGI), of which chlamydia infection may account for up to 50% in the UK, may present as urethritis, cervicitis or proctitis. Other relevant organisms include mycoplasmas and uroplasmas. Genital chlamydia infection is thought to be the commonest STI in England, with prevalances of 2-12% detected in studies of GP attendees. The rates of diagnosis

Diagnosis In men a Gram-stained urethral smear shows an excess of polymorphonuclear leukocytes but no gonococci, and is supportive of a diagnosis of non-gonoccoal urethritis. In men and women chlamydial infection is confirmed by identifying antigen at the site of infection, or by culture. Management Chlamydial infection and most other NSGI responds to tetracycline therapy. The usual is doxycycline (100 mg daily) for at least 7 days, or azithromycin 1 g orally as a single dose. Erythromycin (500 mg twice daily) may be used as an alternative and is the first choice in pregnancy and in tetracycline allergy. Relapse or recurrent infection is common in both sexes. There may be symptoms of a postinfective urethritis, with no signs of infection. Sexual partners of both sexes should always be examined and treated to identify asymptomatic infection, to prevent serious complications of untreated infection in the contact, such as pelvic inflammatory disease, and to avoid reinfection of the index case.

Congenital Chlamydia trachomatis infection Chlamydia trachomatis infection is now frequently seen as a cause of ophthalmia neonatorum. The infected baby develops a conjunctivitis about 10 days after birth. Investigation should include culture of pus, or a monoclonal antibody test for Chlamydia trachomatis. The organism may also be a cause of pneumonia in the neonate. Treatment is with erythromycin syrup. The baby's parents should always be examined for Chlamydia and other genital infections. 12

LYMPHOGRANULOMA VENEREUM Lymphogranuloma venereum (LGV) is caused by L1, L2 or L3 serotypes of Chlamydia trachomatis. It is most prevalent in parts of Africa, Asia and South America.

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Clinical features The most common primary lesion of LGV is a shallow ulcer appearing on the genitals of men or women 3-10 days after exposure to infection. In men there may be an associated lymphangitis of the dorsal penis. More commonly in men there may be an inflammation and swelling of the inguinal lymph nodes 10 days to 6 months after infection. The inguinal bubo is unilateral in about 60% of cases and may enlarge, causing pain, and rupture. About 20% also have involvement of the femoral lymph nodes. This creates a groove over the inguinal ligament - the characteristic 'groove sign'. LGV may also cause a rectal infection. After initial inflammation of the rectal mucosa a chronic inflammatory process may follow; this invades the bowel wall, with noncaseous granulomas and crypt abscesses forming. A partial or complete stricture of the rectum may develop.

the extremities. Gonococcus is an important cause of acute septic arthritis (p. 1158). Disseminated gonococcal infection is commoner in women than in men. Signs include fever, pustular rash and arthritis. Infection in pregnancy may cause abortion or premature labour and is associated with high perinatal mortality. The baby can be infected in utero, at birth or postnatally, and at worst develops disseminated infection. Ophthalmia neonatorum is the more common sign of neonatal infection.

Diagnosis and management Diagnosis is based on a positive complement fixation or microimmunofluorescent (micro-IF) test. Doxycycline (100 mg daily for 2-4 weeks) is the therapy of choice.

Management A typical treatment regimen is ampicillin (3g) plus probenecid (1 g orally). This combination allows singledose treatment, probenecid delaying excretion of the penicillin. Recommended alternative regimens are ciprafloxacillin 500 mg orally, or ofloxacin 400 mg orally, both as a single dose. These are preferred for the treatment of pharyngeal infection as ampicillin (and spectinomycin) has poor efficacy in eradicating infection from this site. The prevalence of penicillinase-producing strains in the UK is less than 5%, and quinolones remain highly active against these resistant strains. The prevalence of quinolone-resistance strains in the UK is less than 2%, but has risen since 1993. The prevalence of strains resistant to both quinolones and penicillin is high in some parts of the world, particularly southeast Asia, and this needs to be considered in treating possible imported infection. In these cases alternative regimens include cefotaxime 500mg (i.m.) or spectinomycin 2mg (i.m.), both as a single dose. Coinfection with Chlamydia trachomatis occurs in up to 20% of men and 40% of women presenting with gonohorroea, and should be suspected if symptoms persist a week after treatment of gonoccocal infection. Combining effective anti-microbial therapy against Chlamydia with singledose therapy for gonorrhoea at first presentation may be appropriate, and should be considered if there is doubt about follow-up. Sexual contacts should be traced, examined and treated. 1

NEISSERIA GONORRHOEAE (GONOCOCCUS) INFECTION Gonorrhoea is an important STD that causes urethritis, endocervicitis or proctitis. The annual incidence of cases reported by clinics in the UK declined markedly in the 1980s, probably as a result of behaviour changes in response to the HIV epidemic. Since 1994 there has been a rise in the incidence of gonorrhoea cases, both heterosexually and homosexually acquired, suggesting that such behaviour modifications may not have been sustained. In 1998,20% of all cases of gonorrhoea were among homosexual men. Clinical features The incubation period is between 2 and 7 days. In men there is urethritis, with a creamy discharge, dysuria and frequency. Homosexual men also develop proctitis, with pruritus, tenesmus and rectal discharge, often containing blood. In women the infection is usually asymptomatic (discovered by contact tracing or during a routine examination at a GUM clinic) or causes vaginal discharge, dysuria, frequency and lower abdominal pain. Pharyngeal infection follows oral sex but is usually asymptomatic. Complications Ascending infection causes pelvic inflammatory disease, with salpingitis, peritonitis or abscess formation in 10-20% of infected women. Septicaemia may occur, with a rash on

1 458

MCQ 11.7

Diagnosis Microscopy of Gram-stained smears shows pus cells and both intra- and extracellular Gram-negative diplococci. Specimens should be taken from the endocervix in women: a high vaginal swab is inadequate. Culture is essential, as penicillin-resistant gonococci are becoming more common. Serology is not helpful in diagnosis.

Syphilis Syphilis is caused by Treponema pallidum (TP), one of a small group of treponemes. TP is 6-15 um in length and is narrow, with regular tight spirals, and mobile in all axes. Transmission is usually by sexual contact, although transplacental infection may occur. Exposure to moist mucosal or cutaneous surfaces is required; transmission is commonly during the first 1-4 years of infection. The incidence of syphilis in England and Wales fell after the intro-

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CASE STUDY 11.2 URETHRAL DISCHARGE A 22-year-old homosexual man presented to a genitourinary medicine clinic with a 2-day history of urethral discharge and dysuria. He had no other symptoms but reported a history of oral sex and protected receptive anal intercourse with a new male partner 10 days ago. He also had a history of a condom accident with a casual partner 6 months ago, but no other history of unsafe episodes of sexual intercourse. He had been treated 4 years previously by his GP for scabies, but otherwise had no other relevant history. On examination he had a mucopurulent urethral discharge. Testis, scrotum and anorectal examination was normal. Small bilateral inguinal lymph nodes were palpable. Questions 1. What is the differential diagnosis? 2. How would you manage this patient?

Discussion This 22-year-old man presents with a urethral discharge and a recent history of a new sexual partner. Clinically he has urethritis and the differential diagnosis includes infection with either Neisseria gonorrhoeae, or Chlamydia triachomatis, or a non-specific urethritis. Microscopy of a urethral smear will show polymorphonuclear leukocytes, and a Gram stain should be undertaken to look for Neisseria gonorrhoeae. In men presenting with symptomatic gonococcal infection urethral microscopy is diagnostic in 90% of cases. In asymptomatic men the diagnostic sensitivity of a urethral smear is lower. A urethral swab for culture of Neisseria gonorrhoeae should be taken to confirm infection and allow for antimicrobial sensitivity testing. Urethral screening tests for Chlamydia infection should be performed. In view of this man's sexual history, rectal and pharyngeal cultures for gonorrhoea and routine serology tests

duction of antibiotic therapy (see Fig. 11.1), but there was a resurgence during the 1970s in males. These cases were mainly in homosexual men with numerous sexual partners. In the 1980s and 1990s there was a decline in the incidence of syphilis, with homosexual transmission now accounting for only one-quarter of all cases diagnosed in GUM clinics in 1998. Fifty per cent of all infectious syphilis in England was acquired outside the UK. However, very recently, in 2000, there has been reported a 2-3 fold increase in the number of cases of infectious syphilis amongst homosexual men in different cities in the UK. Worldwide there was a marked increase in reported cases in eastern Europe and Russia in the 1990s. Clinical features Syphilis is classified as acquired or congenital. Acquired syphilis may be divided into early or late. The stages of early syphilis are primary, secondary and early latent (less than 2 years of infection), and of late syphilis are late latent (more than 2 years of infection), tertiary and quaternary. Primary The primary lesion is a chancre (Fig. 11.21a), which starts as a painless pink papule and may develop into an ulcer.

for syphilis should be undertaken. A full sexual history should be taken from any patient presenting with symptoms of a possible sexually transmitted infection, and the appropriate diagnostic screen for a coincident sexually transmitted infection be offered. Referral to a genitourinary medicine clinic for management is strongly encouraged. In this man an HIV antibody test should be discussed and offered. In addition, if serological tests for either viral hepatitis B or A show he is nonimmune, he should be offered appropriate vaccination. His recent sexual partner should be traced and screened for sexually transmitted infection. He should avoid sexual intercourse until he and his partners have completed treatment and follow-up. The opportunity should be taken to give further advice on safer sex practices.

The ulcer has a button-like feel on palpation. The base is initially pink and shiny, becoming grey later. Painless inguinal lymphadenopathy is common and may be unilateral. On occasions the chancres may be multiple and painful. A chancre usually appears about 3 weeks after exposure to infection (range 10-90 days), and heals. Men, especially homosexual men, are infected more often than women. In the male the common genital sites of infection are the coronal sulcus, glans penis and prepuce. In the female chancres may be found in the vagina, and on the labia, fourchette and cervix. In both sexes infection can occur in the pharynx and anus. In the anal area a chancre resembles a fissure and may be painful. Chancres, because they can be small and painless, are often missed. Secondary The secondary stage may take 3 months or more after infection to appear (average 6 weeks). At this stage there is bacteraemia. Systemic upset is common, including low-grade fever, malaise, headache, generalized lymphadenopathy, including the epitrochlear glands, and rarely hepatosplenomegaly and transient proteinuria. Arthralgia, acute meningitis and cranial nerve palsies are rare features.

459

The skin is most frequently involved; a non-pruritic rash is common. The lesions are usually papules or plaques, and early on tend to be symmetrical and widespread. The palms, soles and face are often involved. Scaling is common and the lesions can resemble psoriasis. Later lesions tend to be fewer and asymmetrical. Patchy and partial hair loss can occur, giving a moth-eaten appearance (Fig. 11.21b). Other signs include patchy alopecia, erosive lesions of the mucous membranes (mucous patches), common in the mouth, and soft, flat-topped and highly infectious warts found in the perianal area, known as condylomata lata. At this stage all tests for syphilis are positive. The venereal disease research laboratory slide test (VDRL, see below) shows a very high titre. 1 12

skin ulcers, and may destroy the nasal septum. Lesions in bones and joints lead to fractures and joint destruction. Liver involvement causes fever and local tenderness. Gummas respond remarkably rapidly to treatment. Quaternary Quaternary syphilis is either neurosyphilis (p. 1428) or cardiovascular syphilis, which is due to endarteritis obliterans

Latent period If untreated, syphilis will go into a latent phase, when clinical symptoms and signs are absent. This is termed early latent syphilis if it is within 2 years of infection, or late latent after 2 years. Before the latent period there may be periods of infectivity: over 90% occur in the first year. These relapses may be characterized by rashes and lymphadenopathy. During the latent phase sexual transmission is rare, although fetomaternal transmission may occur. Transplacental passage becomes unlikely in late latent syphilis. The VDRL will be negative or have very low titre, e.g. 1:8. The T. pallidum haemagglutination assay (TPHA) and fluorescent treponemal antibody absorption test (FTA-Abs) - (see below) - are always positive. Late (tertiary) syphilis Tertiary syphilis is now rare, as effective treatment prevents progression. The characteristic pathological lesion at this stage is a gumma, which is a destructive granuloma sometimes associated with vasculitis. Treponemes are very scanty and not usually seen under the microscope. Gummas can involve any organ. They cause punched-out

SUMMARY 3 Sites of involvement in secondary syphilis The proportion of cases is given in parentheses Skin (90%) Lymph glands (50%) Mouth and throat (35%) CNS symptomatic (20%) asymptomatic (2%) Kidneys (rare) Gastrointestinal tract and liver (rare) Bones and joints (rare)

1

460

Case 11.7

2

Fig. 11.7

3

Figs 11.8,11.9

FIG. 11.21 Clinical features of syphilis A Chancre of primary syphilis B Alopecia in secondary syphilis.

of the vasa vasorum of the aorta. This causes aneurysm, most commonly of the ascending aorta (p. 600). Congenital syphilis TP crosses the placenta after the third month of pregnancy, usually when the mother has early disease. If she is not treated, infection of the fetus may cause abortion, stillbirth, or the birth of a child with congenital syphilis ©• The child may have signs of infection at birth, similar to those of secondary syphilis in adults, or may be asymptomatic but develop signs of late congenital syphilis, equivalent to adult tertiary, after the age of 2 years. The predominant signs in early presentation are snuffles and a rash, which may vesiculate. Possible late signs are facial abnormalities, including frontal bosses, saddle nose, protruding mandible, Hutchinson's incisors (peg-shaped, splayed), interstitial keratitis, eighth-nerve deafness, periostitis and Clutton's joints. As in adult syphilis, diagnosis depends on serology in the later stages. Diagnosis Primary syphilis is diagnosed by identifying TP with darkground microscopy. TP can be identified in serous exudate from the surface of the chancre. A negative result does not exclude the diagnosis, as topical (e.g. antibiotic ointments) or systemic therapy may alter the findings. The FTA-Abs is positive in approximately 70% of cases at this stage. Later stages require serological testing for confirmation of the diagnosis. Serological examination of the CSF is necessary if neurosyphilis is suspected. Antibodies to treponemal antigens are present, i.e. positive TPHA and FTA-Abs, in 80% of cases of primary syphilis. Two types of antibody test are employed (Table 11.9): • Non-treponemal tests (e.g. VDRL; rapid plasma reagin card test or RPR). These detect cardiolipin antibodies in serum. A high titre indicates an active infection. They

become negative after therapy or during the latent phase of untreated syphilis. False positive results may be found in acute febrile illness, autoimmune diseases, and after immunizations. False negative tests may occur in secondary syphilis due to the prozone phenomena from using undiluted serum. • Treponemal tests (e.g. FTA-Abs; TPHA). These detect antibodies against the treponemal antigen. They are positive earlier in the infection, but remain positive after therapy and in latent syphilis. Yaws, another treponemal disease caused by T. pertenue (see p. 329), gives a serological picture similar to that of untreated syphilis. A careful history is necessary to differentiate the cause, and if doubt about the diagnosis persists, treatment for syphilis is given. Management Table 11.10 shows acceptable treatment regimens. Benzathine penicillin does not effectively cross the blood-brain barrier. Patients may (but do not commonly) experience Jarisch-Herxheimer reaction (a transient fever) 1-2 hours after the first dose of penicillin. This is more commonly seen in secondary syphilis. In cardiovascular syphilis the inflammatory response to antibiotic therapy may result in small vessel occlusion in the coronary ostia. The use of prednisolone (24 hours before and up to 48 hours after commencing therapy) may prevent this. Serological examinations are repeated for at least 1 year after treatment, to

TABLE 11.10 Treatment for syphillis Primary, secondary or early latent syphilis Late latent syphilis or tertiary syphilis (not CNS) Neurosyphilis

TABLE 11.9 Serological tests for syphilis Test Disease/stage

VDRL or RPR*

TPHAf

FTA-Absf

Primary syphilis Secondary syphilis Latent (over 2 years) syphilis Latent (over 2 years) late syphilis Yaws Treated syphilis

Negative >1:64 <1:16

Positive/negative Positive Positive

Positive Positive Positive

Negative/<1 : 2

Positive

Positive

Negative/<1 : 2 Negative/<1 : 2

Positive Positive

Positive Positive

* Tests for cardiolipin antibodies: VDRL = Venereal Disease Research Laboratory slide test; RPR = rapid plasma reagin card test. Tests specific for treponemal antibodies: FTA-Abs = fluorescent treponemal antibody absorption test; TPHA = T. pallidum haemagglutination assay. f

11

HIV positive all stages Penicilin allergy Acquired syphilis <2yrs Penicilin allergy Acquired syphilis >2yrs Pregnant and penicillin allergy Acquired syphilis <2yrs Pregnant and penicillin allergy Acquired syphilis >2yrs

600 000 units procaine penicillin daily 600 000 units procaine benzylpenicillin (procaine penicillin) daily 2.4 million with procaine benzylpenicillin (procaine penicillin) daily 500 mg oral probenecid q.d.s. Neurosyphilis regimen Oral doxycycline 100 mg b.d. (or oxtetracycline 500 mg q.d.s.) Oral doxycyline l00 mg b.d. (or oxtetracycline 500 mg q.d.s.) Oral erymromycin 500 mg q.d.s. followed by oral doxycycline 100 mg b.d. after delivery* Oral erythromycin 500 mg q.d.s. followed by oral doxycycline 100 mg b.d. after delivery

10-14 days 14-21 days

17-21 days

21-28 days 14-21 days 30 days 15 days 15 days 30 days 30 days

* Treat newborn with procaine benzylpenicillin (procaine penicillin) at birth and advise mother not to breast feed during doxycycline treatment. An alternative to procaine benzylpenicillin (procaine penicillin) as first line therapy is: Eary syphilis: IM benzylpenicillin 2. 4 MU x 1-2 (days 1 & 8) Late latent syphilis: IM benzylpencillin 2.4 MU x 3 (days 1, 7, 14).

461

ensure treatment response and identify relapse. This is of especial value in primary and secondary syphilis. Tracing the partners of patients is an integral part of treatment. If the erythromycin regimen is used for a pregnant patient it is always advisable to treat the baby at birth with the appropriate dose of bicillin. Because erythromycin is not a fully reliable treatment, the mother should be treated with doxycycline after delivery. Like all tetracyclines, doxycycline is of course contraindicated during breastfeeding. 1

TRICHOMONIASIS Trichomonas vaginalis (TV) is a pear-shaped flagellate protozoan that causes vaginal discharge and urethritis in women and urethritis in men. It is a sexually transmitted infection. Clinical features Most women with TV have an offensive vaginal discharge associated with vulvovaginal pruritus, and occasionally

1 MCQ 11.8 462

dysuria and dyspareunia. Clinically the vulva is erythematous and excoriated; the vaginal discharge may be seen at the introitus. The discharge is grey, yellow or green and may be frothy. Vaginal erythema and punctate haemorrhages of the cervix may be seen. It is a rare cause of nonspecific urethritis in men. Diagnosis and management Examination of the discharge on a wet mount is essential. The trichomonads are easily seen. Metronidazole (2 g as a single dose, or 400 mg twice daily for 5 days) is effective, but recurrence is common. Sexual partners should be treated.

FURTHER READING ON GENITOURINARY MEDICINE Adler M W (ed) ABC of sexually transmitted diseases, 4th edn. London: British Medical Association, 1999. UK National Guidelines for Sexually Transmitted Infections and closely related conditions. Sexually Transmitted Infections 1999;75:Suppl 1.

12

Cardiovascular Didease J Malcolm Walker and Lip-Bun Tan

The scope of modern cardiology 463

Normal and disordered physiology

Complications of myocardial infarction 560

463

Prognosis after myocardial infarction 566

Symptoms and signs of heart disease 467

Management of myocardial infarction survivors 567

Cardiac investigation 476

Diseases of heart muscle 570

Heart failure 488

Infective endocarditis 574

Arrhythmia 500

Non-infective endocarditis 580

Resuscitation 517

Cardiac tumours 581

Valvular disease of the heart 520

Cardiac disease and pregnancy

Congenital heart disease 533 Cyanotic congenital heart disease

582

Secondary heart disease 583

536

Pericardial disease 586

Acyanotic congenital heart disease 538

Systemic blood pressure and hypertension 589

Coronary heart disease (CHD)

Vascular disease 600

542

Peripheral vascular disease 602

Myocardial infarction 554

THE SCOPE OF MODERN CARDIOLOGY More than 40% of patients admitted to medical wards in the UK have some form of heart disease. Coronary artery disease, heart failure and cardiac arrhythmias are among the commonest causes of emergency hospital admission. Ischaemic heart disease is the most important cause of death in the western world. It causes more than a million deaths per year in the USA and about 160000 deaths annually in the UK (Fig. 12.1), where it accounts for 40-50% of all deaths and is the main reason for men not reaching their seventh decade. A recent concerted effort to change lifestyles with respect to smoking, diet and exercise, as well as better control of hypertension, appears to have led to a decline in coronary artery disease deaths in the USA and the more

affluent northern European countries, but has yet to make a major impact in the UK. Rheumatic heart disease has declined rapidly in importance in the west over the last 30-40 years (p. 580). It now accounts for less than half the cases of heart valve disease coming to surgery and, with only a small number of new cases presenting, its importance will probably decline further. However, it is still a major cause of morbidity and mortality in the developing world. Congenital heart disease is one of the principal causes of neonatal death and is likely to remain a significant cause of morbidity and mortality in childhood. However, more cases are now treatable by cardiac surgery in childhood, and major cardiac defects can now be detected during pregnancy, raising the possibility of neonatal, or even antepartum, cardiac surgery. The development of sophisticated methods of investigation in cardiology now allows great precision in diagnosis, enabling full advantage to be taken of the advances in cardiac surgery and catheter-based treatments. Diagnostic methods have expanded from simple ECG and X-ray to include an ever-widening range of techniques, using ultrasound (both imaging and Doppler), isotope imaging, angiography, intracardiac electrophysiology and 24-hour ECG recording, pressure measurement and magnetic resonance imaging. Therapeutic options have also increased, to include complex cardiac surgery possible at all ages, pacemaker therapy and non-surgical interventions such as angioplasty. The efforts of cardiac surgeons and bioengineers have produced a generation of patients with prosthetic heart valves, implanted pacemakers, modified congenital heart disease and heart transplants. These present a new spectrum of pathology and altered natural history.

NORMAL AND DISORDERED PHYSIOLOGY CONTRACTION Cardiac muscle is striated and shares with skeletal muscle the same basic contractile unit, the sarcomere. The components of the sarcomere are the myosin thick filaments, and the thin filaments composed of actin, troponin and tropomyosin. A local increase in calcium concentration allows an interaction to occur between the heads of myosin molecules and the thin filaments, which produces crossbridges between the filaments. A confirmational change between the globular head of the myosin molecule and its rod-like tail causes a tension in the cross-bridge, making the filaments slide past each other (Fig. 12.2). Relaxation is brought about by a decrease in intracellular calcium and the hydrolysis of adenosine triphosphate (ATP) by myosin ATP-ase to produce adenosine diphosphate (ADP) and inorganic phosphate (Pi).

463

FIG. 12.2 Diagrammatic representation of sarcomere contraction A In the relaxed state (diastole) tropomyosin inhibitory subunits prevent the interaction of the myosin heads with actin. B In the presence of calcium, this interaction can take place enabling contraction (systole) to occur,

FIG. 12.1 Mortality from cardiovascular disease A Causes of death from cardiac disease (England and Wales, 1999). B Deaths due to coronary artery disease in Scotland and the USA in the years 1968-1992, England and Wales to 1999 (UK Government Statistics). Note the steep decline in mortality in males and females in the USA.

Energy for contraction ATP is stored in only small amounts in heart muscle, so its production must occur at a rate equal to its consumption. Free fatty acids (FFA) are the major source of myocardial energy, yielding 2.5 times more ATP per gram weight than glucose. Glucose breakdown can occur in the absence of oxygen, but only two molecules of ATP are produced per molecule of glucose metabolized to pyruvate (instead of the 36 obtained by aerobic metabolism of glucose to carbon dioxide and water). The normal heart consumes lactate, which, by the action of lactate dehydrogenase, yields pyruvate.

The action potential 464

Rhythmic contraction and relaxation of myocardial cells

is achieved by the sequential release of calcium near the myofibrils and its subsequent removal. The sequence of events is outlined in Figure 12.3. The action potentials from different regions of the heart have different configurations, the most important of which is the spontaneous depolarization during diastole in the pacemaker cells of the sinoatrial node (Fig. 12.4, action potential A). This rise in membrane potential in diastole triggers the next depolarization and sets the heart rate. Areas distal to the sinoatrial node are inhibited from showing their intrinsically slower pacemaker potential, but will do so if the impulse from the sinoatrial node is absent or delayed. The rate of sinoatrial node depolarization is greatly influenced by p-adrenoreceptors. Sympathetic stimulation increases this rate and therefore speeds the heart rate, whereas parasympathetic stimulation produces opposite effects mediated by acetylcholine. Circulating catecholamines and changes in serum potassium and magnesium are among the other factors that affect the basic electrophysiological properties of cardiac cells. In non-pacemaker cells the wave of depolarization from adjacent cells is the stimulus for the inward flow of sodium ions that starts the cardiac cycle. Periods of absolute and relative refractoriness follow the prolonged plateau phase. Average action potential durations are about 300ms, but shorten in response to increasing heart rate and adrenaline. The rate of conduction of impulses through the heart is determined by the action potential shape. Depolarization is accompanied by a short-lived inward current, producing the fast upstroke of the classic cardiac action potential (Fig. 12.4, B, D, E). The fast inward current is maximal when the

12

FIG. 12.4 Action potentials from different regions of the heart A Sinoatrial node; B atria; C atrioventricular node; D Purkinje network; E myocardium; F is the electrocardiogram. FIG. 12.3 Relationship between action potential, transmembrane ionic movements, sarcomere contraction and muscle tension A With the onset of the action potential, sarcolemmal sodium channels open. B This is followed by release of calcium from the sarcoplasmic reticulum into the cytosol and sarcomere shortening. c Relaxation follows resequestration of calcium into the sarcoplasmic reticulum. Repolarization is accompanied by loss of potassium from the cell.

foregoing resting membrane potential (Vm) is most negative, the situation found in the Purkinje cells of the ventricle, where conduction velocities are at their highest. In the specialized tissues of the sinoatrial and atrioventricular nodes the upstroke of the action potential is slow and dependent on calcium influx (Fig. 12.4, A and C). These features account for the slow conduction through the atrioventricular node. Ischaemic injury can cause depolarization of cells in affected regions of the heart, leading to regional variation in conduction velocities and areas of conduction block.

HEART PUMP PERFORMANCE Normal function The basic physiological factors that influence the power of myocardial contraction and pump performance are: • Inotropy. dependent on the neurohormonal and ionic environment • Preload: the myocardial fibre length at which the contraction begins • Afterload: the force against which the muscle contracts • Rate and rhythm: dependent on the rate and pattern of stimulation. Inotropy The myofibrils produce tension in proportion to the

free calcium released into the cytosol, until saturation is reached and tension rises no further. Calcium entry into the cell occurs during the action potential plateau, and variations in contraction strength occur by the release of variable amounts of calcium from intracellular stores, or by a change in sensitivity of the myofilaments to calcium. In a steady state, calcium entry into the cell with each action potential is balanced by a loss to the extracellular space. Accumulation of calcium in intracellular stores is facilitated by increased levels of extracellular calcium or by high intracellular sodium, which may occur when the sodium pump is blocked by digoxin. Under normal conditions extracellular calcium concentration plays no part in the beat-to-beat control of the heart's performance. This is mainly affected by sympathetic discharge and circulating catecholamines, which produce an increased heart rate (chronotropic drive) and also enhance myocardial contraction. The final common pathway of this latter effect is achieved by increased myofibrillar calcium sensitivity. Changes in extracellular concentrations of potassium and pH affect myocardial contraction, but, as these concentrations are generally kept constant by homeostatic mechanisms, they do not control heart activity in normal circumstances, although they may considerably affect it in disease. Preload Venous return to the heart is dependent on right atrial pressure. During inspiration intrathoracic pressure falls, causing an accentuation of venous return to the right heart. Standing up tends to diminish this, but in the upright posture exercising muscles provide extravascular compression and maintain venous return. Cardiac output in the normal heart is very responsive to venous return (the Frank-Starling curve), but the failing heart is less sensitive owing to a flatter ventricular function curve (Fig. 12.5).

465

FIG. 12.6 The relationship of LV volume to pressure in a normal cardiac cycle (A-B-C-D) At A systole begins. The pressure rises isovolumetrically until at B the aortic valve opens. The ventricle ejects to C and then isovolumic relaxation occurs until D at which point filling occurs. The dotted blue line shows the relationship in a failing ventricle with reduced inotropy and increased diastolic stiffness. Following the cardiac cycle A-B-C-D it can be seen that a smaller stroke volume is generated (ABCD). Increasing inotropy (dotted red line) would restore or increase stroke volume.

FIG. 12.5 Relationship between ventricular output and filling pressure A The black line shows a normal right ventricular (RV) function curve, where an RV output of 7 L/min (dotted line) is achieved with a filling pressure of 1 mmHg. The left ventricle (LV) must produce the same output (A1), so that the normal LV (blue line) requires a filling pressure of 8 mmHg. If the LV is failing (LVF, light blue line), a filling pressure of 18 mmHg (A2) is required to maintain this output. B A similar relationship is shown for the normal (black line) and failing (grey line) right ventricle.

An increase in intrapericardial pressure with the accumulation of an effusion impedes venous return and cardiac filling and, with marked effusion, a low stroke volume and cardiovascular collapse follow, a condition called tamponade (p. 587). Some drugs affect venous tone: for example, some of the therapeutic benefits of nitrates are related to venodilatation, lowering wall stress and thus reducing myocardial oxygen demand. Normal ventricular filling occurs principally in early diastole, with atrial systole giving a final 'top-up'. The latter may be particularly important in hypertrophied hearts, which fill poorly in early diastole. Here atrial systole provides a much greater fraction of ventricular filling. In these

1

466

MCQ 12.1

patients, loss of atrial contraction (due to atrial fibrillation) may lead to marked reduction in stroke volume. Afterload During systole the ventricles eject blood once the diastolic pressure in the arterial circuits is exceeded. Afterload is the load that affects the ventricles during ejection. This can be equated with the peripheral vascular resistance, which, together with vessel wall elasticity, determines the diastolic arterial pressure. Increasing afterloads (Fig. 12.6) decrease cardiac output, and this relationship is worse in failing hearts. The treatment of patients with impaired ventricular performance now includes the use of drugs that reduce the peripheral vascular resistance and hence reduce afterload (p. 496). Rate and rhythm Changes in the rate of stimulation of the heart muscle can alter contractile performance, independently of changes in muscle length (or preload). These mechanisms affect output to a lesser degree than preload and afterload. However, increases in heart rate may also change cardiac output by altering the time available for cardiac filling and coronary flow. 1

Ventricular dilatation The cardiac chambers dilate either with abnormal volume loads or as a consequence of impaired myocyte function,

as in cardiomyopathy. The larger-volume ventricle is an adaptive response, allowing the maintenance of stroke volume despite a reduction in the shortening capability of the myofibrils. However, although the response is initially adaptive, there is a cost. From the Laplace equation, a dilated ventricle with an increased diameter can only generate the same pressure with an increased wall tension. This increased wall tension can only be sustained by an increase in oxygen consumption, which may outrun the supply, leading to further ischaemia and dilatation.

Ventricular hypertrophy Cardiac myocytes hypertrophy in response to: • Loss of adjacent myocytes. • An increase in ventricular wall stress - the resultant increase in wall thickness effectively reduces the stress each sarcomere has to generate. With mild hypertrophy, the capillaries increase in density proportionally to the hypertrophy, but beyond a certain extent the capillary growth lags behind the hypertrophic process, thus rendering the less well supplied subendocardium liable to ischaemia. The hypertrophic process, accompanied by deposition of more collagen fibres, leads to reduced compliance and impaired diastolic function. • Cellular mechanisms of cardiac adaptation. The adult cardiac myocyte is not capable of cell division but remains synthetically active, regenerating contractile proteins every 30-90 days. Under conditions of increased stress the myocyte is stimulated by a large number of factors via sarcolemmal receptors. These include growth hormone, angiotensin II, noradrenaline (norepinephrine), tumour necrosis factor-a, interleukins, growth factors and nitric oxide, among others. Acting via intracellular second messengers, the cells revert to a more fetal phenotype, resulting in cell growth and hypertrophy, often accompanied by impaired contractile function.

SYMPTOMS AND SIGNS OF

HEART DISEASE Symptoms arising from the heart are not specific and it often requires a careful history to differentiate them from similar complaints arising from chest disease, dyspepsia or anxiety. Chest pain, breathlessness, oedema, palpitations, dizziness, syncope and fatigue can all be caused by heart disease. Exercise capacity is limited in most forms of heart disease, and the limiting symptom may be obvious, such as pain and breathlessness, or much more subtle, such as excessive exhaustion. The degree to which symptoms have begun to limit normal activities requires careful definition, as patients may not always volunteer the information, wrongly thinking that age alone is enough to account for their increasing inability to exert themselves without dyspnoea or dizziness. Others may prevent angina or

breathlessness by greatly restricting their lives. In assessing the effectiveness of treatment it is useful to have an idea of the activities that can and cannot be performed, using relevant examples from the patients' own lives, the ease with which they can walk and talk, or how they manage household chores. Improvements in patients' performance may then be judged by their own yardstick. Patients sometimes need considerable encouragement to re-establish more normal patterns of activity after being treated.

12

Chest pain Chest pain arising from the heart and great vessels may be caused by cardiac ischaemia, pericardial inflammation, aortic dissection or massive pulmonary embolism. The history may allow differentiation between the various possibilities, but the severity of the symptom has virtually no relationship to the potential severity of the underlying cause. Many patients suffer pains in the chest which are probably cardiac in origin but for which no adequate explanation is possible; for example, some patients may describe abnormal sensations produced by ectopic beats as pain. Cardiac ischaemic pain In a typical case the discomfort associated with myocardial ischaemia is described as a pressure or tightness in the chest, which may also be felt in the throat, producing the choking feeling that led to the symptom being called angina pectoris. The characteristics of angina include common patterns of radiation to the arms, more commonly the left, the jaw and teeth and, less commonly, through to the back. The pain, and its sites of radiation, are often reproducible, but incomplete or mild attacks may not have the same full distribution of the more severe episodes. In angina, which represents episodes of reversible ischaemia, the precipitating causes are typically those that will increase myocardial oxygen demand beyond the coronary supply. The patient may report discomfort only when having to run, or when they try to walk in the face of a cold wind or after a heavy meal. Emotional upsets are powerful precipitants of angina in some patients, even without physical exertion. The discomfort may be very severe and be associated with frightening feelings of impending death. It can also be a mild discomfort or ache in the chest, which may be thought trivial and ignored. Many patients do not experience their angina as a pain, and feel it as a faint constriction in the chest. Some attacks of myocardial ischaemia are unaccompanied by any discomfort (silent ischaemia}. Angina usually disappears fairly rapidly if the patient rests, or takes glyceryl trinitrate (GTN). Angina builds up over several seconds and is usually not greatly influenced by posture, unlike musculoskeletal chest pain (which may also occur with exertion). Although similar in nature and radiation, the pain of myocardial infarction

467

lasts much longer than angina. It is more intense and does not pass off with rest or GTN. In an attack, a patient with cardiac ischaemia usually looks pale and sweaty, unlike someone with an attack of indigestion, who often appears flushed. Other causes of chest pain Pericardial pain (p. 587) can be easily confused with the pain of myocardial infarction or angina, but is often influenced by posture, sometimes being relieved or worsened by leaning forwards, and aggravated by swallowing. It is more often described as a burning or dull pain, and is less likely to be associated with breathlessness than is myocardial ischaemia. The pain of dissection of the ascending aorta (p. 600) is a severe, tearing pain, often starting suddenly, usually felt retrosternally at first, and sometimes radiating through to the back or to the left shoulder. Massive pulmonary embolism can also produce a retrosternal constricting discomfort indistinguishable from myocardial ischaemia; smaller peripheral emboli may be responsible for more pleuritic-type pains (p. 681). Oesophageal spasm due to reflux can produce a severe retrosternal pain which may be confused with that of myocardial ischaemia, and may be relieved by GTN. The pain of oesophageal rupture can be confused with myocardial infarction. Sharp, stabbing precordial pains are common in highly strung patients. They may have a muscular origin, but occasionally coincide with the accentuated postectopic contraction of the heart, which is perceived by the patient as a knife-like pain. 1

Dyspnoea or shortness of breath This symptom is a feeling of laboured, or unnaturally difficult, breathing. In heart failure it is due to the lungs becoming stiff and difficult to ventilate, owing to the rise in pulmonary venous pressure. The reduced cardiac output limits the oxygen-carrying capacity of the circulation, precipitating anaerobic metabolism. The acidosis produced causes increased ventilation, which persists for longer than normal after exertion. Thus, even minor exertion produces disproportionate and prolonged dyspnoea. Finally, in severe left heart failure with pulmonary oedema, arterial oxygen desaturation adds to the distress. Dyspnoea (or angina) can be categorized using the New York Heart Association scale (Table 12.1). Severe forms of left heart failure are associated with dyspnoea at rest, worse when supine. This degree of pulmonary venous hypertension is commonly accompanied by a dry, nonproductive cough. Dyspnoea at night can be graded on

1

468

MCQ 12.2

TABLE 12.1 New York Heart Association grading of dyspnoea or angina Grade

Criteria

1

Symptoms only occur on severe exertion. Almost normal lifestyle possible Symptoms occur on moderate exertion. Patient has to avoid certain situations, such as carrying shopping up several flights of stairs Symptoms occur on mild exertion. Activity is markedly restricted Symptoms occur frequently, even at rest

2 3 4

the basis of the number of pillows required to enable the patient to sleep (orthopnoea). Patients with left heart failure may be woken from their sleep by severe dyspnoea resulting from pulmonary congestion. This passes off on sitting up, or walking about slowly, and is known as paroxysmal nocturnal dyspnoea (PND). This may be the first symptom of left heart failure and may be difficult to distinguish from nocturnal asthma, as some patients with left heart failure develop a considerable degree of wheeze with bronchospasm.

Palpitations A careful interpretation of what the patient means by the word 'palpitations' is essential. It may be simply an awareness of the normal heart beat, which may be more forceful or faster than usual because of anxiety. It may, however, be indicative of a serious cardiac arrhythmia. It may be useful to ask the patient to tap on the table to indicate the rate and rhythm during the attack. It is helpful to determine the following: • Onset and cessation of the attacks. Is it sudden, with a thump (ectopic), or gradual? • Are there any symptoms to suggest cardiac decompensation (failure) during the attacks? • Was there irregular thumping (ectopics or atrial fibrillation)?

• Was there chest pain (the occurrence of angina implies a very fast and potentially dangerous heart rate)? • Has there been any fainting or near fainting with the attacks? True syncope indicates an urgent need for investigation, as the arrhythmia is potentially fatal. Polyuria sometimes occurs on cessation of supraventricular tachycardias, but is not usually described by the patient unless a leading question is asked.

Syncope and presyncope (dizziness) Sudden collapse with loss of consciousness during exertion almost always has a cardiac cause. It is due either to an obstruction to outflow from the left or right ventricle, which prevents an adequate increase in cardiac output on exertion, or to a cardiac arrhythmia induced by the

exertion. Both may result in a sudden fall in blood pressure and cerebral perfusion. Some mental confusion due to cerebral anoxia is common. Syncope after exertion is not uncommon and may simply be due to blood pooling in the legs and a poor venous return. However, syncope under other circumstances may be cardiac, and an eyewitness account is invaluable. Cardiogenic syncope usually occurs without warning; the collapsed patient is vasoconstricted and grey, and the pulse is either absent or very slow. In a classic 'Stokes-Adams' attack (p. 503) the unconscious patient blushes dramatically with the return of circulation and subsequent return of consciousness. Syncope may also occur in severe tachycardia. A prolonged period of unconsciousness is unlikely to be cardiogenic, as cardiac asystole or a malignant cardiac arrhythmia sufficiently rapid to cause unconsciousness is unlikely to last long without proving fatal. Other forms of syncope 'Vasovagal' syncope. The common faint, often triggered by pain or an unpleasant sight, gastrointestinal upset, haemorrhage or pyrexial illness, is a vagal phenomenon, and the syncopal episode is followed by profuse cold sweat, a feeling of sickness or actual vomiting, and bradycardia. Micturition syncope and cough syncope are rarely cardiogenic, but are probably triggered by a Valsalva manoeuvre, the first when initiating micturition with a full bladder and the latter after repeated bouts of coughing, which inhibit venous return. Presyncope or dizziness is a common and much less well defined symptom, and has a variety of causes as well as heart disease. It may result from a cardiac arrhythmia, but even then is much more common in elderly patients with associated cerebrovascular disease.

Oedema Right heart failure causes pitting oedema of the feet and legs, worse at the end of the day and relieved by rest and elevating the legs. Unlike other causes of oedema it may be associated with other symptoms of heart failure, such as dyspnoea and fatigue. The oedema may spread to the thighs, abdominal wall, sacrum and back. There may be ascites and hepatic congestion, with abdominal distension. The hepatic congestion may be worse on exertion, with pain over the liver (usually epigastric) during exercise and for several minutes afterwards - hepatic angina. The differential diagnosis of cardiac oedema includes fluid retention from other causes, such as nephrotic syndrome and cirrhosis of the liver, oedema of one or both legs from venous insufficiency, or lymphatic insufficiency.

Fatigue Fatigue is a non-specific and often neglected symptom. It is, however, a very real feature of heart disease, a result of the reduced effort tolerance and lactic acidosis produced by anaerobic muscle metabolism and changes in the skele-

tal muscle. It is a prominent symptom in low cardiac output states, e.g. severe left ventricular failure.

12

EXAMINATION OF THE CARDIOVASCULAR SYSTEM The general examination Traditionally, and ideally, the cardiac examination is undertaken in a warm, quiet and well-lit room with the patient se'ated on the bed or couch with the upper body supported and at an angle of 45° to the horizontal. The general appearance of the patient and his or her comfort and general wellbeing or illness is noted. Certain cardiac diseases are associated with anormalities of habitus, specifically Marfan's syndrome (p. 526), where aortic dissection and mitral valve disease are to be expected, or other chromosomal abnormalities that produce associated congenital cardiac lesions, such as Down's and Turner's syndromes (p. 535). The 'mitral fades' A thin face with prominent 'rosy' cheeks, which on closer examination are tinged with blue (cyanosis), used commonly to be seen as a consequence of chronic mitral stenosis, but now is more frequently associated with any condition where the cardiac output is low and the venous pressure high. Skin - pallor As in any medical examination a note is made of pallor, as symptoms indistinguishable from those of cardiac failure and even angina may be caused by profound anaemia. A low cardiac output may itself produce generalized pallor, often associated with cool fingers, toes and nose. Skin - cyanosis Peripheral cyanosis can also be produced by low cardiac output, when the cool extremities take on the characteristic blue tinge. Central cyanosis is caused by intracardiac shunting (right to left heart, as in the Eisenmenger reaction, see p. 536); the lips and tongue are blue and the colouring made more intense by the frequently associated polycythaemia. The periphery is often warm in these circumstances, and in congenital cardiac defects clubbing of the finger- and toenails is found. Skin - hands and nails Clubbing may occur in cyanotic congenital heart disease, but may be acquired in chronic infective endocarditis (p. 576). Infective endocarditis also accounts for several other findings, including splinter haemorrhages, which appear as small dark subungual petechiae. They are also seen in other diseases, such as polyarteritis nodosa. The appearance of new splinter haemorrhages during an acute episode of pyrexia in a patient with a murmur strongly suggests endocarditis or persistent infection in an established treated case. Osier's nodes are tender palpable spots on the pulps of the fingers occasionally detected in endocarditis.

469

Skin - xanthomata and arcus senilis Characteristic firm nodules form on the tendons of the knuckles and over the elbow, and thicken the Achilles tendon in hypercholesteraemia. 1 Indeed, these xanthomata might be the first sign of familial hypercholesterolaemia (p. 1023) and bring the patient to the doctor before there are manifestations of coronary heart disease. More commonly there is arcus senilis, which is a pale ring, usually incomplete, encircling the iris in young persons with hyperlipidaemia; the ring is commonly present in older people even without any lipid disorder. In hyperlipidaemia the periorbital area may also develop flat, mildly raised, pale yellow xanthomata.

Arterial pulses The information sought in examining the arterial pulses includes the following:

Mouth Poor dentition and recent major dental work are documented sources of infection in endocarditis, so an assessment of the oral hygiene of patients is essential.

The pulse volume rate and rhythm are assessed from the right radial pulse. The contralateral radial should also be briefly examined to confirm its presence and volume. Some indication of the state of the arterial wall can be obtained from the thickness of the radial and brachial arteries. Next the carotid pulses are examined, where the pulse character can be appreciated. At the carotid pulses thrills may be felt and bruits heard. The same examination is made of the femoral arteries, where in addition the pulse is simultaneously felt in the radial and femoral arteries. Coarctation of the aorta (p. 540) produces either absence of the femoral pulse or a reduced volume beat, which is delayed in comparison to the radial pulse upstroke so-called radiofemoral delay. In the legs the popliteal arteries and both dorsalis pedis and posterior tibial arteries are examined.

Dyspnoea Movement, dressing and undressing may reveal breathlessness, and orthopnoeic patients may not be able to tolerate lying flat. Oedema Pitting oedema is classically seen in the dependent regions: the ankles and feet in ambulant patients, 2 and the sacral area in those in bed. The oedema may be extreme and involve the thighs, pudenda and lower abdominal wall, when a 'peau d'orange' effect is seen. In these circumstances ascites is nearly always present, but may surprisingly occur before much peripheral oedema has developed. Cardiac cachexia Although weight gain due to fluid accumulation is usual in heart failure, late stages of the severe disease may produce profound muscle wasting and weight loss closely analogous to disseminated malignancy; this condition is called cardiac cachexia.

Arterial pulses and blood pressure Blood pressure A mercury sphygmomanometer is usually used to measure the systemic arterial blood pressure. This is often performed early in the examination; however, blood pressure is often highest at this time, owing to an 'alerting' response in the patient, and a lower reading may be obtained at the end of the consultation. The room should be warm and the measurement repeated in both arms and again with the patient standing. Details of blood pressure measurement are to be found on page 590.

1 470

Figs 12.1-12.3

2

Fig. 12.4

• Presence and equality of volume of the pulses on both sides of the body • Rate, rhythm and character of the pulse waveform • The state of the arterial wall • The presence of arterial bruits • The carotid pulse, which can help to time events when auscultating the heart (S1 just precedes the upstroke of the pulse) • The presence or absence of radiofemoral delay.

Rate and rhythm It is important to count the pulse accurately when there is a tachycardia (pulse >100) or a bradycardia (pulse <60). Heart rates of 150 bpm (±5bpm) are almost always due to atrial flutter. A small variation of heart rate with respiration is normal, and more marked in young people (sinus arrhythmia). Intermittent irregularities in the pulse are often due to ectopic activity, producing a slight pause in the normal regular beat followed by a beat of larger than usual volume. A pulse which is totally irregular with constantly varying volumes is likely to be due to atrial fibrillation (AF) and is called the irregularly irregular pulse. Frequent ectopics can cause confusion with AF, and the irregular rhythm may be missed if the fibrillation is well controlled owing to therapy. The heart rate is best assessed by auscultation when the pulse is irregular, although the use of the difference in pulse rate measured at the wrist and by auscultation at the cardiac apex (the apex-radial deficit) is of limited practical value as there is always a difference in the presence of a fast apical heart rate in AF. Pulse amplitude The pulse amplitude at the wrist depends on the stroke volume, which varies with cardiac output and pulse interval. It also depends on the state of vasodilatation of the skin of the hands, with a smaller radial pulse volume when cold than when warm. A thready, low-volume and rapid

pulse may be felt in shock due to haemorrhage, and a largevolume pulse in thyrotoxicosis or CO2 retention in pulmonary disease. Pulse character With the exception of collapsing pulses, this is most reliably assessed by examining the carotid pulses in the neck, although the femoral and brachial arteries are useful when the neck is difficult to examine. The collapsing pulse. This is a sign of aortic regurgitation but may be present in any condition that produces the combination of a large pulse volume with a rapid run-off into the periphery owing to a reduced impedance to flow (e.g. pyrexia, pregnancy, thyrotoxicosis, arteriovenous fistula). The sign is best appreciated by gripping the forearm with the left hand, the examiner's fingers being pressed fairly firmly against the medial aspect of the forearm. The arm is then raised up by the examiner's right hand, which is holding the patient's hand in a handshake position. In the presence of a collapsing pulse the fingers will feel a 'knock' in the forearm muscles. Associated features are a low diastolic blood pressure reading and, in severe cases, visible arterial pulsations in the neck, Corrigan's sign. The slow rising, anacrotic or plateau pulse. This sign of aortic stenosis is usually most reliably found by examining the carotid pulses. The carotids are best felt with the patient sitting at 45°, resting the head on a pillow and looking straight ahead. The pulse is felt halfway up and medial to the sternocleidomastoid muscle at the level of the major skin crease. The slow rising pulse contrasts with the transient flick that the normal carotid systolic pulse produces. It can be a difficult physical sign to appreciate and, as its name implies, the pulse may be felt to caress the fingertips as it rises slowly to a more sustained peak. It is often of low volume and may have an associated thrill or judder. It may be masked in stiff arteries of the elderly. The jerky pulse. This is felt at the carotids as described, and is one of the few physical signs to be found in hypertrophic cardiomyopathy (p. 571). It is therefore potentially important, as it should alert the physician to the possibility of the presence of this serious condition affecting the young. Severe mitral regurgitation can produce the same physical sign. Rarer forms of abnormal arterial pulse. Pulsus alternans consists of a beat-to-beat alternating large and small pulse volume with a regular rhythm, and is seen in severe left heart failure. Pulsus paradoxus represents an accentuation of a normal physiological variation in the pulse volume with respiration. It consists of a greater than l0mmHg fall in systolic pulse pressure with inspiration and occurs in pericardial tamponade or constriction (pp. 587 and 588), but may be seen in cardiomyopathy, massive pulmonary embolism, and sometimes with normal cardiac function in severe asthma. It may be felt by the fingers on the radial pulse but, if mild, is better elicited by using a sphygmomanometer and detecting the different systolic pressures during inspiration and expiration. Pulsus bisfe-

riens is a pulse that can be felt to have a double systolic peak. It can be a feature of mixed aortic valve disease, where a degree of stenosis complicates dominant aortic regurgitation.

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The jugular venous pulse (JVP) The JVP can be a difficult physical sign to appreciate, and the subtleties of its waveforms have fascinated physicians and terrorized medical students for generations. Despite its archaic nature the JVP remains a useful bedside indicator of circulating blood volume, it being invisible in fluid depletion or haemorrhage and raised in fluid overload or heart failure. Its waveforms can indicate the nature of some cardiac arrhythmias and make the diagnosis of pericardial tamponade. The internal jugular is used; despite its being deep in the tissues under the sternocleidomastoid muscle, pulsations arising from this vein can be seen at the skin surface. The height of the JVP is measured vertically from the sternal angle; normally, in a patient seated at 45° it does not exceed 3cm. The normal waveform can be appreciated in most people at the root of the neck, but they may have to be lying rather flatter than at 45°. What is seen is a regular pulsation in the neck, with two peaks and two troughs for each radial pulse (if sinus rhythm is present). Unlike arterial pulses, the venous pulse is most obvious by the rhythmic inward movement of the skin overlying the vein; arterial pulses produce a dominant outward, brisk skin movement. Inspiration causes a fall in the JVP (Table 12.2). The JVP can be so high that the neck looks generally full and the upper limit of the venous column is not appreciated; sitting the patient upright or making him stand may make the top of the JVP column come into view. A low JVP can be made to appear by gentle abdominal pressure - hepatojugular reflux: in a normal person the JVP may rise 2-3 cm, but rapidly falls, whereas in cardiac failure the bolus of extra blood supplied to the right heart by squashing the splanchnic bed cannot be accommodated, so the JVP rises, and this is sustained for several seconds. When

TABLE 12.2 Differentiation of the JVP from an arterial (carotid) pulse

Waveform Pressing at root of neck? Variation with respiration? Palpable pulse? Change with posture? Pressure on abdomen (hepatojugular reflux)

Venous

Arterial

Two peaks per beat (in SR) Obliterates wave form Normal JVP falls with inspiration Not usually, except in tricuspid reflux May fall if patient sits up or stands JVP rises

Single peak No effect No effect Yes No change No effect

471

• • • •

FIG. 12.7 Relationship of venous waveform to heart sounds The a wave of atrial contraction is followed by the x descent. The cwave is not usually visible. The I'wave coincides with ventricular systole.

the JVP is massively raised but does not show waveforms during the cardiac cycle, it is likely to be owing to superior vena caval obstruction, such as in malignancy. The JVP waveform The two peaks, a and v, are due to atrial and ventricular systole (Fig. 12.7). The two descents are x and y, with a transient pressure 'hump' on the first (x) descent being called the c wave. The a wave is generated by atrial systole, and therefore disappears in atrial fibrillation. Extra-large a waves are called cannon waves and are seen when atrial systole occurs with a closed tricuspid valve; this occurs intermittently in complete heart block, occasionally with ventricular ectopics, and regularly in nodal rhythm. Large, or giant, a waves are associated with a poorly compliant right ventricle increasing the impedance against which the atrium has to eject blood, such as in pulmonary hypertension. When the tricuspid valve leaks, the right ventricle is in communication with the great veins and the rise in pressure during systole produces a very large v wave, sometimes called the s wave. Abnormalities of the x and y descents can be difficult to time correctly. The y descent is slow in tricuspid stenosis, which is a rare valve lesion. In pericardial tamponade and constriction (pp. 587 and 588) the JVP is very high and demonstrates an abrupt fall in systole (x descent); complicated by myocardial involvement the dominant descent may occur in the early part of diastole (y descent). 1

The precordium Scars and deformities may give useful clues to the past history; the former might indicate a previous closed mitral valvotomy (generally a subtle left-sided inframammary thoracotomy scar) and the latter congenital heart defects. Pulsations of the apex beat or dyskinetic movements of a left ventricular aneurysm may be seen. Palpation is undertaken to detect the following: • Presence of thrills - these are palpable murmurs felt as high-frequency vibrations 1

472

MCQ 12.3

The position of the apex beat The character of the apex beat The presence of a parasternal heave Palpable heart sounds.

Thrills The commonest thrills are those arising from the aortic valve in aortic stenosis, and are felt either side of the sternum in the upper part of the anterior chest wall. Diastolic thrills down the sternal edge and at the apex can occasionally be felt in very severe aortic regurgitation; mid to low central sternal thrills may occur in small ventricular septal defects. The apex beat This is defined as the lowest, most lateral detectable cardiac pulsation; its position is normally in the fourth intercostal space at or medial to the midclavicular line, and is felt when the patient is sitting in the standard 45° position. Displacement of the apex downwards and laterally is due to left ventricular dilatation. Many adults, especially those who are obese or have overexpanded lungs, do not have palpable apex beats; in a very small minority this will be due to dextrocardia. The character of the apex beat can be determined in most cases by palpating the apical region with the patient in the left lateral position. It is generally a very localized pulsation covering no more than the pulp of two examining fingers. A thrusting apex beat pushes the fingers outwards with each systole and is a feature of left ventricular hypertrophy. In aortic stenosis the apex may be thrusting and not displaced. In a volume-overloaded ventricle, such as in mitral regurgitation, the apex beat is usually displaced and may be thrusting in nature. A tapping apex which is not displaced is a feature of mitral stenosis and is caused by a loud (palpable) first heart sound. Dyskinesia of the apex may affect larger portions of the precordium and are associated with ventricular aneurysms. The whole apex may then rock under the palpating hand, and the apex beat may have a double impulse. This latter sign may also be felt in hypertrophic cardiomyopathy. The apex beat is abnormal in dilated poorly functioning ventricles when it may be very diffuse, with a weak but widespread pulsation. Parasternal heave This is felt by applying the heel of the hand to the lower third of the sternum with modest pressure. Right ventricular hypertrophy produces a feeling of lifting of the hand during systole. Similar lifting sensations, slightly more to the left of the sternum, can be produced by the rapid expansion of the left atrium in systole due to severe mitral regurgitation.

Auscultation Successful cardiac auscultation requires a comfortable

and familiar stethoscope of good quality and a relatively quiet environment. The bell is designed to accentuate low-frequency sounds and is therefore particularly suited to detect third and fourth heart sounds, as well as the diastolic murmur of mitral stenosis, but it can perform more like the diaphragm if pressed hard against the skin, a feature used to advantage on occasion (see below). The diaphragm filters out low-frequency sounds and is therefore most suitable for listening to the first and second heart sounds, as well as high-frequency murmurs such as that produced by aortic regurgitation. The aim of cardiac auscultation is to detect the following:

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• Normality of the first (S1) and second heart sounds (S2), loudness and splitting - diaphragm; • Presence of added third (S3) and fourth (S4) heart sounds - bell, lightly applied; • Presence of clicks - diaphragm; • Presence of murmurs, their timing, location, intensity and radiation - both diaphragm and bell; • Other noises, such as rubs and venous hums - both diaphragm and bell. A suitable examination begins with the diaphragm applied to the upper left sternal edge to determine the first and second heart sounds - a finger or thumb on a carotid pulse will aid the timing. The diaphragm may then be moved over the chest, down the sternal edge to the apex; after listening to both S1 and S2 here, the change is made to the bell and the process repeated in reverse. At this point the patient can be moved into the positions necessary to bring out murmurs (see below). The relationship between the heart sounds and various types of murmurs is illustrated in Figure 12.8A. Heart sounds First and second heart sounds (SI and S2) The first heart sound slightly precedes the carotid pulse upstroke. It signals the beginning of systole (Fig. 12.9) and, although complex in origin, is produced mainly by the closure of the mitral and tricuspid valves. Normally, only the mitral component is audible, but delayed systolic events in the right heart (e.g. in right bundle branch block, or volume overload in atrial septal defect) may allow splitting of S1 to be heard (mitral followed by tricuspid closure). A loud S1 is heard in mitral stenosis (p. 522) and in situations where atrial systole is very close to ventricular systole, such as with a short PR interval; conversely, mitral regurgitation and long PR intervals are associated with a quiet S1. The second heart sound is caused by closure of the aortic and pulmonary valves. Audible splitting of S2 (aortic valve A2 followed by pulmonary valve P2) occurs in most normal people during inspiration and can be heard with the diaphragm applied to the upper left sternum (pulmonary area), but not at the apex where P2 does not

FIG. 12.8 Heart murmurs A Diagrammatic representation of murmurs. S1 and S2 = first and second heart sounds; A2 = aortic valve closure sound; P2 = pulmonary valve closure sound; OS = opening snap. B The precordial areas where murmurs are usually heard maximally. A = aortic; P = pulmonary; M = mitral.

radiate unless it is abnormally loud, e.g. in pulmonary hypertension. Third and fourth heart sounds (S3 and S4) Both these sounds are produced by ventricular filling, are very low pitched and require the bell to be lightly applied to be heard. It can be very difficult to tell them apart, particularly at fast heart rates. The third sound occurs early in diastole and can be heard in normal young

473

An opening snap is characteristic of mitral stenosis, where the valve remains compliant. It occurs early in diastole owing to the sudden tensioning of the mitral valve apparatus and can be differentiated from an S3 by its higher pitch and sometimes wide radiation. An opening snap is audible with diaphragm and bell, S3 only with the bell. Pericardial rubs are variously heard as creaky rustling, shuffling noises which can be differentiated from pleural rubs by their continuation even during breath-holding. Tumour plops can uncommonly be associated with a large atrial myxoma, when a curious 'plop' may be produced intermittently, and sometimes with a change in posture - usually as the patient takes up the left lateral position.

FIG. 12.9 Relationship between pressures in the aorta, left ventricle and left atrium The timing of the heart sounds (S1 and S2) are shown (a and v represent the a and v waves).

people and some slim athletic adults, who have a relative bradycardia. It is also heard in hyperdynamic states and volume-overloaded ventricles, such as with thyrotoxicosis and significant mitral regurgitation, respectively. In older people an S3 is taken as indicative of heart failure. A higher-pitched and loud S3, sometimes called a 'pericardial knock' is produced by the very abrupt end to ventricular filling that occurs early in diastole owing to pericardial constriction. The fourth heart sound is generated by atrial systole in the presence of a raised left ventricular enddiastolic pressure. It indicates an impairment of ventricular compliance, often due to hypertrophy. It is typically a feature of hypertension, but can also be heard during myocardial ischaemia. Gallop or triple rhythm In heart failure, if S3 and S4 are loud, a characteristic cadence of the heart sounds is heard which sounds like a galloping horse. A loud combination of the sounds leads to the summation gallop, which may be heard when a tachycardia complicates the cardiac failure. Other added sounds Ejection clicks are very high pitched and sound as their name implies. They are a feature of young patients with pulmonary and aortic valve stenosis when there is a pliable valve which domes upwards in systole. Midsystolic or non-ejection clicks may be single or multiple and are a feature of floppy or prolapsing mitral valves (p. 525), and much less commonly of tricuspid valves.

1

474

MCQ 12.4

Heart murmurs Murmurs are found where there is turbulent flow, and their radiation follows the direction of blood flow. Although the precordium is classically divided into various valve areas (Fig. 12.8B) they may not always be the sites where murmurs arising from those particular valves are best heard. Murmurs may be palpable and produce precordial thrills. Their full characterization and clinical importance may depend more on the associated physical signs elicited on examination than purely on their ausculatory features. Thus a loud ejection systolic murmur in a patient with a normal apex beat and carotid pulse is of less concern than a quieter but similar murmur associated with a displaced, thrusting apex and a slow carotid pulse upstroke. The former may be a benign flow murmur, the latter represent critical aortic stenosis. Causes of murmurs Murmurs may be generated by a high-velocity jet, such as a stenotic or regurgitant jet, passing from a high-pressure to a lower-pressure chamber or vessel. They may occur with increased flow velocity in a normal vessel, or with flow into a dilated or distorted vessel, such as the aorta in hypertension or the pulmonary artery in sternal depression. Murmurs do not therefore always indicate valve pathology. They may indicate a high flow, such as in pregnancy, or a minor anatomical distortion not amounting to true pathology, so-called innocent murmurs. Description of murmurs Murmurs are described in terms of their timing, precordial location, radiation, relative intensity and, if warranted, the influence of respiration and posture (Fig. 12.8). It is possible to grade the loudness of murmurs from 1/6 (almost inaudible) to 6/6 (a murmur which can be heard in a quiet room without using a stethoscope). These grades are, however, of limited value, as they are highly subjective and the loudness of a murmur varies considerably depending on circumstances. The length of a diastolic murmur can be expressed on a scale of quarters, 1/4 being very short, and 3/4 an almost full-length diastolic murmur.

Systolic murmurs Ejection murmurs are crescendo-decrescendo (diamondshaped) (Fig. 12.8) and are characteristic of flow across a stenotic aortic or pulmonary valve, or flow into a dilated aorta or pulmonary artery. They may also occur with increased flow across these valves (innocent murmur). Sometimes, in severe stenoses it is impossible to distinguish an ejection from a pansystolic murmur. The associated signs will often help. Pansystolic murmurs are generated by jets passing from a high-pressure to a low-pressure chamber throughout systole, including the normally isovolumetric phases of contraction and relaxation. The best example is mitral regurgitation, but tricuspid regurgitation and ventricular septal defects produce similar murmurs. The murmur obscures both S1 and S2 and is of almost even intensity throughout systole. Late systolic murmurs. Mitral valve prolapse and papillary muscle dysfunction give rise to a high-pitched murmur of even intensity starting halfway through systole, often preceded by a midsystolic click. Posterior papillary muscle dysfunction can give rise to a mitral pansystolic murmur, which may be loud in the aortic area. Diastolic murmurs Diastolic murmurs are always pathological, but are often much harder to detect than systolic murmurs. Mitral and tricuspid mid-diastolic murmurs. The mitral (and tricuspid) stenotic jets induce a low-frequency, largely subsonic vibration. These are heard as low-pitched, rumbling murmurs starting after the opening snap, best heard with the bell. They are localized and are often missed by the inexperienced, who are expecting to hear a much higher-pitched sound. The mitral diastolic murmur is accentuated by the patient lying on the left. If short, it can be confused with a third heart sound. Early diastolic murmurs start immediately after the second heart sound. They are high-pitched noises, which can be very short or persist throughout diastole. Aortic diastolic murmurs are often faint and are best heard with the patient leaning forwards in expiration. A soft aortic diastolic murmur is often missed. Other types of murmur Musical or mewing murmurs may occur in systole or diastole if a valve cusp adjacent to a jet vibrates at a characteristic frequency. These murmurs can be very loud, but the jet causing them may be small. A mewing murmur is characteristic of a small hole in an aortic valve cusp as a complication of endocarditis. 'Innocent' murmurs Many midsystolic and ejection systolic murmurs are unaccompanied by any signs or features of heart disease. These murmurs are common in children and in pregnancy. They are maximal in the pulmonary area, but may also be heard along the left sternal edge and at the apex, and often have a low-pitched vibratory quality. They are usually of low

intensity. If there is doubt as to their 'innocent' nature, an echocardiogram and, particularly, a Doppler study can rule out a small ventricular septal defect, pulmonary stenosis or unsuspected trivial mitral regurgitation.

12

Accentuating murmurs - dynamic auscultation Unless murmurs are perfectly well heard with the patient sitting at 45°, all patients should be examined in the left lateral position (mitral murmurs) and sitting forward in exhalation (which accentuates the early diastolic murmurs of aortic regurgitation). Exercise, such as sit-ups, can be used to increase cardiac output and so increase the loudness of mitral stenotic murmurs. Increased venous return, with inspiration or passive leg raising, will transiently increase the loudness of many right heart murmurs. In hypertrophic cardiomyopathy the LV outflow tract murmur can be diminished by asking the patient to squat, whereas in mitral valve prolapse this manoeuvre will increase the murmur loudness. 1

Concluding a cardiovascular examination The examination is incomplete without examination of the lung bases for signs of cardiac failure, the sacrum and ankles for oedema, and assessment of the peripheral pulses, dentition, skin and nails. • The lungs are examined not only for signs of failure, but also because chronic lung disease can complicate and add to the symptoms and signs generated by heart disease. • A patient with angina may well have atheromatous peripheral vascular disease, shown by loss of pulses in the legs. Examination of the carotid arteries for signs of atheromatous carotid stenosis may reveal loss of a carotid pulsation, a carotid bruit or loud systolic murmur. Atrial fibrillation may have caused embolic loss of some pulses. If the patient is hypertensive with a systolic murmur, radial and femoral pulses should be felt to detect any delay and weakness of the femoral pulse indicating coarctation. Possible aortic aneurysm should lead to careful assessment of the pulses and the blood pressure in both arms. • Tricuspid regurgitation is confirmed by finding a pulsatile liver. If the patient has hypertension, the abdomen is examined for renal enlargement or bruits. A patient in right heart failure may well have ascites and considerable liver enlargement. • Atrial fibrillation or tachycardia may be caused by thyrotoxicosis, so the thyroid is examined for goitre and signs of thyroid overactivity. • If the patient is hypertensive, the optic fundi are examined for hypertensive retinopathy. They should be examined regularly in patients suspected of having endocarditis.

475

FIG. 12.10 Normal ECG

CARDIAC INVESTIGATION THE ELECTROCARDIOGRAM The electrocardiogram (ECG) is a fundamental part of cardiovascular assessment. It provides information on the heart rhythm and underlying cardiac morphology. A 'normal ECG' (Fig. 12.10) at rest can be reassuring but also misleading, as it can be found even with life-threatening coronary disease; in the absence of symptoms, a routine ECG is thus of limited value.

Recording an ECG The patient should be relaxed and warm (not shivering) before the 10 skin electrodes are applied to skin previously mildly abraded with spirit. The limb leads provide an electrical 'view' around the heart in the frontal plane, and the

1

476

Fig. 12.5

2

Fig. 12.6

six ventricular leads view the heart from the complementary horizontal plane (Fig. 12.11). By convention, the lead connections have been made to show a positive deflection when the wave of depolarizing current travels towards the electrode. The final shape of the ECG is determined by the lead being sampled and by the angle (vector) at which it 'views' the activity in the heart; the magnitude of the recorded deflection is affected by the mass of tissue undergoing electrical activation. Understanding the ECG therefore requires that the anatomy of the heart, the route taken by electrical activation and the viewpoint of the electrode are known. Differences in anatomy and minor variations in lead positions can account for some of the variability in clinical ECGs; pathological processes account for the rest. Standard gain settings (1 cm/mV deflection) and paper speed (25 mm/s) complete the ECG recording.

Atria I activity and the P wave In the normal heart the dominant pacemaker is to be found in the high right atrium at the sinoatrial node. The depolarizing wave front moves through the right atrium first and arrives at the left atrium fractionally later. The wave front moves towards +60° (see Fig. 12.14). The surface ECG records a P wave which is positive and best seen in

12

FIG. 12.12 Normal and abnormal P waves A On the left is shown the direction of atrial activation that produces the normal P waves shown in lead II. In P pulmonale (PP) the P wave is abnormally tall and peaked. When activation is retrograde (nodal rhythm shown by dashed line), the P wave is inverted, B In left atrial hypertrophy (e.g. in mitral stenosis) a broad bifid P wave is seen in lead II and a prominent negative deflection in lead V1; this is P mitrale (PM).

the depolarizing wave front, and may be seen when atrial activation is initiated at the atrioventricular (AV) node low in the right atrium. Other ectopic atrial rhythms may produce P waves of varying shapes.

The PR interval

FIG. 12.11 Position of leads and electrodes in the ECG [A] Frontal plane. B Horizontal plane. Four limb leads and six precordial leads are routinely used, the anatomical landmarks for the latter being: V1, right sternal edge, 4th intercostal space; V2, complementary position to left of sternum; V3, between V2 and V4; V4, midclavicular line, 5th space; V5, anterior axillary line; V6, midaxillary line, horizontally in line with V4.

leads II, V1 and I. Right atrial hypertrophy produces a tall (>2.5mm) peaked P wave, sometimes called the P pulmonale 1 from its association with the pulmonary hypertension of pulmonary disease. Left atrial hypertrophy (P mitrale) 0 produces a broad notched P wave (>0.12s duration) in leads II or III, with a negative secondary deflection in V1 which exceeds the right atrial positive deflection in that lead (Fig. 12.12). P waves that are inverted in lead II are caused by an abnormal direction of

Between atrial and ventricular depolarization, the ECG signal records a flat isoelectric line for 0.12-0.20 s (Fig. 12.13). This is the delay encountered by the depolarizing wave front in the AV node before rapid propagation to the ventricular myocardium. The PR interval will diminish at increased heart rates and under the influence of adrenaline (epinephrine). It increases in diseased AV nodes, with certain drugs and, occasionally, in normal people.

The QRS complex and ventricular activation Normal QRS The normal QRS parameters are shown in Figure 12.13. Ventricular activation is complete within 0.12s, with virtually simultaneous activation of the left and right ventricles owing to the system of specialized rapidly conducting muscle cells that form the bundle of His and the Purkinje network. Activation of the interventricular septum begins first from left to right and accounts for the small q wave (duration <0.04s and depth <25% of R wave height) seen in leads V5, V6 and, usually, V4. This wave is matched by the r wave in V1 and V2. Because the left ventricular

477

pattern, with a small initial r wave and large secondary R wave, is seen in the right-facing chest leads V1, V2 ± V3, as right ventricular forces occur late and unopposed by left ventricular contraction; this is also manifested by late deep slurred S waves appearing in V4 to V6. Left bundle branch block causes a delay in left ventricular activation, which occurs from right to left, causing a marked axis shift (greater than -60°) and loss of q waves in V5 and V6. Lead V1 shows only a qS wave and the lateral leads (V5 and V6) the characteristic slurred RsR or 'M' pattern. Left bundle branch block is virtually always pathological, the commonest cause being ischaemic heart disease. Right bundle branch block may be a normal finding, but the change from normal conduction to one or other of these patterns implies heart disease. FIG. 12.13 Normal PQRST parameters A Duration. QT interval varies with rate. B Height.

muscle mass is greater than that of the right ventricle, it is the left ventricular forces that dominate the chest leads, with rS waves in leads V1 and V2 and qR waves in leads V5 and V6, with an intermediate transition zone to be found between leads V3 and V4. The mean frontal plane vector (QRS axis) This is obtained from the limb leads and describes the direction of the dominant electrical forces. It can be determined for all the major ECG deflections (P wave, QRS complex and T wave), but is mainly used to summarize ventricular depolarization as the mean QRS axis. It is roughly estimated by choosing the lead with the smallest equiphasic deflection and assuming that the vector is at 90° to this lead. On this vectorial line the limb lead that shows a positive deflection indicates the direction of the axis. The units are degrees, with values above the equator (0°) being prefixed negative (Fig. 12.14). The vector is normally about +60°. Left axis deviation is variously defined, but a shift further than -30° is definitely abnormal; right axis deviation is definite at greater than 120°. The latter can be due to right ventricular hypertrophy or, less commonly, to abnormal patterns of activation caused by interruption of the posterior fascicle of the left bundle branch, in left posterior hemiblock. Left axis deviation is an 'electrical' phenomenon, caused by interruption of the anterior fascicle of the left bundle branch. It is associated with the loss of the normal septal depolarization and hence the loss of q waves in V5 and V6. This is called left anterior hemiblock; in these conditions the QRS duration remains less than 0.12s.

478

Bundle branch block Interruption of the right or left bundle branches produces a bundle branch block pattern characterized by broad QRS complexes of more than 0.12s duration (Fig. 12.15). With right bundle branch block an rSR or 'M'-shaped

Rate-dependent bundle branch block Occasionally, normal QRS morphology is present at low heart rates, but a bundle branch block pattern appears at faster rates. This is usually right bundle branch block, as its refractory period is generally longer than that of the left bundle branch. Rate-dependent bundle branch block may occur with a supraventricular tachycardia, where the broad QRS complexes may wrongly suggest the diagnosis of ventricular tachycardia. Ventricular hypertrophy The tallest R wave should not exceed 27mm, nor the deepest S wave 30mm, and the sum of the tallest R wave and the deepest S wave should not exceed 40mm (Fig. 12.13). Left ventricular hypertrophy (LVH) is diagnosed when these criteria are exceeded, with a normal total QRS duration of less than 0.12s. The intrinsic deflection is delayed by more than 0.04s in the left-facing leads, this measurement being taken from the onset of the QRS deflection to the point at which the R wave swings abruptly downwards. Associated ST segment depression and T inversion occur in the left-facing limb and precordial leads, particularly with pressure-overloaded ventricles, and is said to represent ventricular 'strain'. Right ventricular hypertrophy (RVH) is suspected when there is a dominant R wave in V1, associated with a rightward QRS axis shift (>+90°) in a QRS complex of less than 0.12s duration. There is also ST segment depression and T inversion in the right precordial leads, and often also clockwise rotation of the ventricular leads with the normal transition zone (V3-V4) moving towards V5-V6.

The ST segment The ST segment begins where the QRS ends, and is normally on the isoelectric line curving upwards into the T wave (the J or junction point). There may be 1-2 mm of elevation in the high anterior chest leads (V1 and V2), but greater elevation is seen with myocardial infarction, the so-called current of injury (p. 556, Fig. 12.63), and pericar-

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FIG. 12.14 Determining the mean frontal plane axis A Lead aVL has the smallest biphasic signal. The axis is perpendicular to this and its direction is given by the upward deflection produced in lead II. The axis, shown by the arrow, is therefore +60° (normal axis). B The axis is -90° (perpendicular to I and away from aVF). This is left axis deviation. C The smallest and most biphasic complex lies between II and aVF and the axis is therefore greater than 120° (severe right axis deviation).

ditis (p. 587, Fig. 12.66). A normal variant, in which there is marked anterior ST elevation, is frequent in young black men. Depression of the ST segment (p. 545, Fig. 12.57) is the hallmark of cardiac ischaemia. This can vary from subtle loss of the normal slight upward curvature and acute angulation with the T-wave origin, to more marked depression, sloping downwards before abruptly changing direction with the T-wave onset. The degree of depression of the ST segment is a rough indication of the severity of the myocar-

dial injury. The ST segment is encompassed within the QT interval. This shortens with increasing heart rate, but may be prolonged (>0.40s or >50% of previous R-R interval) by hypocalcaemia or hypomagnesaemia.

The T wave: myocardial repolarization There is more variability in T-wave amplitude and orientation than in other parts of the ECG, so that criteria for normality have to be more flexible. The T wave may be flat

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amplitude and shares the T-wave orientation. It is best seen in lead V3 and is enlarged in hypokalaemia. Its genesis is uncertain. 1

Exercise electrocardiography The normal 12-lead resting ECG often shows no abnormalities in patients who develop symptoms on exercise. The exercise test, on a treadmill or cycle ergometer, may be performed for the following reasons: • To reproduce the symptoms, so that the patient can describe them as they happen under standardized exercise conditions; • To assess 'functional capacity', i.e. the amount of work that can be performed before the patient becomes limited by symptoms, and also how rapidly the patient recovers from exercise; • To ascertain whether the symptoms are accompanied by any objective evidence of myocardial ischaemia, cardiac arrhythmia, hypertension or other events that would make unsupervised exercise hazardous; • To monitor treatment with serial studies; • To assess prognosis in patients with known cardiac disease.

FIG. 12.15 Bundle branch block A Left bundle branch block. B Right bundle branch block.

or abnormal in non-cardiac disease and in some normal patients. It is asymmetrical in shape, with a slower upstroke than downstroke and a smooth rounded peak. Symmetrical peaked T waves may indicate ischaemia, whereas notching may be a feature of pericarditis. T-wave height should not exceed 10mm in the precordial leads; larger heights without LVH suggest acute myocardial infarction or hyperkalaemia. T-wave orientation is normally upright in leads with R waves over 5 mm in height, so that, in the normal adult, T waves are upright in I, II and V3 to V6, are always inverted in aVR, and may be inverted in aVL, aVF, III, V1 and V2. The evolution of acute infarction (Fig. 12.63, p. 556) involves T inversion in leads affected by the injury, and these changes may persist.

The U wave The U wave follows the T wave (Fig. 12.13), is small in

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480

MCQ 12.5

The exercise load is started at an easily managed level, kept stable for 1.5-3 minutes at each load, and then serially increased with the aim of 'exhausting' the subject within 15 minutes (although in submaximal tests exhaustion is not usually the end point). The patient is connected to an ECG monitor and the blood pressure is also recorded. A defibrillator is available. The absolute indications for stopping the test are: • • • • • • • • •

Severe ischaemic symptoms Fall in systolic blood pressure >10mmHg ST depression >3 mm New arrhythmia Patient requests it. The relative indications for stopping are: Achieves target heart rate Systolic blood pressure >220 mmHg Tired patient Angina.

Interpretation The exercise test is conclusively positive if the patient develops classic anginal pain, and downsloping ST segment depression (>2mm) is shown on the ECG (Fig. 12.57, p. 545). Minor degrees of upsloping ST segment depression are common, particularly in anxious individuals and especially in young women. T-wave inversion is not necessarily ischaemic in origin. A commonly used criterion is 1mm ST depression more than 0.08s after the previous QRS complex. Severe ischaemia is shown by widespread ST depression in several leads which takes several minutes to return to normal. There may be a sudden drop in blood

pressure during exercise; this may be unaccompanied by ECG changes but is diagnostic of severe ischaemia and is an absolute indication to stop the test.

CHEST X-RAY Because of the almost uniform density of its components, the cardiac shadow on a PA chest film is a silhouette of a three-dimensional structure displayed on a twodimensional film (Fig. 12.16). Examination of a cardiac X-ray requires a logical approach, and includes the following:

which may result in an abnormal appearance of the heart. Lateral films may show a depressed sternum or abnormal sternal segmentation. There may be rib notching, suggesting coarctation.

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Heart size and cardiothoracic ratio Minor variations in heart size can be technical in origin. It is usual to measure the cardiothoracic ratio (the maximum transverse diameter of the heart compared with that of the ribcage), which is 0.5 or less in normals. This commonly accepted criterion is, however, rather rigid and needs to be modified with athletes and people of African descent, many of whose hearts exceed this limit but are by other criteria physiologically normal. When comparing successive chest X-rays, an increase in transverse diameter of the heart of more than 1.5cm is regarded as significant.

• A check of the technical quality of the film (PA film, full inspiration, no rotation); • An assessment of heart size (and changes from previous films if available); • A search for evidence of specific chamber enlargement and abnormalities of cardiac anatomy; • An examination of the lung fields and vessels; • Identification of valve or other calcification.

Anatomy and specific chamber enlargement

An AP film is only of value in assessing the lung fields or gross changes in heart size. There may be evidence of thoracotomy, rib resection, scoliosis or severe kyphosis,

The border-forming structures of the cardiac silhouette in the PA and lateral views are shown in Figure 12.16. The approximate positions of the heart valves are also shown.

FIG. 12.16 Composition of the normal cardiac silhouette on chest X-rays [2 PA view. B Lateral view. RV and LV = right and left ventricles; RA = right atrium; LA = left atrium; SVC = superior vena cava; Ao = aorta; RPA and LPA = right and left pulmonary arteries.

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Left atrium (LA) LA enlargement may produce widening of the angle of bifurcation (carina) into the main bronchi, with lifting of the left main bronchus. The increased density of an enlarged LA may make it visible within the right heart border, or it may protrude beyond it. Enlargement of the LA can cause straightening, and even bulging, of the left heart border. On lateral chest X-ray, enlargement produces posterior displacement of the upper posterior cardiac border. Left ventricle (LV) The LV makes up the cardiac apex and part of the left heart border on PA X-rays, and much of the posterior heart border on lateral views. LV enlargement usually displaces the apex of the heart downwards and laterally on the PA view, whereas on the lateral view the LV produces a prominent convexity of the lower half of the posterior border of the heart.

Aorto In young adults the upper right cardiac border may not include the ascending aorta, but with ageing the aorta elongates and becomes more tortuous and prominent on chest X-ray. Prominence of the ascending aorta may thus be due to age as well as to hypertension, poststenotic dilatation or aortic dilatation from aortic valve disease, aneurysm or dissection. CT, ultrasound or angiography may be needed to define the cause of a prominent aorta. The aortic arch may also be prominent in any of these conditions. Calcification of the ascending aorta occurs in syphilis, but is very common in the arch and descending aorta in normal individuals.

Lung fields and vessels Assessment of pulmonary vascularity tends to be subjective and demands a good-quality film. Normal pulmonary vascularity will show larger vessels in the lower zones, with symmetry between the two lungs. There is a steady diminution in vessel size peripherally. Pulmonary venous hypertension If the pressure in the pulmonary veins rises above about 15mmHg the upper lobe vessels dilate and become larger than the lower lobe vessels, which constrict with perivascular cuffing. There is redistribution of flow to the upper lobes. If the venous pressure rises higher than about 20-25 mmHg the pulmonary lymphatics become engorged, and appearances of interstitial oedema are seen on the chest X-ray. These are the appearance of Kerley B lines (horizontal septal lines best seen at the costophrenic angles) and increased haziness of the perihilar regions, sometimes resulting in the classic but uncommon 'bat's wing' appearance of the chest X-ray, often with small effusions (Fig. 12.17). Further rises in pressure above 30 mmHg result in alveolar oedema, with dense opacification of the lung from fluid collection. Increased lung blood flow With increased blood flow to the lungs (as in a left-toright shunt) the lungs are vascular, with quite large vessels running to the periphery. This can be distinguished from left heart failure by the lower lobe vessels remaining larger than the upper lobe vessels. Pulmonary oligaemia Pulmonary oligaemia (as in severe pulmonary stenosis) is

Right atrium (RA) Enlargement of the RA is seen as prominence of the lower half of the right heart border and is usually accompanied by superior vena cava (SVC) prominence. The SVC forms the highest part of the right border of the cardiac silhouette and is prominent in right heart failure, SVC obstruction, or displacement of the SVC by the aorta. Right ventricle (RV) The RV is an 'internal' structure on the PA X-ray unless there is massive RV dilatation with the LV rotated posteriorly. RV dilatation results in a more globular appearance to the heart on PA film, with the cardiac apex being more elevated - the so-called coeur en sabot.

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Pulmonary conus and trunk The pulmonary trunk is more prominent in young subjects than later in life. A dilated pulmonary trunk may indicate a poststenotic dilatation, pulmonary hypertension, increased pulmonary flow, or can be idiopathic. It therefore needs to be interpreted along with the appearance of the lung fields.

FIG. 12.17 Radiological features of left heart failure PA chest X-ray showing bilateral shadowing spreading from the hila, typical of acute pulmonary oedema. The heart size is increased.

associated with an avascular appearance of the lung fields but normal-sized central pulmonary arteries (although the pulmonary trunk may be dilated as a poststenotic dilatation in pulmonary stenosis). A region of oligaemia (e.g. left upper zone) may be detected after a moderate or large pulmonary embolism. Pulmonary arterial hypertension The presence of pulmonary arterial hypertension gives rise to large central pulmonary arteries which are rapidly pruned peripherally, with relatively avascular-looking lung fields.

Calcification Calcification is usually best seen on penetrated PA and lateral films, as much of the calcification seen within the heart overlies the spine on PA films. The mitral and aortic valves may both calcify. On lateral films the latter is usually lying above a line joining the tracheal bifurcation and the costophrenic angle, whereas the mitral is predominantly below the line. Calcification is also sometimes seen in the great vessels, the wall of a rheumatic LA, the pericardium, and within the LV in thrombus in an LV aneurysm.

ULTRASOUND TECHNIQUES If a beam of ultrasound is directed into the thorax through a suitable 'acoustic window' the various tissue interfaces in the line of the ultrasound beam reflect some of the sound back towards the transmitting transducer, and the red blood cells in its path scatter the ultrasound. The reflected ultrasound takes varying times to get back to the transducer, depending on the depth of the interface from which the reflection occurs. Ultrasound imaging allows for a detailed, painless and safe investigation of the heart and great vessels which can be repeated many times. Anatomical and functional information can be obtained rapidly in virtually any circumstance, from the bedside in and out of hospital to intensive care units and operating theatres, and even in the unborn fetus. The limitation of obtaining a suitable imaging window on the chest wall (transthoracic echocardiography, TTE) has been surmounted, at least in part, by using small probes inserted endoscopically and viewing the heart from the oesophagus and stomach (transoesophageal echocardiography, TOE).

Echocardiography The method of obtaining the M-mode echocardiogram is illustrated in Figure 12.18. This imaging method remains important in producing a very accurate resolution of distance and time (the ECG provides the timing index) so that the movement of ventricular walls and valve leaflets can be measured to within 2mm and 10ms. The dimensions

of the left ventricular walls in systole and diastole, plus the size of the left atrium, proximal aorta and right ventricle, are the parameters most commonly taken from these recordings. Others, such as valve leaflet excursion and the extent of thickening and thinning of the LV walls, are also used. The two-dimensional echocardiogram, produced by swinging the ultrasound beam through an arc or sector, produces pictures that are immediately recognizable as cardiac anatomical structures (see Figs 12.19 and 12.20A). Their pattern of movement can also be seen in 'real time', adding to the value of the assessment. This method is particularly well suited to the demonstration of LV function, being able to demonstrate regional as well as global disturbances of contraction. Valves can be seen to open and close during the cardiac cycle, and vegetations of >3.0mm in size may be detected (see bacterial endocarditis, p. 574). It is the method of choice for the demonstration of pericardial fluid and atrial tumours, and can reveal intracardiac thrombus following myocardial infarction. Using peripheral venous injections of fluids containing microscopic bubbles (usually agitated normal saline in a bolus of 1025 ml) intracardiac shunts can be demonstrated - contrast echocardiography. Newer commercial contrast agents have been developed with echogenic particles of >6um which can pass through the pulmonary capillary bed (10 um). These agents may become useful in defining left ventricular function and viability. Echocardiography can be used to map regional left ventricular function to compare images obtained at rest with those immediately after exercise or during infusion of an inotropic agent such as dobutamine. Stress echocardiography can indicate the extent of regional dysfunction produced by ischaemia in coronary artery disease, particularly in patients with atypical symptoms and normal LV function at rest. An improvement in contraction of a region of LV with inotropic stimulation differentiates stunned from dead myocardium, an important difference if surgery or angioplasty (PTCA) is being considered.

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Doppler ultrasound The technique of Doppler ultrasound makes use of the change in frequency of the backscattered ultrasound energy from the red blood cells. This change of frequency is proportional to the blood velocity; thus, if the beam of ultrasound is aligned with the jet of blood within the heart, accurate measurements of blood velocity can be made and gradients across the valves calculated (Fig. 12.20B) from the equation P = 4V2

where P is the pressure gradient in mmHg and V the velocity in ms. The predicted pressure gradient from Doppler measurements is the instantaneous pressure gradient, whereas cardiac catheterization usually measures the peak-to-peak pull-back gradient (Fig. 12.22).

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FIG. 12.18 M-mode echocardiography The diagram shows the position of the transducer and directions of the ultrasonic beam. In A the beam traverses the left ventricle (LV) below the mitral valve. Systole (S) and diastole (D) are indicated. In B the beam is aimed to demonstrate the mitral valve (MV). In C the aortic valve (AV) and aorta (Ao) are shown.

FIG. 12.19 Two-dimensional echocardiography Parasternal long axis views of the heart in systole and diastole are shown. (The direction of the beam is equivalent to that shown by line B in Figure 12.18A.) The opening and closure of the aortic and mitral valves are clearly shown.

Doppler ultrasound is used predominantly for measuring pressure gradients and can also be used to demonstrate the presence and severity of valvular regurgitation. It is extremely sensitive in detecting minor degrees of regurgitation, which are often unexpected. Colour flow Doppler imaging Colour flow Doppler uses a form of pulsed wave Doppler to superimpose a colour image of the blood velocity and

1

484

Figs 12.7, 12.8

direction on a two-dimensional image of the heart. By convention, blood flowing away from the probe is coded blue and that towards it red. Very high velocities are associated with multicoloured pixels. This type of imaging does not lend itself to quantification, but is very sensitive at detecting regurgitant jets and unusually directed high-velocity jets such as appear in leaks around prosthetic heart valves. Colour flow Doppler has now become a routine part of the echocardiographic examination; it gives a rapid overall assessment of intracardiac flows and makes the rest of Doppler technology easier to use and appreciate. Transoesophageal echocardiography (TOE) All ultrasound techniques are limited by the size of the acoustic windows, which must avoid bone and lung. The windows are large in babies and children (almost complete in the fetus) but become smaller in adults, especially those with lung disease. Miniaturized probes mounted on endoscopes allow some of these deficiencies to be overcome (Table 12.3). Virtually all the imaging planes available transthoracically can be achieved, and in addition the atria, their appendages and the descending aorta can be seen. The technique is more invasive, being equivalent to an upper gastrointestinal endoscopic procedure. Doppler tissue imaging (DTI) This is a modification of conventional colour flow imaging where low-frequency motion is encoded and the high velocities of the red cells are filtered out. The velocity, direction and acceleration of motion of the myocardial

12 FIG. 12.20 Two-dimensional echocardiogram and Doppler ultrasound A Apical four-chamber view of the heart. B The continuous wave Doppler signal shows a diastolic jet (upwards towards the transducer). An abnormal systolic jet away from the transducer, due to mitral regurgitation, is also shown. The velocity trace indicates peak velocities of 2ms and 5ms respectively (corresponding to peak gradients of 16 and l00mmHg).

TABLE 12.3 Indications for transoesophageal echocardiography • • • • • • • • •

Poor views on transthoracic echocardiography Investigations of prosthetic heart valves, especially mitral and aortic Endocarditis (better resolution, to 1 mm with high-frequency transducers) Aortic dissection or aneurysm (to view descending aorta) Mitral stenosis - intra-atrial clot can be excluded prior to balloon valvuloplasty Mitral valve disease prior to surgical repair Systemic embolism (looking for a cardiac source) Suspected atrial mass (tumour or clot) Intraoperative, e.g. exclusion of mitral regurgitation during valve repair

cells and valve structures are colour coded, as in conventional colour flow imaging. This technique is used to detect regions of wall motion abnormality and is particularly useful in stress echocardiography as well as in quantifying regional diastolic dysfunction.

Limitations on use The combined techniques of echocardiography and Doppler ultrasound save many patients, particularly children, from invasive studies, as in many cases the complete pathology can be demonstrated with ultrasound. These techniques cannot, however, measure chamber pressures, such as the left ventricular end diastolic pressure, or show the coronary arterial anatomy.

NUCLEAR IMAGING Two major nuclear techniques are used in cardiology, myocardial perfusion imaging (MPI) and radionuclide ventriculography. Isotopes, principally y-emitting agents such as technetium-99m and thallium 201, are used to image heart function. The commonest use for nuclear techniques in cardiology is in coronary heart disease, where perfusion imaging can differentiate normal from reversibly ischaemic from infarcted myocardium.

Ventriculography, using gated pool scanning, is used to quantify ventricular function by calculating the ejection fraction (EF) of the ventricle. Very short-acting positronemitting isotopes have been used to measure myocardial metabolism and its alteration in ischaemic states, but they remain a research tool as the isotopes must be produced on site by a cyclotron.

Nuclear ventriculography Nuclear ventriculography uses intravenously injected 99m Tc-pertechnetate bound to erythrocytes. In the first-pass technique, a discrete bolus of labelled blood is followed through the heart and data are collected by an externally placed gamma camera for 30-50s. A fresh injection is required for each view. Short-lived isotopes such as 195 Au enable rest and exercise studies to be performed with relatively low cumulative exposure and background. In an equilibrium study the whole of the circulating blood is labelled and data collection can take much longer, with serial views obtained over time. Resolution of the gamma camera image is increased by taking a large number of images over several cardiac cycles, and the images from different phases of the cardiac cycle are averaged. This process is accomplished by 'gating' with reference to the ECG as a time marker and dividing the cardiac cycle into a series of time intervals. This provides a non-invasive assessment of the ventricular ejection fraction (EF) and wall motion. 1 Derived images and measurements Ejection fraction (EF) The ejection fraction is normally above 50%, and should rise with exercise by at least 5%. Regional wall motion abnormalities are' shown by quantitative colour coding of emission over the heart. Limitations of nuclear ventriculography In severe right heart failure, a peripheral venous injection of isotope is dissipated through a large mixing volume before it reaches the heart. Tricuspid regurgitation aggravates the problem, leading to greatly degraded imaging. Time-gating over many cycles is not usually possible in patients with atrial fibrillation or other significant arrhyth-

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mias. More than a minor degree of movement of the thorax relative to the gamma camera also tends to limit studies during exertion.

Myocardial perfusion imaging (MPI) The technique of myocardial perfusion imaging depends on the radionuclide being taken up by viable myocardium that is normally perfused. Generally two sets of images are required, one obtained at peak stress and the other at rest. 1 Areas of viable myocardium which are not perfused during stress appear as areas that 'fill in' during the resting scan. Stress defects on the scan that do not perfuse on the resting images represent infarcted myocardium. Although bicycle ergometry is the commonest stress used in MPI, those patients who are unable to exercise are given vasodilator agents such as adenosine or dipyridamole by infusion. Alternatively, catecholamine derivatives, dobutamine or arbutamine are used. Radionuclides used for MPIU studies are thallium-201 (201T1) and 99mTc-MIBI (Cardiolite) on 99mTc-tetrofosmin (Myoview). The latter two agents require reinjection, but no overall superiority of one agent over the others has been established. • Perfusion imaging has a high prognostic capability. The risk of a future cardiac event in a patient with normal myocardial perfusion is less than 1% per year, even in the presence of angiographically proven coronary artery disease. The converse is true, severe defects being associated with a poor prognosis. • In addition to providing vital prognostic information in patients with known or suspected stable coronary disease, MPI performed within 3 days of myocardial infarction can identify low-risk patients. It is used to stratify the risk of non-cardiac surgery in patients likely to have widespread vascular disease.

MAGNETIC RESONANCE IMAGING (MRI) Cardiovascular MRI (CMR) has the capacity to provide high-quality tomographic images of the heart and great vessels, combined with reproducible functional assessment. New technology means that scans may take only 20 minutes to acquire. The advantages of CMR include its non-invasive nature and freedom from ionizing radiation. Cost and patient tolerability (because of claustrophobia) have been limitations which are diminishing with speedier image acquisition. CMR has a particular role in the diagnosis and assessment of anatomical abnormalities, such as aortic aneurysm, dissection and coarctation. Its use in complex congenital

A Fig. 12.9 0 Fig. 12.10

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TABLE 12.4 Indications for MPI in chronic coronary artery disease • Detection and quantification of ischaemia in symptomatic or selected asymptomatic patients • Risk stratification prior to non-cardiac surgery • Selection of 'culprit' coronary lesion prior to PTCA • Symptom evaluation after PTCA or CABG • Evaluation of viable myocardium

heart disease is becoming routine in some centres. CMR can provide imaging where echocardiography is impossible, and it can usefully quantify valve regurgitation to a degree unobtainable with other techniques. Regional and global ventricular function can be obtained, as well as unique insights into myocardial tissue in diseases such as sarcoid and iron overload due to transfusion (e.g. thalassaemia) or haemochromatosis. Angiography of the neck vessels and the renal arterial system is now well established. Imaging of coronary arteries is improving but only superior to current radiological methods in certain rare circumstances, such as the assessment of aberrant coronary arteries.

COMPUTED TOMOGRAPHY X-ray technology using ultrafast CT scanners has developed to the point of allowing rapid scans of the heart, flow and morphological detail to be obtained. The spiral CT scan is now the diagnostic tool of choice in suspected moderate or large pulmonary embolism.

CARDIAC CATHETERIZATION Cardiac catheterization is a diagnostic procedure in which a flexible tube is introduced under local anaesthetic, into the brachial or femoral veins and passed into the right side of the heart, or from the brachial or femoral arteries to the left side of the heart. In children, the procedure may require a general anaesthetic. In right heart catheterization the catheter can be passed to the right atrium, right ventricle and pulmonary artery in turn. Using an end-hole catheter, an indirect LA pressure can be obtained by wedging the catheter in a small pulmonary artery. Left heart catheterization from a peripheral artery enables cannulation of the aorta, the coronaries and, by passing the catheter retrogradely through the aortic valve, the LV cavity.

Use of cardiac catheterization Catheterization allows pressure measurements to be made and cine angiograms performed by the injection of contrast agents. Selective catheterization of the coronary arteries provides high-quality angiographic views of the coronary

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FIG. 12.21 Radionuclide ventriculography: the multiple uptake gated acquisition (MUGA) scan The blood pool is labelled and counts over the left ventricle are related to defined proportions of the cardiac cycle (1-15 in the diagram). These are summated to give an average radioactivity for end systole (B) and end diastole (A), from which the ejection fraction can be calculated.

tree to demonstrate its anatomy. 2 This has become the major use of cardiac catheterization, complementing noninvasive techniques such as echocardiography and nuclear imaging. In addition to its diagnostic role catheterization is now the tool by which many therapies are achieved, in particular the use of angioplasty balloons and stents to dilate narrowed blood vessels in the heart and circulation. Devices can be introduced to close shunts, e.g. atrial septal defects or patent ducts, as well as instruments to retrieve foreign bodies lost in the circulation. In valvular heart disease many of the uses of catheterization have been supplanted by the non-invasive techniques discussed in this chapter. Nevertheless, catheterization may still be required to obtain the following information: • To measure chamber pressures and valve pressure gradients (Fig. 12.22); • To estimate valve areas in stenoses from the approximation: Valve area in cm2 =

Cardiac output in L/min Pressure gradient in nimHg mmHg

• To perform angiography by using radio-opaque contrast agents to show cardiac anatomy, assess valve or conduit regurgitation and assess ventricular function. • Measurement of oxygen content for demonstration of shunts (Fig. 12.23). Sampling in the different chambers of the right side of the heart can be used to demonstrate the presence and size of a left-to-right shunt by the rise in oxygen content (saturation) of the blood. Persistent arterial desaturation, despite the patient breathing 100% oxygen, demonstrates the presence of a right-to-left shunt. Measurement of pulmonary artery and systemic arterial blood oxygen content, together with mea-

FIG. 12.22 Cardiac catheter pressure tracing in aortic stenosis As the catheter is withdrawn from the left ventricle into the aorta, there is an abrupt drop in pressure demonstrating a gradient across the aortic valve of 140mmHg. Lower tracing is the ECG.

TABLE 12.5 Complications of cardiac catheterization • Peripheral arterial damage (dissection, haematoma) • Cardiac arrhythmia (SVT, VT, VF) • Thromboembolism, due to clot on catheter, air embolism, dislodged atheroma • Dissection of a coronary artery • Cardiac tamponade • Renal dysfunction - especially in diabetes, or - when performed in the presence of other nephrotoxic drugs, including biguanides.

surement of oxygen uptake by timed expired air gas collection (or, in many centres, estimated oxygen uptake from normograms of patient's surface area), are used to calculate cardiac output. The use of cardiac catheterization in coronary angiography is described on page 546.

Complications of cardiac catheterization The complications of cardiac catheterization are shown in Table 12.5. The risks are small (<0.1%) and are minimized by current techniques. They are increased if the patient has small vessels, is in heart failure, or has very severe coronary artery or valvular disease, and at the extremes of age (Table 12.6).

FURTHER READING ON CARDIAC INVESTIGATION ACC/AHA Task Force Report 1995 Guidelines for clinical use of cardiac radionuclide imaging. J Am Coll Cardiol 25: 521-547. ACC/AHA Guidelines for cardiac catheterization and cardiac catheterization laboratories 1991 ACC/AHA Ad Hoc Task Force on Cardiac Catheterization. J Am Coll Cardiol 18:1149-1182.

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treatment of heart failure is solely to correct these secondary defects and to relieve the symptoms, missing out therapy to improve the heart's function. Secondly, pathological states of the vasculature may produce syndromes similar to heart failure, but the heart may not actually be failing. Examples are severe hypertension (when there is excessive vasoconstriction) and the so-called 'high-output failure' (such as that produced by significant arteriovenous shunting). In these conditions the heart is required to perform supernormally and is unable to do so. To refer to these conditions as 'heart failure' is a misnomer, and to treat them in the same way as other forms of heart failure, e.g. by administering positive inotropic agents to augment cardiac pumping, is inappropriate. FIG. 12.23 Oxygen saturation in the cardiac chambers and great vessels in ventricular septal defect A step-up in saturation occurs in the right ventricle. Ao = aorta; PA = pulmonary artery; RV = right ventricle; LV = left ventricle; RA = right atrium; LA = left atrium.

TABLE 12.6 Relative contraindications to cardiac catheterization • Recent CVA • Significant renal impairment or worsening renal function • PUO • Anaemia, Hb<10g/dL • Uncontrolled hypertension • Significant electrolyte disturbance • Uncontrolled diabetes or thyrotoxicosis • Anticoagulated state (warfarin, INR < 2.0; heparin, ACT > 200s) • History of previous contrast reaction • Severe anxiety state or psychological disturbance • Use of biguanide drugs within 48 hours

Bellenger N, Pennell D J 1999 Magnetic resonance imaging in cardiology. J Roy Coll Phys (Lond) 33:12-18. Brown K A 1996 Prognostic value of myocardial perfusion imaging: state of the art and new developments. J Nucl Cardiol 3: 516-538. Chambers J B, de Belder M A, Moore D 1997 Echocardiography in stroke and transient ischaemic attack. Heart J 78(suppl 1): 2-6. Krahninkel W, Marwick T, Gulker H (eds) 1997 Stress echocardiography: a well established diagnostic tool. Eur Heart J 18(suppl D).

HEART FAILURE

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Heart failure can be defined simply as failure of the heart to function as it should to maintain an adequate circulation. Such failure has several physiological consequences, which together produce the clinical syndrome of heart failure. It is not enough to define heart failure as a clinical syndrome consisting of congestion and hypoperfusion. First, this might lead to the wrong assumption that the definitive

The spectrum of cardiac performance The main difference between the hearts of an elite athlete, a sedentary healthy subject and a heart failure patient lies in their peak cardiac performance, not in their cardiac performance at basal resting states (they all have comparable cardiac outputs of 5-7 L/min and cardiac power outputs of 0.8-1.3 W). Elite athletes can attain cardiac outputs of up to 35 L/min and power outputs of up to 11 W, whereas the values for normal subjects are 15-20 L/min and 4-6 W. Patients with moderate heart failure achieve 10 L/min and 2.5 W. It is the deterioration in peak cardiac performance that heralds the onset of heart failure; this deterioration is progressive. A point will be reached when, even at maximal stimulation, the hearts of some patients in severe heart failure or in cardiogenic shock are not able to attain the basal resting values observed in normals. These patients have a very grave prognosis.

PATHOPHYSIOLOGY OF HEART FAILURE The major effects of heart failure are organ hypoperfusion, arrhythmia, congestion, vasoconstriction and redistribution of regional blood flow. Arrhythmia in heart failure may be secondary to ischaemia, abnormal mechanical loads and the production of areas conducive to the formation of re-entry circuits (see p. 506). It is important to remember that the primary defect lies in the heart. The secondary defects, such as fluid retention and excessive vasoconstriction, are compensatory adaptive mechanisms invoked to maintain as normal a circulation as possible. They are mediated by neuroendocrine activation and produced by the primary cardiac dysfunction. Together with the primary defects, they produce the symptoms and signs of heart failure (see below). The tertiary defects are the detrimental effects of treatment. Categorizing the defects in this way is helpful in planning treatment (Table 12.7).

Primary defects The definitive treatment of heart failure should be directed

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TABLE 12.7 Defects in heart failure and their management Defect

Clinical response

Primary Pump dysfunction

Establish a cause and remedy if possible

Secondary Fluid retention Vasoconstriction Hypoperfusion Flow redistribution Arrhythmia Tertiary (usually due to treatment) Electrolyte imbalance (diuretic Px) Arrhythmia (diuretics and digoxin) Skeletal muscle deconditioning (bed rest)

Diuretics ACE inhibitors; other vasodilators (e.g. nitrates, hydralazine) Volume replacement (if acute); decrease diuretics Inotropes (if acute); ACE inhibitors Correct tertiary defect; antiarrhythmic drugs

Monitor biochemistry, potassiumsparing diuretics Review drug (proarrhythmic effects, e.g. digoxin) Exercise training

at diagnosing and correcting the primary defects. Examples might be the removal of cardiodepressant drugs, aspiration of pericardial fluid in tamponade, control of arrhythmias, a pacemaker for complete heart block, repair or replacement of faulty valves, stripping of pericardium in constrictive pericarditis, or surgical closure of intracardiac shunts. By far the most common defect causing heart failure is cardiac myocyte loss, as a consequence of myocardial infarction or cardiomyopathy. Because cardiac myocytes are unable to undergo regeneration, the necrotic myocytes are replaced by connective tissue. The remaining viable myocardium contracts harder and undergoes hypertrophy to compensate for the loss. There is as yet no definitive therapy for this type of defect. Ultimately cardiac transplantation or cardiomyoplasty may be necessary. The extent to which a primary defect compromises overall cardiac performance can be measured by how much cardiac reserve is reduced. A schematic representation of progressive damage to cardiac functional reserve by sequential myocardial infarctions is shown in Figure 12.24.

Secondary defects In the event of heart failure or a normal heart facing excessive haemodynamic burden, the heart relies on cardiovascular compensatory mechanisms to maintain an adequate circulation. The main mechanisms are: • Fluid and salt retention, invoking the Starling effect through an increase in ventricular filling. • Neuroendocrine responses (sympathetic stimulation followed by activation of the renin-angiotensin-aldos-

FIG. 12.24 Progressive damage to the heart by sequential myocardial infarctions With the first infarction there is initial loss of cardiac functional reserve with no compromise of cardiac performance at rest. Further damage results in more loss of reserve, which may be accompanied by depressed cardiac function at rest. Finally, when the cardiac reserve is insufficient even to maintain adequate output at rest (cardiogenic shock), death ensues.

FIG. 12.25 The renin-angiotensin-aldosterone system in cardiac failure Activation of the renin-angiotensin system by failing cardiac output leads to salt and water retention and worsening cardiac output (ACE = angiotensin-converting enzyme).

terone system; Fig. 12.25) to increase cardiac pumping rate and force, and increase vasoconstriction to maintain normal blood pressure and divert the limited blood flow to the vital organs. • Myocardial hypertrophy, which is variable and incompletely understood but may reduce ventricular wall stress and thus augment function. • Readjustment of skeletal muscle metabolism such that the same physical work can be performed with a reduced cardiac effort.

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Decompensation occurs in heart failure when some of these compensatory mechanisms become excessive. Too much fluid and salt retention results in tissue oedema, which impedes tissue perfusion and reduces vasodilatory capacity. Gut and hepatic congestion impairs absorption and metabolism, contributing to cardiac cachexia (and rendering enteral medication less effective). The ensuing hypoalbuminaemia further worsens the oedema. Pulmonary oedema causes orthopnoea and dyspnoea, impairs gaseous exchange and increases the work of ventilatory muscles, which in turn imposes an extra demand on cardiac performance. Excessive cardiac dilatation causes functional AV valve regurgitation, further reducing ventricular pumping efficiency. Excessive vasoconstriction (due to activation of the sympathetic, renin-angiotensin and vasopressin systems) imposes a higher afterload on the heart. Vasoconstriction is exacerbated by diuretic therapy, which stimulates the renin-angiotensin system and the release of vasopressin. Excessive vasoconstriction of the renal arterioles leads to reduction in renal blood flow and glomerular filtration rates. The resulting azotaemia and oliguria compounds the management of heart failure. Chronic overstimulation of the sympathetic system depletes myocardial noradrenaline (norepinephrine) and causes B-receptor downregulation, reducing myocardial chronotropic and inotropic responses. Excessive myocardial hypertrophy causes cardiac diastolic dysfunction and makes the subendocardial region more prone to ischaemia.

Tertiary defects

490

Pharmacological treatments that alter physiological homeostatic controls lead to complications, some of which can be detrimental. The commonest is probably electrolyte imbalance. The powerful loop diuretics lead to loss of potassium and magnesium, both of which can increase the likelihood of tachyarrhythmias. Dietary replenishment of potassium supplements does not fully compensate for the losses. A better way of avoiding this complication is to use the so-called potassium-sparing diuretics, which also conserve magnesium. Diuretic therapy in severe heart failure can also lead to significant hyponatraemia, which is associated with a poorer prognosis. Diuretics must be used carefully to avoid this pitfall. Arrhythmia is an important consequence of electrolyte imbalance. Hypokalaemia, hypomagnesaemia and hyponatraemia all cause arrhythmia, the latter being especially hard to treat. Overdiuresis can also produce hypovolaemia. This leads to further hypoperfusion, postural hypotension and worsening renal function. Vasodilators have preferential effects on different vascular beds. Such selective vasodilation may counter the 'natural' redistribution of blood flow that preserves flow to vital organs in low-output states. For example, a-adrenergic blockers such as prazosin counteract the redistribution of blood flow effected by noradrenaline (norepinephrine), but prazosin does not improve exercise

tolerance or the prognosis of heart failure patients. Vasodilators that redistribute blood into the splanchnic or cutaneous vasculature may help in acute severe heart failure, but do not improve exercise capacity or mortality in chronic heart failure. Angiotensin-converting enzyme (ACE) inhibitors are immensely useful, but can be counterproductive by worsening renal function in patients dependent on the angiotensin-induced renal efferent arteriole vasoconstriction to maintain glomerular filtration rates. Certain positive inotropic agents (e.g. catecholamines) are potentially toxic, causing arrhythmias and cardiac myocyte necrosis.

CLASSIFICATION There are three main ways of classifying heart failure: • Acute vs. chronic. Although this temporal classification may seem clinically obvious, the pathophysiology and therapy of the two conditions have important differences. In acute heart failure the haemodynamic derangement is severe enough to result in obvious symptoms at rest. In chronic heart failure, however, the circulation at rest is adequate but there is inadequate cardiac reserve to pursue daily activities. Acute heart failure may occur as a consequence of a sudden recent myocardial injury, e.g. myocardial infarction, or as an exacerbation of previously compensated chronic heart failure. • Systolic vs. diastolic (or forward vs. backward). Systolic or forward failure results in low output and low arterial pressure states, whereas diastolic or backward failure results in congestion. Systolic failure is due to inadequate overall myocardial contractile capability, and diastolic failure relates to abnormalities in relaxation. Although heart failure is due most often to systolic dysfunction, some patients have normal systolic function and the failure is due to abnormal diastolic function. The cause is either within the heart muscle itself (hypertrophy, restriction) or in the pericardium (effusion or constriction). In ischaemic heart disease systolic and diastolic dysfunction often coexist, because ischaemia also impairs myocardial relaxation. • Left- vs. right-sided. This classification arose from a simplistic clinical division into whether there is pulmonary congestion (left heart failure) or systemic congestion (right heart failure). However, the right and left sides of the heart are connected in series, and in juxtaposition, enclosed in the pericardium. This complicates the simple division into right and left heart failure. Marked hypertrophy and dilatation of the left ventricle can impinge on right ventricular filling (the Bernheim effect) and cause systemic congestion without intrinsic right ventricular dysfunction.

Epidemiology In western countries approximately 0.5-2% of the popula-

tion is affected by heart failure, and the prevalence is greater with increasing age to about 10% in those over 75 years old. The annual incidence of heart failure is about 3 per 1000 for men aged 45-65 years and 8 per 1000 for men aged 65-75 years. Both the prevalence and incidence have more or less doubled since the 1960s.

Aetiology The main causes of heart failure in the west are ischaemic heart disease, idiopathic cardiomyopathy, hypertension and myocarditis. In the Framingham (Massachusetts, USA) population study (1955-1971), over 75% of those who developed heart failure had antecedent hypertension. More recently the incidence of hypertensive heart failure has decreased markedly, which is probably owing to improved antihypertensive treatment.

Prognosis and natural history Like neural cells, cardiac myocytes do not undergo division: growth is by hypertrophy. In adulthood there is a natural attrition rate of cardiac cells with increasing age. It has been estimated that there is an aggregate loss of about 35% of myocyte cells in the ventricles from young adulthood to old age. This rate is increased by disease. The prognosis of patients with heart failure is poor, and is worse in those with advanced heart failure. Overall, the 5-year survival rate of patients with all degrees of heart failure is approximately 50%. In patients with severe heart failure, the 1-year mortality rate is greater than 50%. About half of these patients die suddenly and the other half die of progressive heart failure.

PROGRESSIVE VENTRICULAR DYSFUNCTION Clinical features The main symptoms and signs of heart failure are those related to congestion and hypoperfusion, either at rest (as in acute heart failure) or during exertion (as in chronic heart failure). In taking a history, the symptoms and signs must be noted and information about the likely cause of heart failure and the severity of its effect on the patient's life should be sought.

Symptoms and signs The symptoms of congestion in the lungs are exertional dyspnoea, orthopnoea (dyspnoea and cough on lying down), paroxysmal nocturnal dyspnoea (breathlessness that wakes the patient from sleep), 'cardiac asthma' (wheeziness due to congestion of the bronchial mucosa) and, rarely, haemoptysis (see p. 522). In some patients the dyspnoea at rest may be episodic, raising the possibility of paroxysmal arrhythmia. The physical signs of pulmonary congestion are fine

SUMMARY 1 Symptoms and signs of heart failure Symptoms • Fatigue • Shortness of breath - on exertion - on lying flat • Paroxysmal nocturnal dyspnoea • Haemoptysis • Weight gain • Swollen ankles • Abdominal distension • Abdominal pain • Lethargy

Signs • Raised JVP • Gallop rhythm • Pitting oedema • Hepatomegaly • Basal crackles • Positive hepatojugular reflux • Cardiomegaly • Ascites • Pallor • Peripheral cyanosis • Cold extremities • Pulsus alternans

inspiratory crackles at the lung bases, but throughout the lung fields in severe cases. These are usually associated with tachypnoea. Expiratory wheeze may be present and should not be assumed to be due to airways disease. Occasionally dyspnoea is atypical, more like Kussmaul respiration (deeper and slower), and is due to lactic acidosis secondary to marked tissue hypoperfusion. Some of these patients may be labelled 'hyperventilators' until the severity of the underlying left ventricular dysfunction is appreciated. In severe pulmonary oedema due to acute left heart failure the patient is in respiratory distress and producing white frothy sputum through the mouth or nostrils. They are pale and cyanosed, and, if pulmonary oedema is unrelieved they progress to a moribund or unconscious state. The clinical features of systemic congestion are raised JVP, peripheral pitting oedema, abdominal distension with discomfort or pain, and dyspnoea due to pleural effusion. In mild failure the oedema only involves the ankles and feet, and it may be dependent (occurring after prolonged upright posture). Patients with chronic leg oedema may develop lower leg ulcers with or without cellulitis. With more severe failure the oedema may involve the thighs, sacrum, abdomen and upper body. Abdominal distension may be due to ascites or hepatic congestion. The latter may induce pain, especially during exercise (hepatic angina). Long-term hepatic congestion and gut oedema lead to weight loss and cardiac cachexia. Occasionally there may be sparing of lower limb oedema, and the patient presents with abdominal and/or upper body congestive features. In bedridden patients oedema may only be found on the sacrum. The symptoms of hypoperfusion include fatigue, lethargy, cold peripheries and dizziness. The latter is often due to postural hypotension. The physical signs include tachycardia, hypotension with a small pulse pressure, pallor and feeble peripheral pulses. In more severe failure or cardiogenic shock, the signs are of cool, clammy and cyanotic peripheries, oliguria or anuria, and blunted mental function. Cardiac examination and the history alone may reveal

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491

SUMMARY 2 Treatment of acute pulmonary oedema Emergency measures • Sit patient upright, with the legs over the edge of the bed if necessary • Oxygen by 28% mask at 5-10L/min; non-invasive ventilation, it necessary • Reassure the patient whilst drugs are prepared • Apply one or two 10mg GTN patches • i.v. access by large-gauge cannula in peripheral vein (12-17 gauge in forearm or brachial vein) • i.v. bolus furosemide (frusemide) 40-80 mg or bumetanide 1-2 mg (higher dose only if previously known to require large doses, such as in renal failure patients) • i.v. bolus diamorphine 1-5 mg plus 10mg metoclopramide, if patient in pain or severe distress • Extreme hypertension can produce pulmonary oedema, especially if the pressure rise has been rapid. Lowering blood pressure has to be done progressively, and although i.v. GTN may be adequate to achieve this, more reliable and controllable pressure reduction can be performed by i.v. sodium nitroprusside infusion (40-75 g/min). The precise ideal rate of blood pressure reduction is not known. • Monitor EGG for HR & rhythm, BP, respiratory rate, oxymetry, urine output • Investigations: ECG, chest X-ray, blood gas (arterial), blood count and urea and electrolytes (venous) as emergency • Venesection of 200 ml aliquots of blood remains an effective and rapid method of alleviating pulmonary oedema in the volumeoverloaded or overtransfused patient. Pulmonary wedge pressure measurement helps to determine how much blood to remove. Stabilization period (10-20 minutes after emergency measures) • If systolic BP>100mmHg set up an i.v. infusion of nitrate: - i.v. GTN 1 mg/h (or isosorbide dinitrate). Titrate upwards to 10mg/h. Dose can be increased each 5min according to response, heart rate (aim <120) and systolic blood pressure (>90)

the cause of heart failure (valvular lesions, acute infarction, rhythm or conduction defects, pericardial effusion or constriction). Frequently, a chest X-ray, ECG, and, increasingly, echocardiography, are needed to diagnose the primary defect.

ACUTE HEART FAILURE Diagnosis and management

Pulmonary oedema Although the commonest cause of pulmonary oedema is acute left ventricular failure following acute myocardial infarction, there are many important non-cardiac causes. These include overtransfusion, shock lung in septicaemia,

O Figs 12.11,12.12

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0 Case 12.1

If systolic BP<100mmHg patient requires CCU or ITU care for Swan-Ganz catheterization via a central vein to monitor filling pressures of the right heart and the pulmonary capillary wedge pressure (the indirect measure of LA pressure), and possibly direct intra-arterial pressure monitoring SBP<100mmHg and oliguric/anuric- consider inotropic support: - i.v. infusion dobutamine: 2.5-10 g/kg/min and dopamine infusion at 2.5-5 g/kg/min - When severe hypotension is present (SBP <70mmHg) consider use of intra-aortic balloon pump in centres well practised in its use Arterial gases po2 < 9.3kPa or pco2 > 7kPa - consider positivepressure ventilation. It is worth trying the effect of mask positivepressure (nasal cPAP) or non-invasive ventilation first. Treat arrhythmia. Fast AF, VT or atrial flutter are all best treated by emergency DC cardioversion and maintained in sinus rhythm with drugs. Dual-chamber pacing may be required to treat heart block.

Maintenance and diagnostic stage • Establish the precise cause of left ventricular failure. If LVF has complicated acute myocardial infarction, there is a need to consider the use of ACE inhibitors, -blockers when haemodynamically stable. • Echocardiography is an important investigation to establish the nature and extent of left ventricular dysfunction and valve dysfunction, or the presence of other acquired defects, such as VSD, aneurysm, thrombus. • In the majority of patients, treatment with ACE inhibitors and blockers should be started and doses titrated up cautiously. Exceptions are those with renal artery stenosis for ACEI, and true asthmatics and claudication for -blockers.

aspiration of gastric acid, paraquat poisoning, and inhalation of certain toxic fumes. The common feature is accumulation of oedema fluid in alveolar spaces, leading to dyspnoea. The lungs become stiff, increasing the work of breathing. Gas exchange is impaired and, if unrelieved, progressive hypoxaemia and hypercapnia follow as the patients tires; this can lead to death. Not all inspiratory crackles are due to pulmonary oedema. Experienced clinicians may be able to distinguish crackles of oedema from other pulmonary pathology. Crackles in the absence of upper lobe blood diversion (pulmonary venous hypertension) on chest X-ray are most unlikely to be due to pulmonary oedema. Confirmation with direct measurement of pulmonary venous pressure may rarely be necessary. Pneumonia often coexists with pulmonary oedema, especially in elderly patients. The production of discoloured sputum (other than white and frothy) should alert the clinician. The chest X-ray shows upper lobe venous engorgement and blood diversion; intralobular oedema in the small horizontal lines best seen at the lung bases (Kerley's 'B' lines); severe intra-alveolar oedema

causing acute bilateral lung shadowing often most prominent in the perihilar regions. O

Treatment Treatment is summarized in Summary 2, page 492. In acute left ventricular failure initial management consists of manoeuvres to decrease left atrial pressure, increase oxygenation, increase cardiac output and BP if significantly depressed, and diminish fear and anxiety, which increase the sympathetic drive and lead to increased myocardial work. Diamorphine and morphine have threefold beneficial effects - anxiolytic, analgesic and venodilation - but are also powerful respiratory suppressants, which may precipitate Cheyne-Stokes respiration or respiratory arrest. They should therefore be used with great caution. Venodilation may be more safely achieved with i.v. nitrates and anxiolysis by agents such as benzodiazepines. Treatment of brady- or tachyarrhythmias is crucial. Maintenance of a regular sinus rhythm is the objective in the presence of haemodynamic compromise. Withdrawal and counteraction of culprit agents (e.g. digoxin) may be necessary. Physical therapy (DC cardioversion, artificial pacing) is usually more efficacious, but appropriate pharmacotherapy is often required to maintain sinus rhythm and to avoid recurrences. In general, the reduction in preload with diuretics and nitrates is associated with some impairment of tissue perfusion (demonstrated, for example, by minor elevations in urea and creatinine). This is usually transient. If the reduction in preload by diuretics and nitrates is excessive or prolonged, tissue perfusion may become greatly compromised and the patient develop multiple organ failure (e.g. renal failure) that is more difficult to treat than the original oedema. These situations can be avoided by reducing diuretics once euhydrate, maintaining adequate systolic pressures, or using inotropic support if necessary. The use of positive inotropic agents and, to a lesser extent vasodilators and diuretics, is contraindicated when treating hypertrophic cardiomyopathy, especially of the obstructive type. © Acute right heart failure Pulmonary embolism (see p. 675), cor pulmonale (see p. 662) or acute inferior or posterior myocardial infarction are the usual causes. The features of acute right heart failure in myocardial infarction include a raised JVP associated with a low blood pressure and usually clear lung fields. The right ventricular function curve has flattened (Fig. 12.5, p. 466), so that a higher right atrial filling pressure is needed to support the same cardiac output. These patients need expansion of the circulating volume with synthetic plasma expanders to improve output and blood pressure. Injudicious use of diuretics or nitrates to 'treat' the high JVP can lead to serious falls in cardiac output, and precipitate shock. Acute tamponade Cardiac tamponade presents as acute heart failure, and is described on p. 587.

Cardiogenic shock In cardiogenic shock severe cardiac pump dysfunction causes tissue perfusion to be so inadequate as to fail to meet basal metabolic demands. Clinically it is recognized by hypotension (systolic BP <80mmHg or mean BP <60 in normotensives, and <110 in chronically hypertensive subjects), associated with oliguria or anuria, cold sweaty skin, mental confusion and lactic acidosis. It is not necessary for all these features to be present before making the diagnosis of cardiogenic shock. Causes of cardiogenic shock are massive myocardial infarction (usually loss of >40% of total myocardial muscle), mechanical complication of infarction (e.g. VSD and papillary muscle dysfunction or rupture), severe brady- or tachyarrhythmia, rejection in the transplanted heart, myocarditis, and infiltration of the previously normal myocardium. It is important to exclude the effects of any myocardial depressant or vasodilatory agents (e.g. excessive diamorphine; -blockers or verapamil. In the presence of right ventricular infarction, a shift of blood volume centrally by elevation or the application of positive pressure to the lower body, or a fluid challenge to raise the pulmonary wedge pressure to >15mmHg should be made before making the diagnosis of cardiogenic shock. The incidence of cardiogenic shock in patients admitted with acute myocardial infarction is 5-10%. The advent of thrombolytic therapy has not altered this significantly. The hospital mortality rate is still 50-70%. The continuation of function in the heart is also dependent on its own output. When the aortic pressure falls below the critical pressure for coronary perfusion (mean 60mmHg), left ventricular myocardium becomes more ischaemic, further impairing performance. Medical therapy of cardiogenic shock is described on page 564. The following general principles are the basis of management:

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• Optimizing heart rate, ideally between 80 and 130bpm, with pacing if necessary (preferably AV sequential pacing; see p. 504). • Treating tachyarrhythmia using agents with minimal negative inotropic effects. Digoxin is still useful in fast AF. Give 500 g in 100 mL 5% dextrose over 30 minutes. If required, this may be repeated over 1 hour. A third dose over 2 hours is rarely given. Amiodarone i.v. is frequently used but requires central venous access to avoid serious thrombophlebitis. Give 300 mg (<5mg/kg) in 5%

SUMMARY 3 Clinical features of cardiogenic shock Hypotension (<60mmHg mean aortic pressure) Oliguria/anuria (<60mL/h) Cold sweaty skin Mental confusion Lactic acidosis Biventricular heart failure is the rule

493

•

•

• •

dextrose in 1 hour, 900 mg i.v. total in 2-4 hours, with a maintenance infusion of 1200 mg in 24 hours. Directcurrent cardioversion is preferred over 'cocktails' of antiarrhythmic drugs, provided the patient can be maintained in sinus rhythm afterwards. Optimizing LV filling pressure by monitoring PA wedge pressure using a balloon-tipped flotation pulmonary artery catheter (Swan-Ganz) and aiming to maintain PAW pressure between 15 and 20mmHg by balancing diuresis and fluid intake. Correcting metabolic acidosis with bicarbonate is rarely necessary. Intermittent positive-pressure ventilation, either non-invasively or via endotracheal intubation, may be required (although this may occasionally worsen the haemodynamic status). Avoiding pure vasodilators (e.g. nitroprusside, ACE inhibitors), negative inotropic agents (e.g. -blockers, verapamil, disopyramide). Using positive inotropic agents (see p. 497).

In managing cardiogenic shock it is important to investigate whether the heart, which is obviously depressed in the basal resting state, possesses any reserve function, and whether this reserve exceeds that necessary to sustain normal body basal metabolism (e.g. peak cardiac power output >1 W, see Fig. 12.25, p. 489). Cardiac reserve can be measured by stepwise infusion of dobutamine and noting the peak cardiac power output attained. If the peak is >1 W, medical therapy, including the use of inotropic agents to maintain adequate pressure and flow, can be sufficient. Nevertheless, remediable defects should be dealt with. If the peak is below 1W (or simple bedside observation of peak attainable systolic BP is <90mmHg despite maximal dobutamine stimulation), then death is expected unless urgent and appropriate definitive treatment of primary defects is obtained (e.g. urgent mitral valve replacement, coronary angioplasty, bypass surgery, other curative operation) or insertion of an artificial mechanical heart pump or cardiac transplantation. If the definitive treatment is delayed, artificial circulatory support in the form of intra-aortic balloon counterpulsation or ventricular assist devices should be instituted (p. 520). If the surgical option is ruled out, frantic therapeutic efforts should be avoided and the patient allowed to die peacefully.

SEVERE CONGESTIVE CARDIAC FAILURE

494

Many patients, particularly the elderly, are admitted to hospital with acute exacerbations of chronic heart failure. As in all cases, whether acute or chronic, the cause must be established to allow a rational approach to therapy. A frequently encountered syndrome consists of a patient with a dilated, poorly contracting ventricle, who suffers increasing degrees of fluid retention, sometimes to enormous proportions. Gross leg oedema may prevent walking, tense oedematous skin with poor perfusion is subject to accidental laceration, infection and the development of cel-

lulitis and venous thrombosis, both superficial and deep. Ascites may be present and contribute to poor breathing and orthopnoea due to diaphragmatic splinting. Associated oedema of the intestinal mucosa may produce diarrhoea, but more frequently accounts for variably poor absorption of drugs (especially diuretics). Many of these patients have been previously treated with diuretics and digoxin, so that electrolyte disturbance and digitalis toxicity may complicate the picture. The mainstay of initial management in hospital is to generate a gradual and progressive loss of oedema fluid, best monitored by daily weighing. A rate of weight loss of 0.5-1.5 kg per day is ideal. This is best achieved by using intravenous diuretics combined with fluid restriction to 1.5L/day and a reduction in salt intake. Daily or twicedaily bolus injections of frusemide 40-160mg or bumetanide 1-4 mg are common (patients with moderate to severe renal impairment may need very much higher doses, e.g. 120-500mg furosemide (frusemide)). Electrolytes are maintained by simultaneously prescribing a potassium-sparing diuretic (amiloride 5-10 mg daily, or spironolactone 25-100mg twice daily). Occasional patients are resistant to these measures. In these cases adding a thiazide diuretic orally for several days may initiate the diuresis (e.g. metolazone 5-10mg/day, or bendroflumethiazide (bendrofluazide) 2.5-5 mg/day). An alternative method is to infuse dopamine (2.5-5.0 g/kg/min) via a central line to avoid thrombophlebitis. Very rarely haemofiltration, ultrafiltration or dialysis may be needed to relieve the patient of intractable fluid congestion. Hypokalaemia needs to be corrected in patients who have been on long-term diuretics. Because of a simultaneous loss of magnesium, replacing the magnesium by infusion often helps restore potassium equilibrium and diminishes the tendency to arrhythmia. ACE inhibitors may need to be withheld during the acute phases of treating congestion because of their known effects of vasodilating the efferent glomerular arterioles, thereby probably diminishing GFR. ACE inhibition is (re)started as congestion resolves, unless the patient is hyponatraemic. Perindopril, because of its less first-dose hypotensive action, is the drug of first choice. After a test dose of 2mg the patient is kept under observation; blood pressure is checked every 15 minutes for 90 minutes, and 2-hourly thereafter. Provided that profound or symptomatic hypotension does not occur, maintenance perindopril or another ACE inhibitor is started and blood pressure checks revert to the routine 4-hourly observations. Uptitration of dose to the highest tolerated may be undertaken prior to discharge. Digoxin still has a role even in sinus rhythm; digitalization by 0.75-1 .Omg in the first 24 hours is followed by an appropriate maintenance regimen (125-250 g/day) monitored by plasma levels. Renal function should be closely monitored; overintense diuresis may decrease preload (and hence cardiac output and tissue perfusion) so much that prerenal failure is precipitated. It is worth emphasizing that medical

management of heart failure is almost impossible without functioning kidneys. Preservation of renal function should therefore be a high priority. Maintenance of systolic blood pressure above lOOmmHg is important and helps to avoid serious derangement of renal function. During the bed-rest stage anticoagulation with low molecular weight heparin by subcutaneous injection should be used. Once a stable balance is achieved, oral diuretics replace i.v. treatment. ACE inhibitors have a diuretic 'sparing' action, so that diuretic doses may well have to be reduced some days or weeks after starting ACE inhibitors, otherwise the patient may become dehydrated and develop fatigue, postural hypotension and worsening renal impairment.

CHRONIC HEART FAILURE IN OUTPATIENTS Management - general measures The cause of heart failure must be established and remediable causes sought and treated. These might include the replacement or repair of valves, stripping of the pericardium in constriction, or the closure of significant intracardiac shunts. The essential investigations are outlined in Summary 4. The overall aim of treatment in chronic (non-surgical) heart failure is to relieve symptoms, to improve quality of life and functional capacity, and lastly to improve longevity. The general measures should include stopping smoking, reducing alcohol intake, fluid restriction, and possibly regular exercise training. Bed rest is helpful only in acute myocardial infarction, active myocarditis, infective endocarditis and intractable congestion unresponsive to conventional doses of diuretics (see above). The disadvantages of bed rest (skeletal and myocardial deconditioning, muscular atrophy and weakness, bedsores, deep vein thrombosis, autonomic maladjustment) outweigh the benefits. Patients who are asymptomatic at rest should be encouraged to mobilize as soon as possible, as exercise rehabilitation may improve functional capacity even in severe chronic heart failure. Drug therapy to improve prognosis is now possible, and (3-blockers, ACE inhibitors, spironolactone and nitratehydralazine combinations are the most effective, although the prolongation of survival only averages 6 months. About

SUMMARY 4 Essential investigations in chronic heart failure • ECG • Chest X-ray

• Urea, electrolytes, creatinine, thyroid function? BNP • Echocardiogram • Direct/indirect measures of cardiac functional reserve.

20-50% of patients in heart failure die suddenly. No antiarrhythmic agent has been shown to be effective in reducing this incidence, although the use of amiodarone appears promising. Patients with life-threatening arrhythmia may need AICD.

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Drugs used in chronic heart failure Diuretics This class of drug is still the first-line treatment for symptomatic congestive cardiac failure because it is the most effective at relieving the symptoms of congestion, thereby producing the greatest impact on quality of life. They are all natriuretic and aquauretic; some of them conserve K+ and Mg2+, whereas others induce losses. Injudicious use of diuretics may lead to severe electrolyte imbalance (resulting in arrhythmias and sudden death) and hypovolaemia (resulting in tissue hypoperfusion and renal failure). Thiazide diuretics These are used principally to treat hypertension, but may occasionally have a role in controlling mild oedema and, when added to loop diuretics, may induce a diuresis when resistance to loop diuretics has arisen. Hypokalaemia and hyperuricaemia are two of the more commonly encountered problems with these drugs. To combat the former, combination with potassium-sparing agents is advised. Metolazone is a curious thiazide-like diuretic with a very powerful ability to induce diuresis when combined with loop agents in patients with renal impairment or resistance to loop diuretics. However, it is also remarkably potent in inducing electrolyte disturbances, and the most difficult one to correct is severe hyponatraemia. It should therefore be used sparingly, and stopped before hyponatraemia occurs. Bendroflumethiazide (bendrofluazide) Hydrochlorothiazide Metolazone

2.5-5.0mg per day 25-100 mg per day 5-10 mg per day

Potassium-sparing diuretics It is almost always necessary to add these agents to the treatment of patients taking diuretics alone. ACE inhibitors usually diminish the need for potassium-sparing agents and when used in this combination close monitoring of serum potassium (aimed between 4.5 and 5.5mmol/L) is essential because severe hyperkalaemia may occur. Spironolactone, an aldosterone receptor antagonist, at a dose of 25 ing/day, has been shown to be safe and extend the lives of patients with heart failure treated with loop diuretics and ACEI. Its antiandrogenic effects (e.g. gynaecomastia) may not be tolerated by some male patients, in which case amiloride may be used instead. Amiloride Spironolactone Triamterene

5-20mg/day 25-200 mg/day 50-250 mg/day

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Loop diuretics These are the cornerstone of diuretic therapy in all but the mildest degrees of heart failure. They share with thiazides the tendency to produce metabolic disturbance and need the addition of potassium-sparing agents to avoid these pitfalls. Bumetanide Furosemide (frusemide) Torasemide

l-10mg/day 40-1000 mg/day 2.5-40 mg/day

Combination diuretics Combinations of diuretics, incorporating fixed doses of potassium-sparing agents, are very widely prescribed. It is accepted that combinations of diuretic with potassium supplements are likely to be less effective at maintaining potassium homeostasis, and unhelpful for magnesium homeostasis. Coamilofruse (Frumil) Frusene

1-2 tablets/ day 1-2

Dyazide

1-2

furosemide (frusemide) 40 + amiloride 5 furosemide (frusemide) 40 + triamterene 50 triamterene 50 + hydrochlorothiazide 25

A suggested management algorithm for chronic heart failure is illustrated in Figure 12.26. Vasodilators Vasodilator drugs are used to decrease both preload and afterload. Excessive preload reduction may result in loss of Starling's effect and compromise ventricular output. Excessive afterload reduction can cause hypotension, reduce coronary perfusion, and exacerbate myocardial ischaemia and cerebral hypoperfusion, leading to dizziness and syncope. ACE inhibitors ACE inhibitors are the vasodilators of first choice in the treatment of chronic moderate and severe heart failure. There are many ACE inhibitors available: Captopril Enalapril

6.25-50 mg t.d.s. 2.5-20mg b.d.

Lisinopril Perindopril

5-40mg o.d. 2-4 mg o.d.

Ramipril

1.25-5 mg b.d.

Short-acting Intermediate duration of action Long duration of action Long-acting, least firstdose hypotension Long-acting

It is still unclear whether the different properties exhibited by the different types make any significant difference to their clinical efficacy.

496

• Up to 10% of all patients do not tolerate ACE inhibitor therapy owing to unacceptable coughing. • First-dose hypotension at the start of ACE inhibitor therapy can occur unexpectedly in patients with chronic heart failure, especially in those with unsuspected renal artery stenosis. Certain precautions should be heeded.

ACE introduction should be avoided if the patient is relatively hypovolaemic (as judged clinically by the absence of oedema, low JVP, dehydration, postural hypotension, elevated serum urea with normal serum creatinine), in which case the diuretics should be withheld for a day or two before introduction. Patients with significant renal artery stenosis can present with the syndrome of heart failure, and ACE inhibition is contraindicated unless medical autonephrectomy is indicated. Patients with markedly elevated blood pressure (especially acutely) despite features of heart failure should be investigated to rule out renal artery stenosis before the introduction of ACE inhibitors. Sometimes hospital admission for close BP monitoring may be required. A suitable regimen might start with 2mg of perindopril, as this has been shown to be least likely to cause first-dose hypotension, and the dose subsequently increased to 4 nig o.d. or switched to another ACE inhibitor. • The most problematic adverse effect is impairment of renal function. In a significant minority inhibition of angiotensin-induced constriction of the efferent glomerular arteriole and overall renal function is affected. Rising creatinine (>200 mol/L) is a reason to withdraw this therapy. Nitrates In patients with heart failure secondary to coronary heart disease nitrates have a distinct role, particularly as ACE inhibitors do not have any specific antianginal activity. Long-acting nitrates are used, leaving a 6-8-hour nitratefree period to avoid tolerance to the haemodynamic effects of nitrates. Isosorbide mononitrate modified release

40-120 mg o.d.

Other agents The combination of high-dose nitrate with hydralazine (50-75 mg q.d.s.) has been shown to improve function and prognosis for severe heart failure, but the drug combination can be difficult to tolerate. Calcium antagonists are not generally useful in heart failure. p-Blockers With indication for use in heart failure, p-blockers can now be claimed to be a ubiquitous cardiological drug. Trial data have shown that they can improve the prognosis, in terms of survival and hospitalization. There are no conclusive data to show that they improve functional capacity or quality of life. Clinician concerns (which led to these drugs being previously categorized as contraindicated for use in heart failure) are still valid, as inappropriate use in some patients may precipitate exacerbation of heart failure. It is therefore vital that -blockers should be introduced by trained personnel, starting with the lowest doses, which may be increased very gradually if tolerated. Carvidelol is a non-cardioselective -blocker with ocreceptor blocking activity, which produces vasodilatation. It was the first to be reported to provide remarkable survival improvements in heart failure.

12 Blood tests: Biochem FBC TFT Chest X-ray ECG Urine dipstix Cause known? eg. previous Ml previous myocarditis elderly patient with BP

Another cause for symptoms No

No

Yes

Echo Yes

Regional ?IHD

Surgical cause e.g. aortic stenosis pericardial constriction

Global 3 cardiomyopathy

Look for reversibilit; e.g. FDG nuclear medicine scan Cardiac catheter

Revascularization for CAD

Primarily systolic failure? e.g. MI/IHD alcohol myocarditis or diastolic failure? e.g. hypertension hypertrophy HCM

No

Don't know

Echo

Yes

Surgical candidate?

No

Yes

REFER

Caution with diuretic ACE

Diuretic ACE I

May still need antifailure treatment

Sinus rhythm

?p-Blocker verapamil

No

YES

If severe HF

AF

Bradycardia & heart block

Tachyarrhythmia

Dual-chamber pacemaker

Antiarrhythmic agent ±AICD

FIG. 12.26 Management of chronic heart failure

Not all -blockers are equally prognostically beneficial to heart failure patients. Bucindolol has recently been shown not to confer similar benefit. Bisoprolol and metoprolol have been shown to be beneficial in improving survival.

Inotropic agents Positive inotropic agents are not without potential dangers (e.g. arrhythmogenicity, and liability to induce worsening cardiac myocyte necrosis). In viral myocarditis they should

497

TABLE 12.8 Digoxin dosage Digoxin • Loading dose 15 g/kg in 3 doses every 6 hours • Maintenance doses 62.5-3.75 go.d. depending on age and renal function • Dose adjusted according to plasma levels (therapeutic range 1.0-2.6 mmol/L) Digitoxin Mainly non-renal metabolism. Very long half-life and rarely used

be avoided, unless as a bridge to transplantation. With the exception of digoxin (see below and Table 12.8), chronic oral inotropic therapy (with 2 stimulants and phosphodiesterase inhibitors) has been very disappointing. Digitalis preparations (digoxin, medigoxin, digitoxin, ouabain) are now well established as of value as mild positive inotropic agents in chronic heart failure. Digoxin is still the only oral positive inotropic agent available. Antiarrhythmic agents These drugs often have to be used in heart failure patients. Most intravenous antiarrhythmic agents are cardiodepressant to varying degrees. The most negatively inotropic are p-blockers, verapamil and disopyramide, and these are generally avoided in severe heart failure. In therapeutic doses the following intravenous agents exert little negative inotropism, and may be used in heart failure: lidocaine (lignocaine), mexiletine and procainamide. Orally, amiodarone, digoxin, mexiletine and procainamide are virtually devoid of negative inotropic effects. In heart failure the most effective and least proarrhythmic antiarrhythmic agents for supraventricular and ventricular tachycardia are -blockers and amiodarone. The oral preparation of amiodarone is virtually devoid of negative inotropism and is therefore suitable for use in patients with severe heart failure who are intolerant of (3blockers. Their concurrent use with amiodarone requires a reduction in dose of digoxin and warfarin. O

CARDIAC TRANSPLANTATION Since the first human heart transplant in 1967, the technique has become an accepted form of treatment for patients dying of heart failure and for whom no other form of treatment offers any help. The current annual rate of cardiac transplantation worldwide is approximately 3000. The number of patients requiring transplantation each year in the USA alone is estimated to be 35 000-70000. The shortfall is mainly due to the shortage of donor hearts, and

Q MCQ12.6

498

is responsible for the plateauing of the transplantation rate in the USA and Europe. Cardiac transplantation will not become the panacea of heart failure treatment, and selection of recipients will necessarily remain strict.

Indications The vast majority of patients who undergo cardiac transplantation have either terminal idiopathic dilated or ischaemic cardiomyopathy. Other indications include peripartum cardiomyopathy, congenital heart disease and cardiac tumours. The patient must have reached end-stage heart failure and have a very limited life expectancy. The best available method of measuring the prognosis of these patients is estimation of their cardiac reserve (see p. 494). Contraindications to transplantation of the heart alone include increased pulmonary vascular resistance, blood group incompatibility, or any coexisting systemic illness that may significantly limit life expectancy.

Surgery There are two main surgical procedures: • Orthotopic transplantation. The recipient's heart (except the venous attachment side of the atria) is excised and replaced by the donor's heart. This is the commonest procedure. • Heterotopic transplantation. The recipient's heart is not excised and the donor's heart is anastomosed side to side to the corresponding atria and great vessels of the recipient's heart. Contrary to popular belief, the surgery itself is simpler than most open heart surgical procedures. The main operative problem is the preservation of the donor heart during transit.

Management By far the most difficult part of cardiac transplantation is the postoperative care. The two major complications are graft rejection and infection, which account for most of the early mortality. There is as yet no early and accurate noninvasive method of detecting rejection. Apart from clinical suspicion and loss of R wave in the ECG, the most reliable method of diagnosing rejection is by percutaneous endomyocardial biopsy. Immunosuppressive regimens include combinations of ciclosporin, azathioprine, corticosteroids, cyclophosphamide, antithymocyte globulin (ATG), use of monoclonal antibody against the CD3 molecule on mature T cells, and occasionally vincristine or methotrexate. The need for immunosuppression means that patients are at increased risk from bacterial infection. Opportunistic fungal infections and reactivation of primary viral infection (notably cytomegalovirus) occur. Late complications include accelerated coronary disease in the donor heart, hypertension, and an increased incidence of malignancies (especially

lymphoproliferative), and bone diseases (osteoporosis, a vascular necrosis).

Prognosis Current survival rates of cardiac transplantation are as good as those of renal transplantation, with overall 1-

and 5-year survival rates of about 80% and 70%, respectively, for orthotopic transplantation. The survival rate for heterotopic transplantation is less good, with a 5-year survival of about 50%. Factors that negatively influence prognosis include major HLA mismatch, prolonged cold preservation of the donor heart, the presence of preformed circulating antibodies and advanced donor age.

12

CASE STUDY 12.1 ACUTE ONSET OF BREATHLESSNESS AND ARRHYTHMIA A 66-year-old man presented to his GP feeling generally unwell and breathless. He felt he had 'flu'. Initially he had felt feverish with mild nausea and diarrhoea. This had been some weeks before his current presentation, which consisted of significant limitation in exercise tolerance. Anything other than minor exertion produced breathlessness without chest pain. His sleep was very poor. He would fall asleep then wake in the middle of the night with breathlessness. His abdomen felt bloated and he was unable to eat comfortably. He was aware that his heartbeat was much more forceful, fast and irregular. In the past he had had no significant medical history except for being a heavy cigarette smoker which he had managed to stop 10 years prior to presentation. Twenty years previously he had had a period of excess alcohol consumption, but this had been resolved and he was now teetotal. He was taking no medication. The GP found him to be dyspnoeic on minimal exertion. He had a pulse rate of 104 which was irregularly irregular. Blood pressure was 110/70. The jugular venous pressure (JVP) was elevated to the angle of the jaw and he noted mild ankle swelling and some abdominal distension. His heart sounds were rapid on auscultation and there was a suspicion of a systolic murmur. The chest revealed bilateral absent breath sounds and basal dullness above which there were a few fine crepitations. The GP referred him up to the cardiology clinic with a diagnosis of cardiac failure and atrial fibrillation.

Questions 1. Is this diagnosis appropriate? What differential diagnoses should be considered? 2. What investigations should be arranged? 3. What would be the principles of treatment for this patient assuming that there were no surgically remediable cause for his heart failure?

Discussion Heart failure is a clinical syndrome which was diagnosed confidently and correctly by the GP. The features in support were the symptoms of exercise limitation. His nocturnal symptoms could represent orthopnoea with some features of paroxysmal nocturnal dyspnoea (PND). The GP noted the findings consistent with right heart failure in that the JVP was elevated and he had peripheral oedema. The abdominal distension could represent ascites and possible enlargement of his liver. He had dull lung bases which could be bilateral pleural effusions and the crepitations heard above this area of dullness could be evidence of left heart failure producing pulmonary oedema. He was noted to have a fast irregular pulse most likely due to atrial fibrillation complicating the heart failure or indeed contributing to it. There was a possible systolic murmur. Having detected the clinical syndrome, it is important for the doctor to establish remediable causes. These might include non-cardiac causes of heart failure such as thyrotoxicosis, anaemia and excessive

alcohol intake. Cardiac causes of heart failure that need to be excluded would be ischaemic heart disease, valvular disease or pericardial disease. Investigations are designed to establish a diagnosis behind the presenting clinical syndrome of heart failure. Blood tests will exclude anaemia and thyrotoxicosis. The plasma biochemical profile should include renal and liver function to give baseline values because treatment may affect renal function adversely. When the presentation is relatively acute it is important to include cardiac enzymes in the investigation to exclude silent myocardial infarctions as a possible cause of heart failure. An ECG will confirm the presence of atrial fibrillation and also give clues to the aetiology of heart failure particularly if there are any changes consistent with either acute or chronic ischaemic heart disease. Chest X-ray would confirm the presence of pleural effusions and the clinical suggestion of pulmonary oedema. Calcification around the pericardial sac, or elsewhere in the heart, might be seen. The size of the cardiac silhouette and any contribution from coexistent pulmonary disease will be established. An echocardiogram can be used to establish whether the heart failure relates to valvular disease or is a primary problem of the heart muscle. In this patient the problem is likely to be due to viral myocarditis leading to the appearance of thin-walled, very poorly functioning left and right ventricles. A degree of mitral regurgitation was noted secondary to

499

CASE STUDY 12.1

CONTINUED

left ventricular dilatation and this accounted for the systolic murmur. In a man of this age, exclusion of myocardial ischaemia is important even in the absence of any other pointers such as chest pain or ECG change. This is because occasional silent presentations of the severe ischaemia can be adequately treated by revascularization, usually by cardiac bypass surgery. Consideration therefore would be given, in this age group, to a myocardial perfusion scan using thallium and to cardiac catheterization with coronary angiography. The treatment would begin by management of the acute symptoms produced by his presumed post-viral myocarditis. Fluid retention would be

treated by the use of loop diuretics such as furosemide (frusemide) with the addition of the potassium-sparing diuretic spironolactone. His atrial fibrillation should be treated. The heart rate should be controlled with digoxin and anticoagulation with warfarin is indicated. After adequate anticoagulation subsequent DC cardioversion to sinus rhythm would be an option if mitral regurgitation was not severe and if the left atrium was not severely dilated. ACE inhibitors should be introduced as they improve survival from myocardial failure and will allow the use of lower doses of diuretics in the long term. In addition -blockers should be introduced into treatment, although careful titration starting at

Heart-lung transplantation Patients with end-stage pulmonary vascular hypertension (primary or Eisenmenger's syndrome) and with parenchymal lung disease (mostly cystic fibrosis) have the option of heart and lung transplantation. The two classes of disease each constitute about half of the transplanted cases. The 1- and 3-year survival rates are currently about 65% and 50%. A major difficulty in management is that the diagnosis of rejection is more difficult in the lung than in the heart. FURTHER READING ON TRANSPLANTATION O'Connell J B, Bourge R C, Costanzo-Nordin M R, Driscoll D J, Morgan J P, Rose E A, Uretsky B F 1992 Cardiac transplantation: recipient selection, donor procurement, and medical follow-up. A statement for health professionals from the Committee on Cardiac Transplantation of the Council on Clinical Cardiology, America Heart Association. Circulation 86:1061-1079.

ARRHYTHMIA Arrhythmia is a general term for any cardiac rhythm or conduction abnormality. Anatomically the arrhythmia

O Fig. 12.13

500

very low doses is necessary in this context. The particular -blockers of use in this situation are carvedilol and propranolol. In randomized trials both of these drugs have shown improvement in prognosis when given in heart failure. Cardiac transplantation is an option although in this age group the success rate is greatly diminished. For this reason some centres do not accept patients in this age group for transplantation. Acute post-viral cardiomyopathy has been treated successfully by temporary mechanical ventricular assistance devices. This patient's chronic and slightly less severe problem is unlikely to be suitable for this management.

may originate supraventricularly (atria or AV junction) or ventricularly. The most compelling clinical feature is whether the arrhythmia causes haemodynamic disturbance; however, its implications depend more on the type of arrhythmia, so that ventricular tachycardias have a poorer prognosis than supraventricular tachychardias.

INVESTIGATIVE TECHNIQUES The principal method of analysis of arrhythmia is the 12-lead ECG. The correct interpretation of the ECG may depend on comparison with previously acquired recordings.

24-hour ECG (Holter monitor) Recorders can monitor two channels of an ECG in ambulant patients over a continuous 24-hour period (Fig. 12.27). Some rhythm disturbances may occur very infrequently and require alternative equipment. Event recorders can be applied by the patient during symptoms and record a few seconds of ECG in a solid-state memory. This can subsequently be replayed or transmitted by telephone to a central station, where a doctor can advise on the nature of the event. For those patients who receive no warning of impending rhythm disturbance, there are newer implantable automatic solid-state recorders (ILR, implantable loop recorders) that sample the ECG over long periods but only memorize significant events, or events triggered by the patient.

but not the ventricular, activity; this is most commonly encountered in complete heart block (p. 503 and Fig. 12.31). Sinus arrhythmia is the quickening of the heart rate that occurs cyclically with each inspiration. It is most marked in individuals (often young) with high vagal tone.

12

EGTOPIC OR EXTRASYSTOLIC BEATS These are defined as beats that arise outside the normal heart pacemaker. They may be generated in the atria, the AV node, the bundle of His or the ventricles. They may also arise as 'escape' beats in sinus bradycardia.

Atrial ectopics FIG. 12.27 24-hour continuous ambulatory ECG monitoring At 19.20 hours the sinus rhythm is interrupted by ventricular ectopic beats and a short run of ventricular tachycardia. O

Exercise EGG The exercise test has a role in managing certain patients with arrhythmia. Those with recurrent ventricular tachycardia, or Wolff-Parkinson-White syndrome, may undergo exercise testing to check the efficacy of their drug treatment. However, not all these patients have exerciseinduced arrhythmia and may instead require more sophisticated electrophysiological (EP) studies.

Intracardiac electrophysiological testing The techniques of cardiac catheterization enable localized intracardiac ECGs to be recorded, using catheters similar to pacing catheters but with electrodes mounted distally. The activity of the atria, AV node, bundle of His and ventricles can be recorded independently. By combining recording with artificial stimulation from intracardiac pacemakers, a detailed analysis of intracardiac conduction can be made. This has proved useful in studying patients with tachycardia, in whom the abnormal rhythm may be induced and its origin (ventricular or supraventricular) confirmed. The site, number and potential danger from accessory AV bypass tracts (e.g. in Wolff-Parkinson-White syndrome) can be mapped and the tracts ablated. The effectiveness of drug regimens and the potential for using antitachycardia pacemakers are also tested using EP studies.

NORMAL SINUS RHYTHM Each ventricular (QRS) complex is preceded by a P wave with a normal P-wave axis (i.e. from the sinus node, P-wave axis = 0° to +90°) and normal PR interval (0.11-0.20s). In some circumstances sinus rhythm may control the atrial,

Atrial ectopics or atrial premature beats (Fig. 12.28A) are usually preceded by a P wave of different shape, different PR interval and, frequently, a different axis to the sinus P wave. The following QRS complex is normal. Atrial ectopics are common even in normal hearts, although, like all extrasystoles, they may be felt as uncomfortable fluttering, palpitation or 'skipped beats' in the chest. Stimulants, such as alcohol or caffeine-containing drinks and cigarettes, may be precipitants.

Junctional ectopics Junctional ectopics may arise from the AV node or proximal bundle of His, although this differentiation cannot normally be made, hence the less specific term 'Junctional' rather than the older 'nodal beat'. Atrial activation occurs retrogradely, so that the P wave is positive in aVR and negative in II, III and aVF. The delay between ectopic activation and ventricular activity depends on its site of origin and will vary the timing of the P wave. This can precede, be buried in, or follow the QRS complex, which has a configuration identical to that in sinus rhythm.

Ventricular ectopics Ventricular ectopic (VE) beats, by definition, are not preceded by a P wave and have a broad QRS configuration (Fig. 12.28B). There is no prognostic significance attached to whether the ectopic beat has a left or right bundle branch block pattern. However, when frequent or multiform VEs are found in association with underlying coronary heart disease or cardiomyopathy, there is an increased risk of sudden death. Control of VEs with drugs may improve symptoms, but may not improve the prognosis; the severity of the underlying heart disease is probably a more important influence on survival. In addition, the drugs used to suppress VEs may themselves precipitate serious ventricular arrhythmias.

Clinical features Ectopic beats, whether from atria or ventricles, are commonly found in normal individuals and generally not per-

501

FIG. 12.28 ECGs showing ectopic beats fAl An atrial ectopic beat, demonstrated by the varying shape of the P wave. B Coupled ventricular ectopics (bigeminy).

ceived by the patient. In some patients the frequency of ectopics is increased and they may produce the feelings of a 'missed beat' or even atypical chest pain (see p. 467). Ectopics are frequently more obvious to the patient at rest, presumably owing to the relative bradycardia allowing an ectopic focus to activate. Suppression with exercise that increases the heart rate is common and a good prognostic sign. Explanation of the cause of the symptom and avoidance of certain common precipitants of ectopics, such as alcohol, caffeine and cigarette smoke, may be all that is needed to treat the patient. Some patients improve when given (3blockers (e.g. metoprolol 25-100mg b.d., sotalol 20-80mg b.d. or bisoprolol 2.5-5.0mg o.d.)

BRADYCARDIA AND HEART BLOCK Bradycardia Defined as a heart rate less than 60bpm, bradycardia may be due to vagal tone in athletes or, more commonly, be an unwanted effect of -adrenoreceptor-blocking drugs. It generally requires no treatment, unless severe and producing symptoms. In an emergency (e.g. severe bradycardia complicating a myocardial infarction), it responds to atropine (600 g i.v. repeated to a maximum of 2.4 mg in 2 hours). If persistent, a temporary artificial pacemaker should be implanted. Chronic bradycardia may be a manifestation of the sick sinus syndrome (p. 516) and may benefit from permanent pacemaker implantation.

Sinus node block and sinus arrest Both sinus node block and sinus arrest are associated with a pause in the normal train of sinus rhythm, leading to a delay in the appearance of the P wave. In sinus node block the resultant pause between P waves is approximately double the preceding sinus (P-P) interval. The essential pacemaker rate remains constant but a normal discharge does not occur. In sinus arrest the pause is not a Fig. 12.14

502

FIG. 12.29 ECG showing first-degree heart block Note prolonged PR interval (0.28s).

multiple of the sinus interval, implying a transient change in pacemaker automaticity which has led to the loss of the P wave. Chronotropic incompetence is a poorly defined condition affecting some patients whereby they are unable to increase their heart rate in response to exercise. Their maximum heart rate may reach only 75-80% of the agepredicted maximum (220/age). Atrial rate-responsive pacemakers are indicated in this relatively uncommon condition. Many cardiac drugs may produce sinus node dysfunction, particularly those used as antiarrhythmics. (3Adrenoceptor blockers, the calcium antagonists verapamil and diltiazem, as well as amiodarone, propafenone and flecainide, are all potential causes. Occasionally cimetidine, lithium and phenytoin may interfere with sinus node function. Although idiopathic degeneration of the sinus node, particularly with ageing, may be the commonest cause apart from these drugs, hypertension, myocardial ischaemia and rarer conditions such as sarcoid may account for sinus node dysfunction.

First-degree heart block In first-degree heart block (Fig. 12.29) the PR interval is prolonged (>0.20s). This may occur in otherwise normal patients and is caused by delayed propagation within the AV node. A modestly prolonged PR interval may also accompany vagally induced bradycardia. However, long PR intervals in the presence of a normal or fast heart rate imply an intrinsic defect in the AV node. This is generally benign. The development of first-degree heart block in the context of infective endocarditis usually means aortic root abscess formation. Similarly, widespread conducting tissue disease is suggested by the combination of firstdegree block, left axis deviation and bundle branch block. Symptomatic patients may require a pacemaker. Firstdegree block may also occur following myocardial infarction (p. 562).

Second-degree heart block Second-degree heart block (Fig. 12.30) is defined as intermittent failure to conduct an impulse from the atria to the ventricles, and may be temporary or permanent. It occurs in two major forms. The Wenckebach phenomenon or Mobitz type I block The Mobitz type I block (Wenckebach phenomenon)

12

FIG. 12.30 ECGs showing second-degree heart block S3 Mobitz type I showing progressive lengthening of the PR interval until the P wave is not conducted to the ventricles (arrow). B Mobitz type II. Four sinus beats are followed by cessation of conduction following the P wave (arrowed).

produces successively increasing PR intervals until a P wave is not conducted; the cycle then repeats itself. There are usually 3-5 beats in a cycle. This block occurs within the AV node and is probably relatively benign. It may complicate acute inferior myocardial infarction and generally does not require specific treatment. It may also be seen in patients with generalized conducting tissue disease, and as part of the sick sinus syndrome (p. 516).

FIG. 12.31 Three rhythm strips demonstrating complete heart block A Atrioventricular dissociation with a relatively rapid ventricular rate and narrow QRS complex (with acute inferior infarction). B A slow idioventricular rate with broad QRS complexes, [c] The unusual combination of complete heart block and atrial fibrillation (no P waves).

Mobitz type II block In the Mobitz type II block an unheralded failure to conduct a P wave occurs. The site of the block is below the AV node in the proximal bundle of His. This condition has a tendency to progress unpredictably to complete block, which may cause Stokes-Adams attacks or even death. This conduction disturbance is much less common than type I block, and because of its implications usually requires treatment with an artificial pacemaker.

may be within the AV node, when the escape ventricular rhythm will be within the lower regions of the node or bundle of His, giving narrow, normal configuration QRS complexes and heart rates of about 40bpm. Complete heart block may also occur at the level of the bundle of His, so that ventricular or distal bundle pacemakers control the heart rate, producing a much slower pulse (about 30bpm) and wide bundle branch block QRS complexes. O

Other special forms of second-degree block During atrial tachycardia (e.g. atrial flutter) there may often be conduction of alternate beats to the ventricles in a ratio of 2 P waves to 1 QRS complex. When a tachycardia is present this block constitutes the normal physiological function of the AV node, and the block can often be increased further (to 3:1 or 4:1 or more) by manoeuvres that stimulate vagal activity, such as carotid sinus massage. In the absence of an atrial tachycardia, established 2:1 conduction represents a form of second-degree block. Highgrade block is present when the ratio of P waves to QRS is 3:1 or greater. In either case, artificial permanent pacemaker implantation is the treatment of choice when the arrhythmia persists.

Clinical features

Complete or third-degree heart block In complete or third-degree block (Fig. 12.31) the atrial impulses fail to be conducted to the ventricles. The block

Symptoms First-degree heart block is asymptomatic, as are many cases of second-degree block, but patients may be aware of the dropped beat and the stronger post-pause beat in Mobitz types I and II. In complete heart block the most dramatic symptoms are related to recurrent asystole or the ventricular arrhythmias that complicate severe bradycardia. However, complete heart block may present without symptoms, despite a marked bradycardia; with heart failure secondary to a low cardiac output; and in the elderly as a confusional state secondary to poor cerebral perfusion and multiple syncopal episodes. Stokes-Adams attack Stokes-Adams attacks can be caused by transient asystole or a transient burst of tachycardia. They are usually unheralded and the patient may first be aware of lying on the ground or falling. Recovery is usually rapid and complete.

503

Skin pallor may be followed by flushing. If the anoxia lasts more than a few seconds a convulsion may occur and, on occasion, incontinence. Incomplete attacks are common, presenting with transient giddiness (without true vertigo) or near fainting (presyncope). Attacks are sporadic and random. There may be months to years between symptoms in some patients with intermittent block, so that 24-hour ambulatory ECG recordings may have to be made repeatedly for the diagnosis to be made. Occasionally, treatment with a pacemaker is warranted on the basis of the history alone, although intracardiac electrophysiological studies may help in these patients. Signs There are few clinical signs in heart block. The first heart sound is quiet in first-degree block, and intermittent dropped beats will be felt at the pulse in second-degree block. In complete heart block a slow pulse and intermittent cannon waves will be seen in the JVP, caused by occasional simultaneous contraction of the atria and ventricles. The large stroke volume and collapsing pulse with a systolic murmur may mimic aortic valve disease.

Management In congenital complete heart block there is a surprising degree of tolerance to the slow heart rate, which may show modest rate responsiveness with exercise. Nevertheless, adults with this condition may risk sudden death, and permanent pacemaker implantation is warranted. In acute inferior myocardial infarction complete heart block is due to transient ischaemia of the SA and AV nodes, and may not need a temporary pacemaker unless symptoms of heart failure occur (p. 562). In extensive anterior myocardial infarction complete heart block is related to extensive muscle damage and carries a poor prognosis. Drug treatment of complete heart block with isoprenaline slow-release capsules is now hardly ever justified, and permanent pacemakers should be offered to virtually all patients. Like sinus node disease, idiopathic fibrotic degeneration of the AV node is the most frequent cause of heart block. It may be precipitated after ischaemic damage or secondary to calcific degenerative aortic or mitral valve disease. Aortic valve surgery and congenital heart defect repairs may cause heart block, acutely or after delays of months to years. O

THE PERMANENT ARTIFICIAL PACEMAKER The basic pacemaker consists of a small battery container which can be implanted under the skin and connected by O MCQ12.7

504

an insulated electrode to the heart. Small electrical impulses can be transmitted through the electrode to stimulate the heart to contract. Since 1960 there has been a great increase in their use, and 1 million people worldwide now live with an implanted pacemaker. The initial sole indication for pacing was the treatment of chronic complete heart block, but now a major indication is the treatment of the sick sinus syndrome (p. 516). More recently, units able to treat tachycardias and administer internal DC cardioversion have been developed. Pacemakers that respond to the patient's activity by changing the pacing rate are now in common use. Early pacemakers were fixed rate. Modern pacemakers, however, are almost exclusively demand (or standby) units, providing a pulse only when the heart rate falls below certain predetermined limits, and have battery lives of 8-15 years. They may offer considerable adjustment and analysis via transcutaneous telemetry. The complexity of cardiac pacemakers has increased for a number of reasons: • To increase battery life by reducing unnecessary pacing and by reducing output to the lowest safe limit; • To allow fine control of the pacing heart rate and, with dual-chamber devices, to restore the atrial contribution to filling, which may be very important to individuals with impaired ventricular function or valve disease; • To detect when the patient needs an increase in heart rate (e.g. with exercise); • To detect tachycardias and abort them by programmed bursts of pacing (antitachycardia). A letter coding system, used internationally, describes the type of pacemaker used. In some pacemakers a facility allows the interval between the last natural beat and the paced beat to be longer than the pacing interval. Thus, only when a pause corresponding to a very low heart rate is exceeded will the pacemaker step in and gradually accelerate to its programmed paced rate. This stops the pacemaker inserting beats for trivial slowing of the heart (e.g. during sleep).

Dual-chamber pacemakers Dual-chamber pacemakers have been developed to achieve a more physiological situation than is possible with ventricular pacing alone. These require the implantation of electrodes in the right atrium and right ventricle. They use more complex, and therefore more expensive, generators. In addition, the capacity to 'fine-tune' the multiplicity of programmable functions to each individual patient requires both time and the availability of skilled pacemaker technicians or doctors in pacing clinics. Nevertheless, these units are justified in certain groups: • Patients with AV block but normal SA activity, in whom a true physiological situation can be achieved, with normal rate increase with activity, and maintained AV sequential contraction. This is usually reserved for young or active elderly patients.

• Patients with poor ventricular function or valve disease, where the atrial contribution to filling is of prime importance. • Patients with the 'pacemaker syndrome': a small number of patients develop severe symptomatic hypotension with pacing of the right ventricle alone. • Patients with carotid sinus sensitivity. Dual-chamber pacemakers should be avoided in patients with unstable SA activity or atrial fibrillation.

Dual-ventricular pacemakers It has been recognized that improvements in cardiac output and hence patients' symptoms may be gained by pacing the left ventricle in some individuals with conduction disturbance (LBBB). Electrodes are placed in a branch of the great cardiac vein via the coronary sinus in conjunction with the usual leads in RA and RV. The pacemaker thus provides synchronized LV and RV contraction, with claimed benefits in patient exercise capacity.

Pacemaker implantation and complications Permanent pacemakers are almost always inserted by a cardiologist using local anaesthesia and full surgical sterile technique. Like temporary pacemakers (p. 562), the pacing electrode is passed down a central vein (usually the cephalic or subclavian) to the right heart. The electrode and generator box are then buried subcutaneously, above the pectoralis major on the high anterior chest wall. Complications of implantation are similar to those of temporary pacemakers. Infection is rare, but when it occurs it requires major revision of the entire system and accounts for considerable morbidity and a small mortality. Lead displacement and fracture are very rare with modem pacing systems. Specific pacemaker malfunction is now very rare. With current telemetry the pacemaker (and lead) function can be assessed transcutaneously, so that premature battery failure can be predicted, problems with lead impedance

TABLE 12.9 Pacemaker description Letter position Function Pacemaker types

1

2

3

4

Chamber paced A = atrium V = ventricle D = dual A+V

Chamber sensed A V D

Response to sensing

Rate responsiveness

T = triggered I = inhibited D

R = Rate responsive

An entry of '0' in one position denotes the absence of that function, e.g. VOO would be an 'old-fashioned' ventricular pacemaker with no sensing and hence no response to sensing - the old fixed-rate pacemaker.

(electrical resistance), current leak and failure to sense can often be diagnosed, and the unit reprogrammed to compensate for problems until replacement is required. Failure to sense the patient's electrical activity and intermittent failure to capture may sometimes cause problems. Dualchamber pacemakers, although potentially much closer to normal physiology, carry their own problems, the most serious being the capacity to generate pacemaker-induced arrhythmia. Fortunately, these problems are rare. Interference with pacemaker function by external sources of high magnetic and electromagnetic fields is less of a problem than might be expected; few problems arise in the normal environment of most patients. However, magnetic resonance imaging is contraindicated, and cautery during surgery has to be performed with care, avoiding placing the ground electrode near the generator and altering the unit to a fixed-rate mode.

12

THE TACHYCARDIAS Tachycardia is defined as a heart rate above 100 bpm, and is divided according to the origin of the pacemaker impulse. A classification is given in Table 12.10 and a guide to the use of antiarrhythmic agents in Table 12.11. A decision tree to aid in diagnosis is shown in Figure 12.32.

Mechanisms of production of tachycardias Three basic mechanisms have been established: abnormalities of automaticity; early after-depolarizations with triggered activity; and abnormal impulse conduction or re-entry. Abnormalities of automaticity Under normal circumstances only SA and AV node cells display automaticity. Abnormal automaticity may be displayed by diseased atrial and ventricular muscle. Stretch, alkalosis, temperature increases and hypoxia all increase the rate of repolarization and reduce the resting membrane potential (Vm), thereby accentuating the tendency to abnormal automaticity. Cardioactive drugs also influence heart rate and rhythm via these mechanisms. Therapeutic doses of some antiarrhythmics achieve their beneficial effects by decreasing the rate of depolarization (Table 12.11). Toxic doses may cause atrial and ventricular tachyarrhythmia by increasing the diastolic depolarization slope and lowering Vm. Early after-depolarizations ana triggered activity Following an action potential there may be a further spontaneous depolarization, which can occur early during repolarization or late. Single 'after-depolarizations' can precipitate further spontaneous beats, to produce a rapid cycle of spontaneous activity. Factors that encourage their occurrence include hypoxia, hypercapnia, high circulating

505

CASE STUDY 12.2 AN EPISODE OF COLLAPSE A 78-year-old woman presented to casualty having collapsed in the street whilst walking to a restaurant. The collapse was witnessed by her niece. They were walking at a good pace along a normal pavement on the flat. The patient was talking when she became silent and then slumped to the ground without warning. She struck her forehead on the pavement causing a small graze. She looked very pale at this moment but recovered within seconds. She was not incontinent and had no limb twitching. On recovery she was distressed but completely orientated. They attended casualty where she was found to be well orientated with no significant injuries. Physical examination was normal. She was normotensive and had a regular heart rate of 86 beats per minute with occasional pauses noted at the radial pulse. An ECG confirmed sinus rhythm, the PR interval was 334 msec and the QRS complexes were narrow and normal. During the 12-lead ECG, a 1.8 second pause in heart rhythm was detected. This appeared to be sinus arrest and the patient was not aware of this pause. During history taking she admitted that for the previous 2 weeks she had had waves of 'panic' attacks. These consisted of short-lived episodes when she felt very uncomfortable and was aware of a rapid fluttering in her chest associated with feeling faint. She was clear that the fall precipitating this admission was not preceded by any fluttering in her chest. She had seen her GP for these 'panic attacks' and

he had ordered a 24-hour halter monitor ECG. That revealed a background of sinus rhythm with a long PR interval and occasional pauses up to 2.3 seconds. Several episodes of narrow-complex, irregular tachycardia of up to 150 beats per minute were noted during the 24 hours. One of these which lasted 4 minutes was associated with the patient's symptoms in the chest.

Question What is the diagnosis and how should this patient be managed? Discussion This very fit 78-year-old woman has had a single syncopal fall which had the characteristics of a Stokes-Adams attack. This did not appear to be preceded by symptomatic arrhythmia on this occasion. Her 24-hour ECG revealed that she has episodes of tachycardia which punctuate normal sinus rhythm which itself was interrupted by occasional pauses of up to 2.3 seconds on this 24-hour recording. Her baseline ECG confirmed sinus rhythm but revealed a very long PR interval with no other conduction abnormality. This patient has the tachycardia-bradycardia or 'tachy-brady' syndrome, otherwise known as sick sinus syndrome. As is often the case, it is occurring in an otherwise healthy person with no other predisposing illnesses. Management must include the control of the tachycardia as well as

catecholamines, non-specific muscle injury and stretch. There is evidence that this activity occurs frequently and is important in producing tachycardia, particularly in the long QT syndrome (p. 517) and with drugs of the VaughanWilliams classes IA and III (Table 12.11).

Abnormal impulse conduction and re-entry

506

A wave of depolarization may sometimes circle endlessly

prevention of further syncopal episodes. It can be assumed that her collapse leading to the casualty admission represented a prolonged pause with sino-atrial arrest. Even without such a presentation, the current resting ECG indicates that it would be difficult to give her prophylactic treatment against paroxysmal atrial fibrillation (AF) because of the very long PR interval and occasional pauses. The risk would be that standard treatment of AF, such as a -blocker such as sotalol, or a class one agent such as flecainide, or a class three agent such as amiodarone, may all exacerbate the pauses and lead to the development of more profound arrhythmia. This patient received a permanent pacemaker. A dual chamber system was used to maintain atrioventricular synchrony. It is a demand pacemaker which will be inhibited during normal sinus rhythm but provide synchronized atrial and ventricular pacing if it detects a pause of greater that 1 second's duration. In order to prevent further bouts of paroxysmal AF she has been successfully treated with sotalol 40 mg b.d. Modern dual pacemakers have algorithms which may also help with the prevention of paroxysmal AF that has been generated by bradycardia pauses and atrial ectopics. These are known as DDRP pacemakers and their use is increasing although it is not yet determined whether their use will be an advantage over standard dual chamber pacemakers combined with drug therapy in this clinical setting.

around a loop of cardiac tissue. The mechanism of re-entry is shown in Figure 12.33. The loops of myocardial tissue may be found as a combination of alterations in anatomy (congenital or acquired), and abnormal function of parts of the heart. The best-known is that due to the presence of anomalous pathways connecting the atria with ventricular myocardium. This is the basis of the pre-excitation syndromes, so called because of the tendency of the aberrant pathways to excite

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TABLE 12.10 Features and classification of tachycardias Clinical

ECG

Type Supraventricular Sinus Atrial Paroxysmal atrial tachycardia Atrial fibrillation Atrial flutter

Rate (bpm)

>100

120-250

>140

150

Response to carotid sinus pressure

Symptoms and signs

P waves

QRS complex

Normal Abnormal shape

Normal Regular and normal aberrant conduction produces broad QRS of RBBB or, less commonly, LBBB type. Broad QRS also if BBB already present Irregular Very regular QRS complexes

Transient minor slowing May terminate tachycardia

Palpitation Palpitation, dizziness, breathlessness, chest pain may occur Diuresis on cessation

Transient slowing Conduction may decrease from usual 2:1 to 4:1 or less

As above As above

Absent Flutter waves; sawtooth pattern in lead V1

Junctional AVNRT* AVRT**

180-240 180-240

None seen (buried in QRS) Inverted P waves after QRS; QP interval < PR

Normal and regular Normal and regular

None, or abrupt cessation None, or abrupt cessation

As above As above

Ventricular Ventricular tachycardia

150-250

Dissociated P waves diagnostic, but can be difficult to see None seen

Regular broad QRS > 120ms sometimes >140ms. QRS look similar in V-leads 'concordance' Loss of regular discernible QRS features

No response

May cause collapse; sometimes well tolerated

Inappropriate

Collapse with rapid loss of consciousness

Ventricular fibrillation Ventricular flutter

150-300

* AVNRT = AV nodal tachycardia **AVRT = AV re-entrant tachycardia

areas of adjacent ventricle and produce the delta wave on the ECG (Fig. 12.34); the clinical syndrome that results is the Wolff-Parkinson-White (WPW) syndrome (p. 516). Slow conduction in the anomalous pathways is the basis for the arrhythmia in WPW, whereas in ischaemia segments of diseased ventricular muscle with slow conduction or unidirectional block are the cause.

SUPRAVENTRICULAR TACHYCARDIAS Supraventricular tachycardias (SVT) arise in the atria or AV node. They are characteristically associated with narrow QRS complexes, but there are important exceptions: • When there is pre-existing bundle branch block - a situation impossible to diagnose with certainty unless there are ECGs available in normal sinus rhythm - before or after the arrhythmia; • When there is rate-dependent bundle branch block; • In the pre-excitation syndromes (although the delta waves often do not show during tachycardia, as the anterograde conduction may be normal), orthodromic tachycardia.

Clinical features Common symptoms of SVT are an unpleasant awareness of rapid heartbeats or palpitations in the chest. Associated cardiac disease may dominate the picture, causing the arrhythmias to lower cardiac output, producing complaints of breathlessness, dizziness, fatigue or chest pain. The tachycardia may precipitate acute LV failure. Patients who suffer paroxysmal SVT, particularly those with structurally normal hearts, may notice polyuria during, or after, the attack.

Diagnosis Differentiating between the many forms of SVT may occasionally be difficult. The ECG is the basic diagnostic tool, although aspects of the history and, occasionally, physical examination can give clues. Very fast heart rates may produce ST and T-wave changes on the ECG which persist for some hours after cessation of the arrhythmia.

Sinus tachycardia Sinus tachycardia is a persistent sinus rate over 100 bpm. It is regarded as pathological when inappropriate and

507

TABLE 12.11 Guide to use of antiarrhythmic drugs VaughanWilliams classification

Electrophysiological action On action potential

Increased threshold for activation Slow rate of rise of action potential? (Inhibit fast sodium channel)

QRS and QT prolongation, especially quinidine

Disopyramide

Comment

Toxicity now limits use. Effective in VT, and may convert AF or A flutter to sinus rhythm

Gl disturbance Proarrhythmogenic Interacts with digoxin and numerous other drugs

Now rarely used in UK practice

Not used long term, owing to side-effects. Acute i.v. for ventricular and supraventricular arrhythmia Ventricular and supraventricular arrhythmia Prophylaxis in paroxysmal AF Ventricular arrhythmia during and after myocardial infarction Phenytoin useful for digoxin toxicity arrhythmia

Lupus syndrome Other autoimmune disorders Negative inotropy Anticholinergic side-effects

IB Lidocaine • (lignocaine) Mexiletine Phenytoin .

Inhibit fast sodium channel Shorten action potential

Usually none

1C Flecainide 1 Propafenone

Inhibit fast sodium channel Inhibit His-Purkinje network with QRS widening

QRS duration prolongation and QT lengthening

Mainly ventricular arrhythmia

Bradycardia

SVT Exercise-induced VT Rate control of AF, as adjunct to digoxin For i.v. use, ultra short acting

Transient i LV function

Pneumonitis, proarrhythmia, interference with thyroid function, photosensitivity Profound hypotension p-blocker side-effects

Class II: p-Adrenoreceptor blockers e.g. Propanolol Slow diastolic depolarization Atenolol

Esmolol Class III: Amiodarone

CNS side-effects

Apart from lidocaine (lignocaine) in the acute situation little use in UK

Major proarrhythmic potential with flecainide

Have largely taken over class 1 treatment

Hypotension, wheeze Negative inotropy Claudication worsens

Prolongs action potential

QT prolongation

Prolongs action potential Additional p-blocking effects Prolongs AP

QT prolongation QT prolongation

Extremely wide-spectrum against SVT, VT and VF For life-threatening arrhythmia i.v. for resistant VF SVT and VT

QT prolongation

Acute termination AF

Proarrhythmia

Class IV: Calcium antagonists e.g. Verapamil Inhibit slow calcium channel

None

SVT, except acute AF

Hypotension Profound AV nodal block

Unclassified Digoxin

Inhibits Na/K ATPase

None

Control of AF rate

Adenosine

AV nodal block

None

SVT. Differentiation of SVT andVT

Digoxin toxicity Proarrhythmic Transient block; angor animi

Bretylium tosylate Sotalol Ibutilide

chronic, e.g. with diseases such as thyrotoxicosis, or when secondary to heart failure. Under these circumstances treatment consists of control of the underlying disorder. A number of diseases of sinus node function produce a chronic sinus tachycardia, such as the dysautonomia of diabetes, cardiac infiltration with amyloid, and extrapyramidal disease of the Shy-Drager syndrome.

Atria I tachycardia 508

Toxic effects

On ECG

Class I: Membrane-stabilizing drugs IA Quinidine

Procainamide

Indications

In atrial tachycardia (Fig. 12.35) the ECG shows abnormal

Not in general use in UK

P waves at rates from 120 to 250 bpm. The mechanism of the arrhythmia is usually enhanced, or abnormal, automaticity in the SA node or other site in the atria. Causes include coronary heart disease, cardiomyopathy, rheumatic heart disease and the sick sinus syndrome. The normal AV node may not conduct at rates much greater than 200 bpm, so that very fast atrial rates may be associated with intermittent failure of contraction. This may lead to an atrial tachycardia with 2:1 conduction or higher degrees of block. Conduction through the AV node may be further impaired by disease or drugs such as digoxin. Indeed, one

12

509

FIG. 12.33 Mechanism of re-entry tachycardias Q] Normal conduction. B An area of abnormal conduction affects one limb of the circuit. This interrupts the antegrade conduction (large grey arrow) but is able to conduct retrogradely some moments later (black dashed line). This combination allows re-entry of the impulse (black arrow) and a tachycardia ensues.

FIG. 12.35 ECG showing atrial tachycardia with 2:1 conduction Dots indicate position of P waves. (Atrial rate is 300/min.)

FIG. 12.34 ECG characteristics of the Wolff-Parkinson-White syndrome Note the short PR interval and pre-excitation of the ventricle, producing the slurred upstroke of the R wave (delta wave, arrowed in V4). O

of the manifestations of digoxin toxicity is atrial tachycardia (at a relatively slow rate) with block.

Management Withdrawal of digoxin is important if toxicity is suspected. Otherwise, measures to control ventricular rate include intravenous verapamil (slow bolus of 5mg repeated to a maximum of 10-20mg in 20min) when there has been no prior -blocker therapy, and intravenous digoxin when glycoside toxicity is not the cause. Patients who have received -blocker therapy should be given verapamil with great caution, for fear of precipitating severe bradycardia or high-grade AV block. Intravenous -blockade (e.g. atenolol 2.5 mg i.v. over 2-5 min, repeated 2-3 times over 30min; esmolol 500 g/kg for 1min then 50 g/kg/min for up to 10 min) may also terminate the tachycardia, as will DC cardioversion or atrial overdrive pacing.

Atrial fibrillation Atrial fibrillation (AF) is probably the most common arrhythmia, and in many patients may be permanent. It is characterized by a chaotic, rapid and low-amplitude wave-

Q Fig. 12.15

510

Fig. 12.16

FIG. 12.36 Rhythm strips showing atrial fibrillation and flutter H Atrial fibrillation. Note the irregular ventricular rate. B Atrial flutter with typical sawtooth P waves and a regular ventricular response (4:1). C Atrial flutter with a variable ventricular response. ©

form on the ECG (Fig. 12.36). The ventricular response is characteristically completely irregular in rhythm, and usually shows a narrow QRS complex unless there is preexisting disease or rate-dependent bundle branch block. Despite an atrial activity of 350-600 impulses/min, the AV node conducts only intermittently and randomly. The nodal rate is usually less than 200 impulses/min, or even less in the presence of AV nodal disease or drugs suppressing nodal activity (e.g. digoxin). An exception to the rule of irregular ventricular activity in AF is when it coexists with complete heart block, when a subnodal pacemaker provides a slow, regular ventricular complex (Fig. 12.31). The rhythm is believed to be caused by localized re-entry circuits within the atria, and is a frequent consequence of chronic atrial distension from any cause. The causes of AF are shown in Table 12.12. The most common underlying condition is probably hypertension. Some patients develop

TABLE 12.12 Causes of atrial fibrillation With structural heart disease • Rheumatic mitral valve disease • Hypertension • Cardiomyopathy Dilated Hypertrophic • Atrial septal defect • Coronary heart disease

Without structural heart disease Alcohol Thyrotoxicosis Acute pericarditis Constrictive pericarditis Pulmonary embolism Sick sinus syndrome Myocarditis Coronary heart disease

there is associated rheumatic mitral valve disease, especially mitral stenosis. Stroke due to embolism is nearly five times more common in patients with AF than in those in sinus rhythm, and this relative risk rises to 17-fold if there is associated mitral valve disease.

12

Clinical features Clinically, the symptoms are determined by the rate of the arrhythmia and the underlying cardiac state, but they do not differ significantly from those of any SVT. The pulse is of variable rhythm and volume. Very early beats, especially with fast AF, may not produce sufficient stroke volume to produce a pulse at the wrist, producing an apex to radial pulse deficit in 'uncontrolled' AF. The venous pulse shows only a single waveform, corresponding to ventricular systole (the v wave).

RECENT ADVANCES ATRIAL DEFIBRILLATOR

Patients with intractable and poorly tolerated paroxysmal atrial fibrillation, especially those with left ventricular dysfunction, are being considered for nonpharmacological interventional therapy. These may include AV nodal ablation followed by dual-chamber pacemaker insertion, or operative procedures (e.g. 'maze or corridor' operation) to restore sinus rhythm while preserving atrial transport. An alternative currently being explored is the insertion of an implantable atrial defibrillator, similar to the implantable ventricular cardioverter/defibrillator. This device detects atrial fibrillation with satisfactory sensitivity and specificity. With improvements in electrode design, and by keeping the shock duration short and energy low (<1.5 J), intraatrial shocks are reasonably well tolerated by patients. The risk of proarrhythmia (inducing ventricular tachyarrhythmias) in humans has yet to be evaluated and kept below 1% per year (as in acceptable antiarrhythmic drug therapy). The final hurdle is cost, as these devices are significantly more expensive than permanent pacemakers.

the rhythm for no discernible reason and are said to be suffering lone atrial fibrillation; they appear to have a normal prognosis. For other patients the immediate consequence of the arrhythmia and its long-term prognosis are determined by the underlying condition. AF may be paroxysmal or permanent. Even when structural heart disease is absent paroxysms of AF can sometimes be symptomatically disabling, and although drug therapy to control the ventricular rate during an attack is reasonably effective, there may be considerable difficulty in providing adequate prophylactic therapy. The loss of a mechanical atrial systole can be very important in patients with severe heart disease, and in some is sufficient to precipitate heart failure. The loss of atrial contraction predisposes to stasis of blood in the atria and atrial appendages. Thrombi form, which pose the threat of systemic embolization. This tendency is accentuated where

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The aim of treatment is control of the ventricular rate, both at rest and during exercise. In individuals with paroxysmal AF, prevention of recurrences is attempted. Consideration should be given to converting all patients to sinus rhythm, unless there are grounds to believe that successful cardioversion is highly unlikely or reversion to AF almost inevitable. Patients falling into the latter category might be those with long-standing mitral valve disease and hugely dilated atria, or those discovered to have been in the rhythm for many years. The risk from cardioversion lies in the possibility of systemic embolization from the previously fibrillating left atrium. The risk of having intra-atrial clot due to AF rises rapidly with the time that the patient is exposed to the rhythm, so that cardioversion in anything other than emergency situations should be deferred in those who have been in AF for more than 48 hours without adequate anticoagulation. Acute AF Severely haemo dynamically compromised patient. Central line cannulation is needed for the infusion of amiodarone: 5mg/kg diluted in 250 mL of 5% dextrose and infused over 20-30 minutes. Significant electrolyte disturbances are excluded or treated and oxygenation maximized by treating pulmonary oedema, if present (p. 492). Arrangements are made to undertake DC cardioversion under a general anaesthetic. The initial slow bolus of amiodarone should be followed by an infusion of 1200 mg over the succeeding 24 hours, even if DC cardioversion is successful. Anticoagulation is not an issue in these patients. An alternative and older protocol is to use intravenous digitalization prior to DC cardioversion, since degeneration to ventricular fibrillation is unlikely in the absence of digoxin toxicity. Digoxin is given as 500 g in l00 mL 5% dextrose infused over 30 minutes. This may be repeated with a second dose of 500 g infused over 1 hour, or ouabain for much faster digitalization: Img in 100 mL 5% dextrose over 1 hour. In a compromised patient, negative inotropic agents such as verapamil, flecainide and -blockers should be avoided.

511

Haemodynamically stable patient with AF > 130bpm. The aim is to control ventricular rate to achieve a resting AF rate of 90bpm or less, and produce a 'chemical cardioversion' within 48 hours. If this conversion is not achieved the patient is discharged on maintenance drugs designed to control the ventricular rate, and anticoagulants prior to elective DC cardioversion. Oral digoxin is used to initiate ventricular rate control: digoxin 15 g/kg divided into three doses over first 24 hours. The maintenance dose of digoxin is established with reference to the level of this drug in the blood (see p. 518). In patients with good left ventricular function improved control of the heart rate may be achieved by using oral verapamil 40-80 mg 8-hourly. Caution should be exercised with combinations of digoxin and verapamil, because verapamil increases the plasma levels of digoxin. In the absence of structural heart disease or ischaemia, flecainide by i.v. bolus (slow injection of 2mg/kg up to 150 mg) is gaining popularity. Anticoagulation. All patients should be anticoagulated with heparin unless there are specific contraindications, such as very recent surgery. Heparin is given as a bolus of 5000U followed by 24000-48000U/24h adjusted according to the clotting times, aiming for a 2.5-3.0-fold increase over control clotting times. If cardioversion is not achieved the patient should be converted to oral anticoagulation with warfarin (aiming for an INR = 3.0) with a view to elective cardioversion after 3-6 weeks' adequate anticoagulation. Chemical cardioversion. This means using drugs to achieve what is usually undertaken with DC shock. It may be achieved with oral amiodarone or intravenous flecainide. The regimens are: a. Amiodarone 200 mg oral t.d.s. for 1 week, 200 mg b.d. for the second week, maintenance 100-200 mg daily. (NB: It is necessary to reduce the digoxin and warfarin doses if they are used concurrently.) Amiodarone is effective but may take several days to restore sinus rhythm. It may be combined with digitalization, but there is an interaction between these drugs, so digoxin doses should be reduced and plasma levels checked. b. Flecainide: 2mg/kg i.v. slow bolus over 10 minutes minimum. Maintenance with oral flecainide 50 mg 12hourly, increasing to a maximum 300mg/day. A recent report suggests that oral loading with 300 mg flecainide, followed by standard maintenance regimens, is as effective as i.v. treatment. In patients with good ventricular function (3-blockade with esmolol, the ultra-short-acting agent, has been successfully used (see p. 518 for treatment regimen). Maintaining sinus rhythm. If cardioversion is immediately successful, the patient with very recent-onset AF in

Fig.

512

12.16

an otherwise normal heart does not require anticoagulation. Digoxin is not continued, and if there has been an obvious precipitating event to the AF, such as excess alcohol, the appropriate advice is given and no preventative drugs are prescribed. If the AF, albeit of recent onset, was poorly tolerated, owing, for instance, to the coexistence of ventricular hypertrophy and poor LV compliance, treatment designed to prevent further attacks is advisable (see below under Paroxysmal AF). Patients who required anticoagulation or were electively cardioverted after some weeks in AF should continue to receive anticoagulants for up to 3 months, as well as prophylactic antiarrhythmic treatment continued for that time. If they remain in sinus rhythm and do not have severe cardiac abnormalities as the substrate for the rhythm, all antiarrhythmics may be discontinued at the 3-month review. Patients with severe cardiac abnormalities, or those in whom AF was poorly tolerated, should probably continue treatment in the long term. Chronic sustained AF Treatment aims to reduce the resting ventricular rate to about 90 bpm, with a modest increase on exertion. Digoxin alone, although effectively controlling the resting heart rate, is insufficient to control the response to exercise in a large proportion of patients. A combination of digoxin with verapamil (or digoxin with a -blocker) is superior to digoxin alone in these circumstances. Anticoagulation with warfarin reduces the risk of emboli and is essential when rheumatic valve disease is present, or if the heart (particularly the left atrium) is enlarged. It is indicated in patients with a previous history of systemic emboli, and where the cause of AF is thyrotoxicosis. Paroxysmal AF can be disabling. Commonly used prophylactic treatments are shown in Table 12.13. Digoxin is less effective at preventing attacks. The symptoms may be

SUMMARY 5 Digoxin points

Rapid loading

I.V.

Oral

500 g diluted over 30 min Second 500 g over 60 min

15|ig/kg in 3 divided doses in 24 h

Slow loading

125-250 g oral b.d. for 1 week

Maintenance

62.5-375 g o.d. (therapeutic range 1.0-2.6 mmol/L)

Reduce all dosages in: • elderly patients • renal impairment (by 30-70%, according to GFR) • combination with verapamil • combination with quinidine • combination with amiodarone

12

TABLE 12.13 Drug treatment of paroxysmal atria I fibrillation Amiodarone • Loading dose - 200 mg t.d.s. (to a total of 1.2-1.6 g) Maintenance dose -100-400 mg/day Flecainide • Upto150mgb.d. Propafenone • Up to 900 mg/day in divided doses Disopyramide • 250-800 mg/day in divided doses • Must be used with digoxin • Valuable in bradycardia-dependent AF

helped by verapamil, which lowers the peak heart rate during a paroxysm of AF. Ablation of the AV node and pacemaker implantation are used in intractable cases; this does, however, render the patient pacemaker dependent. Atrial flutter Atrial flutter is an arrhythmia caused by multiple re-entry circuits producing atrial contraction at 300 ± 50 bpm. Conduction block at the AV node (most commonly 2:1) is almost always present, producing a regular pulse of 150 bpm. This pulse rate should always lead to the clinical suspicion of atrial flutter. Vagal slowing of AV conduction produced by carotid sinus massage will temporarily increase the degree of AV block, and the sudden halving or more of the ventricular rate can easily be detected at the bedside. On the ECG monitor, P waves previously concealed within T waves become visible as a sawtooth pattern, thus establishing the diagnosis (Fig. 12.36C). O Physical examination may show flutter waves in the neck. The causes of atrial flutter are the same as those of AF (Table 12.12), but flutter is rarely permanent. Drugs are less effective in flutter compared with fibrillation, and DC cardioversion is the therapy of choice. Energies of 25-50 J are frequently sufficient to achieve successful cardioversion to sinus rhythm. Intravenous verapamil will successfully convert many patients to sinus rhythm, as will pacing the atria at or below the tachycardia rate (underdrive pacing), or rapidly for a few minutes (overdrive pacing). Chaotic atrial tachycardia and wandering atrial pacemaker Chaotic atrial tachycardia is characterized by multiple wave shapes and PR intervals. It is quite common in elderly patients, whereas in younger patients it is usually associated with severe respiratory disorders. It requires no specific intervention, except for control of any associated illness and withdrawal of digoxin if this has previously been prescribed. Conversely, a sustained rhythm may be slowed by digoxin or verapamil.

FIG. 12.37 AV nodal re-entry tachycardia Note rapid narrow QRS complex tachycardia (rate 185 bpm).

The wandering atrial pacemaker is a slower arrhythmia often associated with variations in vagal tone, allowing various subsidiary atrial pacemakers to become established. It requires no special treatment.

JUNGTIONAL TACHYCARDIAS AV nodal and AV re-entry tachycardia or paroxysmal supraventricular tachycardia The mechanism involved in these tachycardias is re-entry through a functionally distinct area of the AV node or tissues surrounding it. They are common, particularly in (young) patients with structurally normal hearts. There is a 1:1 relationship between atrial and ventricular activity. P waves generally cannot be identified; if they can be seen, they will be buried within the QRS or immediately follow it (Fig. 12.37). The onset is abrupt, usually precipitated by an atrial extrasystole, and an equally abrupt cessation is the rule, although the latter may not be appreciated by the patient as a sinus tachycardia may follow the arrhythmia. The usual rates are about 180-240 bpm, with narrow QRS complexes, except if there is pre-existing or rate-dependent bundle branch block. If manoeuvres or drugs induce a lower degree of conduction than 1:1, AVNRT is excluded and a paroxysmal atrial tachycardia or flutter is the more likely diagnosis. Management Treatment may not be necessary if the attacks are transient and infrequent. Several vagotonic manoeuvres may be helpful (Table 12.14), all of which can be taught to the patient who suffers paroxysmal attacks. Failing these simple approaches, drug therapy is usually successful. Intravenous adenosine is the drug of choice, although intravenous injections of verapamil, -blocker, disopyramide and amiodarone adenosine may also prove useful. Atrial and

513

TABLE 12,14 Simple procedures to terminate paroxysmal SVT

!

• Carotid sinus massage. If effective, the rhythm is abruptly stopped; occasionally only moderate slowing occurs • Cold water splash on face (to mimic the diving reflex). This may be effective, but is often difficult to administer • Performance of Valsalva's manoeuvre (often effective) • Swallowing cold drinks • Inducing vomiting (a few patients discover this themselves)

ventricular pacing may also be used, the former following a similar procedure to that used to convert atrial flutter. A more elegant approach is to interrupt the re-entry circuit with critically timed ventricular or atrial ectopic impulses using chronically implanted antitachycardia pacemakers. Long-term prevention can often be achieved with (3blockers, amiodarone, flecainide and propafenone. Transcatheter ablation of accessory pathways or the AV node can be undertaken. These latter techniques need a prior definitive intracardiac electrophysiological study (p. 501), but with the advent of radiofrequency catheter ablation are the treatment of choice in significantly symptomatic patients.

TABLE 12.15 Differentiation of VT from SVT with aberration or bundle branch block (BBB) Feature

Value in differentiation

Broad QRS complex (>120ms)

Very broad (>160ms) - almost always VT Broader than 140ms favours VT, but may be due to pre-existing BBB

Bizarre QRS morphology, similar in V1-V6 and not resembling any BBB pattern - concordance

Characteristic of VT when present

Independent P-wave activity

Diagnostic of VT, when found

Fusion beat with QRS between sinus and tachycardia morphology

Diagnostic of VT, when found

Variability of rate from 10 to 20ms; except for fusion/capture beats

Not good

Hypotension, shock and collapse

No value

When V-A conduction occurs with 2:1 block

When ventricular rate is shown to be greater than atrial, the rhythm is VT

Non-paroxysmal AV nodal or functional tachycardia Non-paroxysmal AV nodal tachycardia is a narrowcomplex tachycardia associated with inverted P waves in II, III and aVF. Characteristically, it is caused by ischaemia and digoxin toxicity, although junctional rhythms may be precipitated by most forms of heart disease; the mechanism is enhanced automaticity. Because the atria and ventricles are stimulated virtually simultaneously, the P waves may precede the QRS complexes with a short PR interval. Alternatively, they may be buried within the QRS complex or follow after it. The onset of the tachycardia is gradual and the established rates, between 60 and 130bpm, considerably slower than the paroxysmal forms of tachycardia. Therapy is along the same lines as for AV nodal and reentry tachycardias, although lignocaine may also be useful. Withdrawal of digoxin may be all that is required when toxicity is implicated.

BROAD-COMPLEX TACHYCARDIAS The hallmark of ventricular rhythm is the broad QRS complex. Ventricular fibrillation and flutter do not cause diagnostic difficulties, but ventricular tachycardia (VT) is often wrongly diagnosed as SVT with rate-related aberra-

FIG. 12.38 Ventricular tachycardia (monomorphic) A rapid, broad QRS complex tachycardia illustrating the similarity of appearance in complexes from V1 to V6 (concordance). O

tion, or with pre-existing bundle branch block. There is often a reluctance to diagnose VT, particularly on the part of less experienced physicians, probably because the implications for the patient are so much worse than for SVT. Guidelines for their differentiation are given in Table 12.15. In the context of acute infarction, or when there is severe underlying myocardial disease, the observation of a broad-complex tachycardia should always be assumed to be ventricular in origin until proved otherwise.

Ventricular tachycardia Q Fig. 12.17

514

VT (Fig. 12.38) is defined as the appearance of three or more ventricular ectopic beats in a sequence. When sustained, the rate is between 150 and 250 bpm and regular.

Unsustained VT can be seen in people with normal hearts, but organic heart disease is suspected if the rhythm is sustained or produces symptoms. Causes are coronary heart disease, cardiomyopathy or myocarditis. VT carries the risk of sudden death, usually due to degeneration of the rhythm to ventricular fibrillation (VF). Even with the guidelines to diagnosis given in Table 12.15, VT can in some circumstances be difficult to diagnose, and prolonged examination of the ECG or the use of an oesophageal ECG lead may be necessary. In about half of patients the sinus node continues to fire independently, so that atrial P waves dissociated from ventricular activity can sometimes be observed, if not buried within the QRS complex. O In a few patients, retrograde activation of the atria occurs; this may be recognized by finding inverted P waves. In paroxysmal VT (150-250bpm) the onset is abrupt, usually following a critically timed ectopic beat. A slower form of VT, accelerated idioventricular rhythm (rate 60130bpm), occurs as an enhanced automatic rhythm during periods of suppressed sinoatrial activity. It is usually seen in acute infarction and its prognosis - unlike that of paroxysmal VT - is generally good. Management Acute In the presence of acute haemodynamic disturbance or acute myocardial infarction, immediate DC cardioversion with a synchronized shock is the treatment of choice; this is followed by an intravenous lidocaine (lignocaine) bolus dose of 100 mg (or 1 mg/kg), followed by an infusion, starting at 4 mg/min for 30 min, reducing to 2 mg/min for 2 hours and continued at 1 mg/min thereafter, for approximately 24 hours. This approach is generally successful, particularly in acute infarction, when there is rarely any indication to continue to chronic oral antiarrhythmic therapy. In resistant or recurrent cases an alternative therapy is amiodarone. Mexiletine, flecainide or bretylium may be required in certain instances, although the acute use of many different antiarrhythmic drugs should be avoided. The serum potassium must be maintained at or above 4.5mmol, and acidosis and hypoxaemia reversed. Chronic Episodic or paroxysmal VT complicating organic heart disease (e.g. hypertrophic cardiomyopathy, chronic coronary heart disease and cardiomyopathy) requires prophylactic therapy. In choosing the drug, information on its

SUMMARY 6 Treatment of tachycardia where doubt persists as to SVT or VT

EQ

• DC cardioversion if haemodynamics are compromised. • Do not use verapamil. • Try i.v. adenosine (0.05-0.25 mg/kg) - it will terminate an SVT but will not affect VT or haemodynamics. • Try i.v. lidocaine (lignocaine) (1 mg/kg bolus) - it may terminate VT.

efficacy in the individual patient should be taken into account. The response to exercise testing and monitoring the effectiveness of therapy with Holter 24-hour ECG recordings is helpful. In those patients in whom VT is inducible by exercise, -blocking drugs may be useful; sotalol, with its class III effects (Table 12.11), may be the rational first choice. Patients with poor ventricular function are probably most at risk from VT. The choice of drug for these patients is very limited, owing to the negative inotropy of most antiarrhythmic agents. Amiodarone or mexiletine are the most useful in these patients. A new form of therapy for those patients in whom drug therapy fails is the use of small implantable automatic defibrillators (AICD) which detect the arrhythmia (VT or VF) and, after an appropriate pause, deliver a DC shock. Surgery and catheter ablation Certain patients have an anatomical basis for their ventricular arrhythmia - either a ventricular aneurysm or a localized area of ischaemically injured myocardium. Treatment options now include excision of the aneurysm or electrically abnormal tissue by surgery, or ablation using catheters capable of delivering radiofrequency ultrasound.

Torsade de pointes ventricular tachycardia Torsade de pointes VT is an uncommon but important arrhythmia, characterized by a VT, often of modest rate but associated with an undulating QRS height owing to a slow but continual variation in the QRS axis (Fig. 12.39). Its importance is owing to its precipitation by antiarrhythmic drugs, particularly if electrolyte disturbances coexist.

Management Acquired forms are treated by withdrawal of the offending agent and correction of electrolyte abnormalities. In

FIG. 12.39 Rhythm strip illustrating torsade de pointes, a broad-complex ventricular tachycardia Note the fluctuation in size of the complexes.

515

OTHER ARRHYTHMIC SYNDROMES Sick sinus syndrome

FIG. 12.40 Rhythm strip showing ventricular fibrillation

less stable situations an infusion of isoprenaline, or increasing the heart rate with a temporary pacemaker, is the appropriate remedy. Congenital syndromes can be caused by abnormalities in sympathetic supply to the heart. These are best treated with (3-blocking agents.

Ventricular fibrillation and ventricular flutter VF is characterized by rapid, irregular and uncoordinated electrical activity in the ventricles, probably due to re-entry circuits within localized areas of myocardium. The ECG shows more or less coarse, irregular waveforms, without discernible P, QRS or T waves (Fig. 12.40). In ventricular flutter the entire tracing appears as a rough sawtooth with a rate of 160-250 bpm, without normal QRS morphology. If either rhythm occurs effective contraction and cardiac output cease, leading to unconsciousness within seconds. These rhythms do not usually revert spontaneously and are often precipitated by an ectopic beat or runs of VT, particularly when they complicate acute myocardial infarction. VF is probably the arrhythmia responsible for most cases of sudden death in the community (p. 561). In the context of acute myocardial infarction, when VF occurs early, within 24-48 hours of onset of the illness (primary VF), and is successfully treated, the prognosis for the patient is not adversely affected. However, VF occurring late in the course of acute infarction (secondary VF) often follows extensive muscle damage and carries a grave prognosis. Management Witnessed collapse due to VF (usually seen only in coronary care units) requires immediate action; a precordial chest thump (p. 519) may convert up to 15% of cases without the need for electrical defibrillation. In all other circumstances basic cardiopulmonary resuscitation should begin until the treatment of choice is available, namely defibrillation by the application of an external DC shock (p. 519). Correction of acidosis, hypoxaemia and electrolyte imbalance improves the likelihood of conversion to a stable rhythm. Drug treatment and long-term prophylactic therapy are the same as for VT. Primary VF does not generally require subsequent prophylactic therapy. O O MCQ12.8

516

O

MCQ12.9

The sick sinus syndrome (SSS) is a relatively common condition, characterized by episodic arrhythmias combining episodes of profound bradycardia and heart block with episodes of tachycardia (it is sometimes called the tachycardia-bradycardia syndrome). The bradycardias may be paroxysmal or sustained sinus bradycardia, episodes of sinus arrest, or SA block producing long pauses in pulse rate and pauses after atrial ectopics. Immediately following a tachycardia there may be a prolonged pause or very slow sinus rhythm sufficient to cause dizziness or a Stokes-Adams attack. The tachycardias are mostly supraventricular, with AF, flutter, chaotic atrial rhythm and atrial tachycardia being the most common, although VT (especially torsades de pointes) is occasionally seen, as is chronic AF with a slow ventricular rate. The pathology is probably degeneration and fibrosis in the sinus node and conducting tissues. The AV node is often involved in the degenerative process. Ischaemic heart disease and amyloid infiltration of the heart may be the cause in some patients, and SSS has also been associated with many other pathologies, from cardiomyopathy to Friedreich's ataxia. Drugs such as digoxin, (3adrenoreceptor blockers or quinidine may mimic SSS. Apart from discomfort and Stokes-Adams episodes, the condition carries a risk of systemic embolization and is the cause of episodic heart failure. Sick sinus syndrome is often unmasked when drugs are given to treat tachycardia, and profound bradycardia or heart block is produced, necessitating the implantation of a pacemaker. Management and prognosis Treatment is with a combination of antiarrhythmic drugs and pacemaker implantation. The prognosis is generally good, but mainly dependent on any underlying condition.

Wolff-Parkinson-White syndrome The ECG abnormality of short PR interval (<0.12s) with abnormal QRS widening due to delta wave (Fig. 12.34) is relatively common. The clinical syndrome, WolffParkinson-White (WPW) syndrome, with paroxysmal tachycardias is much less common, although the precise incidence of arrhythmia in individuals with the ECG abnormality is not clearly established. The syndrome generally occurs in an otherwise normal heart, although it may complicate Ebstein's anomaly (p. 538) or mitral valve prolapse (p. 525). The abnormality is due to an accessory pathway between the atrium and ventricle allowing a reentry or reciprocating tachycardia to develop (p. 506). The tachycardia produces narrow QRS complexes without the delta wave, because conduction is anterograde through the AV node. Thus, the diagnosis of WPW may not be made until an ECG in sinus rhythm is obtained. There is an

increased incidence of AF. In a small proportion of patients who have a short refractory period in the accessory pathway AF may conduct very rapidly (1:1) to the ventricles; this may degenerate to VF and is the usual cause of sudden death in these patients. Investigation and management Electrophysiological studies establish the site, number and refractory period of the accessory pathway(s). Treatment may include antiarrhythmic drugs, but often requires ablation of localized accessory bundles during electrophysiological (EP) testing. Digoxin and verapamil should be avoided, as they can increase accessory pathway conduction. Lown-Ganong-Levine syndrome

Patients with Lown-Ganong-Levine syndrome (LGL) have short bypass tracts that connect the atria to various portions of the proximal bundle of His or distal AV node. The ECG manifestation is of a short PR interval (<0.12s) without pre-excitation (no delta waves). Such patients are subject to paroxysmal tachycardias, but are less commonly threatened by rapidly conducted AF. Treatment is the same as for WPW syndrome.

Long QT syndrome Several congenital disorders are described which are characterized by a long (>0.45 s) QT interval. They are caused by increased action potential duration and predispose to ventricular tachycardia, and are associated with sudden death, exceeding 60% at 15 years in untreated symptomatic patients. The Romano-Ward syndrome is autosomal dominant and more common than the autosomal recessive disorder Jowell-Lang-Nielsen syndrome. The nuclear basis for these disorders has been characterized and mutations on the genes coding four cardiac action potential ion channels have been identified: LQT1, LQT2,LQT3 and SCN5A. The clinical course of long QT syndromes is influenced by the associated mutations, so that one group (LQT1 patients) is susceptible to physical and emotional stresses as triggers for VT, and LQT3 patients are more at risk during sleep. Treatment has reduced mortality to 3-4% within 10 years of the first symptom. The mainstay of treatment consists of -blockers, cardiac sympathetic denervation, and the use of pacemakers whenever there is bradycardia or pause-induced syncope. Gene-specific therapies remain an exciting prospect for the future.

SYNOPSIS OF DRUG TREATMENT OF ARRHYTHMIAS A decision tree for the diagnosis of tachycardias is shown in Figure 12.32. Summaries of the treatment of, and drug doses used in, arrhythmias are given in Tables 12.11,12.16 and 12.17. O

12

TABLE 12.16 Emergency drug treatment of common arrhythmias Arrhythmia

First-line therapy

Second-line therapy

Atrial fibrillation

i.v. flecainide bolus plus infusion. DC cardioversion if BP low DC cardioversion (50-1 00 J)

3-Blockers Verapamil DC cardioversion Verapamil Vagotonic manoeuvres Atrial pacing DC cardioversion Digoxin (if not digoxin toxicity) 3-Blocker Disopyramide Flecainide Amiodarone DC cardioversion DC cardioversion

Atrial flutter Atrial tachycardia and junctional tachycardia SVT and AVNRT or AVRT type

Vagotonic manoeuvres Adenosine Verapamil Vagotonic manoeuvres Adenosine Verapamil

SVT in WPW with

Adenosine

narrow QRS SVT in WPW with broad (delta wave) QRS VT and VF

Bradycardia Complete heart block

Amiodarone Flecainide Adenosine DC cardioversion Lidocaine (lignocaine)

DC cardioversion Bretylium Amiodarone Flecainide Mexiletine

Atropine Isoprenaline Pacemaker Isoprenaline

RESUSCITATION

Within 20 seconds of cardiac inactivity the victim falls unconscious, breathing soon ceases and the pupils dilate. Sudden death affects about 50000 people a year in the UK. Half of these are not previously known to have coronary artery disease. About 60% of deaths due to myocardial infarction occur within an hour of the first symptom (see Fig. 12.62), the majority occurring outside hospitals. The commonest rhythm disturbance (over 60% of cases) is VF. Cardiopulmonary resuscitation (CPR) may involve: • Basic life support, requiring training but no special equipment; • Advanced life support, which requires equipment and specialized skills. Many cities in the UK and other industrialized countries are involved in training the public in basic life support skills, and provide specialized ambulances with very rapid response times and facilities for advanced life support and DC cardioversion. Examples are Belfast and Brighton in the UK, and Seattle in the USA. With such basic life support available about 20% of victims may reach hospi-

517

TABLE 12.17 Doses and methods of administration of drugs commonly used in acute arrhythmia Drug

First dose

Method

Maintenance

Side-effects

Amiodarone

2-5mg/kg

i.v. slow bolus

Usually required 600-1 200 mg/day i.v. infusion

iBP Need central venous access

Atropine

0.6-1. 2 mg

i.v. bolus

Not used

Anticholinergic side-effects

p-Blockers Atenolol Metoprolol

5-10 mg 5-1 5 mg

i.v. bolus i.v. bolus

50-1 00 mg oral/day 1 00-400 mg oral/day

4 Heart rate;

Very short acting

Esmolol

500ng/kg

i.v. bolus 1 min

50u.g/kg/minfor4min

Bretylium

5-10mg/kg

i.v. rapid in emergency

Optional 1-2mg/min (i.v. infusion)

Digoxin

0.5 mg

i.v. slow bolus

Optional 0.75-1 .Omg for first 24 h, then 0.25 mg/day (oral)

Flecainide

1-2mg/kg

i.v. bolus over 10-30 min

Optional 0.15-0.25mg/kg/h (i.v. infusion)

Isoprenaline

50 g

i.v. rapid in emergency

Optional 0.02-0.1 8 g/kg/min

Lidocaine (lignocaine)

100mg

i.v. bolus

Essential 4mg/min reducing to 2mg/min for 24 h (i.v. infusion)

Verapamil

5mg, repeat with 10mg after 10 min

i.v. slow bolus

Optional 0.005 mg/kg/min for 1h (i.v.) or 80-1 20 mg/8-hourly (oral)

Adenosine

0.05-0.25 mg/kg (3-1 8 mg)

i.v. bolus (fast)

Not usual

tal and 11% live to be discharged. These numbers are halved when basic life support is not available. Survival is worse in older patients, and when arrest occurs at home or in the street. In hospital, when cardiac arrest due to VF occurs within 4 hours of symptoms and is successfully treated, 80% of patients are alive 3 years later.

BP; bronchospasm

BP; nausea Toxicity: lower dose in renal impairment and in elderly BP; cardiac failure Heart rate CNS toxicity

BP;

Transient

heart rate; AV block

BP; chest pain; angor animi

TABLE 12.18 Basic cardiac arrest procedures A Assessment Patient unconscious or asleep? Call for help if unconscious. Is airway clear? Clear it, pull chin up. B Breathing

BASIC LIFE SUPPORT

518

The basic cardiac arrest procedures are given in Table 12.18. Initial assessment is rapidly followed by establishing a clear, open airway. This is done by head tilt with chin lift and jaw thrust. In the absence of airway obstruction, rescue breathing begins with the mouth-to-mouth technique. Recommendations vary, but in the UK, four quick breaths are advocated. In the USA, two slow breaths (1-1.5s each) have been suggested, in order to diminish the likelihood of gastric distension with air, and subsequent vomiting (risking inhalation of vomit into the unprotected airway). Protective masks and airway equipment should be provided for personnel most often exposed (ambulance and paramedical staff), even though the risk of infection (such as from hepatitis B or HIV) is likely to be very small. Bag and mask techniques are taught to nursing and

If patient is breathing: turn to recovery position. If patient is not breathing, but is choking: Heimlich manoeuvre. If patient is not breathing, but is not choking: start mouth-to-mouth resuscitation. Call for assistance. C Circulation If no pulse: start external cardiac massage call for assistance continue ventilation

medical staff, but are frequently more difficult to use and less effective in inexperienced hands than is mouth-tomouth ventilation. Closed cardiac compression follows at a rate of 60-80 compressions/min. Training in the technique is essential. Midsternal compression is carried out with the heel of one hand to depress the sternum by 2-4 cm. The patient should

be on a rigid, flat surface with the resuscitator kneeling alongside. The arms are kept straight and compression is produced primarily by body-weight movement. Closed chest compression achieves a cardiac output by virtue of cyclical changes in intrathoracic pressure, rather than by squeezing the heart. A single-handed resuscitator should provide 15 chest compressions for every 2 mouth-to-mouth breaths. If two people are available, the ratio should be 5:1. CPR must be continuous, and pauses to reassess the situation or allow for advanced life-support techniques should not be greater than 10 seconds. The first response to a witnessed arrest should be a forceful precordial thump. This may be sufficient to convert VF or VT to a more stable rhythm by localized myocardial depolarization, or even to initiate a rhythm in cases of acute asystole.

ADVANCED LIFE SUPPORT Advanced life support (summarized in Fig. 12.41) consists of defibrillation with DC shock, endotracheal intubation, and the use of drugs and pacemakers.

DC defibrillation In VF, the earlier DC shock is given, the more successful the outcome. When defibrillators are immediately avail-

able, such as in coronary care units, the first procedure following the precordial thump should be defibrillation at 200 J. This will be sufficient to revert 85% of cases to a more stable rhythm. In 10% of patients a further 200 J shock is required and is successful. If these approaches are unsuccessful, life support must be begun immediately. Outside coronary care units, basic life support must be begun and interrupted only when the defibrillator is ready to produce the first shock of 200 J. If no monitor is available, major pulses are checked and, if absent after 3s, 15 chest compressions are given with the appropriate mouth-to-mouth breaths. A second shock follows the same pattern of events and, if VF persists, intravenous lidocaine (lignocaine) (100 mg i.v. bolus) is given before the third shock at 400 J. Adrenaline may be given before the fourth shock at the highest energy and, if an acidosis is demonstrated by arterial gases, bicarbonate (Immol/kg) is given before the fifth high-energy shock (Fig. 12.41). The technique of DC shock administration can be taught to nursing and paramedical personnel. Early defibrillation administered out of hospital by ambulance crews has been shown to improve survival from VF. Defibrillation paddles are placed on the chest with firm pressure, one under the right clavicle and one just lateral to the usual cardiac apex. Skin impedance is reduced with conducting gel or pads, and the administrator of the shock ensures that no-one is touching the patient before the shock is delivered. Complications are remarkably few, although very high-energy shocks or many repeated shocks carry the risk of some myocardial damage.

12

Endotracheal intubation If there is no recovery after a few minutes of basic life support, endotracheal intubation is necessary. This is a skilled technique which can be mastered by medical and paramedical staff alike, but which requires frequent practice. After the cardiac arrest it may be necessary to continue ventilation, via a mechanical ventilator, of seriously ill patients, those with a damaged ribcage from cardiac massage and those who sustain cerebral damage.

Drugs in advanced life support The number of drugs of proven benefit is small, despite the large number available to treat ventricular arrhythmia.

FIG. 12.41 Flow diagram of resuscitation procedures

(Based on recommendations of the UK Resuscitation Council.)

• Adrenaline (epinephrine) is the inotropic and chronotropic agent of choice. It is given intravenously in a dose of Img (ImL of 1/1000) or 2mg via the endotracheal tube. • Lidocaine (lignocaine) is given after VF and during attempts to treat VF. A bolus of Img/kg (or 100 mg) is followed by an infusion (4mg/min, reducing to 2mg/min over 24 hours). A second half-dose bolus can be given 10-20 minutes after the first. • Sodium bicarbonate. Bicarbonate infusion is only used in established acidosis, which is a relatively late event.

519

An average dose is Immol/kg of 4.2% sodium bicarbonate solution. • Calcium chloride is useful in specific circumstances, such as resuscitation after cardiopulmonary bypass and in calcium antagonist overdose. The usual dose is 10 mL of 10% calcium chloride. • Other drugs. The treatment of resistant VF or ventricular tachyarrhythmias may require the use of one or other of the alternative drugs available (p. 517). None, however, has a proven role as 'standard' therapy in CPR, and their indications have to be determined individually at the time of the resuscitation attempt.

RESUSCITATION FROM CHOKING Collapse due to acute airway obstruction is often caused by a lump of food. In the UK it is still recommended that active coughing with gravity drainage be encouraged while the subject is still conscious. This is supplemented by back blows and, finally, the abdominal thrusts known as the Heimlich manoeuvre. The latter depends upon gripping the subject from behind and, with clenched fist, producing a rapid, powerful upward thrust in the upper abdomen. This produces a rapid airflow, which may be sufficient to dislodge the obstruction.

Special techniques Cardiac pacing Cardiac pacing can be used to treat bradycardia, heart block and, sometimes, asystole. Asystole, unless it has been caused by drugs, rarely responds to cardiac pacing. Intra-aortic balloon counterpulsation Highly specialized techniques such as intra-aortic balloon counterpulsation have a limited role in specialized centres, where they can be used to support the circulation until a definitive procedure can be performed. Intracardiac injection Intracardiac injection has been used to administer calcium or adrenaline during cardiac arrest with asystole. Central venous cannulation delivers drugs to the heart with much less hazard.

When to stop Rigid rules cannot be given, but guidelines are possible. Resuscitation is almost never successful in patients who have a cardiac arrest complicating another serious illness, such as pneumonia or malignancy. It is important, therefore, that the staff likely to be first to witness a collapse should have had clear guidance concerning the desirability of resuscitation in individual patients. In general, the outlook for a useful neurological recovery is poor if the arrest occurred out of hospital and was not witnessed, or if more than 4 minutes passed without even basic life support being attempted. If no spontaneous respiration or cardiac output is achieved after 30 minutes of adequate advanced life support, then further attempts at resuscitation are questionable. The state of the pupils, whether widely dilated and reacting or not, is unreliable with respect to outcome. Age should not be used as the sole determinant of policy on resuscitation. O

O MCQ 12.10 520

VALVULAR DISEASE OF THE HEART AETIOLOGY AND NATURAL HISTORY In western countries, rheumatic heart disease was, until recently, the commonest cause of valve disease, and in most developing countries this is still the case. Various forms of degenerative valvular disease are increasingly being seen, some based on congenital abnormalities of the valve, others apparently arising de novo in middle age or later. For both rheumatic and congenital heart disease, it is often difficult to predict the progression of what initially may seem a trivial lesion of no consequence, to one that may be life-threatening 30 or more years later. What dictates progression of the valve lesion? Mechanical forces must be involved; pressure and shear forces on the valve probably make it thicken and even calcify. The tolerance of the myocardium and the advent of myocardial disease add to the difficulty in prognosis.

THE EFFECTS OF STENOSIS AND REGURGITATION Heart valve disease can occur either because of a narrowing of the valve (stenosis), causing obstruction to blood flow through the valve, or when the valve leaks, when the lesion is termed regurgitant, incompetent or insufficient. A combined or mixed lesion is common.

Valve stenosis Mild degrees of stenosis may produce an audible murmur and also a risk of endocarditis, but place an insignificant physiological burden on the heart. For significant symptoms to result, stenosis has to progress until the valve is narrowed to less than 30% of its normal area. Flow through the valve is maintained at close to normal levels by a compensatory increase in pressure in the chamber of the heart upstream of the stenotic valve. This chamber therefore hypertrophies.

TABLE 12.19 Relationship between valve area, blood velocity and pressure gradient Area (cm2)

Condition of valve Stenosis alone Normal Mild stenosis Severe stenosis Stenosis and regurgitation Normal area, no regurgitation Normal area, 50% regurgitation Mild stenosis, 50% regurgitation Mild stenosis, 66% regurgitation

Velocity (m/s)

Pressure gradient (mmHg)

3

1

4

1.5 0.6

2

16 100

5

3

1

4

3

2

1.5

4

16 64

1.5

6

144

2

The Bernoulli equation (P = 4V ), relating blood flow velocity (V) to pressure gradient (P) across a valve, shows the effects of regurgitation on the pressure gradient if the forward stroke volume is maintained. The figures are chosen for simplicity. With 50% regurgitation, the forward stroke volume and (theoretically) the flow velocity doubles; with 66% regurgitation, they increase threefold. In practice, the flow time also increases.

The severity of the stenosis is quantified by the pressure drop across the valve. In a normal valve this drop is not measurable by conventional techniques. However, in severe aortic stenosis the left ventricular pressure may rise to as much as 200 mmHg more than the aortic pressure, and the valve area may be less than 25% of normal. In mitral stenosis the left atrial pressure cannot rise above 40 mmHg because the pulmonary capillaries are unable to withstand a higher pressure. Thus, the mitral valve gradient is usually much less than the aortic valve gradient in significant stenosis, and the residual valve area accordingly greater. It follows that there are three ways of assessing the severity of a valve stenosis: • The pressure gradient across the valve. This indicates the additional work required to push blood through the valve. However, this is flow dependent (no flow, no gradient); if there is heart failure, with low flow, the valve gradient is smaller. • The valve area. Formerly, this could only be calculated from cardiac catheterization data, but direct measurement is now possible from ultrasound. There is, however, controversy over the accuracy of the measurements, because of the beam spread and lateral resolution of the ultrasound. • The peak blood velocity across the valve. Measured by Doppler ultrasound, this bears a very simple relationship to the pressure gradient (Table 12.19).

Valvular regurgitation Normal human valves are highly efficient. The aortic valve closes as the flow decelerates, and is fully closed with about 97% efficiency. However, severe mitral or aortic valve

regurgitation can be associated with up to 80% regurgitation (efficiency 20%). The forward flow then has to be five times greater than normal to allow for this leakage, and the chamber supplying the blood dilates accordingly. In aortic regurgitation the left ventricle enlarges; in mitral regurgitation the left atrium and left ventricle both enlarge greatly. Acute regurgitation (such as mitral valve chordal rupture, or aortic regurgitation from acute endocarditis) is badly tolerated, as the left ventricle and left atrium have not had time to increase in volume. The rapid increase in left ventricular diastolic pressure or left atrial pressure has severe consequences for left ventricular perfusion and pulmonary capillary pressure.

12

Combined valve lesions The combined effect of even mild stenosis with regurgitation is potentially catastrophic. Because the forward flow with as little as 50% regurgitation is twice normal, even a 50% stenosis becomes highly significant. This is shown in Table 12.19, where it can be seen that, with a combined lesion, the regurgitation greatly potentiates the effect of the stenosis. This is particularly true of the mitral valve, where pressures need to rise much less before producing symptoms.

MITRAL STENOSIS Aetiology Although a rare congenital form exists, mitral stenosis is almost always a consequence of rheumatic heart disease, and is the commonest valvular manifestation of the disease. The two valve cusps become adherent along their commissures, producing progressive stenosis with a 'fish mouth' orifice. Initially the cusps remain fairly pliable, but become increasingly rigid with time and eventually calcify. The increasing degree of stenosis produces a rise in left atrial pressure and left atrial dilatation. The raised pulmonary venous pressure can induce pulmonary oedema and lead to progressive pulmonary hypertension, with secondary incompetence of the tricuspid valve. Clinical features Mitral stenosis, which is commoner in women, may remain asymptomatic for many years with little limitation of exercise tolerance. However, an additional load on the heart, such as pregnancy, exertion, emotional stress or intercurrent chest infection (which is more common in patients with mitral valve disease because of the pulmonary vascular congestion), may produce the first symptoms of left heart failure. The onset of fast AF in middle age is a common presentation, often leading to left heart failure, and thrombus formation with the risk of embolism. Right heart failure eventually develops as a consequence of pulmonary hypertension.

521

The typical facial appearance of a patient with mitral valve disease - ruddy complexion, with red or vaguely cyanosed cheeks (mitral fades] - is now more commonly encountered in severe non-rheumatic causes of heart failure. Symptoms Of left heart failure The symptoms of left heart failure (p. 488) are shortness of breath on exertion, orthopnoea, paroxysmal nocturnal dyspnoea, pulmonary oedema, and haemoptysis of fresh blood occurring from rupture of a congested bronchial or pulmonary vein (uncommon with other causes of left heart failure). Haemoptysis may also be due to pulmonary infarction, which is more common in mitral valve disease. Due to atrial fibrillation The raised left atrial pressure may lead to AF, sometimes paroxysmal at first, but then sustained. The loss of atrial contraction and the shortened diastolic filling period can change an asymptomatic patient into one severely disabled by breathlessness, and may convert a quiescent stenosis into a life-threatening condition. Systemic embolism. Thrombus can form in the enlarged left atrium and give rise to systemic emboli. A hemiplegia may occur and embolism to other sites is frequent. The patient in sinus rhythm is also at risk from embolism, but to a lesser extent. The greatest risk is in the patient who, having been in AF, reverts to sinus rhythm, as the return of coordinated atrial contraction can dislodge clot. Due to a raised left atrial pressure Long-standing raised left atrial pressure often leads to constriction of pulmonary arterioles and thickening of the capillary basement membranes. There is increased resistance to flow through the lungs, and hence pulmonary hypertension. Right ventricular hypertrophy compensates for the increased load on the right ventricle. When pulmonary hypertension is severe, right ventricular failure follows, usually (but not always) associated with left heart failure. Right ventricular dilatation may lead to tricuspid regurgitation, with its attendant symptoms and signs (p. 531). Less frequently, tricuspid valve disease (regurgitation more frequently than stenosis) occurs through direct involvement in rheumatic fever. Massive enlargement of the left atrium can lead to hoarseness from pressure on the recurrent laryngeal nerve, dysphagia from oesophageal compression, and bronchiectasis from distortion of the left main bronchus.

522

Signs The main signs of mitral stenosis are listed in Summary box 7. Pure mitral stenosis in sinus rhythm without pulmonary hypertension is relatively uncommon. The signs are then purely auscultatory, as cardiac output is maintained and there is no significant right ventricular hypertrophy. The auscultatory signs are:

• An opening snap (OS, Fig. 12.42B) best heard halfway between the apex and the left sternal edge. It occurs close to the aortic second sound in severe stenosis, but is more separated from it in mild stenosis. • A rumbling diastolic murmur. This commences with the opening snap and fades rapidly in mild stenosis, but is full length and runs into the presystolic murmur in severe stenosis. • The presystolic murmur coincides with atrial systolic flow through the valve. It is of the same character as the mid-diastolic murmur and is sometimes heard when the latter cannot be heard. It is absent in AF. • A loud first heart sound. In the mobile stenotic valve the cusps are still fully open as systole starts, and so they close with a louder sound than normal. This is an unreliable sign. Later signs are AF and pulmonary hypertension. These patients also have signs of a low cardiac output, mitral fades, small stroke volume with small-volume pulse, a raised JVP, right ventricular hypertrophy, and a middiastolic murmur following the opening snap. When the cardiac output is very low the mitral murmur may be virtually inaudible, especially if the patient is in heart failure - so-called silent mitral stenosis.

Investigation In sinus rhythm the ECG may show P mitrale (Fig. 12.12, p. 477). Severe pulmonary hypertension may produce right ventricular hypertrophy or 'strain', but this aspect of the ECG is often unhelpful.

SUMMARY 7 Symptoms and signs of mitral stenosis Symptoms Of left heart failure

Shortness of breath, orthopnoea, paroxysmal nocturnal dyspnoea, haemoptysis

Of atrial fibrillation

Palpitations and syncope (at onset) May precipitate left heart failure Systemic embolism to CNS, limbs, gut and kidneys

Of pulmonary hypertension

Weight loss and cachexia Right heart failure

Signs Uncomplicated (auscultatory only)

Opening snap Mid-diastolic murmur Presystolic murmur

With atrial fibrillation

Irregular pulse

With pulmonary hypertension

Parasternal lift (RVH) Loud P2 Tapping apex (loud S1)

If very severe

Mitral facies Cardiac cachexia

12

FIG. 12.42 Features of mitral stenosis A Chest X-ray showing cardiomegaly with gross left atrial enlargement. B Diagrammatic illustration of the pressures in left atrium (blue) and left ventricle (black), showing a diastolic pressure gradient (shaded light blue). The timing of an opening snap (OS) and diastolic murmur is shown. S1 and S2 = first and second heart sounds.C Typical M mode. The mitral valve (arrowed) movement is abnormal (compare with Fig. 12.18). D 2D echocardiographic appearance in mitral stenosis. Thickened mitral valve (MV), dilated left atrium (LA) and the LV cavity (LV) are shown.

Chest X-ray. The chest X-ray may show enlargement of the left atrium (Fig. 12.42A), redistribution of flow to the upper zones, left heart failure and enlargement of the right side of the heart if there is coincident pulmonary hypertension. A penetrated lateral X-ray will show a calcified valve in most patients over the age of 50. Echocardiography. The echocardiogram shows thickening of the cusps (Fig. 12.42D), which are fused together so that the posterior cusp moves anteriorly in diastole with the anterior cusp. The severity of the stenosis is assessed by the rate of ventricular filling and direct assessment of the valve area from 2D echo. The echo is extremely useful for examining the size of the left atrium and hence the risk of thrombus formation and embolism. Occasionally, clot can be demonstrated in the left atrium with 2D echo, but is more reliably shown by transoesophageal echo. Doppler ultrasound demonstrates the blood velocity and, by calculation, can give a fair approximation of the pressure gradient across the valve non-invasively. It can also detect mitral regurgitation. Middle-aged adults in the developed countries will almost always be investigated by cardiac catheterization, mainly coronary angiography, prior to consideration for surgery.

Management

who does not require any treatment, with an eventual decision on anticoagulation; • Medical management of the symptomatic patient with a decision on surgery; • Surgical management of the patient with more severe disease.

Medical In the asymptomatic patient in sinus rhythm no treatment is necessary, but the patient should be advised about prophylaxis against infective endocarditis (p. 578) and carefully assessed during pregnancy (p. 582). The onset of AF may lead to the development of symptoms. Even asymptomatic patients in sinus rhythm with moderate stenosis are at risk from thromboembolism from the left atrium, so the relative risks of anticoagulation have to be weighed against the benefits in each case. The indications for anticoagulation in mitral stenosis are listed in Table 12.20. In the symptomatic patient the aim of medical management should be to control the symptoms of left heart failure with diuretics. In AF the ventricular rate should be controlled with digoxin, either alone or in combination with (or substituted by) a -blocker or verapamil (p. 511). The risk of thromboembolic episodes should be reduced by anticoagulation.

Management of mitral stenosis consists of three phases: • Monitoring the asymptomatic patient with mild disease

523

TABLE 12.20 Indications for anticoagulation in mitral stenosis • • • • •

Aetiology

Moderate or severe stenosis Enlarged left atrium Atrial fibrillation - paroxysmal or sustained Sinus rhythm with recurrent palpitations Any symptoms suggestive of arterial embolism

The percentage of valves coming to surgery which are rheumatic is now below 50% in many series. Regurgitation can result from:

Surgical Closed and balloon mitral valvotomy Closed surgical mitral valvotomy is an extremely effective operation, which has been performed successfully even during the second trimester of pregnancy without much hazard to mother or fetus. The operation uses a mechanical dilator to tear the fused commissures. It is introduced via a left thoracotomy, through the apex of the left ventricle. The surgeon also amputates the atrial appendage, thereby removing the source of most systemic emboli. Cardiopulmonary bypass is not required. In recent years the need for this operation has diminished considerably with the development of catheter-based techniques, where a balloon is passed via the femoral vein and across the atrial septum. It is positioned across the mitral orifice and inflated to the appropriate size until the stenosis is relieved. O The balloon technique requires only 1-2 days' hospitalization and avoids the need for a thoracotomy scar, but leaves behind the atrial appendage. The results obtained are comparable to those of the previous surgical series. Symptomatic improvements can be expected to last 4-12 years and sometimes much longer before repeat valvotomy or, more commonly, valve replacement is required. Open valvotomy Open valvotomy through a midline sternal incision, with the patient on cardiac bypass, is necessary if there is doubt about the applicability of valvotomy. It allows direct inspection of the valve and, should regurgitation result from splitting the valve, it can be replaced or even repaired. Valve replacement is essential if there is significant regurgitation or if the valve is heavily calcified. Prognosis

Mitral valvotomy can dramatically improve the symptoms of the patient with mitral stenosis. With time, however, the valve tends to become more rigid and calcify, becoming restenotic even if there is no fusion of the commissures. Often, a degree of regurgitation develops and, occasionally, other valves affected by rheumatic heart disease start to cause problems. OO O Fig. 12.18

524

GMCQ10.11

MITRAL REGURGITATION

Case 12.2

• Dilatation of the valve ring • Damage, retraction or perforation of the valve cusps • Damage to the subvalvular apparatus (chordae, papillary muscle, or the ventricular muscle to which the papillary muscles attach). Non-rheumatic causes of mitral regurgitation are: • Heart failure. Dilatation of the left ventricle will produce 'functional mitral regurgitation' owing to dilatation of the valve ring and a shift in the attachments of the chordae tendinae. This may disappear as the ventricle shrinks with treatment, but may become a permanent feature. • Myocardial infarction. Papillary muscle dysfunction can arise as a result of inferior myocardial infarction, producing a characteristic type of mitral regurgitation which is usually not severe. In contrast, infarction complicated by rupture of the papillary muscle produces catastrophic regurgitation, and is usually fatal unless repaired urgently. • Degenerative changes. These are often seen in mitral valves at surgery. The pathogenesis is not fully understood, as degenerative changes can occur in rheumatic valves or others known to be mildly incompetent for a long period. Rupture of the smaller chordae tendinae can occur slowly and progressively, causing increasing mitral regurgitation. Acute chordal rupture of a major trunk causes sudden severe mitral regurgitation. Other causes In mitral valve prolapse there is prolapse of a mitral valve cusp late in systole, often from a degree of 'redundancy' in the length of the chordae tendinae. It may be a feature of Marfan's syndrome and osteogenesis imperfecta. Elderly patients often develop a minor degree of mitral regurgitation from calcification of the valve ring. This produces a characteristic wheezy systolic murmur. Endocarditis may make even a trivial degree of regurgitation more severe, and acute endocarditis can rapidly destroy a normal valve. There is a degree of mitral regurgitation in most cases of hypertrophic obstructive cardiomyopathy (p. 571). Congenital forms of mitral regurgitation include cleft cusps in AV canal defects and endocardial cushion defects in association with ostium primum atrial septal defects (p. 540). Sharp (stabbing) and blunt (steering-wheel injury) trauma to the precordium, acromegaly and Libman-Sacks endocarditis in systemic lupus erythematosus (SLE) are other rare causes.

IB

Clinical features Symptoms and pathophysiology Chronic The symptoms of chronic mitral regurgitation are essentially the same as those of mitral stenosis, but severe pulmonary hypertension is less common with pure mitral regurgitation. The slowly progressive regurgitation is accommodated by a gradual increase in size of the left ventricle, which ejects the blood into a slowly enlarging and compliant left atrium and pulmonary venous vasculature. Up to 80% of the left ventricular stroke volume may be regurgitant in severe cases, and the left ventricular stroke volume can exceed 250 mL. Symptoms in chronic mitral regurgitation usually develop when the left ventricle begins to suffer deterioration and end-diastolic pressure rises. Usually, systolic function and ejection fraction are well maintained, because the left ventricle is ejecting largely into a low impedance outflow. The symptoms of left heart failure, AF and pulmonary hypertension are the same as for mitral stenosis (p. 522). Acute In acute mitral regurgitation, e.g. complicating acute MI or due to rupture of chordae tendinae, a small left ventricle is regurgitating into a small uncompliant left atrium. This produces a very high pressure pulse or v wave in the left atrium, which may reach 60 mmHg. Left atrial pressure rapidly exceeds that needed to produce pulmonary oedema. The low forward output may precipitate tachycardia, which makes the regurgitation worse. Acute mitral regurgitation thus usually presents with severe pulmonary oedema. Signs Uncomplicated pure mitral regurgitation, if trivial, has only auscultatory signs (Fig. 12.43). However, if the regurgitation is more severe, the left ventricular volume load becomes clinically evident by a hyperactive left ventricle with displacement of the cardiac apex down and laterally. Enlargement of the left atrium in systole may be felt as a parasternal heave. In severe regurgitation the pulse may become small and rather jerky from a shortened ejection time. Severe regurgitation is evident on auscultation by the presence of a third heart sound and short mid-diastolic murmur, produced by the greatly enhanced forward flow through the mitral valve during diastole. The pansystolic murmur of rheumatic mitral regurgitation, or other types of regurgitation with a central jet, is best heard at the apex of the heart and may be louder with the patient tipped to the left. Other types of mitral regurgitation - including the late systolic murmur of the floppy valve syndrome - may be best heard at the left sternal edge, and are often not pansystolic in character. Differential diagnosis from trivial aortic stenosis and ventricular septal defect can therefore be difficult, and requires non-

FIG. 12.43 Features of mitral regurgitation A Illustrates diversion of blood into the left atrium. B Shows the pressures in the left ventricle and left atrium in both mild and severe cases and the accompanying murmurs. PSM = pansystolic murmur; MDM = mid-diastolic murmur. C M-mode echocardiogram through the left ventricle (LV) in a case of severe mitral regurgitation due to valvular disease. The ventricle is dilated and hyperkinetic. D M-mode echocardiogram at the same level in a patient with mitral regurgitation due to poor LV function. The LV is dilated and hypokinetic. IVS = interventricular septum; PW = posterior wall.

invasive tests such as echocardiography and Doppler ultrasound, or even cardiac catheterization.

Mitral valve prolapse Mitral valve prolapse (also known as floppy mitral valve, or Barlow's syndrome) varies in severity from a trivial abnormality picked up on echocardiography, which has little or no consequence to the patient, to severe mitral regurgitation and heart failure. In its mild form there are single or multiple systolic clicks in the mitral area, which may be associated with a late systolic murmur of mild mitral regurgitation. There may be a tendency to supraven-

525

Investigation of mitral regurgitation The ECG is of little value in indicating the severity of the regurgitation. There may be P mitrale and left ventricular hypertrophy, but very severe regurgitation can exist in the presence of an almost normal ECG. Chest X-ray may show enlargement of the left ventricle as well as the left atrium. There may be evidence of raised pulmonary venous pressure. M-mode echocardiography is useful in demonstrating the volume load on the left ventricle and the size of the left atrium. The important distinction of mitral regurgitation due to an abnormal valve from that secondary to poor LV function may be revealed (Fig. 12.44). This has important management implications, perhaps emphasizing a surgical approach for the former and medical antifailure treatment for the latter. The technique will in most cases be able to show a rheumatic thickened mitral valve, mitral valve prolapse or flail cusp. Doppler ultrasound demonstrates mitral regurgitation and distinguishes it from aortic stenosis or a ventricular septal defect. Cardiac catheterization gives a direct measurement of the left ventricular filling pressure and left atrial pressure. Angiography shows the severity of the leak and often its mechanism; it also allows associated coronary disease to be defined. FIG. 12.44 Features of aortic stenosis A Pressures in the left ventricle (black) and aorta (blue) showing a systolic pressure gradient due to aortic stenosis. The ejection systolic murmur is illustrated. B 2D echocardiogram showing severe aortic valve (AV) thickening. Ao = aorta; LV = left ventricle; LA = left atrium; RV = right ventricle. DC] Position of probe and direction of Doppler beam. D Continuous-wave Doppler record showing highvelocity signals. Peak = 4.5 m/s (dottled line), predicting a gradient of 82mmHg.

tricular arrhythmia and atypical chest pain and associated mild skeletal abnormalities, commonly a straight back (loss of thoracic kyphosis). The underlying abnormality consists of redundancy in the chordae tendinae, allowing posterior prolapse of one or other mitral cusp in late systole. More severe degeneration of the subvalvular apparatus is seen in certain patients, particularly those with Marfan's syndrome (Ch. 3, p. 71), although severely floppy mitral valves may occur without obvious cause. Isolated mitral regurgitation, even if severe, can be tolerated for long periods if its development is gradual. A number of patients with the mild 'click-murmur' syndrome suffer significant complications, such as systemic embolization, arrhythmia and endocarditis. Treatment of severe regurgitation is surgical.

O MCQ12.12

526

Management Trivial regurgitation is very well tolerated and requires only endocarditis prophylaxis (p. 578). Moderately severe mitral regurgitation can be well tolerated for years, but the patient may slowly come to accept a diminishing exercise tolerance. The timing of valve replacement can be difficult. Worsening left ventricular function is an indication, as the procedure carries more risk when left ventricular function is poor. Severe regurgitation and acute regurgitation merit early valve replacement. Repair of regurgitant valves is increasingly advocated in anatomically suitable cases. O

MITRAL REGURGITATION WITH STENOSIS The combination of mitral regurgitation with stenosis is almost invariably a result of rheumatic heart disease, but occasionally arises in other conditions, such as LibmanSacks endocarditis in SLE. Mixed mitral valve disease presents later than pure stenosis, and is very common after mitral valvotomy. The physical signs are shown in Figures 12.42 and 12.43. AF is more likely than with pure stenosis. Even a mild degree of regurgitation makes the effective degree of mitral stenosis much greater (p. 521). The predominant lesion can be difficult to assess in the presence of hypertension or aortic valve disease, which will also produce left ventricular hypertrophy. A pansystolic murmur alone may arise from coincident tricuspid regurgitation with pure

mitral stenosis. The degree of mitral regurgitation can vary with the heart rate and the degree of left ventricular dilatation. What may appear to be severe regurgitation when the patient is in heart failure may settle considerably as the patient improves. Management is as for mitral stenosis alone (p. 523). Assessment of the mitral valve with Doppler ultrasound shows that minor degrees of mitral regurgitation are extremely common, even when these cannot be detected clinically.

AORTIC STENOSIS Aetiology Outflow obstruction to the left ventricle can be at the valve itself (valvular), above it (supravalvular) or below (subvalvular). About 1% of cases of 'aortic stenosis' are supraor subvalvular. Supravalvular stenosis is a congenital form of atresia of the ascending aorta, and is associated with a characteristic 'elfin' facies. Subvalvular stenosis is either a congenital ring lesion (which is amenable to surgery) or a variable muscular obstruction produced by hypertrophic obstructive cardiomyopathy (p. 571). Valvular aortic stenosis can result from: • Congenital aortic stenosis, presenting in childhood, the valve having one, two or three cusps; • Bicuspid aortic valve presenting in adulthood. About 1% of the population are born with two, instead of three, cusps. About one-third of these develop calcific aortic stenosis, one-third mixed aortic valve disease, and one-third have no significant valvular abnormality. The valve itself seems to be mechanically unsatisfactory and suffers mechanical stresses, which lead to progressive damage; • Rheumatic heart disease. This involves the aortic valve in about 50% of cases of rheumatic valvular disease, most frequently producing aortic regurgitation, often a mixed lesion but sometimes pure stenosis; • Senile aortic calcification. Although calcification of the valve ring is commonly benign, it can invade the cusps and produce a calcified tricuspid valve as it renders the cusps immobile. This aetiology is more common over the age of 70. The valve cusps are not fused. Pathophysiology

Clinical features

12

Aortic stenosis may remain asymptomatic until it is very severe, and is then life-threatening. The symptoms are: • Left heart failure. Shortness of breath on exertion may precede paroxysmal nocturnal dyspnoea and orthopnoea, or the patient may present with acute pulmonary oedema. • Angina. The thickened myocardium is perfused by a lower than normal perfusion gradient owing to low aortic diastolic pressure and a high left ventricular enddiastolic pressure. For these reasons, angina can occur without any coronary narrowing, although coronary artery disease often coexists in older patients. • Syncope on exertion. This is a sinister symptom which indicates a fixed cardiac output and presages sudden death. The mechanisms may be: skeletal muscle vasodilatation causing a drop in blood pressure; a rise in ventricular pressure producing reflex bradycardia and vasodilatation; myocardial ischaemia triggering ventricular arrhythmia. • Sudden death, probably resulting from myocardial ischaemia and ventricular irritability, leading to a fatal arrhythmia. This may be provoked by exertion. • Right heart failure. Rarely the presentation is right heart failure supervening on left. • Emboli from a heavily calcified valve. These are usually fairly small and cause small strokes or visual disturbances.

The signs of pure aortic stenosis are shown in Figure 12.44. Although the systolic ejection murmur suggests the possible diagnosis, the most important physical sign is the slowrising poor volume pulse, best felt at the carotid, where a systolic thrill may also be evident. The heart is not enlarged unless the patient has been in failure, but the left ventricular apex beat is powerful and 'pressure loaded'. Differential diagnosis from a 'flow murmur' is based on the slow-rising pulse, the presence of left ventricular hypertrophy and the absence of the aortic component of the second heart sound. The loudness of the murmur is a poor index of severity and the murmur may even be absent in heart failure. In congenital aortic stenosis there may be an ejection click as the valve cusps tent as they tension.

Outflow obstruction to the left ventricle leads to: • Concentric left ventricular hypertrophy • Compensatory enlargement of the coronary arterial circulation as the metabolic demands of the hypertrophied left ventricle increase; • A relatively fixed cardiac output. A resting pressure gradient of l00mmHg would have to become 400mmHg for the flow velocity through the valve to double. The heart is incapable of generating such a pressure, and is therefore near its limit at rest.

investigation Electrocardiography A normal ECG virtually rules out significant aortic stenosis, except in congenital disease when the trace may remain remarkably normal despite a large gradient. A number of ECG changes are seen in aortic stenosis: • Left ventricular hypertrophy. Often widening of QRS and T wave changes of 'strain' predominate over voltage

527

SUMMARY 8 Symptoms of aortic stenosis • • • • •

Left heart failure - dyspnoea, orthopnoea, pulmonary oedema Angina Exertional syncope or near syncope Small cerebral emboli Right heart failure

change. T-wave inversion over LV leads may be the only feature. Loss of anterior R waves may occur. • Left axis deviation and, eventually, left bundle branch block may occur either from severe hypertrophy or invasion of the conduction system by calcium from the valve. • Left atrial hypertrophy or 'P mitrale\ A large negative component to the P wave in VI indicates raised left ventricular filling pressure. • Complete heart block.

Medical Treatment of heart failure follows conventional lines (p. 494). Vasodilator agents are contraindicated, as a reduction in systemic resistance can lead to a severe drop in blood pressure, and syncope.

AORTIC REGURGITATION

Chest X-ray The chest X-ray can be normal but may show a poststenotic dilatation of the ascending aorta, prominence of the left ventricle and a calcined aortic valve on lateral chest X-ray. The latter in a patient under 55 suggests tight stenosis; above this age the valve may calcify even with an insignificant gradient. Significant enlargement of the left ventricle occurs with heart failure or coincident aortic regurgitation.

Aetiology

M-mode echocardiography M-mode echocardiography can display thickening and calcification of the valve cusps, but is less useful in congenital stenosis. The compensatory hypertrophy of the left ventricular wall is well shown. 2D echocardiography may give a good view of the aortic valve orifice.

Dilatation of the valve ring occurs classically in syphilitic aortic regurgitation, but can also occur with hypertension and aortic dissection; less common causes include cystic medial necrosis in Marfan's syndrome, and osteogenesis imperfecta. Damage to the valve cusps is a feature of rheumatic aortic regurgitation, infective endocarditis, and less common conditions such as Libman-Sacks endocarditis, mucopolysaccharidoses and pseudoxanthoma elasticum. The seronegative arthritides, ankylosing spondylitis, Reiter's disease and psoriatic arthritis can be associated with an aortitis and cusp damage, leading to aortic regurgitation. Rarely, rheumatoid arthritis is associated with a nodular cusp damage leading to aortic regurgitation. Bicuspid aortic valve (found in 1% of the population) can lead to predominant aortic regurgitation (p. 527). There are other congenital forms of aortic regurgitation, e.g. that associated with a supracristal ventricular septal defect.

Doppler ultrasound Doppler ultrasound measures the jet velocity and predicts the valve gradient. A high blood velocity (>4m/s) indicates a surgically significant gradient, but as jet velocities can be underestimated, a low jet velocity record is a less reliable finding. Cardiac catheterization Measurement of the valve gradient by cardiac catheterization is not essential if the diagnosis is well established. Catheterization is usually indicated where there is doubt about the site or degree of stenosis, a not-infrequent occurrence in older patients, who may be poor ultrasound subjects. It also allows analysis of ventricular function. Coronary angiography is now considered essential prior to operation in all but the very elderly.

Management

528

tomy in children may gain sufficient time for them to reach a reasonable size before having aortic valve replacement. For adults, valve replacement is the only treatment. If the ventricle has already been badly damaged the results are less good, but in the patient with a normal ventricle the left ventricular hypertrophy regresses fairly rapidly. Lesser degrees of stenosis need serial follow-up, as the stenosis may become more significant with time at a rate averaging about 8mmHg/yr, although this may be very variable.

Surgical Tight aortic stenosis has such a poor prognosis that surgery should be offered to all patients. Valvuloplasty or valvo-

The aortic valve cusps normally overlap on closure to the extent of about 25% of the cusp area. Aortic regurgitation can arise from: • Dilatation of the valve ring so that the cusps no longer meet adequately to prevent leakage • Damage to the cusps themselves • In some diseases, a combination of these factors.

Clinical features Symptoms and pathophysiology Aortic regurgitation can be well tolerated for years if it develops slowly. Up to 80% regurgitation can be found in severe chronic aortic regurgitation, but acute regurgitation (such as follows aortic dissection or acute infective endocarditis) is poorly tolerated. The severity of the regurgitation is normally indicated

12

by a low diastolic blood pressure and wide pulse pressure. These may appear more 'normal' in heart failure as the stroke volume falls and the end-diastolic pressure of the left ventricle rises. As aortic regurgitation progresses, the increasing leakage requires a larger and larger forward flow. This is usually achieved not by a tachycardia but by the left ventricular end-diastolic size increasing with an increased stroke volume. Initially, the ejection fraction of the left ventricle is well maintained and exercise tolerance is excellent. However, after an unpredictable time there is a steady or sudden deterioration in left ventricular function, usually with a great increase in heart size and the development of symptoms of left ventricular failure. Eventually, right heart failure follows, with the development of pulmonary hypertension. The development of heart failure indicates serious dilatation of the left ventricle and the need for urgent consideration of valve surgery. Heart failure in aortic regurgitation is associated with rapidly worsening left ventricular function, which may never recover even with valve replacement. Angina can develop because the dilated left ventricle has increased oxygen requirements (as in congestive cardiomyopathy), but is usually associated with coronary artery disease. AF occurs in about 15% of cases, usually those with long-standing failure. Physical signs The physical signs of aortic regurgitation (Fig. 12.45) are related to the large stroke volume, the peripheral vasodilatation and the compensatory increase in size of the left ventricle. The pulse may be collapsing or bisferiens (p. 471), or feel normal if there is heart failure. The blood pressure indicates the large pulse pressure and low diastolic pressure. If the diastolic pressure is well maintained in the presence of severe aortic regurgitation, coincident hypertension should be suspected. The left ventricle is very active, and in severe cases the apex beat is displaced. The increased forward flow is often accompanied by a systolic flow murmur, which, of itself, does not indicate coincident stenosis. The early diastolic murmur is notoriously difficult to hear. The murmur is best heard with the diaphragm of the stethoscope, with the patient sitting forward having breathed out. It may be best heard at the left sternal edge, nearer the apex or in the aortic area, depending on the direction of the jet. Typically, valve ring dilatation regurgitation is better heard in the third right interspace rather than the third left. An Austin Flint murmur may be associated with aortic regurgitation. This is an apical diastolic murmur, similar to that of mitral stenosis, arising from the anterior cusp of the mitral valve, which vibrates in the jet of aortic regurgitation. Because aortic regurgitation may be both difficult to hear and is a frequent lesion in infective endocarditis, a patient with a fever and steadily widening pulse pressure is regarded as having aortic regurgitation and endocarditis until proved otherwise.

FIG. 12.45 Features of aortic regurgitation [A] Pressures in the aorta (blue) and left ventricle (black) are illustrated with the accompanying murmurs (3 = third sound). B Direction of regurgitant flow (arrow) and orientation of M-mode and Doppler beams (dotted lines), C Continuous-wave Doppler signal showing a regurgitant jet throughout diastole with a maximal velocity of 4m/s (upwards signal). The small downward signal excludes aortic stenosis. D M-mode echocardiogram showing flutter of the anterior mitral valve leaf (arrowed), which may close prematurely in severe aortic regurgitation, causing an early first heart sound.

Investigation ECG shows left ventricular hypertrophy of the diastolic overload type, in that, initially at least, voltage changes with prominent Q waves over the lateral leads predominate over T-wave changes. Later, the T waves invert. Chest X-ray shows increasing size of the left ventricle and often some dilatation of the proximal aorta. Generalized cardiac enlargement may follow and, eventually, changes of raised pulmonary venous pressure. Echocardiography. M mode shows the dilated left ventricle and its wall thickness. Calculation can be made of the stroke volume and ejection fraction, which are useful for following progress. In many cases vibration of the anterior cusp of the mitral valve or the septum can be seen, confirming the diagnosis. Doppler ultrasound will confirm the diagnosis but cannot quantify the lesion. Cardiac catheterization is necessary to examine left ventricular function, the severity of the aortic regurgitation and its anatomy, as well as looking for other pathology, such as mitral regurgitation and coronary artery disease.

529

SUMMARY 9 Clinical features of aortic regurgitation Symptoms Left heart failure: breathlessness Myocardial ischaemia, angina Atrial fibrillation (less frequently) Physical signs Large stroke volume with vasodilatation Collapsing pulse Wide pulse pressure Head nodding, capillary pulsation Enlarged left ventricle with dynamic displaced apex Auscultatory High-pitched early diastolic murmur Forward flow systolic murmur Premature first heart sound (in severe cases) Austin Flint murmur

Management Surgery Those in heart failure have been left too late to obtain the maximum benefit from surgery, as a dilated 'myopathic' heart never returns to normal and is associated with a high risk of sudden death. The currently used criteria for surgery are based on echocardiographic dimensions; others are now being developed based on the use of isotope left ventricular angiography. A fall in the ejection fraction of the left ventricle on exercise has been suggested as a criterion for surgery, as the ejection fraction is normally well maintained or even increases. Acute aortic regurgitation requires very close attention and urgent valve replacement at the first sign of heart failure. Delay can result in catastrophic heart failure and death, as the degree of regurgitation and size of the heart rapidly increase.

Medical Medical management of chronic regurgitation consists of treatment of heart failure and control of other problems, such as arrhythmias and endocarditis prophylaxis (p. 578). There is some evidence that using vasodilators such as nifedipine can delay the need for valve replacement when begun in moderate regurgitation. O

Investigation and management Assessment of combined lesions has been greatly helped by Doppler ultrasound and echocardiography. The gradient measured by Doppler ultrasound may appear much greater than the pull-back pressure gradient measured at cardiac catheterization. Surgery for combined lesions is based on the same criteria as for single lesions. Onset of symptoms means that there is severe left ventricular hypertrophy and probably fibrosis, with consequent poor left ventricular function. Surgery is therefore ideally timed to anticipate symptoms and allow the left ventricular hypertrophy to regress. A gradient of over 50mmHg, the development of a left ventricular strain pattern on ECG, left ventricular dilatation and any evidence of heart failure are all considered indications for aortic valve replacement.

COMBINED MITRAL AND AORTIC VALVE DISEASE Over 50% of patients with rheumatic mitral valve disease will eventually develop evidence of aortic valve disease, most commonly aortic regurgitation, but sometimes stenosis as well. The presence of disease in both valves makes assessment of the severity of the individual lesions more difficult. Mitral valve disease in particular tends to reduce cardiac output and stroke volume, which may make the physical signs of aortic valve disease, such as the carotid pulse, far less evident. Aortic regurgitation and mitral regurgitation both cause a volume load on the left ventricle, so the contribution of each lesion to this is difficult to assess. The auscultatory signs may also be far more difficult to elicit, particularly if the patient is in heart failure.

MIXED AORTIC VALVE DISEASE

Investigation and management

About one-third of patients with aortic valve disease have a combined lesion with significant regurgitation and stenosis. As previously described, regurgitation makes a great difference to the valve gradient (p. 521, Table 12.19), and a stenotic valve with a gradient of 16mmHg in systole would have a gradient of over 60mmHg if twice the flow

The presence of aortic valve disease should be suspected in every patient with rheumatic mitral valve disease, particularly if they have ECG evidence of left ventricular hypertrophy, or a slightly sustained carotid pulse. Fortunately, echocardiography and, in particular, Doppler ultrasound enable the valves to be individually examined for evidence of stenosis and regurgitation. This is far more accurate than inspection of the valves at surgery. If a patient is being considered for mitral valve replacement in the presence of aortic valve disease, it is unwise for the surgeon to leave anything but trivial aortic valve disease.

O MCQ 12.13 530

were accommodated, because of 50% regurgitation. The physical signs of the combined lesion are distinctive, with a large-volume sustained or bisferiens pulse, a markedly hypertrophied left ventricle which is both pressure and volume loaded, and both systolic ejection and early diastolic murmurs. The second sound is single. A combined lesion cannot be caused by syphilis or other pathologies that primarily dilate the aortic root.

12 FIG. 12.46 Features of tricuspid regurgitation fAl Illustration of regurgitant flow and direction of Doppler beam (dotted line). PA = pulmonary artery; SVC and IVC = superior and inferior vena cava. Q] and [C] Continuous-wave Doppler signals, both showing tricuspid regurgitation (downwards signal). In B there is severe (organic) regurgitation with normal pulmonary artery pressure and increased tricuspid forward flow. In C there is pulmonary hypertension with a high-velocity regurgitant jet through the tricuspid valve.

What may seem a trivial degree of aortic regurgitation or stenosis at presentation may become clinically important with replacement of the mitral valve.

TRICUSPID REGURGITATION Tricuspid regurgitation most commonly arises as a result of dilatation of the valve ring secondary to right heart failure with pulmonary hypertension. Less common causes are actual rheumatic involvement of the tricuspid valve leaflets producing 'organic tricuspid disease', and rightsided endocarditis, which is rare in anyone other than intravenous drug addicts. Floppy tricuspid valve may be associated with floppy mitral valve, and some congenital heart disease is associated with tricuspid regurgitation either as a primary phenomenon or secondary to right heart enlargement (e.g. atrial septal defect). Endomyocardial fibrosis, a disease occurring in the tropics, especially Africa, causes mitral and tricuspid regurgitation. Doppler ultrasound has shown that a right-sided cardiac enlargement in rheumatic heart disease is almost invariably associated with a regurgitant jet through the tricuspid valve, very often in the absence of any physical signs. Similarly, it may be the cause of an 'innocent systolic murmur'.

Clinical features Pathophysiology and symptoms The leakage of a small percentage of the right ventricular stroke volume is easily accommodated by the right atrium. As the volume of regurgitation increases, there is increasing enlargement of the right atrium and right ventricle, and the movement of the interventricular septum becomes dominated by the right ventricle and so 'paradoxical'. The large systolic pressure pulse in the right atrium leads to

stagnation and, eventually, reversal of blood flow in the great veins; the liver becomes distended and pulsatile (Fig. 12.46). The high hepatic venous pressure leads to cardiac cirrhosis, and this may occasionally lead to secondary portal hypertension and splenomegaly. The poor venous return, high venous pressures and poor hepatic function are associated, in most patients, with a degree of cardiac cachexia, poor wound healing and difficulties with haemostasis. Tricuspid regurgitation due to disease of the valve is much better tolerated, as the regurgitation is at a much lower pressure than when it is secondary to pulmonary hypertension. The principal symptoms are those of right heart failure, with low cardiac output, fatigue, oedema and pain from hepatic congestion which may arise on exercise - so-called 'hepatic angina', i.e. epigastric or right-sided subcostal pain arising on exercise and gradually (more gradually than 'true' angina) disappearing with cessation of exercise. Signs The patient may have AF and is often slightly jaundiced. In moderate to severe cases there is a highly pulsatile jugular vein with a large v wave and rapid y descent. The height of the v wave peak may be as much as 15cm above the sternal angle, and in these circumstances the jugular vein is palpably pulsatile and can be confused with an arterial pulse. The right ventricle is very active and gives rise to a right parasternal impulse. A pansystolic murmur is heard at the left sternal edge, or even at the cardiac apex, which may be formed by the right ventricle under these circumstances. The murmur is often lower in pitch than a mitral murmur. There can be a right ventricular third heart sound. Abdominal examination reveals a pulsatile liver, which is often visible but is best felt bimanually.

531

Investigation ECG may be unhelpful and is usually dominated by other factors associated with the underlying cardiac disease. Chest X-ray shows right-sided cardiac enlargement, and there may be a fullness in the region of the distended superior vena cava. O Echocardiography shows an enlarged right ventricle with paradoxical movement of the interventricular septum suggesting 'volume load' of the right ventricle. The tricuspid valve leaflets are more easily seen with an enlarged right heart. Doppler ultrasound will confirm a regurgitant jet through the tricuspid valve. The jet velocity will give an indication of the gradient across the valve, and hence the right ventricular pressure and the severity of the pulmonary hypertension (if any).

Management As tricuspid regurgitation is often secondary to pulmonary hypertension, the treatment is frequently that of the underlying cause. Bed rest and diuretics will be effective in many cases, with the murmur and pulsatile jugular veins disappearing. Intravenous diuretics may be required, as the oral drugs may be poorly absorbed. Organic tricuspid valve disease may require surgical treatment by replacement or annuloplasty at the same time as other cardiac surgery.

TRICUSPID STENOSIS Tricuspid stenosis is a very uncommon manifestation of rheumatic heart disease. It mimics mitral stenosis, but produces right heart failure rather than left. It almost always complicates rheumatic involvement of the mitral and aortic valves, and should be suspected if there is a high venous pressure with a slow y descent in the JVP. The diastolic murmur is reputedly enhanced on inspiration and is best heard at the left sternal edge. There can be a tricuspid opening snap, and often coincident tricuspid regurgitation.

Investigation and management The diagnosis can be confirmed by echocardiography, which will show the thickened cusps. Doppler ultrasound can be used to measure the jet velocity and thus calculate the diastolic gradient. Cardiac catheterization with a double-lumen catheter is needed to measure the rather small valve gradient. Treatment is by valve replacement.

O Fig. 12.19

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PULMONARY REGURGITATION Pulmonary regurgitation is usually caused by dilatation of the pulmonary valve ring in pulmonary hypertension. It may also follow pulmonary valvotomy or valvuloplasty. In severe cases the right ventricle is hyperactive from volume loading, and the murmur is difficult to distinguish from that of aortic regurgitation, being an early diastolic murmur at the left sternal edge starting immediately after the pulmonary component of the second sound. It may have a slightly lower pitch and be more obvious on inspiration, but the two can easily be confused. The Graham Steel murmur of pulmonary regurgitation in mitral valve disease is far more frequently due to aortic regurgitation than was formerly believed. Pulmonary regurgitation is usually well tolerated but can be one reason why the heart remains enlarged after surgical correction of Fallot's tetralogy.

PULMONARY STENOSIS Pulmonary stenosis is the second most common form of congenital heart disease in adults; it is commoner in women. Mild cases, with gradients of less than SOmmHg, are common. Stenosis may occur at valvular or subvalvular level, or even in the pulmonary arteries. There is a raised pressure in the right ventricle and, in severe cases, reduced lung blood flow and poor effort tolerance.

Clinical features Most cases are asymptomatic. With gradients of over SOmmHg, the most common symptom is dyspnoea on exertion. In very severe stenosis symptoms of exertional syncope and angina become prominent, similar to those associated with aortic stenosis. In children and young adults, pulmonary stenosis may present with severe right heart failure. The physical signs are of a small volume pulse, a large a wave in the JVP, a right ventricular substernal heave and a harsh systolic murmur in the pulmonary area. The latter appears very long and drowns the heart sounds in severe cases of infundibular stenosis, but can be a short ejection murmur in mild cases. The timing of pulmonary valve closure, which is delayed in severe cases, is a useful indication of severity.

Investigation and management ECG shows right ventricular hypertrophy. The chest X-ray shows oligaemic lung fields; a large poststenotic dilatation with dilatation of the pulmonary conus is common in valvular, but not infundibular, stenosis. The right ventricle is not significantly enlarged unless it has failed. Doppler ultrasound assesses the valve gradient. Echocardiography will show the hypertrophy of the right ventricle and the site of the obstruction.

Surgical valvotomy has been largely replaced as a treatment for pulmonary stenosis by balloon valvuloplasty (see below).

SURGICAL MANAGEMENT OF ACQUIRED HEART VALVE DISEASE The choices in surgical management of heart valve disease have recently become more complex, with closed valvotomy, open valvotomy and balloon valvuloplasty all being possible approaches.

Cardiac bypass In the technique of cardiac bypass the circulation is arrested and there is extracorporeal circulation from a roller pump and external oxygenator. The brain is perfused at relatively low pressure, and the oxygenator and perfusion system introduce microemboli into the arterial circulation. There is therefore a morbidity associated with prolonged cardiac bypass. Most of the morbidity seems to be reversible (e.g. intellectual impairment) but patients with cerebrovascular disease, such as carotid stenosis, are at particularly high risk from cerebral infarction.

Balloon valvuloplasty In balloon valvuloplasty a balloon catheter is inserted through the valve orifice and then dilated to split open the valve. The aortic valve can be dilated in children, and balloon valvuloplasty has been especially successful for pulmonary and mitral stenosis. If torrential regurgitation is produced during mitral valvuloplasty, valve replacement is essential.

Valve repair and replacement Plastic surgical repair to a damaged valve uses pericardial or other tissue to repair defects in the valve cusps, or suturing of the valve ring to a prosthetic former to correct a grossly dilated valve ring. The latter is commonly performed in severe tricuspid regurgitation. The procedures are time-consuming and technically demanding and have had a history of variable results. Prosthetic and biological valves The type of valve used for replacement depends very often on local preference and expertise. Mechanical valves require permanent oral anticoagulation with warfarin. Biological valves do not, but are prone to early failure and calcification. The original prosthetic Starr-Edwards valve essentially a ball in a cage - was built for durability, but early models formed thrombus on the struts and were also rather noisy. Numerous attempts have been made to improve on this, but many have developed mechanical problems and the Starr valve remains the most durable prosthesis currently available. In order to avoid the anticoagulation essential with

mechanical valves, various attempts have been made to use biological ones. Fresh human homografts have been used very successfully in the aorta, but availability has been a problem. The most widely used biological valves are xenografts. Porcine or bovine tissue is usually mounted on a ring or stent; such valves have the advantage of not requiring long-term anticoagulation, nor do they produce the loud prosthetic clicks of mechanical valves. Their disadvantages are that they have an unpredictable lifespan and can calcify and become stenosed very rapidly in young patients. However, most of them last at least 5 years. They may be considered in women of childbearing age who wish to have a family without the teratogenic risks of anticoagulation. Such patients must be prepared to face the subsequent reoperation for valve replacement when the biological valve fails. Under current UK legislation a heavy-goods or publicservice vehicle licence holder cannot drive if he or she is on anticoagulants, and so these patients may have to opt for biological valves if they wish to maintain their occupation.

12

FURTHER READING ON VALVULAR DISEASE Guidelines on the investigation and management of valvular heart disease July 1996 Prendergast B, Banning A P, Hall R J C on behalf of a working group of the British Cardiac Society and the Royal College of Physicians, London

CONGENITAL HEART DISEASE

Incidence and aetiology Congenital heart abnormalities are present in about 8-12 per 1000 live births (excluding bicuspid aortic valve and floppy mitral valve). The simpler abnormalities are commonest, with ventricular septal defect (VSD) accounting for 25-30% of cases and patent ductus arteriosus 10% (Table 12.21). Pulmonary stenosis, atrial septal defect (ASD), coarctation of the aorta, aortic stenosis and tetralogy of Fallot together account for another 35% of cases. Of the complex lesions, transposition of the arteries, AV septal defects and the hypoplastic left heart syndrome are the most frequently seen. The fetal circulation is shown in Figure 12.47. Only a minority of these patients (10-15%) would survive to adolescence and adulthood without the help of cardiac surgery and interventional cardiology. Over the last 15-20 years babies have survived who would previously have died, so that cardiologists and physicians are now more likely to see adult patients with medically or surgically corrected lesions than to diagnose a congenital defect for the first time in adult life. The relative frequency of different lesions at different ages depends on the compatibility of the lesion with longevity. ASD, for example, can present in the patient's

533

TABLE 12.21 Relative frequency of types of congenital heart disease Congenital defect

Frequency (%)

Live births Atrial septal defect Pulmonary stenosis Tetralogy of Fallot Ventricular septal defect Eisenmenger syndrome Patent ductus arteriosus Coarctation of the aorta Other

30 25 10 9 7 7 5 7

Stillbirths Ventricular septal defect Univentricular heart (with tricuspid and mitral atresia) Atrial septal defect Coarctation of the aorta Complete transposition Atrioventricular septal defects Hypoplastic left heart Tetralogy of Fallot Other

35 13 10 9 9 9 6 3

TABLE 12.22 Causes of congenital heart disease Causes

Defect

Rubella

Patent ductus, atrial septal defect, pulmonary stenosis

Drugs Alcohol

Ebstein's anomaly Tricuspid atresia

Thalidomide

Multiple defects

Inherited disease Connective tissue disorders Marfan's Ehlers-Danlos Inborn metabolic errors Mucopolysaccharidoses Homocystinuria Pompe's disease Chromosomal abnormalities Down's syndrome Trisomy 13 and 18

6

Turner's syndrome Other inherited syndromes Di George's Friedreich's ataxia Holt-Oram Kartagener's Tuberous sclerosis

FIG. 12.47 Diagram of the fetal circulation SVC and IVC = superior and inferior vena cava.

OMCQ 12.14 534

Ventricular septal defect

Lithium

Aortic dilatation and incompetence; mitral incompetence Mitral regurgitation; arterial dilatation Valve disease, cardiomyopathy Aortic and pulmonary dilatation Glycogen deposition in myocardium Atrial and ventricular septal defect; Fallot's tetralogy; endocardial cushion defect Ventricular septal defect; right ventricular anomalies; pulmonary stenosis Coarctation of aorta, bicuspid aortic valve; pulmonary stenosis Fallot's tetralogy; aortic arch anomalies Cardiomyopathy Atrial septal defect Dextrocardia Cardiomyopathy

70s, but congenital aortic stenosis or Coarctation of the aorta presents much earlier, either to the physician or as a cause of sudden death. As the cohort of patients with surgically palliated or corrected hearts reaches maturity, so special issues arise involving counselling, the advisability of pregnancy, the likelihood of inheritance in the next generation, and the timing of heart or heart-lung transplantation in the disabled or deteriorating patient. The commonest forms of congenital heart disease seen after birth are shown in Table 12.21. Spontaneously aborted fetuses have a much higher incidence of severe congenital heart disease than do normal-term infants. Congenital heart defects may occur as part of more complex syndromes; there are often associated minor thoracic abnormalities. Most cases of congenital heart disease remain unexplained. Some causes are listed in Table 12.22. Most lesions develop in the first trimester of pregnancy, many at about the 7th week. Many involve 'mistakes' in the complex

IB FIG. 12.48 Diagrammatic representation of blood flow in the systemic and pulmonary circulation A Normal. B Left-to-right shunt. El Right-to-left shunt; the pulmonary blood flow is reduced as a result of development of high resistance. RH = right heart; LH = left heart.

embryological processes of flexing, twisting and formation of septa and the formation and closure of foramina (Fig. 12.48). The formation of a patent ductus arteriosus (more correctly a persistent ductus arteriosus) and coarctation of the aorta appear to be due to physiological mechanisms that go wrong after birth.

CHROMOSOMAL ABNORMALITIES Chromosomal abnormalities can be accompanied by congenital heart disease. Down's syndrome (mongolism or trisomy 21, see Ch. 3, p. 66) is associated with endocardial cushion or AV canal defects (ASD mitral and tricuspid regurgitation), but VSDs and pulmonary stenosis also have an increased incidence. Turner's syndrome (XO) - characterized by stunted growth, web neck, female sexual stunting and cubitus valgus - has a greatly increased incidence of coarctation of the aorta and pulmonary stenosis. Maternal viral illnesses Viral infection in early pregnancy, typically rubella, appears to be the cause of some congenital heart defects. Rubella produces a characteristic association of defects, including deafness, cataract, and often persistent ductus arteriosus, although other lesions may occur. Although rubella is the best-documented viral agent, mumps and influenza epidemics have been shown to increase the risk of congenital defects if the mother has the illness early in pregnancy. Other agents, e.g. cytomegalovirus, herpes simplex and coxsackie virus, have also been implicated. About 5% of cases of congenital heart disease can be explained by viral illness. Maternal illness and drug effects Maternal illness, especially SLE, may predispose to congenital AV block. Drugs taken by the mother can be teratogenic, and drugs now associated with congenital heart disease include alcohol, lithium, amphetamines, phenytoin, oestrogen/progesterone and trimethadione. Counselling, pregnancy and contraception A mother who has congenital heart disease herself, or who has one affected child, can usually be counselled that sub-

sequent pregnancy carries a low risk (1-5%) of congenital heart disease. Concordance rates for identical twins are between 15 and 20%, and for non-identical twins between 3 and 5%, suggesting environmental as well as genetic factor(s) in the development of congenital heart disease. In families with affected first-degree relatives the risk to the fetus increases to 50% when there are three affected relatives. When both spouses have congenital heart disease the risk may be up to 15%. In all these instances professional help from clinical geneticists is invaluable. Fetal echocardiography can be used to screen high-risk pregnancies. Mendelian dominant inheritance is seen in Marfan's syndrome and some families with hypertrophic cardiomyopathy; both conditions present in adulthood. Pregnancy in cyanotic congenital heart disease carries a high risk of complications and accelerated deterioration, and frequently ends in spontaneous abortion. At particular risk are women with haemoglobin above 17g/dL and those with pulmonary hypertension or the Eisenmenger reaction (p. 536). Patients with lesser degrees of cyanosis and polycythaemia may occasionally be brought through successful pregnancies by a combination of rest and prevention of thrombosis, infection or prolonged labour. Sterilization is usually recommended for high-risk (Eisenmenger) women. Even this relatively minor surgical procedure can be dangerous, but is less so than pregnancy. High-oestrogen-containing contraceptive pills increase an already high risk of thrombosis and embolization; it is not clear if the low-oestrogen pills are any safer in this group of women. The potential associated infective risk prevents the use of intrauterine devices. Vasectomy for the male partner and barrier methods are alternatives, but are too unreliable. O

ACQUIRED COMPLICATIONS OF CONGENITAL HEART DISEASE Apart from the simplest conditions of ASD, PDA and VSD, where early surgical correction is associated with few long-term consequences, many operated and unoperated patients develop complications. Pulmonary vascular disease, myocardial failure, arrhythmia, systemic embolization, endocarditis and degeneration of prosthetic valves

535

and conduits are some of the complex problems posed by the survivors of congenital heart defects. Their optimal management calls upon many skills within cardiology and other disciplines. In the future long-term management of this group of patients is likely to be concentrated in a few centralized units containing all the expertise required and a large enough cohort of patients to further define treatment strategies - the so-called GUCHD units (grown-up congenital heart disease).

CYANOTIC CONGENITAL HE ART DISEASE Central cyanosis occurs with an arterial oxygen saturation of <85%. Milder degrees of cyanosis may not be evident at rest but are readily precipitated by mild exertion at the bedside. A degree of shunting through the ductus arteriosus occurs for several hours, or even days, after birth, and this may persist. More commonly, right-to-left shunting occurs through persisting embryonic defects or through the foramen ovale (Fig. 12.48). The persistence of central cyanosis after birth, or its later onset, depends on a left-toright communication and on the resistance to outflow from the right heart being higher than that of the left. High resistance to outflow of the right heart is usually caused by congenital pulmonary stenosis (valvular or muscular) or by acquired pulmonary hypertension due to constriction of the pulmonary resistance vessels. Acquired pulmonary hypertension occurs with high flow through the lungs, so a left-to-right shunt can eventually reverse and become right-to-left, with cyanosis (the Eisenmenger reaction). Cyanotic heart disease produces a characteristic appearance, with central cyanosis (which may vary with activity), clubbing, impaired growth and intellectual development (if severe) and marked polycythaemia after the first year of life. Complications of the right-to-left shunt include cerebral abscess and paradoxical emboli, in which embolism from clot in peripheral veins gains access to the systemic circulation through the shunt. The severe polycythaemia can lead to thrombosis and infarction. Polycythaemia is proportional to the degree of desaturation. Regular venesection may be needed to maintain haemoglobin levels of 16-18 g/dL. Pulmonary hypertension can be complicated by recurrent haemoptysis.

FALLOT'S TETRALOGY Pallet's tetralogy is the commonest form of cyanotic con-

Case 12.3 536

genital heart disease seen after the age of 1 year. The four main features of this abnormality (see Fig. 12.49) are: • A ventricular septal defect (through which the shunting occurs); • Pulmonary stenosis, which may be muscular or valvular, and acts as the obstruction that leads to the right-to-left flow; • An overriding aorta. The aorta is positioned above the VSD; • Right ventricular hypertrophy, due to the pressure and volume load to which the RV is subjected. Incomplete forms of the condition exist in which not all the features are present and the child may be acyanotic - 'pink tetralogy'.

Clinical features The child may be deeply cyanosed at rest and is subject to cyanotic and exertional syncopal episodes which appear to be related to changes in the degree of shunting. The physical signs are cyanosis, clubbing, right ventricular hypertrophy, a harsh systolic murmur at the upper left sternal edge (often with a thrill) and a single second heart sound. Children with tetralogy characteristically learn to squat, which increases systemic vascular resistance and so diminishes R-L shunting.

Investigation The characteristic features of Pallet's tetralogy on investigation are illustrated in Figure 12.49. Chest X-ray shows a characteristic cardiac silhouette of severe right ventricular hypertrophy which lifts the cardiac apex (coeur en sabot) and oligaemic lung fields. ECG shows right ventricular hypertrophy. Echocardiography shows the overriding aorta and VSD and, with Doppler, can demonstrate the pulmonary stenosis, the right ventricular pressure and, sometimes, the flow through the VSD. Cardiac catheterization can be used to measure the pressures and show the severity of the outflow tract obstruction.

Surgical treatment Total surgical correction is now often attempted at an early age, but palliative operations to increase the lung blood flow were common in the past and are sometimes required now to encourage growth of the pulmonary vasculature, prior to complete intracardiac repair. The palliative shunts included the Blalock-Taussig anastomosis (subclavian to pulmonary artery) and aortic to pulmonary shunts, the Waterston and Potts shunts.

Prognosis and clinical features after surgery Without correction, less than 5% survive to adult life; 90% survive with surgery. In future, adult patients will have had

LESS COMMON FORMS OF GYANOTIC CONGENITAL HEART DISEASE

12

Some of the less common forms of cyanotic congenital heart disease are important causes of neonatal and infant death; however, they can be diagnosed accurately with modern imaging techniques and treated surgically. Even in neonates, cardiac transplantation and heart-lung transplantation may make some formerly inoperable conditions amenable to surgery.

Transposition of the great arteries

FIG. 12.49 Features of Pallet's tetralogy A Diagram of abnormality. VSD = ventricular septal defect; PA = pulmonary artery; B = aorta. B Physical signs. C Chest X-ray showing right ventricular hypertrophy, typical 'coeur en sabot'. D EGG showing right atrial and ventricular hypertrophy and right axis deviation.

a total repair at an earlier age, probably without prior palliative surgery. Late mortality, 10-15 years after repair, is low, at 2-7%, and mainly comprises arrhythmia, including complete heart block. The vast majority of patients have normal exercise capacity and those that do not often have residual ventricular septal defects or pulmonary hypertension. These patients virtually all have a crescendodecrescendo murmur. Many have a decrescendo murmur of pulmonary incompetence; signs of a residual VSD are somewhat less common. The chest X-ray can be normal, but often shows cardiomegaly, and right bundle branch block on the ECG is almost always seen. After palliative surgery the radial pulse may be absent or weak on the side of the shunt and arterial collaterals may develop. The shunt may produce a continuous murmur. O

Complete transposition In this uncommon abnormality the atria and ventricles are in normal relationship to each other but the great arteries arise from the wrong ventricles (transposed). The pulmonary and systemic circulations are therefore operating in parallel rather than in series, which is incompatible with life unless there is some communication between the two circuits. About half the neonates have an intact ventricular septum, and death ensues as the patent ductus arteriosus closes naturally. Survival is dramatically improved by a catheter method of producing an ASD (Rashkind procedure). The other half of the group have large VSDs allowing bidirectional shunting and mixing of the bloodstream; 20% have a single ventricle, usually the right, now classified as double-outlet right ventricle (DORV). Double-outlet left ventricle (DOLV) is very rare. The natural history of this group is very variable, with some individuals surviving to adulthood. Children who survive thanks to the Rashkind procedure have few physical signs but remain cyanosed. Corrective surgery The 'Mustard' procedure produces an intra-atrial repair using a pericardial baffle to redirect flow in the atria to the appropriate ventricle. Results have been excellent, with a return to normal saturations, although arrhythmias may be a problem in later life. Concern over the ability of the right ventricle to function in later life has led to the development of an arterial switch operation and the Rastelli procedure, where a valved conduit connects the right ventricle to the pulmonary artery. It is not yet clear whether these two demanding operations will improve on the results achieved with intra-atrial repairs. Mustard baffles may develop stenoses or leaks in later life, requiring careful evaluation by echocardiography and catheterization. Relief of baffle obstruction may be required and achieved percutaneously using balloon dilatation techniques.

Congenitally corrected transposition Here the great arteries are transposed but blood flows

537

correctly, as the left and right ventricles are inverted. Thus, blood flows from the right atrium through a bicuspid mitral valve into a morphological left ventricle and into the pulmonary artery. From the left atrium a tricuspid valve leads to the right ventricle and the aortic valve. Survival without surgery is common and the clinical features are dominated by associated abnormalities and problems (these include VSD, single ventricle - DORV or DOLV - and pulmonary stenosis or pulmonary vascular disease).

Abnormalities of venous return The systemic veins may drain into the left atrium, producing cyanosis with exercise. Both situations are rare on their own and are associated with other serious congenital defects. Total anomalous pulmonary venous drainage (TAPVD) into the right atrium or left innominate vein is associated with right-to-left shunting across an ASD or patent foramen ovale. The physical features are those of an ASD with central cyanosis. Operations to reroute the veins and close the ASD produce excellent long-term results, although adults are susceptible to atrial arrhythmia.

Tricuspid atresia Unoperated adults with this condition do exist, although survival through childhood is unusual without surgical intervention. Blood flows from the right atrium to the left, through the mitral valve into the left ventricle and via a VSD to a not uncommonly stenosed right ventricular outflow tract. The clinical signs are dominated by pulmonary stenosis and VSD murmurs. Cyanosis is variable and depends on the size of the VSD and degree of pulmonary stenosis. Surgical correction is by a BlalockTaussig shunt or connection of the right atrium to the right ventricle, more commonly by Fontan's procedure, where the right atrium is connected to the pulmonary artery.

Ebstein's anomaly of the tricuspid valve This condition is often acyanotic. The septal and posterior leaflets of the tricuspid valve are attached to the right ventricular wall so that a large part of the right ventricle becomes atrialized. The right ventricle is small, but the right atrium becomes enormous. There is often some tricuspid regurgitation, and occasionally the abnormal valve obstructs filling, or even emptying, of the right ventricle. There is a high incidence of patent foramen ovale or ASD, and supraventricular arrhythmias are very common. The condition often presents in adult life. It may remain asymptomatic for years and present with an abnormal chest X-

Fig. 12.20

538

ray or ECG. The patient may, on the other hand, present with right heart failure, dyspnoea on exertion and, sometimes, mild cyanosis and clubbing. Clinically, the heart is large and inactive. There is often a murmur of tricuspid regurgitation and a cV wave in the neck. ECG shows small voltages, right atrial hypertrophy and right bundle branch block. A Wolff-Parkinson-White configuration (p. 516) is common. Chest X-ray shows a globular or flask-shaped heart with a prominent convex right atrial border. Echocardiogram and cardiac catheterization findings are characteristic. Cardiomegaly alone is not an indication for surgical treatment, as arrhythmia and heart failure respond well to conventional medical therapy.

ACYANOTIC CONGENITAL HEART DISEASE Conditions where blood is shunted from left to right may initially be without cyanosis but, if undetected, high flows through the pulmonary vascular bed will eventually lead to a reversal of the blood flow and cyanosis - the Eisenmenger reaction. Thus some acyanotic lesions may later produce cyanosis.

ATRIAL SEPTAL DEFECT ASDs can be of three types - secundum, primum or sinus venosus defect (Fig. 12.50). In adult cardiology they occur in the above order of decreasing frequency. The foramen ovale only acts as an ASD if right-sided pressures exceed left, e.g. in pulmonary embolism. ASD constitutes 10% of congenital heart disease.

Pathogenesis Blood flows from the left to the right atrium, and thence to the right ventricle and lungs. Because the lungs have a low impedance to flow, shunting is considerable. The patient has a limited exercise capacity, as maximal systemic cardiac output cannot be achieved on exercise. The right ventricle hypertrophies and the lung blood flow is increased, which seems to increase the likelihood of pulmonary infections. Symptoms are usually not prominent until middle age and include dyspnoea, fatigue (low exercise cardiac output) and, quite frequently, palpitations caused by atrial arrhythmias. Heart failure, when it occurs, is usually both right and left sided, as any rise in atrial pressure on one side of the septum will shunt the blood to the other side. After middle age the pulmonary vascular resistance may rise, with the development of massive pulmonary arteries (visible on chest X-ray) and, occasionally, reversal of the shunt.

Secundum a trial septal defect Clinical features Secundum ASD (Fig. 12.50A) is usually uncomplicated. The physical signs are the result of right ventricular hypertrophy and increased flow through the right side of the heart; this causes pulmonary and tricuspid flow murmurs and delayed closure of the pulmonary valve. The associated signs are wide, fixed splitting of the second sound and pulmonary systolic murmur; a tricuspid diastolic murmur is usually heard if shunting is significant (Fig. 12.51). Investigation and management Chest X-ray (Fig. 12.51) shows enlargement of the heart, prominent pulmonary arteries, pulmonary plethora and,

usually, a small aortic knuckle. ECG shows right bundle branch block in most cases, with right axis deviation. Echocardiography shows dilated RV with a 'volume load' of the RV. O The shunt can be demonstrated by contrast injection or with colour Doppler. Transoesophageal echocardiography can best delineate the types of ASD, and also the pulmonary venous drainage in relation to the ASD. An occasional finding associated with ostium secundum ASD is mitral stenosis (Lutembacher's syndrome). Cardiac catheterization can demonstrate the size of the shunt. Blood samples taken in the different cardiac chambers show a step-up in oxygen content of the blood occurring at the lower right atrium. The shunt size can be calculated from the oxygen content of the pulmonary artery blood and left-sided samples. Angiography to delin-

ED

FIG. 12.50 Sites of atrial septal defect A Ostium secundum. B Ostium primum (or atrioventricular canal defect). The septal leaflet of the mitral valve is often involved, allowing a communication between the left ventricle (LV) and both atria. C Sinus venosus defect, where the abnormality involves anomalous pulmonary venous drainage. SVC and IVC = superior and inferior vena cava. PV = pulmonary vein.

FIG. 12.51 Features of atrial septal defect A Chest X-ray showing enlarged pulmonary arteries, pulmonary plethora and relatively small aortic knuckle. B ECG showing a vertical axis (normal) and partial right bundle branch block, [c] Phonocardiogram demonstrating wide splitting of second heart sound. D M-mode echocardiogram at the ventricular level shows a volume-overload RV with paradoxical movement of the interventricular septum (IVS) which is out of phase with the posterior wall (PW) of the left ventricle.

539

eate ASD is no longer necessary because transoesophageal echocardiography and MRI are superior imaging techniques for this. Surgical closure is usually advised if the defect is associated with a shunt that gives a pulmonary flow greater than 1.5 times systemic flow even in adults, unless pulmonary vascular resistance and pressure have become so high as to cause a right-to-left shunt (Eisenmenger syndrome) and the patient turns cyanotic. In recent years a number of devices have been developed that allow the closure of ASD by percutaneous catheter-based occluders. For suitably placed and sized ASD these techniques may soon become the closure method of choice.

Primum atrial septal defect This is a much less common form, accounting for 10% of ASDs, but is relatively common in Down's syndrome. Clinical features, investigation and treatment The clinical features are similar to those of secundum ASD, but may be dominated by an associated mitral regurgitation, and the ECG usually shows a left axis deviation. A left ventricular angiogram shows the defect. Surgical correction is more complex than for a secundum defect, and may involve mitral valve repair or replacement.

Sinus venosus defect This is usually a high right atrial defect near the junction with the SVC. It is often associated with anomalous pulmonary venous drainage into the right atrium. O

VENTRICULAR SEPTAL DEFECT VSDs may occur as isolated lesions or be associated with other congenital defects of the heart. They are relatively common (Table 12.21) and have an equal sex incidence. About 50% close spontaneously during childhood. They may occur as muscular, membranous, infundibular or posterior (AV) defects and may be multiple. There is considerable shunting of blood from left to right unless a rise in pulmonary outflow resistance occurs owing to vascular disease caused by the high pulmonary flow. In extreme cases the flow reverses, causing cyanosis and the Eisenmenger syndrome. Small ventricular septal defects Small VSDs are common and are asymptomatic. There is

540

O MCQ 12.15

Fig. 12.21

Q MCQ 12.17

Case 12.4

MCQ 12.16

a loud systolic murmur with a thrill at the left sternal edge (maladie de Roger}, with no associated cardiomegaly and minimal, if any, changes of pulmonary plethora on chest X-ray. The ECG is usually normal. Differential diagnosis is from mitral regurgitation and is simply accomplished with Doppler ultrasound. The only complication of a small VSD is the risk of endocarditis, and antibiotic prophylaxis is essential. Although the surgical mortality and morbidity for closure of small defects are low, surgery is not usually necessary. Moderate and large ventricular septal defects With larger VSDs, systemic cardiac output is limited on exercise and can produce symptoms of fatigue and dyspnoea. As they are both volume loaded, both ventricles enlarge with displacement of the cardiac apex. The pansystolic murmur and thrill typical of maladie de Roger may be softer in these patients, as the jet velocity of the VSD and the pressure gradient between the ventricles becomes smaller the larger the defect. As pulmonary hypertension becomes prominent, the murmur may almost disappear as the pressures in the two ventricles balance. Investigation and management The features of VSDs on investigation are illustrated in Figure 12.52. ECG shows biventricular hypertrophy, and there is increasing right ventricular hypertrophy with pulmonary hypertension. Chest X-ray shows pulmonary plethora and cardiomegaly with both right and left ventricular hypertrophy. As pulmonary hypertension develops, the central pulmonary arteries increase in size and the peripheral vessels become pruned. 0 Echocardiography and Doppler ultrasound can show the location of the VSD, and can be used to calculate right ventricular pressure. Magnetic resonance scanning can demonstrate the defect and measure the shunt. Surgical closure is advised unless pulmonary artery pressure has risen too high. ©

COARCTATION OF THE AORTA Coarctation of the aorta is a narrowing, or even complete interruption, of the aorta distal to the aortic arch, with blood flow to the lower body augmented by flow carried through collateral vessels. Coarctation represents about 5% of adult congenital heart disease, and is seen in males three times as frequently as in females. The condition leads to upper body hypertension and an increased risk of aortic dissection. There is often a bicuspid aortic valve, which can become stenotic (or is congenitally stenosed). Other congenital defects are sometimes associated. There is also an associated risk of subarachnoid haemorrhage from berry aneurysm of the circle of Willis. These are presumed to be an associated congenital anomaly. The coarctation is nearly always at the aortic isthmus distal to the left subclavian artery, but can, rarely, occur

upper half being the left subclavian artery and the lower half the poststenotic dilatation of the aorta. Rib-notching is seen in most adults with coarctation, and is caused by the collateral arteries. Visualization of the coarctation is sometimes possible using 2D echocardiography, and the jet can often be located with Doppler ultrasound. The investigation of choice nowadays is MRI, which can also be used in serial scans to detect any sign of recurrence after surgery. Angiography of the aorta is not always needed, but cardiac catheterization is often performed to look for associated lesions and to confirm the length of the narrow segment.

12

Management and prognosis

FIG. 12.52 Features of ventricular septal defect A The characteristic systolic murmur associated with a widely split second heart sound with a premature aortic second sound (A2) and maintained mobility of P2 with respiration (dashed line on inspiration). B Doppler ultrasound showing highvelocity jet (6m/s). C and D 2D echocardiogram showing the septal defect (VSD).

Significant coarctation should always be corrected in children, either surgically or by balloon catheter. In adults, surgical correction is the definitive treatment, although it carries higher morbidity and mortality owing to the established hypertension, which often still requires treatment even after successful correction. The associated aortic valve lesions may progress and subarachnoid haemorrhage may occur. Endocarditis prophylaxis is necessary in uncorrected coarctation. OO

PERSISTENT DUCTUS ARTERIOSUS proximal to it. It may be due to ductal tissue in the wall of the aorta, leading to progressive stenosis of the aorta, as in ductal closure. The degree of stenosis becomes comparatively more severe as the child grows. The coarctation is followed by a poststenotic dilatation in most cases; however, if there is complete interruption of the aorta there may be some atresia of the descending aorta.

Clinical features Presenting complaints include left ventricular failure, subarachnoid haemorrhage and aortic dissection; however, most cases should be identified in childhood. The coarctation itself may become the site of an endocarditis, as may the bicuspid valve. The physical signs are hypertension, a large-volume pulse in the arms and carotids, and weak, delayed femoral pulses. Occasionally, the left subclavian is involved in the coarctation, producing weak left arm pulses. There is often palpable left ventricular hypertrophy, a systolic murmur over the precordium and in the back, and palpable collateral arteries running over the medial aspects of the scapulae.

Investigation Diagnosis is confirmed by Doppler ultrasound, demonstrating a lower systolic blood pressure in the ankles than in the brachial artery. The chest X-ray often shows the characteristic '3' sign over the aortic knuckle, with the

Persistent ductus arteriosus (PDA) is a congenital abnormality caused by failure of the ductus arteriosus to close and form the ligamentum arteriosum. The result is a shunt of blood from the aorta into the pulmonary circulation. The shunt is from the aorta just distal to the left subclavian artery, and so an increased flow occurs through the left heart and pulmonary circulation but not the right heart. The ductus arteriosus remains patent for a variable time after birth, and failure to close can be associated with congenital abnormalities other than PDA. The isolated lesion is usually diagnosed in childhood from the presence of a continuous or 'machinery murmur' at the upper left sternal edge.

Clinical features Overload of the left heart can lead to heart failure in older patients. The increased lung blood flow in infants can present with the consequences of increased pulmonary vascular resistance: extremely rarely, reversal of the flow through the ductus, with cyanotic blood passing to the distal aorta, occurs, producing clubbing of the toes but not the fingers. Rarely, the ductus may be the site of endocarditis.

Investigation and management Diagnosis is based on the physical findings of the characteristic murmur, a collapsing pulse and a chest X-ray which

541

usually shows a prominent pulmonary conus and increased lung blood flow. Echocardiography and Doppler ultrasound are extremely useful in demonstrating both the lesion and the volume load on the left ventricle. Cardiac catheterization with aortography is not usually necessary in uncomplicated cases, but it may be useful in differentiating the much less common aortopulmonary window, which requires much more complex surgery. Simple cases require ligation and transection of the PDA.

identification of anatomical lesions in the coronary arteries provides information about the feasibility of interventional procedures (bypass surgery or angioplasty), but it is the significance of the physiological effects of stenoses (e.g. angina, dyspnoea, arrhythmias, ECG changes or other investigational manifestations) which provides the indication whether the lesion(s) should be operated upon.

THE CORONARY CIRCULATION Flow in normal and abnormal coronary arteries

COR TRIATRIATUM In cor triatriatum the left atrium is divided by a diaphragm above the mitral valve, which gives rise to obstruction to pulmonary venous return to the left heart. There is a variable-size orifice (or none at all) which is easily opened surgically. The condition is thus eminently treatable.

DEXTROCARDIA Dextrocardia - in which there is a mirror image of the normal heart - is usually quite benign if associated with situs inversus (stomach bubble also on the right); however, it may be associated with other congenital abnormalities and can be confused with dextroversion, in which the heart is rotated rather than being a mirror image.

FURTHER READING ON ACYANOTIC CONGENITAL HEART DISEASE

Flow through the coronary arteries is regulated, with mean flow maintained through wide changes in mean arterial pressure (see Fig. 12.54). However, coronary vascular resistance is greatly affected by extrinsic compression during cardiac muscle contraction. Compression of the intramyocardial vessels during systole means that flow occurs in diastole (Fig. 12.53). This is particularly marked for the left coronary artery. Myocardial vessels are innervated and respond to neural, humoral and local metabolites. The heart has little capacity for anaerobic metabolism and cannot tolerate an oxygen debt. It is therefore dependent on increased perfusion to cope with an increased oxygen demand. Myocardial oxygen extraction is not increased with increasing demand, which must be met by increased coronary flow due to coronary vasodilatation. The coronary vascular resistance will fall to 20-25% of its basal state in response to maximal demand during exercise. This ability to lower the resistance to flow explains why it is possible to maintain normal flow at rest even when there is an 80% reduction in the diameter of a large coronary artery. The relationship between changes in perfusion pres-

Perloff J K 1995 Surgical closure of atrial septal defect in adults. N Engl J Med 333: 513-514

CORONARY HEART DISEASE (CHD) Coronary heart disease (CHD) refers to the consequences of coronary artery disease. Atheromatous disease outweighs all other causes, but coronary arteritis and embolism can cause ischaemia. CHD can still occur in the absence of demonstrable coronary angiographic stenosis, owing either to dynamic coronary artery spasm resulting in Prinzmetal angina, or to microvascular abnormalities too small to be detected by contrast angiography. Conceptually it is important to distinguish the anatomy of coronary artery disease from the physiology of the effects of the coronary stenoses on the myocardium. The QMCQ12.18

542

FIG. 12.53 Coronary arterial flow [A! Aortic pressure. IITI Flow in the left and right coronary arteries. Note the abrupt fall in left coronary flow with the onset of systole.

12 FIG. 12.55 Anatomy of the coronary circulation LAD = left anterior descending, LCx = left circumflex (dotted line represents position of LCx at the back of the heart), RCA = right coronary artery. Section across heart (A-A) shows the approximate distribution of blood supply.

FIG. 12.54 Effect of mean coronary arterial pressure on flow Coronary blood flow (blue line) is maintained constant despite variations in perfusion pressure. At perfusion levels below 60 mmHg coronary blood flow falls because the limit of coronary vasodilation is reached. A maximally vasodilated coronary artery has a linear pressure-flow relationship, as shown (light blue line). Stenoses of varying severity will alter the pressure-flow relationship of the dilated artery as shown by the grey and black straight lines. At rest an individual might have an artery flow at point A (a perfusion pressure approximately 100 mmHg); with exercise the demand rises (dashed line) and flow increases to point B, within the capacity of a normal vessel to dilate. If the individual's coronary artery had a moderate stenosis, only point C could have been reached, which is less than the flow required, so ischaemia (angina) is produced. A critical stenosis may interfere with the delivery of the necessary resting flow (D) so ischaemia at rest ensues.

sure and resistances of coronary arteries and flow is shown in Figure 12.54.

Coronary anatomy The anatomy of the coronary circulation is shown in Figure 12.55. Three major coronary arteries provide the heart with its blood supply. Major anatomical variations are rare. The main stems of the left coronary artery (LCA) and right coronary artery (RCA) arise from the aorta at the sinuses of Valsalva. The main stem of the LCA is a relatively short vessel. It divides into the left anterior descending artery (LAD) - which is responsible for the blood supply to the major part of the left ventricle and the interventricular septum - and the circumflex artery (Cx, usually the smaller branch of the left main stem), which supplies the posterior and variable amounts of the inferior walls of the left ventricle. The RCA supplies the right ventricle and inferior left ventricle. In some individuals variable amounts of the left ventricular apex, septum and posterior wall may be supplied by the RCA. This artery usually (60% of cases) provides the SA and AV nodes with their blood supply. The myocardium has a very rich capillary network, which appears to be regulated by precapillary resistance

vessels. In addition, there is the potential for a network of collateral vessels connecting coronary arterial networks to each other. When developed, these collaterals become important in coronary artery disease. O

ATHEROMA OF THE CORONARY ARTERIES The commonest cause of changes in the luminal diameter of the epicardial coronary arteries is the presence of atheromatous plaques (Fig. 12.56). The lesions may encircle an artery or be eccentric; they may be discrete and localized, or involve the greater length of the vessel. The eccentricity of some plaques may be important when vasospasm is the cause of angina; the normal arterial wall opposite the plaque maintains its ability to contract, producing a very marked reduction in cross-sectional area even if the smooth muscle contraction is modest in degree and the atheromatous plaque small. Acute changes in the plaques may account for unstable angina, myocardial infarction and sudden death. A fissure develops, breaching the thin endothelium that covers a lipid-rich plaque. The subsequent process is shown in Figure 12.56. These events appear to account for many of the more acute forms of coronary disease, and have renewed interest in the role of thrombosis in acute cardiac ischaemia. This has led to the successful use of fibrinolytic agents and aspirin in the treatment of infarction (p. 559). Under some circumstances atheromatous plaques may regress. This has been achieved by drugs that lower LDL cholesterol and triglyceride and increase HDL cholesterol.

Clinical features Symptoms The cardinal symptom is angina pectoris. This is a chest discomfort precipitated by exertion and relieved by rest. It is often described as a pressing or constricting feeling and, less often, as a pain. It remains remarkably constant within each individual, even though its precipitants may vary significantly from day to day. The patient may hold a clenched fist in front of the sternum to indicate the squeezing nature

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A. Normal

B. Atheromatous plaque

C. Plaque dissection and acute expansion

FIG. 12.56 Progression of atheromatous lesion A and B Normal endothelium and structure of atheromatous plaque. C Acute expansion of the lesion occurs when the endothelial cells rupture, allowing haemorrhage into the plaque and platelet aggregation on the endothelial surface.

Crescendo angina and unstable angina Both crescendo and unstable angina may represent states of preinfarction. In crescendo angina a history of increasingly frequent attacks of angina with ever-diminishing levels of exertion is obtained. Unstable angina includes situations where episodes of pain are frequent, may occur without obvious cause and at rest, and where acute infarction has been excluded. Decubitus angina is angina occurring at rest in bed.

Signs There are few physical findings in uncomplicated CHD. An underlying cause, such as aortic stenosis, may give characteristic signs. There may be evidence of hypertension or hyperlipidaemia. Cardiac dilatation, hypertrophy and failure are all late features and are non-specific. Some individuals undoubtedly have significant ischaemic episodes without symptoms. This may be discovered by routine ECG, when pathological Q waves may be found with no history of any antecedent chest pains. Investigations of patients with ambulatory recorders have also shown some individuals to have changes in the ST segments usually associated with ischaemia, despite a total lack of symptoms. Even patients with known angina may have episodes of ST segment change which appear to be clinically silent. Patients with known coronary disease who have silent ischaemia fare worse than those without this finding.

Differential diagnosis of angina

Acute coronary syndromes The above is a description of typical stable atheromatous Fig. 12.22

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coronary artery disease. Several other anginal syndromes occur which are common and account for many hospital admissions and much morbidity.

of the pain, and may describe radiating discomfort in the arm (left more often than right), the jaw or even a choking sensation in the throat. Dyspnoea frequently accompanies angina. There is usually rapid relief of the symptom with sublingual, or spray, glyceryl trinitrate. The pain of myocardial infarction may be similar, but generally begins at rest, does not respond so well to nitrates, lasts longer than 20 minutes, and is often associated with feelings of impending death, nausea, sweating and collapse. Unfortunately, in many patients with CHD the first manifestation of the disease may be sudden death. Prevention of atheroma is necessary to reduce this, although out-of-hospital resuscitation may improve the survival of the few fortunate enough to collapse within reach of a person competent in basic life support.

Vasospastic angina Some degree of arterial spasm is probably present in most episodes of angina, but spasm occurring in an otherwise normal coronary artery has also been observed. It can be severe enough to cause infarction, but is very rare. In Prinzmetal's syndrome rest pain is frequent and is associated with acute ST segment elevation, which resolves to normal with cessation of pain. This condition is rare and almost certainly involves coronary vasospasm.

Valve disease. Angina is a common symptom in aortic stenosis (p. 527) and aortic regurgitation (p. 529), particularly when the valve lesions are severe or acute. In cases of aortic regurgitation due to syphilis, chest pains may be caused by severe aortic reflux, but coronary ostial stenosis may also occur. In hypertrophic cardiomyopathy, hypertrophy may lead to angina. Aortic dissection and pulmonary embolism. These are discussed on pages 599 and 675. Pericarditis. Chest pain may be severe with acute pericarditis and is exacerbated by movement, deep respiration or coughing. It is often relieved by sitting forward and by non-steroidal anti-inflammatory drugs (NSAIDs). The clinical sign of pericardial friction rub may come and go. Oesophageal spasm. The pain of oesophageal spasm may be severe and, because it occurs at rest and can be associated with T-wave changes on the ECG, it may cause con-

siderable confusion and be diagnosed as unstable angina in some patients. Hiatus hernia with oesophagitis can cause chest pain. This can be demonstrated by infusions of mild acidic mixtures into the oesophagus of affected individuals. Radiological and endoscopic methods will demonstrate the abnormalities. CHD may coexist in the same individual. Acute cholecystitis and peptic ulceration can produce severe pains in the lower chest and xiphisternal areas, and may infrequently be mistaken for acute myocardial infarction. Non-specific T-wave changes on the ECG have been observed during these acute illnesses. Da Costa's syndrome (also known by several other names, e.g. neurocirculatory asthenia) has a long history and is characterized by sharp transient chest pains, which occur with relaxation, may disappear with exertion, and are associated with easy fatigue. Mitral valve prolapse. Atypical (for CHD) chest pains may occur in patients with mitral valve prolapse of mild degree. Hyperventilation. Patients who hyperventilate may produce symptoms indistinguishable from those of angina, and may have an abnormal resting and exercise ECG to accompany their symptoms. So-called syndrome X is characterized by typical angina in association with radiologically normal coronary arteries but a positive exercise test. It may be due to microvascular disease. Tietze's syndrome may cause diagnostic confusion until the painful costal cartilage is palpated.

Investigation The aim of investigations is to confirm that the clinical history is due to significant coronary artery disease, to determine at how much risk of infarction or progression the patient may be, and whether any remediable risk factors may be present. Once coronary artery disease has been confirmed using non-invasive tests, an assessment of ventricular function may be necessary and, finally, coronary angiography performed if surgery or angioplasty are being considered. (Investigation of myocardial infarction is considered on pp. 556-558.)

ECG The resting ECG may be normal, even when coronary disease is severe. Signs of ischaemia characteristically involve the ST segments, with depression in the leads corresponding to the myocardial territory involved (Fig. 12.57). The associated T waves may be flattened or biphasic. These ECG signs are not specific, however: they may be found in some normal individuals and may be produced by hyperventilation or a change in posture. Exercise test The exercise test has been described on page 480. Exercise will induce ischaemia with coronary stenoses of 70% or more (Fig. 12.57). If a population of asymptomatic indi-

12 FIG. 12.57 Exercise ECG showing typical and severe down-sloping ST segment depression

viduals is subjected to an exercise test there will be an incidence of false positive tests up to 20%. The predictive capacity of the exercise test depends on the prevalence of the disease in the population (Bayes' theorem). Therefore, exercise tests should be avoided in patients with a low pretest probability of having coronary heart disease, as there are likely to be more false than true positive results. The exercise ECG has several uses: • To detect CHD in patients with suspicious symptoms, especially those with an intermediate probability of disease; • To identify patients at high risk of further infarction or death early after myocardial infarction; • To assess functional capacity and adequacy of treatment. Although changes in the ST segment are the most characteristic features of a positive exercise test (Fig. 12.57), O the development of angina and the workload performed up to the development of symptoms or ECG change also aid interpretation. A normal blood pressure response consists of a rise in systolic pressure by at least 20mmHg. Diastolic pressure falls with exercise, but is so difficult to measure under these circumstances that it is not routinely taken. The gravest prognostic indicator in exercise testing is a failure of systolic pressure to rise, or even a fall. The appearance of multiple ventricular ectopic beats is also associated with severe disease. Radionuclide studies Radionuclide techniques (p. 485) are complementary to the other non-invasive methods used in assessing CHD. Information on ventricular wall motion abnormalities (MUGA scan) and regional perfusion (201T1 scan) can be obtained. Echocardiography and Doppler ultrasound Echocardiography (p. 483) may be useful to assess ventricular function and wall motion abnormalities, as well as excluding non-coronary causes of ischaemia, such as aortic stenosis or hypertrophic cardiomyopathy. Ambulatory ECG (Holter) monitoring Ambulatory ECG monitoring (p. 500) is generally used to detect arrhythmias, but may also detect episodes of ST segment change during normal activities. Some of these episodes may not be accompanied by symptoms of angina

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(silent ischaemia). In the patient with known coronary disease, frequent episodes of silent ischaemia are associated with a high risk of infarction. In the patient with few or no symptoms the implications of this finding are not at all clear. The role of routine 24-hour ECG recording for ST segment analysis in CHD is not established, as it remains to be proven that the information gained is any more useful than that from the exercise test. Left ventricular and coronary angiography The aim of these investigations is to establish the functional state of the left ventricle, to exclude valve lesions that might account for the symptoms (such as occult aortic stenosis), and to obtain detailed pictures of the coronary arteries. O A global left ventricular ejection fraction (EF) of 50-70% is normal, and end-diastolic pressure is usually below 12mmHg. Subjective assessment is often sufficient to describe left ventricular wall motion abnormalities without recourse to the numerical estimation of EF. The coronary arteries are selectively intubated and cineangiograms taken in several projections. A 50% reduction in the diameter of an artery is generally considered to be a clinically significant stenosis. Cardiac catheterization provides unambiguous information on the location of coronary artery stenoses. However, the clinical significance of stenoses is sometimes difficult to judge; the exercise test and thallium scan may provide complementary information. Cardiac catheterization is indicated in all patients in whom coronary angioplasty or coronary bypass surgery is being contemplated. In some patients with troublesome symptoms and a low likelihood of CHD this examination is performed to finally exclude the possibility of coronary artery disease. This group may comprise between 10 and 20% of all patients undergoing cardiac catheterization. The invasive nature of catheterization is necessarily associated with a morbidity (<1.0%) and mortality (<0.1%). This means that angiography cannot assume the role of a screening test for coronary disease.

MANAGEMENT OF CHRONIC STABLE ANGINA Once the diagnosis is established, treatment should be aimed at restoring a normal exercise capacity. Investigations should establish the individual's risk, and contributory risk factors be reduced as far as possible. A flow diagram of the management of angina is shown in Figure 12.58.

General measures All patients should be advised to stop smoking, achieve O Fig. 12.10

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FIG. 12.58 Flow diagram of management of angina PTCA = percutaneous transarterial coronary angioplasty.

their ideal weight and have raised blood pressure controlled. Lipid measurements should be made. Those with total cholesterol >5.2mmol/L, HDL/LDL <20%, triglyceride >2.0mmol/L should be given an appropriate diet (Ch. 5, p. 136) until repeat estimations are within the recommended ranges. First-degree relatives of young patients with CHD should have their lipid levels measured. The patients with angina of effort, a normal resting ECG and chest X-ray, and whose symptoms are well controlled on simple treatment can probably be managed adequately without further investigation. The prognosis in CHD is dependent on the severity of the stenoses, the number of coronary arteries involved and on left ventricular function. This information can only be obtained accurately at cardiac catheterization, which should be offered to patients below 40 years of age, whose risk is highest. The risk of death is approximately 4% per year in other patients, but increases to between 7 and 9% if there are associated abnormalities in the resting ECG. Thus, although a resting ECG may be sufficient investigation for many patients, further determination of the risk to the individual is obtained by non-invasive tests, especially the exercise test and myocardial perfusion scanning with Tl201 (p. 486).

12

TABLE 12.23 Drugs commonly used in the treatment of angina Drug

Route

Dose

Frequency

Nitrates Glyceryl trinitrate (GTN) Tablets Spray Buccal Patches

Sublinguai Oral Buccal Skin

0.3-0.6 mg 0.4mg/spray 1-1 Omg 5-10 mg

PRN and prophylaxis PRN and prophylaxis PRN and prophylaxis Daily (omit for 8-12 hours)

Isosorbide dinitrate (ISDN)

Oral (some sustained release)

10-80mg

4-8-hourly

Isosorbide mononitrate

Oral (some SR)

10-1 20 mg

6-24-hourly

Parenteral preparations GTN ISDN

i.v. i.v.

0.6-1 2 mg/h 1-12mg/h

Infusion Infusion

fi-Blockers. Many alternatives, including: Atenolol (fa selective) Bisoprolol Propranolol (non-selective)

Oral Oral Oral

50-200 mg 5-1 Omg 30-360 mg/day

Daily Daily 6-hourly

Calcium antagonists Nifedipine Long-acting Diltiazem Modified release Verapamil Slow release

Oral Oral Oral Oral Oral Oral

10-20mg 30-90 mg 60-120 mg 90-240mg 40-120 mg 90-240 mg

8-hourly (12-24-hourly for sustained release) Daily 8-hourly (12-24-hourly for sustained release) 12 hourly-daily 8-hourly (12-24-hourly for sustained release form) Daily

New agents Nicorandil (ATP-sensitive K+ channel opener) Trimetazidine

Oral Oral

10-20mg Not available in UK

12-hourly

Catheterization may then be required for those with a positive test at low workloads, those with large reversible Tl201 perfusion scan defects, and those in whom medical treatment is not being successful.

Drug treatment The drugs commonly used in the treatment of angina are listed in Table 12.23.

Aspirin Although not a symptomatic treatment, all patients should be given 75-150 mg of aspirin per day as an antithrombotic agent. Nitrates Therapy begins with sublingual tablets or aerosol spray nitrates. These are used to treat an anginal episode and can be successfully used in prophylaxis by patients with predictable symptoms. The aerosol spray has the advantage of a long storage life compared to glyceryl trinitrate (GTN) tablets, which deteriorate rapidly in their container once

opened. The onset of action is very rapid (within 1-2 min) and its duration can be up to 20 minutes. With all nitrates troublesome headache can prevent their use in certain susceptible individuals, although this side-effect usually stops after a few days of treatment. Longer-acting nitrate preparations include glyceryl trinitrate given via the skin, using sustained-release plasters or patches. Isosorbide dinitrate is absorbed from the gut and metabolized by the liver to the active mononitrate. The duration of action is longer than short-acting nitrates, but 4-8-hourly doses are needed to maintain blood levels. Mononitrates are absorbed in the gut and do not require hepatic conversion; thus, some variability in effectiveness due to liver metabolism is avoided. Their duration of action is longer, so one or two daily doses are adequate. An idiosyncratic reaction to GTN (and also other nitrates) is syncopal attacks. Clinically, this has to be distinguished from syncope secondary to angina, which is suggestive of an arrhythmia, whereas nitrate-induced syncope is associated with bradycardia and hypotension (a vasovagal type of reaction).

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RECENT ADVANCES IN ISCHAEMIC PRECONDITIONING There is good experimental evidence that heart muscle is able to adapt to conditions of ischaemia, so that short bursts of ischaemia (in the order of 2-5 minutes, singly or repeated over a short period) will render the myocardium resistant to a much longer period of lack of blood supply. In laboratory conditions 30-60 minutes of coronary occlusion will produce infarction of 40-60% of the muscle supplied by that coronary artery. Merely occluding the artery temporarily, for 2-3 minutes once or twice before the long occlusion, can reduce infarct size to just 10-20% of the muscle at risk. This phenomenon is called preconditioning, and is associated not only with reduced infarct size, but also with a dramatic reduction in reperfusion arrhythmia. These observations are being extended to human heart muscle suffering global ischaemia, as in cardiac surgery, or regional ischaemia, as in angina and PTCA. The mechanisms underlying preconditioning are being sought, but there is good evidence to suggest adenosine receptors and opening of ATP-sensitive potassium channels may be involved. This opens up the prospects of using drugs to mimic ischaemia-induced preconditioning.

Tolerance Tolerance to nitrates develops as sulphydryl (SH) groups on the vessel walls become oxidized by constant exposure; this prevents the production of nitric oxide and stimulation of guanilate cyclase, which is believed to be fundamental to the smooth muscle relaxation produced by these drugs. A nitrate-free period of 6 hours in every 24 is sufficient to allow recovery of SH groups when longer-acting preparations are used. The tendency for patients to develop a tolerance to longacting nitrates (tachyphylaxis) limits their usefulness. No controlled trials have demonstrated an improvement in mortality with stable angina or after myocardial infarction. Their primary use therefore remains as an effective symptomatic treatment of coronary heart disease.

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-Blocking drugs |3-Adrenoreceptor blockade has become established as a cornerstone in the treatment of angina. Although many -blocking drugs with varying pharmacological properties are available, there is no overwhelming evidence to suggest that one is any better than the others. Some patients find they are unpleasant owing to a 'sedative' action and an interference with exercise capacity. They are specifically contraindicated in patients with asthma, and relatively contraindicated in diabetes and in those with peripheral vascular disease, bradycardia or heart block. A number of patients may have been mislabelled as asthmatics in the past. A safe way of testing whether -blockade may be used in these patients is by infusing esmolol (50-

200 g/kg/min), because it has the shortest half-life and any detrimental effects may be reversed relatively rapidly. A cardioselective -blocker (selective for blockade of 1 receptors > p2) may then be used as maintenance treatment, e.g. bisoprolol (2.5-5mg o.d.). In angina, these drugs achieve their benefit by reducing myocardial oxygen demand consequent on a fall in heart rate, blood pressure and myocardial contractility. There is good evidence that -blockers improve prognosis after myocardial infarction. However, no prospective trial has extended this observation to the treatment of stable angina. Calcium antagonists Calcium antagonists are effective in angina, achieving their effect by smooth muscle relaxation in the coronary arteries and peripheral circulation, increasing myocardial supply and reducing myocardial work. The three types of calcium antagonist available for clinical use are the dihydropyridines (e.g. nifedipine, nicardipine, amlodipine, felodipine), diltiazem and verapamil. They vary in their pharmacological properties, and so their indications may be different. The mode of action varies with the type of drug, all of which inhibit cellular calcium entry but differ in their tissue specificity. The dihydropyridines act primarily by arteriolar vasodilatation with minimal effects on the SA node and the myocardium. They may cause a reflex tachycardia. The action of diltiazem is more marked on the SA and AV nodes, producing a mild bradycardia, but less negative inotropy than verapamil. It is advisable to avoid using a dihydropyridine as monotherapy in angina. These drugs are best used in combination with a |3-blocker. If a |3-blocker is contraindicated, or when monotherapy with a calcium antagonist is desirable, then the use of verapamil (40-120mg t.d.s., SR 240mg o.d. or b.d.) or diltiazem (SR 90-120 mg b.d.) is recommended. The negative inotropic and chronotropic effects of verapamil are useful in antianginal treatment in those without heart failure or heart block. In heart failure the least negatively inotropic calcium antagonists are to be used, such as nicardipine, felodipine or lacidipine. Calcium antagonists are a useful symptomatic treatment for angina, with added beneficial blood-pressure-lowering action. As with nitrates, there are no prospective trial data that suggest any effect of these drugs on prognosis. There are some data to suggest that patients with good LV function may do better on diltiazem or verapamil after transmural and non-Q-wave myocardial infarction.

Nicorandil Nicorandil is now accepted as another class of antianginal agent. It is the first potassium channel opener (KCO) that has been shown to be effective in the treatment of angina. It can be used in preference to some of the above drugs in coronary artery spasm, angina in asthmatics and diabetics, and in patients with heart failure or peripheral vascular disease. It is an arterial and venous vasodilator which combines the arteriolar vasodilation of ATP-sensitive

potassium channel opening with a nitrate-like venodilatory capacity. A major prospective trial on the drug in stable angina will report in 2001/2002. Other compounds Amiodarone was introduced as an antianginal preparation but its use is now limited to the treatment of serious arrhythmia. Perhexilene alters the metabolism of cardiac muscle from FFA to glucose, and can be effective in refractory angina. In certain identifiable genotypes, however, it can have serious side-effects, including hepatotoxicity and peripheral neuropathy. Trimetazidine is marketed in some parts of Europe. It has a poorly characterized mode of action. ACE inhibitors Although there has been a demonstrable mortality benefit when these drugs are used in patients following MI, particularly when LV function is impaired, there are no convincing data on their use in stable angina. Drug combinations in angina There is a progression in therapy before medical treatment can really be said to have failed. Most patients begin treatment with nitrates or KCO and a (3-blocker. A calcium antagonist is used if -blockers are contraindicated. Elderly patients may well be adequately controlled with nitrates and a reduction in activity, and many find that -blockers induce unpleasant lethargy. Younger patients may not wish to reduce their activity, and find the prophylactic action of -blockers or calcium antagonists a considerable advantage. Verapamil and diltiazem produce profound bradycardia or heart block when used with a (3blocker, so these combinations should be used cautiously. Patients with severe disease commonly require 'multiple therapy' to control their symptoms, but the benefits of these three- or four-drug combinations are dubious. Practical prescribing in angina Provided there is no contraindication to the use of the drugs in individual patients, the schema of drug therapy shown in Figure 12.59 may be adopted: • It is generally wise to start antianginal medication by selecting the shortest-acting drugs and small doses several times a day, and build up the doses gradually if clinically indicated and in the absence of adverse reactions. In this way any unexpected adverse reaction will not be as prolonged or as severe as if larger doses and longer-acting versions had been used. Drug compliance is generally not problematic (as it can be in the treatment of hypertension). • The exception to the above rule occurs when treating coronary arterial spasm and arrhythmia secondary to myocardial ischaemia. In these conditions it is imperative to institute full therapeutic cover for the entire 24 hours using known effective doses, which can subsequently be reduced if side-effects supervene. • In vasospastic or Prinzmetal's angina the aim of treat-

ment is to prevent the powerful vasoconstriction: combination therapy using long-acting isosorbide mononitrate, dihydropyridine calcium antagonists and nicorandil may be required. p-Blockers may have to be added to counteract the reflex tachycardia and to reduce the intensity of angina by reducing oxygen demand during an attack. • In patients with other conditions concomitant with angina, drugs that precipitate angina (e.g. theophylline, digoxin, thyroxine) may have to be reduced or stopped, and an alternative therapy sought. In angina patients with heart failure and low blood pressure, or with hypertension, it may be necessary to replace their prescribed vasodilators (e.g. ACE inhibitors, a-blockers, hydralazine) with those possessing antianginal properties.

12

Coronary artery bypass graft surgery (CABG) Effective surgical treatment has had a profound effect on the management of CHD in the developed world. Coronary artery bypass grafting can now be performed with an overall operative mortality of under 1 %. Symptoms can be eradicated in 80-90% of patients and improved considerably in a further 5-10%; a few are no better or, indeed, are worse following surgery. It might therefore be asked why this form of therapy, which aims to 'revascularize' the heart, is not offered to all patients with angina. Several factors are responsible, including: • Finite morbidity from surgery • Deterioration of grafts • Survival advantage for surgical treatment has been proven for only moderate- and high-risk subgroups of patients • Benefit in symptoms has to outweigh the cost in wellbeing for up to 12 weeks postoperatively. Deterioration of grafts Saphenous vein bypass grafts have an appreciable rate of deterioration: more than 90% are patent immediately after surgery, but then occlude at a rate of approximately 2% of grafts per year between 5 and 10 years, and at 4% per year thereafter. About 60% of grafts are patent after 10 years. This implies that surgery is not a permanent cure, merely another method of symptom control in these patients. Improvements in early vein-patency rates have been achieved by the use of antithrombotic agents, such as aspirin. Even more significant has been the use of the internal mammary arteries (IMA) as grafts. This is more demanding technically, but has been shown to provide greater than 90% patency rates at 10 years. Unfortunately, complete cardiac revascularization is not often possible even when both IMA are used. Survival advantage Survival is improved by surgery in those with left main stem disease and those with three-vessel coronary disease and impaired left ventricular function (Table 12.24). It is

549

FIG. 12.59 Schema for medical antianginal therapy

very likely to improve survival in patients with severe angina, three-vessel coronary disease and normal ventricular function. The situation is less clear for patients with less marked symptoms and those with little in the way of symptoms but with a positive exercise test, although evidence is mounting that this group of patients also benefit from surgery. Surgery appears to be a more effective treatment for patients with continued symptoms not controlled by drugs. There is a diminution in fatal heart attacks, but probably not in non-fatal events. Randomized studies have failed to show any differences between medical and surgical treat-

O MCQ12.19

550

0 Fig. 12.23

Case 12.5

TABLE 12.24 Indications for coronary artery surgery in angina Indication

Comment

Left main stem stenosis Symptoms uncontrolled despite maximal medical treatment Impaired LV function especially with three-vessel coronary artery disease Proximal stenosis in left anterior descending coronary artery with positive exercise test at low workload

Proven survival benefit of surgery Improved survival with surgery in some subgroups of patients Improved survival with surgery Likely improved survival with surgery

ment in the numbers of patients who return to work, or in the amount of recreational activity they take up. However, the sociological measures may not reflect the changes in perceived quality of life in the two groups of patients.

TABLE 12.25 Indications for coronary angioplasty Indication

Comment

All indications for surgery (except left main stem stenosis) where coronary lesions suitable* Symptomatic single-vessel coronary disease

Single- and double-vessel PTCA. Low risk, high efficacy

Coronary disease where surgery impossible ('salvage PTCA') In AMI, especially if thrombolysis contraindicated

PTCA is as good and safe as surgery but patients face a higher incidence of recurrence A suitable approach in the very elderly or infirm Survival advantage over thrombolysis

* Suitable coronary lesions: proximal, discrete, not involving major branches, recent onset, non-calcified, circumferential lesions.

Thus, in general, patients are considered for coronary artery surgery if medical therapy fails to control their symptoms adequately, or if they fall into the above higherrisk groups. These broad guidelines conceal a large number of patients in a rather grey area, in whom individual assessments must be made. These might include young patients with severe stenoses causing highly positive exercise tests, in whom the consequences of occlusion might be a disabling infarction and in whom an internal mammary graft might be expected to be a highly successful treatment. Patients with extensive left ventricular aneurysm may often improve, in terms of heart failure control and anginal symptoms, with plication or resection of the aneurysmal area.

Changes in surgical technique A number of new, less invasive methods of coronary revascularization are currently in use. They share the aim of avoiding the requirement for cardiopulmonary bypass and its attendant complexity and morbidity. Their application is more limited than that of conventional CABG and the long-term advantages over CABG, or indeed angioplasty, have not yet been assessed by trial. O

Percutaneous transarterial coronary angioplasty (PTCA) (Table 12.25) © The indications for percutaneous transarterial coronary angioplasty (PTCA), first introduced in 1977, are similar to those that select for surgery. In most centres one or two stenoses are tackled by angioplasty, and patients with severe three-vessel coronary disease are generally considered for CABG. Patients with left main stem disease are also not considered for PTCA, unless surgery is impossible for technical reasons or because of coincidental disease. Intracoronary stents are now routinely deployed following balloon angioplasty. Debate continues regarding their optimal use, but the great improvement in immediate angiographic appearances, the virtual eradication of the

need for urgent CABG in emergencies, and the rapid reduction in the cost of stents has fuelled their adoption in advance of randomized trials.

IB

Restenosis Initial experience with PTCA revealed a >30% angiographic restenosis rate, with a need for further intervention in up to 25% of patients. The routine use of stents has halved these incidences, and in selected cases symptomatic restenosis rates may be less than 10% at 1 year. Patients with small arteries (<2.5mm diameter) and those with very large arteries (>4.0mm diameter) are best managed without stents, but they form less than 10% of the PTCA population. The determinants' recurrence are unknown, but most patients are given antithrombotic treatment with aspirin and newer antithrombotic agents, clopidogrel or ticlopidine. Some patients receive calcium antagonists and/or nitrates as treatment for vasospasm. Immediate complications such as vessel occlusion, myocardial infarction or the requirement for urgent surgery have diminished dramatically with the development and increased use of coronary stents. Overall, complications for elective PTCA now should approximate 1 %. O

Newer techniques Interventional cardiology is a rapidly evolving field. In

RECENT ADVANCES - INHIBITORS OF PLATELET AGGREG/VTORY RECEPTORS Despite the availability of aspirin, heparin, warfarin and fibrinolytic agents (streptokinase, tPA, urokinase), the treatment of certain conditions such as unstable angina and the result of angioplasty of acute ischaemic syndromes are still unsatisfactory because of unpredictable tendencies to thrombus formation and acute occlusion. Indeed, it has been suggested that intracoronary infusion of fibrinolytic agents can, paradoxically, hasten thrombus formation. There is therefore a need to find more effective agents that will prevent intravascular thrombus formation without causing significant bleeding complications. Platelet IIB/IIIA receptors are necessary to form a meshwork of interlinked platelets, which is an essential process to induce new thrombus formation. Inhibitors of this receptor prevent this and have shown promising results in the treatment of unstable angina and in reducing the incidence of acute occlusions peri- and postangioplasty. Three types of such inhibitors are being tested: monoclonal antibody against the receptor, peptide inhibitors, and chemical non-antibody and nonpeptide inhibitors. The relative efficacies of these agents in the treatment of diverse manifestations of the acute ischaemic syndrome have yet to be elucidated.

551

farction. Symptomatic treatment alone is associated with a mortality of about 12-15%, with a further 12% of patients suffering full transmural myocardial infarction within 12 months. An enormous amount of effort has gone into establishing the most appropriate protocols to manage these patients, particularly as many of the options are technically sophisticated or demand the use of very expensive new drugs.

FIG. 12.60 Technique of coronary angioplasty A The guide catheter is introduced into the coronary ostium. B A steerable guide wire is advanced across the lesion. C The balloon catheter is advanced from the guiding catheter over the guide wire and positioned so that the balloon straddles the narrowing. D Balloon inflation splits and compresses the atheromatous plaque. E After deflation, the balloon is removed and the arterial wall shows irregularity at the site of the narrowing. F A balloon-mounted stent is deployed G The stent remains in situ to be re-endothelialized within weeks.

order to extend the principles of PTCA to more demanding lesions, various devices have been developed. These include laser-assisted PTCA (mostly for occlusions on calcified lesions), atherectomy devices, devices to remove thrombos, and catheters capable of delivering drugs or radiation therapy directly to the lesion. Their precise roles continue to be defined.

ACUTE CORONARY SYNDROMES(ACS)

552

These syndromes, which include the clinical diagnoses of unstable angina, non-Q-wave myocardial infarction and rest angina, share much of the pathophysiology of acute myocardial infarction. Rupture of the fibrous cap over an atheromatous plaque, intracoronary thrombus formation and myocardial ischaemia are common to all. Numerically, the acute coronary syndromes now account for more hospital admissions than acute myocardial in-

Management The diagnosis relies on the clinical history of crescendo angina (p. 544) or rest pain, which is not associated with ST segment elevation on the ECG or with significant cardiac enzyme elevation (CK or CKMB). The patient should be admitted into a coronary care unit where bed rest is imposed. Light sedation can be helpful. Medical therapy includes oxygen, aspirin (150-200mg orally) and heparin with i.v. nitrate. Close monitoring of blood pressure is required during nitrate infusion, and the systolic pressure should not be reduced by more than 20%. p-Blockers and calcium antagonists may be added when symptoms persist despite increased doses of i.v. nitrate. Use of thrombolytics in unstable angina does not improve the prognosis and may even worsen outcome. Opiates should be used if pain is persistent. Heparin and aspirin are well established in the treatment of ACS. Low molecular weight heparin has the advantage of ease of use (subcutaneous injection rather than i.v. infusion), more predictable effects on clotting parameters and probably better outcomes in ACS than with conventional i.v. unfractionated heparin. It is, however, more expensive, although increased drug cost may be mitigated by savings in overall patient care (no i.v. pump, fewer laboratory tests, etc.). Recently, more powerful antiplatelet agents, including the oral agents ticlodipine and clopidogrel and the parenteral platelet glycoprotein Ilb/IIIa receptor inhibitors, have been used in ACS. The former can be used when there is aspirin intolerance or allergy. Several trials of IIb/IIIa receptor antagonists have shown that these parenterally given drugs can reduce the combined complications of death and myocardial infarction. They are very expensive and will initially be used in the highest-risk subgroup of patients, as well as those undergoing urgent angioplasty. The timing of cardiac catheterization and angioplasty in ACS is hotly debated. In the USA and some countries in Europe early investigation and PTCA is the norm. In countries such as the UK, with less well-developed cardiac intervention facilities, fewer patients are investigated, and in those that are, the tests are performed later, sometimes electively in the post-discharge recovery period. Long-term outcomes appear comparable whichever strategy is used.

Risk stratification in ACS (Table 12.26) Straightforward clinical features can be used to identify patients at high risk of death or myocardial infarction from

12

CASE STUDY 12.3 INCREASING CHEST PAIN A previously well man of 68 years came to the emergency department with a history of increasingly severe chest pains. The pains were central and radiated to the angle of the jaw. Although he had initially noticed milder pains precipitated by activity and emotion, for the previous 2 nights he had been woken from sleep with increasingly severe episodes of the same discomfort. The last bout of pain had been about 8 hours previously and had lasted altogether for 40-45 minutes. It was not associated with sweating, nausea or other sensations. The pain had woken him from sleep. Initially he thought it was indigestion, but its persistence, and lack of response to antacids, led him to seek advice. He had no significant past medical history but was having treatment with a statin for a hyperlipidaemia detected by a routine screen by his GP. He was an ex-smoker, having given up 6 months prior to presentation, and he had a strong positive family history of ischaemic heart disease with three first-degree relatives suffering myocardial infarction before the age of 60. In the emergency department his initial ECG was normal, but half an hour later he began to suffer chest pains and a further ECG revealed flattening of the T wave in lead AVL and 1.5mm horizontal ST segment depression in leads V4, V5 and V6. He was given sublingual glyceryl trinitrate (GTN), the pain resolved and ECG returned to normal after 10 minutes.

Question How might the diagnosis of an acute coronary syndrome be confirmed and how should the patient be subsequently managed?

Discussion Acute coronary syndromes rely upon a classical history related to myocardial ischaemia in the absence of transmural infarction. Infarction should be excluded by the absence of evidence from the ECG (ST elevation and subsequent development of Q waves and T-wave changes). In addition, to diagnose acute myocardial infarction a 2-3 fold elevation in creatine kinase enzyme and its isoform CK-MB should be demonstrated. The characteristics of the chest pain in infarction also suggest the diagnosis in that the pains tend to be more prolonged than in an acute coronary syndrome, not responsive to GTN and often associated with other symptoms such as nausea, sweating and breathlessness. Acute coronary syndrome is often therefore a diagnosis of exclusion. In this case the association of ST segment depression with pain is a highly important prognostic factor. Additional important prognostic features include the presence of an elevated myocardial specific enzyme in the blood, either troponin T or troponin I. Elevations of these enzymes during acute coronary syndrome presentation is associated with a much higher incidence of

ACS. Continuation of chest pain despite adequate treatment, the presence of ST depression with chest pain, or the development of T-wave changes identify a high-risk group. An early indicator is the detection of elevations in the cardiac-specific troponins T or I. These patients will generally benefit from cardiac catheterization with a view to revascularization, usually

complications. Indeed patients with angina-type pains in whom the troponins are negative 6-8 hours after the symptom have a very low risk of subsequent events and can usually be discharged safely from hospital for further outpatient evaluation. This patient is in a high-risk subgroup which requires stabilization. Mainstays of treatment include intravenous nitrate therapy plus heparinization using low molecular weight heparin. Beta-blockers are used and help to control the pain. The smooth-muscle potassium channel activator nicorandil causes arterial dilatation and may also improve the immediate situation. There is discussion as to whether all patients with acute coronary syndromes in the higher risk groups should automatically be offered invasive investigation with cardiac catheterization and angiography. This is the most common approach in Europe, the USA and Australia. Cardiac catheterization and angiography are essential if patients have further episodes of pain with or without ECG change despite pharmacological therapy. A case can be made for delaying angiography in those patients whose symptoms disappear on the initial treatment. If patients require cardiac catheterization, additional treatment with drug inhibitors of platelet aggregation (by binding to the Ilb/IIIa cell surface receptor), such as clopidogrel or ticlopidine, further improves their prognosis and decreases the risks of acute . angiography and angioplasty treatment.

by PTCA. Angioplasty and stent treatment is further improved, in terms of both immediate and long-term outcome, if these patients are given bolus plus infusions of Ilb/IIIa receptor inhibitors immediately before or during the coronary intervention. Those patients - often the majority - without ECG changes on troponin elevation (Fig. 12.61) may safely be

553

RECENT ADVANCES IN LASER

TRANSMYOCARDIAL REVASCULARIZATION

FIG. 12.61 Cardiac specific troponin I levels to predict risk of mortality in patients with acute coronary syndromes

TABLE 12.26 Risk stratification in ACS, The presence of just one feature may be sufficient to classify a patient who is clinically at high risk of death or Ml from ACS. Feature

Low risk

High risk

ST depression 3=1 mm with pain 8 hr troponin T or troponin I

Absent

Present

Negative

Failure to control episodes of chest pain T-wave changes Haemodynamic disturbance with pain Conventional risk attributes in acute Ml/ischaemia, e.g. old age, poor LV Previous Ml

Absent

Positive - the higher the enzyme, the higher the risk Present

Absent Absent

Present Present

Absent

Present

discharged early for conventional outpatient investigation by exercise testing or Tl201 scanning, and management similar to that for those with stable angina. The diagnostic work-up should include identification of other conditions that may exacerbate angina, such as anaemia, hypertension, thyrotoxicosis, severe anxiety and cocaine abuse.

FURTHER READING ON CORONARY HEART DISEASE 554

Braunwald E 1998 Unstable angina: an etiologic approach to management. Circulation 98: 2219-2222.

One of the prerequisites of coronary artery bypass surgery or angioplasty is that the coronary arterial stenoses should occur proximally in epicardial coronary arteries. If the stenoses occur distally, especially if the distal intramyocardial vessels are affected, neither of these two procedures will produce much benefit. Certain medical conditions, such as diabetes mellitus, predispose to such distal disease. Hitherto, the only option has been cardiac transplantation, for either severe cardiac failure or intractable angina. Recently, laser transmyocardial revascularization has been developed as a potential alternative. During open chest surgery, thin rays of powerful laser beams are directed from the epicardial surface towards the left ventricular chamber in a myocardial region that has been shown to be viable, and either ischaemic or hibernating. Through a process which has not yet been elucidated, the epicardial portion of these artificial channels spontaneously seals up, leaving intramyocardial channels communicating with the ventricular chamber, and effectively forming new coronary vessels. Preliminary studies suggest that perfusion and oxygenation of these myocardial regions can be restored towards normal, and that symptoms and functional status can be significantly improved in selected patients. The effects on ventricular function need investigation. Clinical studies are currently in progress, and the applicability of this technique in practice will depend on the results.

Shepherd J, Cobbe S M, Ford I et al. 1995 Prevention of coronary heart disease with pravastatin in men with hypercholesterolaemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 333:1301-1307. The Bypass Angioplasty Revascularisation Investigation (BARI) Investigators. 1996 Comparison of coronary bypass surgery with angioplasty in patients with multi-vessel disease. N Engl J Med 335: 217-225. Yusuf S, Zucker D, Peduzzi P et al. 1994 Effect of coronary artery bypass graft surgery on survival: overview of 10-year results from randomised trials by the Coronary Artery Bypass Graft Surgery Trialists Collaboration. Lancet 344: 563-510.

MYOCARDIAL INFARCTION In the UK about 200000 people suffer a myocardial infarction each year. Half die from the infarction, and, of these, half do so before they reach hospital (Fig. 12.62). Most of this group suffer an arrhythmia, and death occurs instantaneously or within 1 hour of the first symptom. Clearly, these deaths will only be avoided by measures that prevent the development of coronary disease, although

TABLE 12.27 Mortality from acute myocardial infarction Class

Definition

1

Uncomplicated, without clinical signs of LV failure Generally asymptomatic, but manifesting a ventricular third sound, basal crackles or raised venous pressure Clinical evidence of pulmonary oedema Cardiogenic shock indicated by a systolic BP below 90 mmHg and at least one of: oliguria (<20mL/h), low skin temperature, or mental confusion

II

III IV FIG. 12.62 Mortality following onset of acute myocardial infarction A high proportion of patients die of ventricular fibrillation within 1 hour of onset.

prehospital and community resuscitation schemes can make an impact. Hospital admissions for infarction total 70-80000 per year in the UK, with an overall in-hospital mortality around 10%, plus a 10% mortality in the first year. The acute mortality varies with the type of infarct, from 3-6% for the patient with an uncomplicated infarction injuring only a limited amount of myocardium, to 50-80% with massive myocardial necrosis and shock (Table 12.27). The amount of muscle damaged determines both early and late outcomes from infarction. The advent of coronary care units (CCU) has led to a reduction in acute mortality, which has fallen from over 20% in 1966-67 to under 10% in the 1980s.

Admissions (%)

Mortality

33

6

38

17

10

38

19

81

12

(%)

Data from: Killip and Kimball 1969 American Journal of Cardiology 20: 457-467.

buccal nitrates. Associated symptoms are sweating, nausea, vomiting, breathlessness and collapse. Like angina, the pain may radiate to the arms, throat and jaw. Many patients believe they are suffering from indigestion and consume antacids. With the advent of thrombolytic therapy, it has become even more important to be aware of possible differential diagnoses in the patient with acute chest pain (p. 544).

Examination DIAGNOSIS OF MYOCARDIAL INFARCTION The clinical syndrome is less precise than the pathological definition, but a working diagnosis includes two of the following: • A typical history • The evolution of characteristic ECG change ending with Q-wave formation • A significant elevation and subsequent fall in creatine phosphokinase, preferably the MB isoenzyme fraction, aspartate transaminase, hydroxybutyrate dehydrogenase, or cardiac troponin-T.

CLINICAL FEATURES History A squeezing or tight, chest or epigastric pain, with its onset at rest, is reported by 80% of patients, a large proportion (40%) of whom may have an antecedent history of angina. The pain lasts longer than angina - typically more than 20 minutes - and is resistant to treatment with sublingual or

There are no specific features that accompany myocardial infarction. During the acute phase patients vary a great deal in their appearance, and the physical signs are largely those associated with pain and fear and are initially dominated by autonomic nervous activity. With acute anterior infarction there is a tendency for sympathetic activity to predominate, with a tachycardia, cool pale periphery and a normal, or even slightly raised, blood pressure in the early minutes. This contrasts with acute inferior infarction, which is commonly associated with massive vagal discharge, producing a cold sweaty periphery, bradycardia, hypotension, nausea and vomiting. The blood pressure tends to fall to lower than normal for the patient within a few hours of infarction, but some may have a hypertensive reaction. The venous pressure is generally normal in the early stages unless there has been extensive right ventricular involvement, which may occur with an inferior or posterior infarction. In left ventricular infarction, heart failure may develop and the pulmonary venous pressure will rise, signifying severe myocardial damage. Auscultation commonly reveals a fourth heart sound and a third sound over the apex in those patients in incipient left ventricular failure. The left ventricular impulse may be anterior and dyskinetic when a large

555

segment of left ventricular wall is moving paradoxically; this is particularly marked later in those individuals who develop an aneurysm. Orthopnoea and basal crackles are present in patients developing pulmonary oedema. A pyrexia develops within 12 hours in patients who suffer significant myocardial injury; it may persist for up to a week and is associated with a polymorphonuclear leukocytosis. Pericardial friction rubs are occasionally encountered soon after infarction, and signify a large loss of myocardium extending to the epicardium. This finding is distinct from the pericarditis and pneumonitis of Dressler's syndrome, which is a rare complication occurring during the first 6 weeks after a myocardial infarction and which has an immunological basis (p. 566). Other physical signs in myocardial infarction are due to the mechanical complications of the condition and are discussed individually below.

INVESTIGATION ECG changes in acute infarction The ECG changes of acute infarction may take some hours to develop, and occasionally are completely absent. Treatment of acute infarction must often begin before there is any objective evidence confirming the diagnosis (a rise in plasma enzyme levels also takes some hours to occur). 57 segment elevation The most characteristic feature of infarction on the ECG is the development of ST segment elevation, with a convex upward pattern in the leads facing the area of ventricle infarcted. The diastolic isoelectric line is depressed, so accentuating the ST elevation that follows it (Fig. 12.63). Reciprocal ST depression is often seen in leads opposite the infarction; this is usually indicative of severe multiplevessel coronary disease, but may on occasion represent a purely electrical phenomenon. ST elevation (the current of injury] is produced by ischaemia, and can occur in the absence of infarcted tissue. Thus, such ST changes can be associated with anginal pain due to coronary vasopasm (Prinzmetal's angina), and resolve rapidly and completely when spasm is relieved and ischaemia reversed. ST elevation during acute infarction lasts for some days but may persist longer. If it is still present some weeks after infarction, left ventricular aneurysm or extensive dyskinesia is likely.

556

T-wave inversion The terminal portion of the T wave begins to invert within hours of infarction and produces symmetrical inversion after a few days (Fig. 12.63). This appearance persists for weeks or months, and is occasionally a permanent feature of the ECG. In some patients at the very earliest stage of infarction the only ECG change may be in the T waves, which become very prominent, peaked and symmetrical.

FIG. 12.63 Evolution of ECG change in an acute inferior infarction Initially there is marked ST segment elevation in II, III, aVF, and reciprocal depression in V2-V4. At 12 hours a Q wave is developing in II, III and aVF, and the ST segment has returned to the baseline. At 48 hours the Q wave has deepened and broadened and there is T-wave inversion.

This appearance is sometimes called the hyper acute pattern of infarction. Symmetrical T inversion alone, without Qwave formation, may indicate a limited infarction in some patients (see non-Q-wave infarction, below) and this has important implications for their management. Q-wave formation Q waves are often the latest change to be seen on ECG. They are often permanent and are sometimes considered the definitive ECG change of infarction. They must have a depth of at least 25% of the succeeding R-wave height (or greater than 3mV) and last longer than 40ms (one small square at 25mm/s). They may appear within 24 hours of infarction and are associated with loss in R-wave height of the corresponding leads. Alternative patterns Ideally, ECG proof of infarction should include successive traces showing the presence and resolution of ST segment elevation. T-wave inversion and pathological Q-wave formation (Fig. 12.63). Often such a classic progression is missing, and the diagnosis may rest on a slightly deeper than normal Q wave in V4, loss of R-wave height or the absence of the small q waves of initial septal depolarization in I, aVL, V5 and V6; this may occur in septal infarc-

12

tion, but is also produced by incomplete left bundle branch block. In the presence of bundle branch block the ECG changes due to infarction may be difficult to detect or absent. With right bundle branch block septal depolarization occurs normally. Changes in ST segments and T waves may appear, but the ECG diagnosis of infarction often cannot be made with certainty. Bundle branch block patterns may precede infarction or be a consequence of it.

Localization of infarction from the ECG Although myocardial infarction can be endocardial, epicardial, or involve the whole thickness of the ventricular wall, these distinctions cannot reliably be made by ECG. Localization to an approximate region of the left ventricle is possible, however. The precordial leads give most information in this respect. If they have been correctly positioned, leads VI and V2 face the right ventricle, although an extra lead (V4R, at the level of V4 on the right of the sternum below VI) is better; V3 faces the interventricular septum; V4 the anterior and lateral borders; and V6 the posterolateral wall of the left ventricle (this is because the apex faces backwards).

FIG. 12.64 ECG of acute anterior infarction ST segment elevation in V1-V6 and Q waves in V2-V4.

Inferior infarction In inferior infarction, changes are seen in leads III, aVF and II, with reciprocal change in I, aVL and the anterior leads. Inferolateral infarction extends to involve lead V6. The right coronary and its posterior descending branch account for most of these cases (Fig. 12.63). Anterior infarction Anterior infarction is extensive when leads V2 to V6 are involved with changes in I, aVL and II. There may be reciprocal changes in the inferior leads II and aVF. Anterior infarction implies involvement of the LAD coronary artery. Infarction may be anteroseptal when the ECG changes are limited to leads V3 and V2. Anterolateral infarction may present with changes in I, aVL and V5, with some involvement in V4 and V6 (Fig. 12.64). Posterior infarction The true posterior infarction is usually caused by occlusion in the circumflex coronary artery, and its hallmark on the ECG is a tall R wave in VI (Fig. 12.65). There is often associated ST depression in leads V2 and V3, with subsequent peaking of T waves in Vl-3. Non-Q-wave and subendocardial infarction Non-Q-wave infarction is a rather imprecise term used to identify patients who have the hallmarks of MI without full ECG change or enzyme rise. Non-Q-wave MI is now more correctly considered with acute coronary syndromes.

Laboratory tests Infarction causes the release of intracellular enzymes into

FIG. 12.65 ECG of acute posterior infarction Inferior ST elevation (in II, III, aVF) and a tall R wave in V1 (mirror of the Q wave) are shown.

the circulation. These may be used to estimate the size of the infarction. Classically, creatine phosphokinase (CK) has been used to detect muscle damage and specificity for cardiac muscle injury improved by assays of a more cardiac-specific isoenzyme (CK-MB). CPK and CPK-MB rise within hours of infarction, and fall within 24-48 hours. The absolute peak of CPK or CPK-MB gives a crude estimate of the size of infarction. Lactate dehydrogenase (or its more cardiac-specific isoenzyme LDH1 is assayed as hydroxybutyrate dehydrogenase (HBD); it appears in blood within 12-24 hours after infarction and may remain elevated for some days (see Table 12.28). Elevations of the contractile protein components, troponin I (cTnl) and troponin T (cTnT) are now taking the place of LDH (HBD) enzymes. Bedside quantitative troponin testing is now widely available and is particularly

557

TABLE 12.28 Biochemical markers of myocardial infarction Marker

Range of time to initial elevation in h

Mean time to peak (h)

CK-MB

3-12

24

cTnl

3-12

24

cTnT

3-12

12h-»2days

LDH

10

24-48

Myoglobin

1-4

6-7

Adapted from Taegtmeyer H Biochemistry of acute myocardial infarction. In: Francis GS, Alpert JS eds Coronary Care. Boston: Little, Brown & Co 1995: 45

useful for stratification in ACS. In patients presenting late, or where CK enzyme analysis is equivocal, the tendency for cTnl and cTnT to persist for days after the event can be diagnostically helpful. Myoglobin is highly specific and appears early, giving promise as a tool for more rapid identification of patients likely to benefit from thrombolytic treatment. A raised polymorphonuclear leukocyte count and an elevated erythrocyte sedimentation rate (ESR) are non-specific accompaniments of acute infarction. A very high ESR in the early stages of infarction raises the possibility of infarction being secondary to a giant cell arteritis or immunological disease such as polyarteritis nodosa.

Imaging techniques Radionuclide studies may be used to measure ventricular function (MUGA scan, p. 487) or document areas of potentially reversible ischaemia (201T1 scan, p. 486). The echocardiogram can be used to assess ventricular function and localize areas of infarction and dyskinesia.

can be produced by the sudden increase in right ventricular work associated with an acute massive pulmonary embolism. Syncope is often the first manifestation of the embolism, which is associated with marked dyspnoea, tachypnoea and cyanosis. Acute pericarditis (p. 586) produces chest pain, often accompanied by a fever and a friction rub.

MANAGEMENT OF ACUTE INFARCTION The aims of management are pain relief, infarct limitation, and the treatment of arrhythmic and mechanical complications. Management is subsequently directed to defining the relatively small proportion of patients at a greater than normal risk in the postinfarction period, and to rehabilitation and secondary prevention.

Analgesia and oxygen Fear and pain exacerbate some of the ill effects of sympathetic hyperactivity. Analgesia and sedation is achieved with opiates, preferably diamorphine (2.5-5.Omg i.v.) or morphine sulphate (4-8mg i.m.). These drugs combine sedation with an advantageous vasodilatory action, which improves haemodynamics. Respiratory depression is rare in the setting of acute infarction. The relief of pain itself may help raise blood pressure and reduce the heart rate. Associated nausea is treated using metoclopramide (10 mg i.v.) or prochlorperazine (12.5-25mg i.m.). An inhaled mixture of nitrous oxide and oxygen (Entonox) provides pain relief prior to arrival in hospital. Oxygen by mask is frequently given to patients with acute infarction to counteract the hypoxaemic effects of pulmonary oedema. However, many patients are not hypoxaemic, and in such cases oxygen delivery to the tissues will not be improved by this treatment.

Acute (3-adrenoreceptor blockade DIFFERENTIAL DIAGNOSIS Acute chest pain syndromes can pose diagnostic difficulties in acute myocardial infarction (p. 544), particularly as there are no specific physical signs in acute infarction and the diagnostic tests may be normal in the initial hours of the attack. With the advent of thrombolysis and acute p-adrenoreceptor blockade used early in the management of acute infarction, diagnostic accuracy has become even more important. The symptoms of aortic dissection (p. 599) may be very similar. Pain indistinguishable from acute cardiac ischaemia

Acute intravenous (3-blockade can be given safely to many acute infarction patients. Large-scale trials have shown a small rate of reduction in early deaths caused by reinfarction and cardiac rupture. An additional effect is a reduction in pain. Acute intravenous -blockade would have to be given to 200 patients to prevent one death, one reinfarction and one cardiac arrest. Chronic therapy after infarction saves two lives for every 100 patients treated for 1 year.

Limitation of infarct size Six hours is the time limit within which it is possible that measures to restore blood supply will salvage ischaemic muscle. If collateral channels are poor, this time limit may be considerably less.

MCQ 12.20

558

Thrombolysis In approximately 80% of patients a myocardial infarction

is caused by thrombotic occlusion of a vessel, usually superimposed on an atherosclerotic plaque. Despite the first use of thrombolytic agents in myocardial infarction as early as 1958, their adoption as one of the mainstays of treatment followed the publication of two giant trials using streptokinase. A single injection of 1.5 x 106 units i.v. over 1 hour within 12 hours of the first symptom reduced mortality by 18%. More than 200000 patients have now been randomized in therapeutic trials with thrombolytic agents. The most widely used agents remain streptokinase and the recombinant tissue plasminogen activator rtPA. Haemorrhagic complications occur, though sufficiently rarely as not to interfere with the overall beneficial effect of therapy. Patients with clotting disorders, a previous history of stroke or peptic ulceration, and those with severe hypertension or any injuries are excluded from this treatment. It is important to exclude aortic dissection, as fibrinolytic treatment can prove catastrophic. Other relative contraindications are a known hypersensitivity to the drug, recent streptococcal infection, survivors from cardiac arrest who have had cardiac massage, and those with heart block who may need a temporary pacemaker. Streptokinase should not be administered within 2 years of a previous treatment. Benefit from thrombolysis is increased if it is given within 6 hours (and preferably 3 hours) of the first symptom. This has led to newer fibrinolytic agents that can be administered at the site of the presenting symptoms, by either the ambulance crew or the GP. Aspirin and heparin Aspirin alone reduces mortality by 25%, and with streptokinase gives a combined reduction of 45%. Continuous infusion of heparin after thrombolysis and after coronary angioplasty is routine in many centres. Patients with large infarctions suffer fewer systemic emboli from ventricular clot if treated with heparin. Bleeding complications and stroke are slightly more common. Heparin treatment is potentially more important after the shorter-acting rtPA, when it should be given for 48 hours. Warfarin treatment is limited to those in AF, or where a large LV thrombus is shown. Angioplasty and surgery Early revascularization during acute infarction may be the revascularization method of choice, but the cost of providing a 24-hour service for these complex, labourintensive techniques is considerable. Individual cases will continue to be so treated in centres where angioplasty or surgical suites are closely linked to the acute admission wards.

Nitrates and calcium antagonist drugs Nitrates by intravenous infusion (2-10 mg/h for isosorbide, 1-12 mg/h for GTN) are frequently used in the acute phase of infarction, where persistent pain is a problem; their use

is associated with a modest reduction in mortality. They have the advantage of causing reduction in preload and afterload, which may relieve left heart failure (see p. 493). Hypotension can be a problem, particularly in patients who are dependent on a high right heart filling pressure to maintain stroke volume, such as those with right ventricular infarction. Cutaneous therapy is best reserved for the less acute stages of infarction, when converting patients from intravenous infusion to maintenance therapy. Calcium antagonist drugs are effective in improving ischaemic cardiac pain, but their use has not been associated with any improvement in infarction mortality. Calcium antagonists, particularly the rate-slowing agents diltiazem and verapamil, can be used when there are contraindications to -blockade. O

12

ACE inhibitors Given within a few days of infarction there is an early benefit, which has now been proved to persist for many years (>4) post MI. These drugs should not be given while patients are hypotensive, particularly during the acute stages of myocardial infarction. Benefit from ACE inhibitors is probably not adequately explained purely by their vasodilatory and antihypertensive effects.

HMG-CoA reductase inhibitors - the statins More than 70% of myocardial infarction survivors in the UK have a total cholesterol >5 mmol/L. There is now convincing evidence that the majority will benefit from being treated with a statin.

Bed rest, mobilization and rehabilitation Bed rest during the acute phase of infarction is aimed at minimizing harmful cardiac remodelling processes. However, prolonged bed rest is unnecessary and can cause complications of its own (such as deep vein thrombosis, pulmonary embolism, deconditioning and bedsores). Prophylactic subcutaneous heparin (12 500 U b.d.) may be indicated if prolonged bed rest is necessary. Mobilization can begin within 24 hours in uncomplicated infarction. Patients can generally be discharged on the 10th day, having demonstrated their ability to walk and manage a flight of stairs before returning home. Mobilization should be slowed if there is a return of chest discomfort, a heart rate below 50bpm or above 120 bpm, the return of ischaemic ST elevation on the ECG, or an increase of more than 15mmHg in systolic pressure with gentle ambulation. Acute myocardial infarction is quite a distressing experience. Patients should be counselled individually and many of them appreciate a clear explanation of the condition and prognosis in simple layman's terms. Advice on risk factors (e.g. stopping smoking) can be initiated at this stage.

559

TABLE 12.29 Thrombolytic agents in myocardial infarction Feature

t-PA

Streptokinase

Anistreplase (APSAC)

Reteplase

Plasma clearance time (min) Fibrin specificity Piasminogen binding Antigen icity Risk of hypotension Method of administration

4-8

15-25

50-90

>20

Minimal Indirect Yes Yes i.v. infusion (1 h)

Minimal Indirect Yes Yes Bolus

High Direct No No Bolus

Licensing

Moderate Direct No No Bolus + i.v. infusion Licensed

Licensed

Licensed

Expense

High

Low

Moderate

Unlicensed in UK ??

TABLE 12130 Contraindications to thrombolytic therapy

TABLE 12.31 Benefits of treatment during and after acute myocardial infarction

Major contraindications Any previous history of haemorrhagic stroke History of stroke, dementia or CNS damage within 1 year Head trauma or brain surgery within 6 months Known intracranial neoplasm Suspected aortic dissection Internal bleeding within 6 weeks Active bleeding or known bleeding disorder Major surgery, trauma or bleeding within 6 weeks Traumatic cardiopulmonary resuscitation

[ACUTE Ml] Deaths prevented/1000 patients treated Treatment i.v. p-Blocker

Relative contraindications Oral anticoagulant therapy Acute pancreatitis Pregnancy or within 1 week postpartum Active peptic ulceration Transient ischaemic attack within 6 months Dementia Infective endocarditis Active cavitating pulmonary tuberculosis Advanced liver disease Intracardiac thrombi Uncontrolled hypertension (SBP >180mmHg, DBP >110mmHg) Puncture of non-compressible blood vessel within 2 weeks Previous Streptokinase therapy (for repeat treatment with SK)

FURTHER READING ON MYOCARDIAL INFARCTION

560

Ball S G (ed) 1995 Myocardial infarction: from trials to practice. Petersfield: Wrightson Biomedical, p. 194 Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology 1996. Acute myocardial infarction: prehospital and in-hospital management. Eur Heart J. 17: 43-63

7

Oral -blocker Aspirin

[POST Ml] Major event prevented (including death and Ml) per 1000 patients treated

21 deaths 21 reinfarction 24

7 deaths 9 reinfarction 3 strokes

Streptokinase and aspirin

52

ACE inhibitor HMG-CoA reductase inhibitor

Smoking cessation

5-8 -

? 7 deaths 11 CABG/PTCA 12 Ml 3CVA 4 heart failures 15 deaths 46 reinfarction

(Adapted from British Cardiac Society ACCSAP Commentary)

•

COMPLICATIONS OF MYOCARDIAL INFARCTION ARRHYTHMIAS Arrhythmias are a common complication of myocardial infarction.

Tachycardias Sinus tachycardia Sinus tachycardia (heart rate greater than 100 bpm) is associated with a poor prognosis if it persists despite control of pain, anxiety and cardiac failure. -Blockers will reduce its incidence but cannot be given to patients with severe impairment of ventricular function or hypotension. Ventricular fibrillation VF is a lethal arrhythmia which can complicate acute myocardial infarction from the moment of coronary occlusion. It is the cause of most cases of sudden death due to CHD. Its peak incidence is in the first few hours of the attack, when it is termed primary VF and, if successfully dealt with in an otherwise uncomplicated infarction, has a good prognosis. Secondary VF occurs several days or weeks after infarction, usually in patients who have suffered extensive muscle damage and heart failure. Its prognosis is then very poor. Treatment is by DC defibrillation; the earlier it is used, the more likely is a successful outcome. The procedure itself is described fully on page 519. Lidocaine (lignocaine) is also given after successful defibrillation to prevent further episodes. Limitations on the use of lidocaine (lignocaine) include its narrow therapeutic margin, central nervous system side-effects being the most common. Doses have to be reduced in the elderly and in those with poor hepatic function. The use of lidocaine (lignocaine) to prevent VF is controversial. Many episodes of VF are preceded by multiple or frequent ventricular ectopic beats, or early ectopics falling on the vulnerable period of the ECG - the R on T phenomenon. Warning arrhythmias give frequent false positive and false negative associations and their treatment does not reduce the incidence of VF. Ventricular ectopic beats At an early stage (6-72 hours) in an acute myocardial infarction, frequent ventricular ectopic (VE) beats (>10VE/h) are seen in 70% of patients. Ectopy then diminishes, so that only 10% of patients have frequent VEs at the time of discharge. Frequent VEs at the time of discharge from hospital carries an increased (two- to threefold) risk of death in the first year. This association appears to be independent of ventricular function. Although drugs to effectively inhibit ectopic activity are available, controlled trials have not shown any benefit and, indeed, some worsening survival associated with treatment of frequent or complex VE. Treatment of frequent VEs is indicated if their occurrence causes symptoms due to an effective bradycardia or diminished output. Ventricular tachycardia Haemodynamic disturbance and degeneration to VF is common with sustained VT in acute infarction. DC shock therapy is indicated in almost all cases, to be followed by intravenous or oral therapy (p. 515). Lidocaine (ligno-

caine) is usually used in the acute situation, followed by other Vaughan-Williams class I drugs and amiodarone. Although drug therapy may suppress the arrhythmia the effect on survival is less certain. Patients with non-sustained VT should probably be monitored carefully, and receive a predischarge exercise test and oral antiarrhythmic therapy for the first few weeks after infarction. The risk of death is increased if VT is present at discharge.

12

Accelerated idioventricular rhythm Occasionally a ventricular rhythm at a rate of 60-90 bpm can arise. It generally has broad complexes, but they may be narrow if the origin is high in the bundle of His. This rhythm rarely requires specific treatment, but may be an indication of profound sinus and AV nodal suppression, which may respond to atropine (0.6-1.2mg). Investigation and adjunctive therapy Patients suffering from VF or early ventricular arrhythmia may be treated conventionally. Those with late or secondary arrhythmia deserve very careful inpatient assessment, including angiography. Revascularization by CABG or PTCA may be necessary. Increasingly, patients who remain at risk of sudden death post MI will be offered treatment with an implantable cardioverter defibrillator (AICD), especially if an arrhythmic tendency persists after adequate revascularization. Supraventricular tachycardia Atrial fibrillation (AF) is the commonest supraventricular tachycardia seen in acute infarction, atrial flutter being relatively uncommon. Tachycardias causing severe haemodynamic disturbance are usually best dealt with by DC cardioversion. In atrial flutter this is generally the treatment of choice, as low energies are often required to convert to sinus rhythm. In AF, digoxin is given by oral loading (p. 511) (0.5-1.0mg a.d.) followed by 0.125-0.25 mg o.d. Control of AF rate may require the concurrent administration of another drug (p. 511). -Blockers are often used, and verapamil or diltiazem are also effective. Paroxysmal atrial tachycardia may complicate acute infarction; if hypotension is severe, DC cardioversion is the therapy of first choice. Intravenous adenosine or verapamil is effective in terminating many of these episodes, and intravenous -blockade (atenolol 5mg or metoprolol 515 mg) may be an alternative. If the first-choice drug fails to produce a satisfactory slowing of the rhythm or conversion to sinus rhythm, it is best to use DC cardioversion to avoid additive negative inotropic effects of antiarrhythmic drugs. An alternative therapy for atrial flutter and atrial tachycardia is overdrive pacing; this has the advantage of avoiding negatively inotropic drugs but requires a temporary transvenous pacemaker placed in the right atrium.

Bradycardia Bradycardia is often transient and requires no treatment.

561

When it produces symptoms or impairs the haemodynamics, treatment with a pacemaker or drugs is required. Sinus fyradycardia Up to 80% of patients with acute inferior infarction develop a heart rate less than 60bpm in the very early stages of the condition. This usually responds to atropine (0.5-1.Omg i.v.), but if symptomatic bradycardia persists a temporary pacemaker is required.

Heart block First-degree heart block The lengthening of the PR interval may be seen during the evolution of an infarction, particularly inferior infarction. When pre-existing it requires no action. However, lengthening PR intervals deserve observation, as this implies interference with AV node function, and progression to higher grades of block may occur. Second-degree heart block Both Mobitz types I and II (p. 502) require very careful observation. Progression to complete heart block and sudden death is uncommon with inferior infarction, where Mobitz type I is a frequent, though transient, complication (about 15% of cases). In anterior infarction with extensive involvement of the interventricular septum, Mobitz type II block may be seen and carries a poor prognosis (80% mortality) which owes more to the associated large mass of muscle loss than to the conduction disturbance itself. Temporary pacemakers should be used in all cases where second-degree block produces symptoms (e.g. syncope) or haemodynamic disturbance, or when antiarrhythmic drugs are to be given. A permanent pacemaker should be considered for survivors of anterior infarction with persistent block. Third-degree or complete heart block Complete heart block is a common complication of inferior infarction (about 10% of cases), when treatment is along the same lines as for second-degree block. It needs no specific treatment if well tolerated, but temporary cardiac pacing should be employed if heart failure, or rates less than 50bpm, occurs. In anterior infarction, complete block (incidence approximately 5% of cases) may occur suddenly or be preceded by bifascicular block (see below). It generally occurs in large infarctions involving the septal tissue where the conducting tissue is concentrated, and always requires treatment with a permanent pacemaker. This may not always improve survival but management is considerably eased. Complete heart block rarely persists, but if it does persist beyond 7-14 days after infarction a permanent pacemaker is required.

562

Bifascicular and trifascicular heart block Interruption of conduction through the right bundle and

either fascicle of the left bundle constitutes bifascicular block. When the anterior fascicle is involved (left anterior hemiblock, LAH) the QRS axis is greater than -30° with small r waves in II, III and aVF and absent initial q waves in V5 and V6. Posterior fascicular block (left posterior hemiblock, LPH) produces a rightward axis shift (greater than +100°) with an S wave in I and Q in III. Trifascicular block is any combination of bifascicular block associated with a long PR interval. The association of right bundle branch block with LPH in anterior infarction indicates considerable ischaemic damage, and its appearance is an indication for prophylactic use of a temporary pacemaker, as progression to complete block may be sudden. Right bundle branch block with left anterior hemiblock does not carry such a poor prognosis, and is a slightly less powerful indication for pacing.

Temporary transvenous cardiac pacemakers The indications for implanting a pacemaker in acute infarction are summarized in Table 12.32. There are various methods by which pacing can be achieved, but in general transvenous routes are the most stable and can be maintained for the few days that are required. The methods require the insertion of a bipolar electrode into the right ventricular apex, usually under radiological control. Pacing thresholds of under 1 V at 2 ms pulse width duration should be established, as the threshold tends to rise after implantation. To achieve this, it may be necessary to try various positions in the right ventricular apex. The pacemaker is an external box which is always set in the demand mode; this ensures the patient's ventricular activity is sensed and pacing only begun when the intrinsic heart rate falls below a preset rate (usually between 70 and 90bpm). A stable position of the temporary electrode is confirmed by establishing pacing at an output of 1 V, and ensuring ventricular capture is not lost during maximal inspiration, coughing or sniffing. There should be sufficient slack in the electrode to accommodate these movements of the thorax without displacing the tip of the electrode. Once the electrode position is finalized it is secured to the skin under a sterile dressing. Except in an emergency, it is rarely justified to manipulate a temporary pacemaker after it has been inserted for some time, as sterility cannot be assured. If displacement has occurred, a replacement pacemaker will be required. Threshold measurements should be checked daily, or more frequently if the patient is pacemaker dependent. The pacemaker settings are adjusted to provide a voltage output of at least three to four times threshold. A threshold of over 2 V is an indication to replace the electrode. Atrial and dual-chamber pacing Although pacing via a ventricular electrode is sufficient in most instances, there are circumstances where atrial or dual-chamber pacing is required. The former can be used to treat atrial flutter or bradycardia-dependent rhythms

TABLE 12.32 Indications for temporary pacemaker in acute myocardial infarction (Ml) A. Indicated regardless of Ml site Symptomatic and drug-resistant bradycardia due to:

B. Indicated in anterior Ml All indications in A

C. Not indicated First-degree heart block alone

sinus bradycardia, sinus arrest, SA block

RBBB + LPHB

Asymptomatic Mobitz type I

second-degree heart block

RBBB + LAHB

Asymptomatic bradycardia or junctional rhythm

third-degree heart block

Trifascicular block:

Sick sinus syndrome with bradycardia-tachycardia Drug-resistant tachycardia DC shock-resistant tachycardia Ventricular standstill Alternating LBBB with RBBB

long PR + LBBB long PR, RBBB + LPHB or LAHB Second-degree heart block, especially if Mobitz type II

12

LAHB ' LBBB RBBB

in isolation

LPHB .

LAHB = left anterior hemiblock; RAHB = right anterior hemiblock; LPHB = left posterior hemiblock; LBBB = left bundle branch block; RBBB = right bundle branch block

when AV nodal conduction is intact. Electrode positioning is more difficult and stability can be a problem. In dual-chamber or physiological pacing, sequential pacing of first the atria, followed, after a suitable pause, by the ventricles, offers a near physiological system maintaining the atrial contribution to cardiac filling. This can be very important in severe ventricular impairment, right ventricular infarction, or when there is associated valvular disease, such as aortic stenosis. The technique requires suitable dual-chamber pacemakers and the expertise to implant atrial as well as ventricular electrodes; availability is thus likely to be limited to specialized cardiac centres.

CARDIAC FAILURE Dyspnoea, basal crepitations and the radiographic signs associated with pulmonary oedema (p. 492) are frequently encountered in the early stages of infarction.

Management Prompt treatment with intravenous loop diuretics (furosemide (frusemide) 20-40 mg or bumetanide 1-2 mg) has been the mainstay of treatment. Larger initial doses are often given, but are rarely necessary and may produce hypotension, worsening the patient's overall condition. Diamorphine 2.5-5.0 mg i.v. is also helpful, and oxygen, given by a close-fitting, low dead-space mask (e.g. MC mask at 4L/min) is indicated. The preferred treatment is now with vasodilatation using intravenous nitrates, reducing preload. Patients with low blood pressure and heart failure are best managed using arterial and indirect left atrial pressure measurement. The latter is obtained with a Swan-Ganz catheter placed in a pulmonary arterial branch (see below). The aim of treatment should be to decrease the indirect left atrial pressure (or pulmonary capillary wedge pressure) to less than 20mmHg, while maintaining systolic blood pressure above lOOmmHg and diastolic

pressure over 60mmHg. Nitrates with inotropes (dobutamine ± dopamine) may be better than diuretics in these difficult cases. A week after infarction, introduction of ACE inhibitors has been shown to improve prognosis.

CARDIOGENIC SHOCK Cardiogenic shock in myocardial infarction is defined as hypotension with a systolic pressure under lOOmmHg; it is invariably accompanied by ventricular failure, peripheral vasoconstriction and oliguria (<20mL/h of urine), and usually arterial hypoxaemia, mental confusion and metabolic acidosis (Table 12.33). Remediable causes, such as uncontrolled pain, arrhythmia or excesses of negatively inotropic or vasodilating drugs (e.g. p-adrenoreceptor blockers or calcium antagonists and diamorphine) should be excluded and treated specifically. Shock is caused by damage affecting 30-40% of ventricular muscle mass and, if untreated, carries an 80-100% acute mortality. Treatment is by early revascularization, especially by PTCA. It may reduce early mortality to 50-60% at 1 month.

RIGHT VENTRICULAR INFARCTION Right ventricular infarction may produce cardiogenic shock, as defined above, but carries a very much better prognosis. The findings are a lower than expected indirect left atrial pressure and a relatively high right atrial pressure. The ECG shows changes of inferior or posterior infarction, and lead V4R may reveal the infarction clearly. Treatment consists of maintenance of a high right-sided filling pressure, which may have been inadvertently lowered by diuretics given to treat the seemingly high venous pressure. The cardiac output and systemic pressure may respond to infusion with colloid. Inotropes and diuretics may thus be avoided altogether in these patients.

563

TABLE 12.33 Cardiogenic shock in myocardial infarction Features (in increasing order of severity) • hypotension (SBP<100 mmHg) • thready impalpable peripheral pulses • pale and cool hands/feet/nose ± peripheral cyanosis • oliguria/anuria • sweat! ness • mental obtundation Exclude shock due to: • absolute/relative hypovolaemia (especially in the presence of RV infarction) • drugs (especially diamorphine, morphine, nitrates, p-blockers) • vasovagal reaction (tends to be bradycardiac) • heart block/bradyarrhythmia • tachyarrhythmia • tamponade • other causes (septicaemia, anaphylaxis) Investigations • echocardiography (essential) • haemodynamic monitoring - thermodilution Swan-Ganz catheter ± arterial cannula

Management Pressure monitoring, including indirect left atrial pressure, systemic arterial pressure and a facility for measuring cardiac output, are the minimum requirements for managing patients with shock. Therapy consists of oxygen,

RECENT ADVANCES p-BLOCKADE FOR HEART FAILURE

564

Following studies showing that angiotensin-converting enzyme inhibitors (ACEIs) can prolong the survival of patients with heart failure, a recent study has shown that carvedilol, a vasodilating (3-adrenergic blocker, used in addition to ACEIs, can further improve survival. This result has produced a major shift in our ideas of managing heart failure, away from that of using positive inotropic and chronotropic agents to enhance cardiac performance to that of using a negative inotropic and heart slowing agent instead. The exact mechanisms of why ACEIs and -blockers produce beneficial effects whereas oral positive inotropic agents (such as milrinone, enoximone, flosequinan) worsen mortality is unknown, but one simple likely explanation is that activation of the sympathetic and renin-angiotensin-aldosterone systems commonly seen in heart failure leads to increased loss of cardiac myocytes, which is further accelerated by positive inotropic agents, and can be substantially diminished by using ACEIs and P-blockers.

inotropic agents, diuretics and, very rarely, mechanical support of respiration by ventilation and of the circulation with intra-aortic balloon counterpulsation (see below). Inotropic agents are required to maintain the systolic pressure to perfuse the tissues, but are arrhythmogenic and may increase oxygen requirements. Diuretics are used to relieve pulmonary oedema, but adequate ventricular filling pressures must be maintained or else cardiac output falls. The inotropic agents of choice are dopamine, dobutamine and phosphodiesterase inhibitors (milrinone, enoximone and amrinone). Dopamine Dopamine has three important actions, which appear at increasing dose ranges. Low-dose dopamine infusion (0.5-2.5 jig/kg/min) primarily produces renal and mesenteric vessel dilatation, and is frequently used at this dose

RECENT ADVANCES IN VENTRICULAR ASSIST DEVICES AND ARTIFICIAL HEARTS With improvements in the treatment of various cardiac diseases (notably myocardial infarction and lifethreatening arrhythmia), the incidence of heart failure rises steadily. The demand for cardiac transplantation cannot be met because of a severe shortage of donor hearts. Alternatives are being explored. Transplanting genetically engineered immunologically compatible animal hearts may become feasible, but there are ethical problems raised by the antivivisection lobby and the theoretical fear of trans-species transmission of unknown viral or prion infections. Technological advances have made the development of a reliable artificial heart a distinct possibility in the next few decades. The first problem was infection, especially at the points of insertion of tubes through the skin. The development of a new battery system, which can be charged across the intact skin, has made possible the implantation of the entire device inside the body. The second major problem is compatibility with blood, which advances in material science have largely overcome. Other problems, such as avoidance of haemolysis, size of device, fracture, bleeding and thrombus formation, have to be surmounted. The comparison of today's pacemaker technology with that of 50 years ago provides optimism that artificial hearts may become a medical reality in this century. In the meantime, those patients who suffer severe transient reversible myocardial hypofunction (for example due to myocardial stunning) may require mechanical support of the circulation to 'rest' the myocardium and allow it to recover. The use of ventricular (usually left ventricular, but occasionally biventricular) assist devices to support the circulation for a short period allows the patient to buy time until myocardial function is restored.

12

CASE STUDY 12.4 CHEST PAIN AND PULMONARY OEDEMA A 67-year-old diabetic man with no previously known cardiac history was transferred as an emergency to the cardiology unit. He had presented a few hours earlier to his local emergency department with a 3-day history of chest pain and was noted to have an ECG consistent with an extensive antero-septal infarction. There were widespread Q waves visible in leads V2-V6, and there were virtually no R waves in the anterior chest leads. 3 mm of ST segment elevation was visible from V2-V4. They were unable to give him thrombolysis due to hypotension; his blood pressure on arrival was 70/40. His chest X-ray showed gross pulmonary oedema, and his oxygen saturation on air was low and could only be barely maintained with a high volume oxygen mask. On arrival to the cardiac unit, he was noted to be tachycardic with a blood pressure of 60/40 and barely conscious. Oxygen saturation was 88% with signs of gross pulmonary oedema. He had an indwelling urinary catheter and a documented urine flow of 50 mL of urine over the previous 3 hours. The ECG was as described by the referring hospital. Arterial blood gases confirmed hypoxaemia with an acidosis giving a pH of 7.14 and a base excess of 13.

Question How should this patient with cardiogenic shock due to recent cardiac infarction be managed? Discussion This man presents the picture of cardiogenic shock due to myocardial infarction. This carries a greater than 80% acute mortality. Firstly he requires resuscitation and stabilization. His gas exchange is poor, he has pulmonary oedema and is exhausted by the effort of breathing. He was therefore intubated as an emergency and ventilated. Unfortunately, the act of intubation led to a further fall in systemic pressure. Although pharmacological support of pressure could have been instituted with dobutamine by intravenous infusion, it was decided to support the circulation by inserting an intraarterial aortic balloon pump. He was transferred to the cardiac catheterization laboratory, where the pump was inserted percutaneously from the right femoral artery. One-toone ventricular assistance was set up with an immediate improvement in mean arterial pressure from 40 to 60 mmHg. Signs of ischaemia on the ECG improved as did blood gases and acidosis.

as a renal protector during times of systemic hypotension. Medium-dose dopamine infusion (5.0-lOug/kg/min) has a direct myocardial inotropic action, and at high doses (>10[ig/kg/min) the drug produces peripheral vasoconstriction (a-adrenoreceptor mediated), thereby raising systemic pressure at the cost of vasoconstriction in tissue beds, including renal. The drug must be infused through a large central vein, and at medium to high infusion rates may precipitate cardiac arrhythmias. Dobutamine Dobutamine is a synthetic dopamine analogue which directly stimulates (3i receptors; unlike dopamine, it does not release noradrenaline (norepinephrine) and so is less affected by the reduction in cardiac stores of this hormone in chronic heart failure. Dobutamine can be used via a

The patient proceeded immediately to angiography which revealed a proximal occlusion on the left descending coronary artery but normal circumflex and right coronary. An infusion of a Ilb/IIIa antagonist was begun and the occlusion re-opened by balloon angioplasty with a subsequent stent insertion. The angioplasty was uncomplicated apart from a short burst of ventricular tachycardia soon after reperfusion. This did not require treatment. He was transferred back to intensive care and was able to be extubated the next day. Cardiogenic shock is an extremely severe complication of myocardial infarction with a very high mortality. It appears likely that mortality is reduced to 40-50% by revascularization using emergency angioplasty. In these circumstances intra-aortic balloon counter-pulsation is the treatment of choice to support the circulation without the complications of additional pharmacological therapy. The patient recovered and was able to be discharged from hospital. He had some residual impairment of ventricular function and subsequent treatment was along the lines of secondary management of a myocardial infarction.

peripheral vein and the dose is usually between 2.5 and 40|ig/kg/min. Its action is primarily inotropic, and hence improves cardiac output while at the same time reducing ventricular filling pressures. Combination therapy Dopamine in low dose to promote renal bed vasodilatation and dobutamine in doses to achieve an improved cardiac output are often used in combination in cardiogenic shock; lower doses of each can thus be used. Filling pressures (measured via a Swan-Ganz catheter) are titrated against systemic pressure and the drug dosages adjusted every 10 minutes to achieve an optimal cardiac output and sufficient perfusion pressure to maintain renal, cerebral and myocardial function while avoiding excessive heart rates and pulmonary oedema. Ideally, therefore, the

565

dose of dobutamine is adjusted every 10 minutes until the cardiac output reaches a plateau. Dopamine is adjusted to achieve a reasonable urinary output (>60mL/h); this may require support with intermittent bolus doses of loop diuretics. Left atrial pressure is maintained between 15 and 20mmHg (below the threshold to produce pulmonary oedema and above the level that begins to impair cardiac output). The right atrial pressure is maintained high enough to support the cardiac output and left atrial pressure. The heart rate is kept between 100 and 120 bpm and systolic blood pressure between 110 and 120mmHg, with a diastolic pressure near SOmmHg. The patient should be comfortable in this state, with near normal arterial oxygen saturation and no acidosis. Mechanical support Mechanical support of the circulation can be achieved using intra-aortic balloon pump counterpulsation. Mechanical ventilation of patients in cardiogenic shock is justified if they are to be offered more definitive therapy. Coronary angioplasty improves the outlook in these patients. The technique involves passing a balloon catheter into the descending aorta, by percutaneous techniques allied to cardiac catheterization. The balloon is then inflated with helium and deflated, triggered to the ECG. This produces an enhanced aortic diastolic pressure.

ACUTE VENTRICULAR SEPTAL RUPTURE AND RUPTURED PAPILLARY MUSCLE Acute ventricular septal rupture and ruptured papillary muscle are uncommon and very severe complications of acute myocardial infarction. They tend to occur 2-10 days after the acute event and produce sudden deterioration, with acute heart failure, shock, and the development of a new systolic murmur. It may be impossible to differentiate the two conditions clinically, although echocardiography and Doppler ultrasound can do so in most cases. Treatment is early surgery in both instances, although mortality remains high. There may be an advantage to allow tissues to 'heal' before closure of a VSD, but unfortunately most patients will succumb before sufficient time elapses. There are some conspicuous successes with early surgery and, when possible, circulatory support prior to operation may be life-saving.

cally by the sudden onset of severe pain followed rapidly by cardiovascular collapse. Resuscitation from this event is unusual; the clinical picture is of electromechanical dissociation (EMD), where an ECG rhythm is present but no output ensues.

VENTRICULAR ANEURYSM Ventricular aneurysm is a late complication of myocardial infarction in 10-15% of patients. True aneurysms cause thinning and paradoxical motion of portions of the ventricular wall. Recurrent arrhythmia, refractory heart failure, embolization and rupture are the complications of true aneurysms, which are manifest clinically by paradoxical precordial pulsation, persistent ST elevation on the ECG and an abnormal LV border contour on the chest Xray. False aneurysms are limited cardiac ruptures whose structure has become organized and stabilized; the main complications include those of true aneurysms as well as a greater tendency for late and fatal rupture. Surgery is the treatment of choice for all false aneurysms and symptomatic true aneurysms. Antiarrhythmic therapy may be necessary and anticoagulation for true aneurysms is wise, as 60-70% of them contain thrombus.

DRESSLER'S OR POSTMYOCARDIAL INFARCTION SYNDROME Dressler's syndrome is an immunological syndrome of pleuropericarditis which may occur in 1-4% of patients, 2-12 weeks after infarction (or open heart surgery). Antibodies directed against the sarcolemma and subsarcolemma of myocytes may be found. The clinical syndrome is similar to acute pericarditis (p. 586), with pain, fever, leukocytosis, a high ESR and a 'pericarditic' ECG in 50% of cases. It must be differentiated from extension of myocardial infarction, pulmonary embolism or pneumonia. Treatment usually consists of NSAIDs, although steroids may be required for severe and recurrent episodes. The prognosis is good.

PROGNOSIS AFTER MYOCARDIAL INFARCTION

CARDIAC RUPTURE

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Cardiac rupture is a much commoner cause of sudden death in hospital than has previously been recognized (10-20% of in-hospital deaths). It typically occurs several days after the acute infarction and appears to be commoner in men, in those with higher blood pressures, and in those who suffer anterior infarction. Acute -blockade protects from this complication, which is manifested clini-

After a myocardial infarction the prognosis of the patient is dependent on the success of treatment of the complications described above, the likelihood of recurrence or extension of the infarct, and the extent of eventual impairment of cardiac function. Despite modern advances in medicine, some 40% of myocardial infarction victims die without reaching the hospital. In the prethrombolytic era the introduction of coronary care units resulted in an

approximate halving of hospital mortality rates from about 30% to about 15%, and the predominant cause of death changed from fatal arrhythmias to heart failure. After surviving an acute myocardial infarction, the prognosis is dependent on: 1. The extent of ventricular impairment 2. The propensity to life-threatening arrhythmia 3. The possibility of further infarction. The extent of left ventricular dysfunction is dependent on: • The state of left ventricular function prior to the infarction • The size and nature of the infarction • The subsequent repair and remodelling processes • The amount of viable myocardium still in jeopardy from ischaemia (inadequate blood supply and cardiac myocytes functioning in energy deficit), stunning (reasonable blood supply but myocyte contraction impaired) or hibernation (reduced blood supply but myocytes downregulated so as not to be in energy deficit). Thus, patients with diminished starting numbers of cardiac myocytes (due to either previous myocardial infarctions or old age - secondary to natural attrition of myocytes, which averages about 35% from the age of 18 to 90 years, or previous cardiomyopathy) or pre-existing ventricular dysfunction from any cause (e.g. valvular or hypertensive heart disease) would not tolerate the same myocardial infarction as well as those with normal or athletic hearts. Obviously, patients incurring a larger myocardial infarction are likely to have a worse prognosis than those with a smaller infarction. The repair processes post infarction may be impaired (e.g. by concomitant therapy with corticosteroids or NSAIDs), leading to a greater likelihood of infarct expansion and ventricular aneurysm formation, resulting in a ventricle that functions less well than one with normal scar tissue formation. The most important long-term prognostic indicator is left ventricular dysfunction. The clinical diagnosis of heart failure is a good indicator of dysfunction; patients with heart failure post infarction have 2-4 times greater mortality rates than those without. The simplest measurements of dysfunction are left ventricular ejection fraction or endsystolic volume, the depression of which has been found to correlate with mortality. These patients deserve a more aggressive approach to treatment, in terms of risk factor reduction, ACE inhibition and, if indicated, revascularization (see below). The presence of arrhythmias at rest or during exertion is an adverse prognostic indicator after myocardial infarction. Arrhythmias can be identified by Holter monitoring, exercise tests or direct electrophysiological studies. Frequent ventricular ectopics or inducible ventricular tachycardia are predictive of sudden death. Late potentials in averaged ECGs and reduced heart variability are also predictive of life-threatening arrhythmias. High-grade AV

block and bundle branch block resulting from myocardial infaction are associated with a poor outcome. Residual myocardial ischaemia, as manifested by postinfarction angina or positive exercise tests, is an important predictor of reinfarction and mortality. High-grade stenosis or occlusion of the infarcted related artery supplying a large portion of the left ventricle is an independent prognostic indicator. Much prognostic information can be obtained from clinical data and non-invasive investigations (e.g. ECG, chest X-ray, exercise tests, echocardiography) and, if indicated by these, more sophisticated or invasive investigations may then be performed. It is important to point out that, although various parameters may be predictive of prognosis, this does not imply that therapeutic attempts to improve these parameters necessarily lead to benefits to patients or improved outcome. A rational approach to management is required.

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FURTHER READING ON PROGNOSIS AFTER MYOCARDIAL INFARCTION Emanuelsson H, Karlson B W, Herlitz J 1994 Characteristics and prognosis of patients with acute myocardial infarction in relation to occurrence of congestive heart failure. Eur Heart J 15: 761-768. Gaudron P, Eiles C, Kugler I, Ertl G 1993 Progressive left ventricular dysfunction and remodelling after myocardial infarction. Potential mechanisms and early predictors. Circulation 87: 755-763. Stevenson R, Ranjadayalan K, Wilkinson P, Roberts R, Timmis A D 1993 Short and long term prognosis of acute myocardial infarction since introduction of thrombolysis. Br Med J 307: 349-353.

MANAGEMENT OF MYOCARDIAL INFARCTION SURVIVORS The objectives of management post infarction are to initiate or continue the management of ongoing complications described above, and to minimize the chances of further myocardial infarction, either as infarct extension or as infarction in a new territory. The ideal treatment for the latter is to produce a regression of all coronary artery stenoses, but this remains unattainable. Current techniques of revascularization (coronary bypass surgery or angioplasty) are not without risk and should therefore be reserved for those with most to gain in terms of symptomatic relief and/or prognosis. Assiduous attention to risk factor management is required as part of the rehabilitation programme.

Investigations after myocardial infarction The objective of investigation is: • To select high-risk patients for therapy which has been shown to reduce mortality, reinfarction or heart failure

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• To establish the cause (s) of symptoms • To exclude patients who will derive little or no benefit from therapy, or are likely to be harmed by therapy • To assess functional capacity and prognosis. To this end many patients would benefit from a formal predischarge or follow-up stress test (e.g. exercise ECGs, exercise/stress radionuclide myocardial perfusion scan) and an assessment of left ventricular function (using either echocardiography or radionuclide ventriculography). (A cautionary note: interpretation of exercise ECGs after infarction requires skill, as false positive results are not infrequently found.) The incidence of subsequent coronary events is low in those who have a good exercise capacity without positive test results. Coronary angiography may be considered in those with stress-induced angina or evidence of myocardial ischaemia, especially in patients with impaired left ventricles. Patients with postinfarction angina, especially after non-Q-wave myocardial infarction, even without positive exercise ECGs, should be considered for coronary angiography.

Drug therapy A simple principle recommended when introducing drug therapy in the coronary care unit is that any cardioactive agent is preferably introduced using small frequent doses of the shortest-acting drugs to avoid major or prolonged adverse reactions, and the doses increased subsequently or changed to longer-acting versions. The exceptions to this rule are the treatment of life-threatening arrhythmias or prevention of coronary artery spasm or acute occlusion, when known full effective doses that will cover the entire 24 hours of the day should be introduced, and the doses reduced or changed to alternatives if side-effects become intolerable. p-Blockers The most successful agents in secondary prevention of further coronary events following myocardial infarction are the (3-blocking drugs. Despite differences in the pharmacology of different agents, it is likely that this effect is common to the whole class of drugs, the only exceptions being those with high intrinsic sympathomimetic activity, such as oxprenolol. Sudden death and reinfarction appear to be successfully prevented. Data from all the randomized trials suggest a 10-25% reduction in mortality. Most events occur within the first 6-12 weeks of infarction. Treatment with (3-blockers is therefore recommended for at least 3 months, and in high-risk individuals for a year. Patients at very low risk of reinfarction or death may not require this form of treatment.

Case 12.6

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ACE inhibitors In clinical trials involving some 105 postinfarction survivors, ACE inhibitors have been shown to reduce mortality significantly by 5-27%, the greater reduction being in patients with clinical heart failure or demonstrable left ventricular dysfunction after infarction. Although mortality reduction is demonstrable when ACE inhibitors are given to unselected patients post infarct, the overall statistical extension of life achieved thereby amounts to only a few days. Hence this approach may not be considered cost-effective. Initiating ACE inhibitors too early following an acute infarction was associated with no benefit, and in some patients it may be harmful. In patients who benefit most from ACE inhibition (i.e. those with heart failure) it is advisable to delay introduction until the haemodynamic status becomes stable. ACE inhibitors are contraindicated in cardiogenic shock or preshock, and in unstable angina vasodilators with antianginal properties should preferentially be used. The initiating dose should be small to avoid protracted hypotension in unexpected cases, and the dose increased stepwise to a maintenance dose of, for example, ramipril 5mg b.d., lisinopril 10 mg o.d. or trandolapril 4mg o.d. Treatment may need to be continued indefinitely in patients with continuing heart failure requiring chronic diuretic therapy, and in whom there is demonstrable left ventricular systolic impairment, provided the ACE inhibitor is tolerated. Those who have intolerable sideeffects may be considered for angiotensin II receptor inhibition (e.g. with losartan), although whether this drug possesses the same beneficial effects as ACE inhibitors requires further studies. Those with transient failure after infarction may need ACE inhibition for about 6 months when the cardiac remodelling processes have stabilized. Antithrombotics Aspirin is a safe antithrombotic. It is economical and well tolerated in the absence of peptic ulcer disease. Its role after infarction is not well established and the precise dosage is contentious. A very small dose of 75 mg dissolved in lOOmL of water every day, or even alternate days, may have advantages over larger doses, as the desired antiplatelet activity is then achieved without the unwanted inhibition of endothelial wall prostacyclin activity. Other antiplatelet drugs, e.g. sulfinpyrazone and dipyridamole, have no demonstrated advantage over aspirin alone. Ticlopidine and clopidogrel may be used in patients who are intolerant of or allergic to aspirin. Anticoagulants Anticoagulation with warfarin following myocardial infarction has been a topic for controversy for many years. Although a small benefit in survival is apparent, particularly for a small subgroup of compliant elderly patients, there are considerable problems associated with its safe usage over many years. Where warfarin has been com-

pared with aspirin, the benefits are equivalent and sideeffects are equally common, although different. However, aspirin therapy requires much less supervision and hence is preferable for patients and physicians alike. Patients with extensive anterior infarction, with demonstrable intraventricular clot (shown by echocardiography), can have the risk of further emboli reduced by warfarin anticoagulation. The risks of emboli are highest in the first few weeks, hence treatment may only be required for 3-4 months. Lipid-lowering agents As in treatment of any condition, there needs to be a weighing of benefits versus risks. Lipid-lowering agents are no exception in possessing unwanted effects, such that, although they are capable of reducing cardiovascular mortality and morbidity, there was a fear that they might increase non-cardiac deaths. Low-cholesterol and low-fat dieting is much safer, and all infarct survivors should be strongly encouraged to adhere to this recommendation. If the serum cholesterol levels are still elevated (above 5.5mmol/L) despite strict dieting, an HMG-CoA reductase such as simvastatin or pravastatin (10-40 mg o.d.) may be introduced. These drugs have been shown to improve longterm (about 6 years) survival as primary or secondary prevention in subjects with elevated cholesterol, although their effect beyond 10 years is unknown.

Cardiac rehabilitation Rehabilitation is a process whereby patients are helped realistically to regain their physical, mental, social, vocational and employment potential in their community. It is an intrinsic component of the clinical management of cardiac disease. In a climate of limited resources, the patients to be targeted are those with the highest potential for health gain. After myocardial infarction, patients with the highest risks (such as those with heart failure, arrhythmia, angina and hypertension) and those in employment prior to infarction are the ones who should be preferentially entered into rehabilitation programmes. In many centres there has been a tendency to select for rehabilitation those who are already in excellent prognostic categories, and the potential for gain is small. Results of rehabilitation studies suggest a benefit in survival with the additional decrease in other coronary events. The phases of rehabilitation are: 1. Week 1 post infarction, either in hospital or at home (if the patient is not admitted) 2. For a few weeks during convalescence 3. The active outpatient hospital-supervised period - up to 6 months 4. Community and long-term follow-up. Hospital-based rehabilitation programmes usually encompass phases 1, 2 and 3, whereas phase 4 takes place in

the primary care setting, health clubs or cardiac patient support groups. The components of rehabilitation include counselling, psychosocial care, risk factor management, education, exercise training, relaxation therapy and vocational assessment. One purpose of counselling is to explain the medical diagnosis, the results of investigations, the pros and cons of intervention, and the prognosis and implications in sympathetic, positive but realistic terms which patients can understand. Another main objective is to encourage behavioural change rather than simply to provide emotional support. Persistent anxiety and depression occur in about 25% of patients and relatives, and these usually respond to correction of misconceptions and addressing their main concerns. Patients who undergo exercise rehabilitation attain their optimal functional state more rapidly, have fewer visits to their doctors and are more likely to return to work. Formal exercise testing is essential to determine the correct individualized exercise prescription. It can also be used to monitor progress. Patients with a negative exercise test at a good workload have an excellent prognosis, and this information is of great psychological benefit. The type of exercise most beneficial for cardiovascular fitness is aerobic isotonic exercise (e.g. brisk walking, cycling, swimming or jogging). The amount and duration of exercise training that is required to produce benefit is 20 minutes of exercise at 75-80% of the maximal heart rate achieved on exercise testing, 2-3 days per week. Training effects may be seen after 6-12 weeks of this degree of effort. Ventricular function and, possibly, myocardial perfusion improve with prolonged exercise training. Most centres encourage the continued use of -blockers throughout exercise programmes. O

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FURTHER READING ON MANAGEMENT OF MYQCARDIAL INFARCTION SURVIVORS Betteridge D J, Dodson P M, Durrington P N et al 1993 Management of hyperlipidaemia: guidelines of the British Hyperlipidaemia Association. Postgrad Med J 69: 359-369. Cleland J G F 1995 Clinical perspective. ACE inhibitors for myocardial infarction: how should they be used? Eur Heart J 16: 153-159. Scandinavian Simvastatin Survival Study Group 1994 Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344:1383-1389. Shepherd J, Cobbe S M, Ford I et al 1995 West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 333:1301-1307. Smith G D, Song F, Sheldon T A 1993 Cholesterol lowering and mortality: importance of considering initial level of risk. Br Med J 306:1367-1373. Tan L B, Ball S G 1994 ACE inhibition after myocardial infarction. London: Science Press, pp. 1-78. Thompson B R, Bowman G S, Kitson A L, de Bono D P, Hopkins A 1996 Cardiac rehabilitation in the United Kingdom: guidelines and audit standards. Heart 75: 89-93.

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TABLE 12,34 Causes of myocarditis Cause

Example

Viral

Coxsackie B, but a wide range of enteroviruses, echoviruses, adenoviruses, polio, influenza Chlamydia and coxiella (Q fever) Infants and immune-compromised adults T. cmzi (Chagas1 disease of S. America) Often toxin-mediated, e.g. diphtheria Radiation, severe hypothermia Emetine, carbon monoxide

Rickettsiae Toxoplasma Trypanosomiasis Bacteria Physical Drugs and poisons

DISEASES OF HEART MUSCLE

MYOCARDITIS The causes of myocarditis are shown in Table 12.34. In the Western world the commonest causes are viral, of which the most important are Coxsackie B and echovirus infections. Toxoplasmosis affects the myocardium in the neonate. Trypanosoma cruzi is the major cause of infective heart muscle disease in South America and is discussed on pages 354-355. Acute viral myocarditis may complicate many severe viral infections and has been described with almost all common viral diseases. Clinically important myocarditis is uncommon, but ECG changes, possibly due to myocarditis, are more frequent.

Clinical features A febrile illness followed by acute unexplained heart failure, cardiac arrhythmias and chest pain are the main presenting features of myocarditis. Chest pain usually results from a myopericarditis. An arrhythmia, such as frequent ventricular ectopic beats, is probably the most frequent manifestation of a mild attack of myocarditis, and is often seen after any viral infection. The physical signs may include gallop rhythm and heart failure with cardiac enlargement.

Diagnosis and investigation Diagnosis is made on the basis of the history and an ECG, which may show a variety of arrhythmias, conduction defects, and myocardial injury with ST and T-wave abnormalities. An echocardiogram is helpful in diagnosis and

Fig.

570

12.24

shows reduced ventricular contractility. Endomyocardial biopsy is occasionally necessary to make the diagnosis. This technique is used to obtain a small piece of myocardium for histological examination. In acute myocarditis there is a marked lymphocytic and inflammatory cell infiltrate. Necrosis of myocytes is seen and, often, interstitial fibrosis. Later in the disease the histological appearances become less marked and merge into those of congestive (dilated) cardiomyopathy (see below).

Management Strict rest is advised until symptoms and signs and ECG abnormalities have resolved. Strenuous exercise is prohibited during this period. Cardiac arrhythmias are treated. Anticoagulants should be considered, as intraventricular clots are common. Although most patients make an apparently full recovery, about 15% have a poor prognosis with continuing evidence of cardiac enlargement and, in some cases, of progressive heart failure. These patients may only be saved by cardiac transplantation. It seems likely that some patients will progress to a dilated cardiomyopathy. Immunosuppressive therapy may be helpful in the more severe cases when they present in the early phases of myocarditis, preferably with histological confirmation of the diagnosis.

CARDIOMYOPATHIES Cardiomyopathy is the term used to describe heart muscle disease, and is usually only used when hypertension and coronary artery disease have been excluded. Cardiomyopathy is more frequent in people of African origin - not only in Africa and the Caribbean, but also in the UK. The reasons for this are still unknown. Cardiomyopathies are now classified into three main groups, shown in Table 12.35.

Dilated cardiomyopathy Dilated cardiomyopathies (DCM, also called congestive cardiomyopathy - COCM) comprise half or more of patients diagnosed with cardiomyopathy. The aetiology is usually not identifiable, because an identical clinical histological and pathological picture can arise after damage to the heart from many causes, including toxins (such as cobalt), drugs (such as adriamycin), or following an attack of acute myocarditis. Chronic alcoholism is associated with DCM, and, as alcohol has a direct suppressant effect on the heart, it is thought to be an aetiological agent in many cases. Other causes are given in Table 12.35. Clinical features Presymptomatic DCM may be present for several years without coming to the notice of a doctor unless there is a routine chest X-ray. At this stage there may be some

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TABLE 1245 Types of cardiomyopathy' Type

Features

Causes

Dilated cardiomyopathy (DCM)

Large cavity, poor contraction. AV valve regurgitation. Low ejection fraction

Hypertrophic (obstructive) cardiomyopathy (HCM or HOCM) Restrictive cardiomyopathy

Idiopathic ventricular wall thickening, often asymmetric. Small cavity. High ejection fraction Thick-walled ventricle or fibrosed endocardium restricts filling, but systolic function (ejection fraction) maintained. Much less common

High percentage unknown (idiopathic) Following myocarditis of any cause Alcohol, cobalt, adriamycin, daunorubicin Systemic illness: amyloid; sarcoid; haemochromatosis Usually familial, may be sporadic, Similar picture may arise in the elderly, secondary to hypertension/aortic stenosis Endomyocardial fibrosis and Lb'ffler's endocarditis Amyloid; sarcoid; haemochromatosis

*Some patients may have features of more than one type of cardiomyopathy, e.g. dilated and restrictive, and individual diseases, such as haemochromatosis, may commonly have features of both.

diminution in maximum effort tolerance, but unless the subject concerned is an athlete, this usually goes unnoticed or is ascribed to normal ageing. Later on, symptoms are dominated by heart failure in severe cases, with both left- and right-sided failure being eventually intractable. AF and thromboembolism are frequent complications and 10% of patients have recurrent chest pain or angina on effort, despite normal coronary arteries. The clinical picture is of a dilated heart that contracts very poorly, with a markedly reduced ejection fraction and a high filling pressure. Physical examination usually reveals cardiomegaly, with a gallop rhythm. Both mitral and tricuspid regurgitation are common when the patient presents in heart failure, and are secondary to the ventricular dilatation. Investigation Chest X-ray reveals the cardiomegaly, which often involves all the chambers of the heart. O The ECG is non-specific and may show features of ventricular hypertrophy, Q waves and widespread T-wave inversion. Echocardiography can be used to exclude a pericardial effusion and haemodynamically significant valve disease. The distinction between cardiomyopathy with mitral regurgitation and heart failure due to valvular disease is important and can be made by echocardiography, which shows vigorous LV contraction when the valvular disease is primary. Management and prognosis When these patients present with heart failure the prognosis is poor, with a 50% mortality in the following 2 years. Treatable causes of heart failure, such as valve disease, must be excluded, and endomyocardial biopsy may be necessary in the young patient to exclude an active myocarditis. Heart failure is treated conventionally (p. 493). Anticoagulation is advised if a high risk of thromboembolism exists.

Hypertrophic cardiomyopathy Hypertrophic cardiomyopathy (HCM) is characterized by marked left ventricular wall thickening and a small left ventricular cavity. Usually, the wall thickening is asymmetric and predominantly affects the interventricular septum; this is known as asymmetrical septal hypertrophy (ASH). The hypertrophy can lead to left ventricular outflow obstruction with abnormal systolic anterior motion (SAM) of the mitral valve; when this occurs, there is almost always a variable degree of mitral regurgitation. The condition is then known as hypertrophic obstructive cardiomyopathy (HOCM). Similar processes can occur, but less frequently, on the right side of the heart, and sometimes both sides of the heart are involved. Aetiology and pathology There is a familial incidence of HCM. It is inherited as an

RECENT ADVANCES IN GENETICS OF HYPERTROPHIC CARDIOMYOPATHY CARDIOMYOPATHY

OF

Hypertrophic cardiomyopathy is a phenotypically and genetically heterogeneous disorder linked to at least four different loci on chromosomes 1, 11, 14 and 15. Three of the disease genes have been identified, encoding for proteins of cardiac |3-myosin heavy chain ([3MHC), cardiac troponin-T and a-tropomyosin. Other loci and genes remain to be identified. In each of these genes, different mutations have been identified which are statistically associated with different disease manifestations and severity. In clinical practice, the identification of these genes and mutations may aid earlier diagnosis and provide prognostic information, complementing information from clinical assessments. However, the implications of these on the treatment and counselling of patients have yet to be evaluated.

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autosomal dominant, but sporadic examples account for most cases. The condition may be mild and show only on echocardiographic examination. Some cases have associated 'triggers' for left ventricular hypertrophy, such as hypertension or aortic valve disease, but there is usually no obvious cause. On microscopy the muscle fibres are thickened and appear to be arranged haphazardly. The appearances are not specific. One theory suggests that the geometrical arrangement of the fibres is such that they pull antagonistically during systole, and that this results in myofibrillar hypertrophy and disruption. A number of genetic mutations have been identified in families with HCM. Statistically, some mutations are associated with a very high risk of premature arrhythmic deaths, but others are associated with a more benign course. When confirmed, these findings will have fundamental implications for managing the disease and for the screening of affected families. Clinical features Syncope and palpitations from a variety of arrhythmias are common and sudden death may occur. Angina can develop without coronary artery disease. The thickened myocardium can produce an inflow obstruction and lead to heart failure from a raised filling pressure. In later stages there is an enlarged heart and a risk of systemic embolism. The physical signs depend on whether there is outflow obstruction. In its absence there may only be third or fourth heart sounds and a rather muscular feel to the left ventricular impulse. In the presence of outflow obstruction, systolic ejection is shortened, there is a jerky carotid pulse (compared with a sustained and weak pulse in aortic stenosis) and the apex beat has a characteristic presystolic lift. Outflow obstruction produces a harsh late systolic murmur, which may be masked by a pansystolic murmur of coincidental mitral regurgitation. The ejection murmur becomes louder on forced expiration or with the Valsalva manoeuvre (creating a positive intrathoracic pressure), or an inhalation of amylnitrite or administration of an arterial vasodilator or positive inotropic agent (e.g. isoprenaline). It becomes diminished on deep inspiration or with Mueller's manoeuvre (creating a negative intrathoracic pressure), or the administration of an arterial vasoconstrictor, owing to the diminution of the ventriculoarterial pressure gradient. The presence of exertional angina, exertional syncope and a systolic murmur with left ventricular hypertrophy can easily lead to a mistaken diagnosis of aortic stenosis. Although the physical signs differ from those of true aortic stenosis, echocardiography has proved invaluable in establishing the correct diagnosis.

Q MCQ 12.21

572

A significant number of sporadic cases are discovered at autopsy in young people, not infrequently when they have collapsed during physical activity or sport. Investigation Chest X-ray is often unremarkable in the absence of heart failure. The ECG is non-specific, showing left ventricular hypertrophy and, occasionally, Q waves. Echocardiography demonstrates the left ventricular wall thickening, particularly ASH, and, with obstruction, shows SAM of the mitral valve (see above). Two-dimensional echocardiography shows that the septal hypertrophy can be a localized bulge, and also the high ejection fraction. Careful echocardiographic examination is required not to miss isolated apical hypertrophic cardiomyopathy. Doppler ultrasound will demonstrate the mitral regurgitation, as well as the highvelocity jet in late systole that develops in the outflow tract of the left ventricle in the presence of obstruction. Cardiac catheterization and angiography are necessary to confirm normal coronary arteries, to judge the degree of mitral regurgitation and to measure the apex-to-base pressure gradient in the left ventricle. Manoc/emenf Sudden death is a continuing hazard even with antiarrhythmic therapy, and various agents are used to control symptoms of palpitations without apparently preventing sudden death. (3-Blockers can abolish outflow obstruction, and may help in the management of heart failure. Calcium antagonists, such as verapamil, have been used to reduce ventricular hypertrophy, with variable results. Both types of drug slow the heart rate and aid diastolic function. Surgical intervention has been used quite extensively, with mitral valve replacement and outflow tract myomectomy being used to abolish outflow tract obstruction. There is a high surgical mortality and, unless the myomectomy is radical, outflow tract obstruction can recur. The role of surgery therefore remains controversial. More recently, therapeutic embolization of septal branches of the left anterior descending artery has been shown to reduce outflow obstruction, leading to clinical improvement. Screening of siblings of those affected reveals a high incidence of mild degrees of asymptomatic asymmetrical hypertrophy. Investigation and monitoring of these subjects may eventually enable the mortality and morbidity of this condition to be reduced, but may also cause great anxiety in an asymptomatic individual.

Restrictive cardiomyopathies O There is a small subgroup of heart muscle disorders characterized by a very high filling pressure to the ventricles resulting from rigidity of the walls owing to infiltration with abnormal tissue. Reasonable systolic function is usually maintained. Clinically, such restrictive cardiomyopathies present with very similar features to constrictive pericarditis, with evidence of severe heart failure and a relatively small heart.

Cardiac amyloid Cardiac amyloid is the commonest cause of death in primary amyloidosis (Ch. 23, p. 1263). The gastrointestinal tract and tongue are often also involved, as are the nerves and skin. Presentation is either with heart failure secondary to poor systolic function (like a DCM), or with severe right heart failure secondary to a restrictive pattern. There may be evidence of tricuspid and mitral regurgitation with a loud gallop rhythm, and echocardiography shows thickening of the ventricular walls with a small left ventricular cavity. Characteristically, the ventricular walls, infiltrated by amyloid, have a very bright echo appearance, and there may be conduction abnormalities which may require a pacemaker. The diagnosis may be confirmed by rectal or gingival biopsy or, sometimes, by cardiac biopsy. There is no specific treatment for these patients, who fortunately present late in life. Haemochromatosis and transfusion haemosiderosis Overload of the body with iron can damage the heart. Haemochromatosis is a genetic disease in which iron overload occurs (see Ch. 16, p. 868). Transfusion haemosiderosis is caused by repeated blood transfusion (usually more than 100 units) for chronic anaemias, such as thalassaemia, and results in similar tissue loading with iron. The iron damages the liver, heart, gonads and pancreas, causing hepatomegaly, heart failure, gonadal dysfunction and diabetes. There is a characteristic dusky skin pigmentation. Cardiac manifestations are found in the majority of patients. Cardiac involvement does not necessarily parallel other organ involvement, although cardiac failure is always associated with high levels of iron in the heart. There is usually myocardial thickening and dilatation, and so the patient presents with features of both a dilated and a restrictive cardiomyopathy. The diagnosis is based on demonstration of excessive iron in the body, with the serum ferritin being particularly high. Cardiac findings are of heart failure and arrhythmias both supraventricular and ventricular - with disorders of conduction. There may be a low-voltage ECG. The main aim of management should be to reduce body iron levels by chelation or, in the case of haemochromatosis, by repeated venesection.

Cardiac carcinoid In the carcinoid syndrome, where a carcinoid tumour (usually ileal) has metastasized widely, over 50% of patients have cardiac involvement, consisting of endocardial plaques of fibrous tissue. This is almost always on the right side of the heart and involves the tricuspid and pulmonary valves, the vena cava and the coronary sinus, producing distortion and valvular stenosis. Serotonin and kinin peptides produced by the tumour are normally inactivated in the liver and lung; thus the left side of the heart is protected. Clinically, the patient has the systemic manifestations of

carcinoid syndrome: flushing, diarrhoea and, sometimes, bronchoconstriction. In addition, there are symptoms and signs of right heart failure, often with pulmonary stenosis and tricuspid regurgitation. The circulating vasodilators may also produce a hyperkinetic circulation with highoutput heart failure.

12

Sarcoidosis Between 20% and 30% of autopsied cases of generalized sarcoid show cardiac involvement, although clinical manifestations are present in only about 5% of patients. Presentation may be with a cardiomyopathic picture of either the dilated or the restrictive type, although it can also present with conduction abnormalities, heart block and sudden death. Heart block in a young patient may be the first manifestation of sarcoid. Diagnosis and management In the presence of the classic pulmonary findings diagnosis does not require myocardial biopsy, but where there is doubt a biopsy can be extremely helpful. Isotope and magnetic resonance imaging may show infiltration. Treatment is on the whole unsatisfactory. Pacing may reduce the risk of sudden death in patients with conduction system damage, and large doses of corticosteroids are usually advocated in an attempt to prevent progressive myocardial infiltration. Endomyocardial fibrosis Endomyocardial fibrosis is relatively common in regions of Africa, particularly Nigeria and Uganda, where it accounts for more than 20% of cardiac deaths. It is also found in other tropical areas and, occasionally, in Europeans who have been resident in endemic areas. Pathologically, there is gross fibrous thickening of the endocardium of one or both ventricles, usually associated with severe AV valve regurgitation. It commonly presents in young people of both sexes, often from low-income groups. Clinical features The clinical presentation of endomyocardial fibrosis depends on whether one or both ventricles are involved. The disease may be heralded by fever, but usually presents with severe heart failure and sometimes arrhythmias. The heart is not usually markedly enlarged, although pericardial effusion is not uncommon. Clinical signs of valvular regurgitation and heart failure predominate. Systemic and pulmonary emboli may complicate the clinical course. Echocardiography, particularly 2D scanning, may demonstrate the thickened endocardium, which can obliterate parts of the ventricular cavity. Intraventricular clot may also be shown. Surgical excision of the thickened endocardium, with tricuspid and mitral valve replacement, has given some encouraging results in a disease that appears to have, for most, a relentless progression. Endocardial fibroelastosis Endocardial fibroelastosis is a condition of infancy, in

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which there is gross thickening of the endocardium, with subsequent heart failure. It may present as a primary condition or follow aortic stenosis, other left-sided heart conditions or cardiac surgery in which endocardial perfusion may have been at risk. Loffler's endocarditis Loffler's endocarditis - a syndrome of prolonged eosinophilia with associated localized or widespread eosinophilic infiltrates - involves the heart in over 90% of cases. The hypereosinophilic syndrome is most commonly idiopathic, but may occur with eosinophilic leukaemia or secondarily with Hodgkin's disease, polyarteritis nodosa, tumours and parasitic infestation. The clinical picture is of a severe progressive cardiomyopathy with a restrictive picture, often with systemic embolism, in a patient with a wasting disease and marked eosinophilia. The disease process starts as an eosinophilic myocarditis, and progresses with the formation of multiple endocardial thrombi. In the third stage there is fibrosis and a hyaline membrane forms over the endocardium. The disease thus has some similarities to endomyocardial fibrosis. The clinical course of the disease can be from a few months to 12 years.

This usually occurs in someone with a pre-existing severe disease. Over the last two decades the clinical spectrum of infective endocarditis has changed greatly. This is owing to the gradual decline in the numbers of patients with rheumatic heart disease, an increase in the number of patients who have had cardiac surgery, invasive investigation being used in elderly patients, and the epidemic of intravenous drug abuse. Nowadays, infective endocarditis occurs quite frequently in elderly patients with degenerative disease of the heart valves and in whom there is no evidence of either rheumatic or congenital heart disease. Furthermore, infective endocarditis is not easily divided into the subacute and acute forms. There are a wide range of infective agents of different virulence, and the same organism, such as Staphylococcus aureus, can behave quite differently on different occasions, depending on the patient's host defences and the particular strain of organism. The intravenous drug abuser may develop infective endocarditis with a variety of unusual organisms, sometimes on apparently normal valves and quite commonly on the tricuspid valve. Bacteria are not the only causes of infective endocarditis. Fungal and rickettsial infections, as well as viral infective endocarditis, can occur. For these reasons, the more general term infective endocarditis is preferred to the earlier classification.

INFECTIVE ENDOCARDITIS

Pathogenesis Infective endocarditis is a multisystem disease caused by infection of the heart valves or adjacent endocardium. It is characterized by prolonged fever, weight loss, embolic phenomena and renal failure.

Classification Until recently, it was usual to divide the disease into two groups: • Subacute bacterial endocarditis • Acute bacterial endocarditis.

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Subacute bacterial endocarditis (SEE) affects relatively young patients with an identifiable pre-existing cardiac abnormality, usually rheumatic valvular heart disease or a congenital abnormality of the heart associated with a jet lesion. The heart valves become infected with an organism of normally low virulence which slowly forms vegetations on the damaged valve and produces progressive valvular regurgitation. This is accompanied by intracardiac abscesses, embolic episodes and a slow, wasting fever, often associated with evidence of formation of immune complexes, leading to glomerulonephritis. Acute bacterial endocarditis occurs in immunocompromised patients or those suffering from a staphylococcal septicaemia. Apparently normal mitral or aortic valves are rapidly destroyed in the course of 24-48 hours, resulting in torrential regurgitation and death from heart failure.

Pre-existing cardiac lesions Endocarditis usually develops in congenitally abnormal or rheumatic hearts in which there is a 'jet' lesion. The altered flow of blood allows bacteria to impact directly on the endocardial surface. Previous damage to the endothelium (e.g. as a result of rheumatic heart disease) facilitates colonization by bacteria present in the bloodstream, which stick to the endocardial lesion and multiply. A chronic lesion, such as one produced by a jet of blood impinging on the endocardium, remains susceptible. However, transient lesions, such as those produced by passing a cardiac catheter or cannula through the heart valves for as little as 15 minutes, heal rapidly and, as a result, rarely become infected. Bacteraemia Transient bacteraemia is common with trauma to the mouth and teeth; the organism most commonly present, Streptococcus viridans, is also very likely to stick to an endocardial lesion and colonize it. Gram-negative bacilli, which can be grown from the blood in Gram-negative infections and at the time of urogenital manipulation and surgery, are less likely to cause endocarditis and stick less readily to endocardial lesions. In practice, any surgical procedure involving manipulation of any organ or part of the body not normally bacteria-free should be regarded as a potential cause of bacteraemia.

Infective endocarditis may occur following a chest or urinary infection or septicaemia. It can also occur following a variety of operative and investigative procedures, but the risk of these procedures producing a bacteraemia is variable. Minor medical procedures that may provoke bacteraemia include the following: • Dental extraction and manipulation. Transient bacteraemia with streptococci and some enterococci lasts from 15 minutes to several hours. Chewing can cause bacteraemia even in edentulous individuals. • Oropharynx. Tonsillectomy, rigid bronchoscopy, orotracheal intubation and nasopharyngeal suction. • Gastrointestinal tract. Barium enema, sigmoidoscopy and colonoscopy. • Urogenital tract. Urinary catheterization, prostatectomy and prostatic massage have all been found to produce a bacteraemia, but normal vaginal parturition does so only occasionally. • Intravenous cannulae. These are a potential source of bacteraemia and should not be used unnecessarily in patients at risk. Growth of the vegetation The vegetation grows as a concretion of bacteria and the reaction of the blood to their presence. The bacteria become covered in platelets and layers of fibrin. The exuberance of the vegetation depends on the organism. Fungal infections with Candida produce large vegetations which can even occlude the orifice of prosthetic valves. Other organisms may provoke so little reaction that the vegetations are too small to be demonstrated by echocardiography (which has a maximum resolution of a few millimetres). Infection can perforate the valve cusps and track into the adjacent myocardium and valve ring, causing abscesses and a variety of complications, depending on the site. These include fistula formation, bundle branch block, complete heart block, infective pericarditis and papillary muscle and chordal rupture. Embolism and immune complex manifestations Embolism of fragments of infective vegetation can produce embolic abscesses in the spleen, kidneys, brain and elsewhere, with 'mycotic' aneurysm of the arterial wall which may result in rupture and sudden haemorrhage. Embolic episodes result in cerebral and peripheral ischaemic attacks, transient haematuria, splenic infarcts and coronary occlusion. Long-standing infection leads to the formation of immune complexes, which may themselves complicate the presentation and course of the disease. These complexes are probably responsible for the glomerulonephritis that may accompany infective endocarditis, and for the skin lesions. Valve involvement The frequency of involvement of the four cardiac valves

is in direct relationship to the mechanical loading on the valves, i.e. mitral, aortic, tricuspid and pulmonary, in descending order of frequency. This is related to the much higher jet velocities usually found on the left side of the heart, although the very low incidence of involvement of the pulmonary valve in pulmonary stenosis remains unexplained. Untreated infective endocarditis of the aortic valve may lead rapidly to infection of the mitral valve, as the regurgitant jet of blood through the aortic valve most commonly strikes the anterior cusp of the mitral valve. Tricuspid valve endocarditis leads to a picture of recurrent lung 'pneumonitis' of a patchy nature caused by embolism of vegetation and organisms into the lung.

12

Infecting organisms Streptococci About 50% of cases of infective endocarditis are caused by cx-haemolytic streptococci from the mouth and oropharynx, formerly classified as Strep, viridans but now subdivided into many organisms, e.g. Strep, mitior and Strep, sanguis. These organisms are most likely to reach the bloodstream after dental extraction or manipulation, bronchoscopy, and tonsillectomy and adenoidectomy. The enterococci of group D streptococci have become more frequent causes and can be found in the gastrointestinal tract, genitourinary tract and periodontal tissue. Accurate identification is sometimes difficult, and the prognosis is worse than for Strep, viridans infection. Strep, bovis, a non-enterococcal organism from group D, is an increasingly common finding in infective endocarditis, and the disease in these cases is very similar to that caused by Strep, viridans. Strep, pneumoniae is a less common agent but still causes some cases of acute infective endocarditis; the infection may be complicated by meningitis. Anaerobic streptococci, organisms that are initially difficult to grow, are found increasingly frequently but necessitate anaerobic cultures. The discovery of Strep, faecalis should lead to investigation of the gut, as colonic carcinoma may be an underlying cause. Staphylococci A staphylococcal septicaemia with Staph. aureus often involves the heart valves; if several positive cultures are obtained, a prolonged course of antistaphylococcal therapy is indicated even without definite evidence of cardiac pathology. Acute endocarditis can damage apparently normal valves very quickly. The same organism can produce a subacute picture. It is a frequent finding in intravenous drug abusers and diabetics with endocarditis. Staph. epidermidis (albus} may be grown as a contaminant of blood cultures, but repeated positive cultures are significant as it is a common cause of infective endocarditis, both in patients with prosthetic valves and in intravenous drug abusers. It is occasionally found in patients with indwelling subcutaneous intravenous lines. Many

575

months may pass between the introduction of the infection and the presentation with endocarditis. Other organisms Neisseria gonorrhoeae and Gram-negative bacilli are relatively uncommon causes of infective endocarditis, but Pseudomonas is becoming more frequent. Q fever endocarditis is uncommon and is diagnosed by finding a rising titre of antibodies in the blood. Fungal endocarditis occurs with prosthetic valves and in patients who have had prolonged periods of antibiotics or corticosteroids, or who are intravenous drug abusers.

Clinical features The clinical features of infective endocarditis can be divided into several categories. Features of chronic infection The features of chronic infection include a remittent pyrexia, myalgia, arthralgia and general fatigue. These symptoms are accompanied by anaemia, anorexia and weight loss. Splenomegaly may be present but is usually not marked. Splenic infarction can lead to pain and a friction rub over the spleen. A splenic abscess can delay resolution of the fever. In long-standing cases cachexia and mild finger-clubbing may occur. Cardiac manifestations Heart murmurs are present in over 85% of cases but may easily be missed, especially in the presence of heart failure. Early diastolic murmurs are notoriously difficult to hear, and a wide pulse pressure is often the first clue that aortic regurgitation is present. Changing heart murmurs are uncommon but, when present, are very suggestive of the diagnosis. Cardiac arrhythmias and conduction abnormalities may follow the spread of infection from the valve ring to form myocardial abscesses. Heart failure can be a presenting symptom. Its presence signifies a poor prognosis and is an indication for early surgery. Sudden heart failure can occur with rupture of a valve cusp or chordae tendinae, or sinus of Valsalva aneurysm. Systemic embolism Embolism is a prominent feature of infective endocarditis and the presentation may be with a cerebrovascular event (e.g. a dense hemiplegia), an ischaemic limb, mesenteric embolus or haematuria from renal infarction. Over 50% of cases exhibit embolic phenomena: fungal endocarditis with large friable vegetations is notorious for producing large emboli. Right-sided endocarditis usually presents with recurrent patchy consolidation (pneumonitis).

Fig.

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12.25

Fig.

12.26

SUMMARY 10 Clinical features of infective endocarditis Infection

Fever, anorexia, weight loss, splenomegaly, cachexia, clubbing. Also arthralgia, bone pain

Cardiac

(History of cardiac murmur, bacteraemic procedure) New heart murmur, increasing valvular regurgitation, conduction disorders

Systemic embolism (about 50%) Arterial Pulmonary

Immunological Renal Skin

CVA, mesenteric, renal Infective emboli cause abscesses and arterial rupture. Recurrent pneumonitis Glomerulonephritis leading to renal failure Nails - splinter haemorrhages Conjunctival and buccal mucous membranes - petechiae Finger and toe tips - Osier nodes Thenar and hypothenar eminences - Osier nodes and Janeway lesions Retina - Roth spots and boatshaped haemorrhages

Immunological phenomena Renal A diffuse glomerulonephritis is present in many patients and is due to the deposition of immune complexes. The renal disease is shown by proteinuria and microscopic haematuria. In untreated endocarditis the blood urea begins to rise, but renal failure develops in less than 10% of cases. Even when advanced, renal failure recovers with adequate treatment of the infective endocarditis. Skin and mucous membranes Typical skin manifestations of infective endocarditis were much more common in the pre-antibiotic era, but are now seen in only 20^0% of cases. Thorough examination of the patient's skin, the mucosae of the oropharynx, conjunctivae and retinae should be repeated during the course of the disease, to check for new lesions. Petechial haemorrhages. Examination of the soft palate, pharynx, conjunctivae, hands, feet and anterior body wall may reveal petechial haemorrhages, often with a pale centre. Subungual or 'splinter haemorrhages' are usually seen as a faint dark line away from the nail margin in the fingers and, occasionally, the toes. O They may also be seen in patients who are debilitated for other reasons, or after trauma. When present, they occur in 'bursts' and indicate disease activity.

Osier nodes are painful, nodular, red to purple lesions that usually form on the fingertips 0 but can also occur on the backs of the toes, soles of the feet, the thenar and hypothenar eminences and, occasionally, elsewhere. Formerly common, they are now seen in less than a fifth of cases. The lesions can last a few hours to a few days. Janeway lesions are painless, 1-4 mm erythematous macules which are most common on the thenar and hypothenar eminences and the soles of the feet, and which blanch on pressure. Retinal lesions. The Roth spot is a 'cottonwool exudate' consisting of a perivascular collection of lymphocytes. It is not specific to infective endocarditis. Boat-shaped haemorrhages with a pale centre and white spots have also been described. All of these retinal and cutaneous lesions have been ascribed to 'septic emboli', but are now thought to be immunological manifestations of the disease.

Diagnosis Infective endocarditis is a possible diagnosis in any patient with a fever and a heart murmur, and is established by taking blood cultures. A patient with a heart murmur may have an intercurrent viral infection or some other cause for fever. Where the source of the fever is not clear, it is essential to take blood cultures before starting antibiotics, should they be considered necessary. This is especially important when a patient at risk of endocarditis develops a fever following a procedure that has not been covered with antibiotic prophylaxis. Any febrile patient who has had open heart surgery (other than coronary bypass grafting) should be considered at risk from infective endocarditis, even if no murmur is evident. In the elderly patient, endocarditis can exist without significant fever. Other signs of chronic infection, such as unexplained anaemia and high ESR in a patient with a heart murmur, should arouse suspicion and lead to blood cultures being taken. Echocardiography is an essental investigation in any patient with suspected endocarditis. It will demonstrate vegetations greater than 1 mm and document valvular and ventricular function. Blood cultures Blood cultures should be taken on six to eight occasions over the first 48 hours. It is not necessary to wait for peaks of fever. Anaerobic cultures should be taken and, although a higher percentage of positive cultures has been claimed for arterial blood culture, venous sampling is usually sufficient. Close liaison with the laboratory is essential so that any organism that grows is kept in subcultures and not discarded. Appropriate culture techniques can then be instituted for poorly growing organisms. Where the clinical evidence of the disease is overwhelming, especially if there is evidence of deteriorating valve function, antibiotic therapy may be started as soon as four to six cultures have been taken and before positive

cultures are reported by the laboratory. There is, however, an inevitable risk that this may interfere with identification of the organism if the initial cultures are negative. Where infective endocarditis is a high probability, and particularly if Strep, viridans is grown from blood culture, a dental opinion on possible septic foci in the mouth should be obtained. It is then possible to time any dental extraction or other dental work to follow by 1 hour or so the initiation of antibiotic therapy. This then removes the possibility of septic foci in the mouth harbouring antibiotic-resistant organisms which can then superinfect the heart after the initial organisms have been eradicated.

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Culture-negative endocarditis In 20% of cases no organisms are grown, despite many other features of the disease being present. This may occur because the patient has been treated with an antibiotic (which may render cultures negative for days or weeks after stopping treatment), because the organism involved is present in very small numbers, or because it is difficult to culture. Even in average cases of endocarditis there may be only 100 organisms per mL of blood and, particularly in long-standing cases with renal failure, the patient's antibodies may render the blood almost sterile, despite the presence of organisms in large vegetations. Repeated blood culture samples of l0mL should be inoculated into 100 mL of culture broth and incubated aerobically and anaerobically. The organisms may require special nutrients and may not grow for several days, or, in a few cases, for several weeks. If repeated cultures are negative, or the patient's condition is deteriorating, it may be necessary to embark on treatment without positive cultures. This course of action must only be followed after close consultation with a microbiologist, who may suggest unusual sampling techniques (occasionally bone marrow or urine is positive when blood is not), and after blood has been taken for fungal and rickettsial antibodies.

Management Successful treatment of infective endocarditis should involve close cooperation between physician and microbiologist. In uncomplicated cases 4-6 weeks of bactericidal antibiotic therapy is required, with serum levels of antibiotic sufficient to penetrate the vegetations and abscesses and eradicate the organism. Bacteriostatic antibiotics and bacteriostatic levels of bactericidal antibiotics are not suf-

SUMMARY 11 Features suggestive of infective endocarditis • • • • •

Fever Evidence of chronic infection A heart murmur suggestive of a jet lesion Positive blood culture on more than one occasion Presence of vegetations on echocardiography

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ficient, even with the host's natural defences, to eradicate the organism. Antibiotic therapy Although oral antibiotic therapy can be used for sensitive Strep, viridans infection, the intravenous route is preferred for initiating therapy and while awaiting 'back titrations'. For intravenous therapy a central venous catheter may overcome the problems of superficial venous cannulae. All cannulae must be inserted under strict aseptic conditions and kept scrupulously clean to prevent the risk of superinfection with fungi. They should be changed at least every third day. After culture and identification of the organism, its antibiotic sensitivity must be urgently assessed. The bacteriology laboratory assists by monitoring the patient's blood levels of antibiotic and titrating to determine what serum dilutions are bactericidal to the organism in culture. A level of 1 in 8 is considered satisfactory. It is essential that the antibiotic regimen for an acute septicaemic endocarditis include antistaphylococcal antibiotics. Where a subacute infection is being treated it is usual to use wide-spectrum antibiotics, such as gentamicin and ampicillin. The response to treatment is then monitored and the treatment changed or continued, depending on whether it appears to be controlling the infection. Culturenegative endocarditis, particularly with large vegetations or other indication of severe valvular involvement, may be an additional criterion for early surgical intervention, particularly if potentially hazardous antibiotics are being used. Monitoring treatment Successful antibiotic treatment ideally results in disappearance of the fever within a few days, a fall in the ESR, a rise in the haemoglobin and an increase in the patient's weight and wellbeing. Measurement of C-reactive protein may give a more reliable guide to response than the ESR. Evidence of microemboli, such as fresh splinter haemorrhages and microscopic haematuria, take longer to go, and large vegetations take several weeks to regress. Occasionally, the fever and high ESR do not settle, although repeated blood cultures remain negative. If other causes for persistent fever (e.g. splenic abscess or superinfection) are eliminated, then the fever may be antibiotic induced and disappear with cessation of antibiotic treatment. Surgery Severe valve failure and uncontrolled infection may require emergency valve replacement. If the patient presents with heart failure early surgery is essential, as even with rapid successful antibiotic treatment of endocarditis, damaged valves shrink and fibrose with progressive increase in the degree of valve regurgitation, and the heart

MCQ 12.22

578

Case 12.7

failure may become irreversible. Prosthetic valve endocarditis almost invariably requires valve replacement for the infection to be eliminated. A few days of antibiotic therapy prior to surgery reduces the risk of valve dehiscence from sewing the new valve into an infected valve ring, and reduces the risk of prosthetic valve endocarditis. A heavily infected valve with large vegetations may be electively replaced where there is risk of major embolism, or where the patient cannot be given effective bactericidal therapy. Tricuspid valve endocarditis with large vegetations can be treated by excision of the tricuspid valve without replacement, while the course of antibiotics is given. The prosthetic valve can then be sewn into a sterile ring. Apart from valve replacement, surgical closure of intracardiac fistulas, such as aortic-to-right-atrial shunts, and limited thoracotomy for epicardial pacing for heart block are occasionally required. Prophylaxis The recommended regimens for endocarditis prophylaxis vary slightly, but all are based on the use of a bactericidal antibiotic to cover a procedure likely to produce bacteraemia. If a general anaesthetic is involved, the antibiotic is given intravenously or intramuscularly. If no general anaesthetic is involved, oral preparations are given if possible. Regimens are shown in Table 12.36. A safe general rule is that prophylaxis should be given for all dental work where the teeth are manipulated, all pelvic, colonic and bladder instrumentation, and surgery. Normal parturition does not need routine cover unless the bladder is catheterized or forceps used. OO

SYPHILITIC ENDOCARDITIS Pathogenesis Syphilis is now much less common as a cause of heart disease. Cardiac involvement is a manifestation of the tertiary stage of the disease, which often follows a prolonged quiescent period. An endarteritis obliterans of the vasa vasorum of the aorta weakens the media, which undergoes a slow necrosis and causes thickening and scar formation in the intima. The changes are irregular, and complicated by fibrosis and calcification. Dilatation of the aorta occurs and can be localized, giving a fusiform or saccular aneurysm; it often also involves the valve ring, causing progressive, and often severe, aortic regurgitation. There may be damage to the aortic valve cusps leading to retraction, but never stenosis. Intimal scarring of the aorta can lead to coronary ostial stenosis. The changes do not always lead to overt heart disease. There is a higher percentage of cases of aortic regurgitation and aortic aneurysms in manual labourers with aortitis, than in sedentary men and women with necropsy evidence of aortitis. Thus, it may be that physical activity produces additional loads on the aorta, which induce these changes.

TABLE 12.36 Endocarditis prophylaxis Procedure

Recommendation

1. Dental procedure under local anaesthetic 2. Dental procedure under general anaesthetic 3. High risk - Refer to hospital • Patients with prosthetic valves • Patients allegic to penicillin or who have had penicillin more than once in the previous month • Patients who have had a previous attack of endocarditis 4. Surgery - upper respiratory tract

A

5. Surgery - genitourinary 6. Obstetrics and gynaecological patients 7. Gastrointestinal procedures

Penicillin allergy-B or C D or E or F

G

Pencillinallegy-H H

G

Penicillin allergy-H As 1 and 2 above Any postoperative antibiotic may have to be given intramuscularly or intravenously if swallowing painful Sterile urine, as 1 and 2 Infected urine - prophylaxis should also cover pathogens involved Cover only for patients with prosthetic valves - D or H Cover only for patients with prosthetic valves - D or H

A: Oral amoxicillin 3 g single dose taken under supervision 1 hour before procedure 1 Children under 10- /2dose Children under 5 - V2 dose

B: Oral erythromycin 1.5g under supervision 1-2 hours before procedure Children under 10- 1/2 dose Children under 5 - 1/4 dose

C: Oral clindamycin 600 mg single dose taken under supervision 1 hour before procedure Children under 10 - 6mg/kg body weight single dose taken under supervision 1 hour before procedure

D: Intramuscular amoxicillin 1g in 2.5 ml 1% lidocaine hydrochloride just before induction plus 0.5 by mouth 6 hours later Children under 10 -1/2 dose

E: Oral amoxicillin 3g dose 4 hours before anaesthesia followed by a further 3g by mouth as soon as possible after operation Children under 10- 1/2 dose Children under 5 - Y4 dose

F: Oral amoxicillin and probenecid Amoxicillin 3 g together with probenecid 1 g 4 hours before operation

G: Intravenous amoxicillin and gentamicin 1 g amoxicillin plus 120mg gentamicin intravenously just before induction, then 0.5 g amoxicillin orally 5 hours later Children under 10 - amoxicillin Ys dose, gentamicin 2mg/kg body weight

H: Intravenous vancomycin 1 g slow infusion over 1 hour before procedure followed by gentamicin 120mg intravenously just before induction Children under 10 - vancomycin 20mg/kg, gentamicin 2mg/kg

Clinical features The patient is usually a man (there is a 3:1 sex ratio for uncomplicated aortitis, but this rises to 10:1 for aortic aneurysm) in late middle age.

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Aortic regurgitation The presentation may be with pure aortic regurgitation with evidence (best shown echocardiographically) of a dilated aortic valve ring, and serological proof of previous Treponema pallidum infection. If untreated, the regurgitation tends to be progressive and severe; indeed, the classic 19th century physical signs described for aortic regurgitation are almost all based on patients with severe symphilitic aortic regurgitation (waterhammer pulse, head rocking etc.). With a dilated aortic root, the early diastolic murmur is louder in the third right interspace than the third left interspace. If there is coronary ostial stenosis severe angina is usually present, often leading to status anginosus (continuous pain), heart failure and death, unless there is early surgical intervention. Aortic aneurysm Aortic aneurysm is much less common than regurgitation. It usually occurs in the ascending aorta or arch rather than the descending aorta, where aneurysms are much more likely to be arteriosclerotic. The clinical features depend on the position of the aneurysm. Classically, the ascending aortic aneurysm produces signs of aortic regurgitation, the arch aneurysm symptoms such as dysphagia, cough, pain and dyspnoea, and the descending aneurysm pain from erosion of the spine. Diagnosis and investigation Serological proof of previous spirochaetal infection is usually followed by CSF examination because of the close association with neurosyphilis. Positive serology cannot be taken as proof of syphilitic infection in patients with yaws scars, who often have persistent positive serology even after treatment. However, the combination of aortic dilatation and positive serology would be taken as confirmatory. Arteriosclerotic aneurysms, cystic medial necrosis of the aorta and aortic dissection are now common differential diagnoses. Aortic regurgitation is investigated with particular emphasis on excluding coronary ostial stenosis. Aortic aneurysm is now often investigated by CT scanning. There is often laminated clot in the aneurysm, and classically, in aortitis there is calcium seen in the ascending aorta. The treatment of syphilis is described on page 461. The Herxheimer reaction is particularly dangerous in aortic regurgitation with coronary ostial stenosis. The regurgitation may progress after effective penicillin treatment, owing to further fibrosis. Surgical treatment is as for other causes of aortic regurgitation or aortic aneurysm, after effective chemotherapy.

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FURTHER READING ON INFECTIVE ENDOCARDITIS Dajani A S, Bisno A L, Chung K J et al 1991 Prevention of bacterial endocarditis: A statement for health professionals from the committee on rheumatic fever, endocarditis, and kawasaki disease of the council on cardiovascular disease in the young, the American Heart Association. Circulation 83:1174-1178. Endocarditis Working Party of the British Society for Antimicrobial Chemotherapy 1990 Antibiotic prophylaxis of infective endocarditis. Lancet 335: 88-89.

NON-INFECTIVE ENDOCARDITIS RHEUMATIC FEVER AND RHEUMATIC HEART DISEASE Rheumatic heart disease is now uncommon in western Europe and North America, but is an important historical cause of what was once the bulk of valvular heart disease. It is still important in the developing world as a disease of childhood and a major cause of heart disease. Its decline in western countries started before the widespread use of antibiotics, and probably reflects increased standards of nutrition and hygiene and, possibly, a decline in the virulence and prevalence of Lancefield group A haemolytic streptococci. Rheumatic fever and chorea are the exclusive causes of chronic rheumatic heart disease, in which there is interstitial muscle fibrosis as well as the heart valve disease. However, some 50% of patients with chronic rheumatic heart disease give no history of either condition. Rheumatic fever develops in about 3% of young people exposed to an epidemic strain of (3-haemolytic Lancefield group A streptococcus. These patients usually have pharyngitis, but may have scarlet fever. After an apparent recovery they develop fever, sweats, skin rashes, arthritis and, sometimes, cardiac involvement from what appears to be an autoimmune disease starting 2-4 weeks after the initial sore throat and lasting 6-8 weeks, but occasionally as long as 26 weeks. Some patients give no definite history of an antecedent sore throat. Following the attack of rheumatic fever, some 70% of patients will eventually have evidence of rheumatic valvular heart disease, although the time interval can be as long as 50 years. On the other hand, the valve disease may become manifest during the attack of rheumatic fever, especially where regurgitation develops. Rheumatic fever may be recurrent, and the chances of valve disease increase with the number of attacks.

Pathology

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Although rheumatic fever follows a streptococcal infection, no bacteria are found in the lesions; however, they may still be present in the pharynx. There is an acute inflammatory reaction, with oedema in the affected tissues,

and then granulomatous lesions develop in the myocardium (Aschoff nodules). Oedema of the valve cusps is followed by verrucous fibrin deposits developing along the lines of apposition of the valve cusps, which eventually adhere at the commissures. In the acute illness there is an acute non-bacterial synovitis in the joints, and granulomata may develop subcutaneously on extensor surfaces of the limbs and over the Achilles tendons (rheumatic nodules). There is usually a high antistreptolysin O titre, and other antistreptococcal titres may also be high. It is thought that cross-reactivity between the streptococcal antigens and host tissue antigens leads to an autoimmune inflammatory process.

Clinical features and diagnosis The diagnosis of rheumatic fever depends on criteria proposed by Duckett-Jones (Table 12.37); two major criteria, or one major and two minor criteria, establish a high probability for the diagnosis. The patient is almost always between the ages of 3 and 30 years (usually 5-15); drenching sweats and a prolonged feverish illness occur, with extremely painful arthritis that moves from joint to joint (usually involving large joints such as the knee and elbow), which become hot, red, swollen and extremely painful for a few days and then recover fully. The flitting arthritis is characteristic, as is the classic skin rash, erythema marginatum. Subcutaneous nodules may develop after several weeks, usually over the elbows. Carditis may be pericarditis, myocarditis or, more importantly for the eventual appearance of valve disease, endocarditis. All may occur at once as pancarditis. The pericarditis is similar to any acute pericarditis (p. 586), with precordial pain, ECG changes (raised ST segments) and often an increase in cardiac silhouette on chest X-ray. Myocarditis is manifest by a tachycardia disproportionate for the degree of pyrexia, gallop rhythm and heart failure; there are also ECG changes, such as prolonged PR interval or greater degrees of AV block and T-wave flattening or inversion, and raised serum creatine phosphokinase AV. Death occasionally occurs from myocarditis. TABLE 12.37 Criteria for the diagnosis of rheumatic fever Major criteria

Minor criteria

• • • • •

• • • • •

Polyarthritis Carditis Subcutaneous nodules Chorea Erythema marginatum

Fever Arthralgia Prolonged PR interval on ECG Raised ESR Raised white blood count or C-reactive protein • Preceding p-haemolytic streptococcus infection • Previous rheumatic fever or inactive heart disease

Endocarditis is indicated by transient or changing murmurs. The classic murmur, which is specific for the condition, is the Carey Coombs murmur; this is a short rumbling diastolic murmur indicating mitral valvulitis. Sydenham's chorea Sydenham's chorea (St Vitus' dance) is usually a separate disease entity but, like rheumatic fever, appears to be related to recent p-haemolytic streptococcal infection and an autoimmune process; occasionally it accompanies the rheumatic fever, although it may follow some weeks later. It is characterized by sudden, jerky, purposeless movements of the face and limbs, such that the child is thought to be clumsy and grimacing. Pure chorea, even when unaccompanied by other evidence of rheumatic fever, is followed by a high incidence of rheumatic valve disease, indistinguishable from that following conventional rheumatic fever.

Investigation Laboratory investigations show a raised ESR, C-reactive protein and antistreptolysin O titre. Blood cultures are negative. Throat swab may be positive for p-haemolytic streptococcus, if the preceding pharyngitis has not been treated with antibiotic.

Differential diagnosis As there is no absolute diagnostic test it is extremely common to find patients who have been diagnosed as having rheumatic fever on weak evidence, such as a childhood fever with a few aches and pains and the presence of a systolic murmur. In one study some 50% of patients with mild congenital heart disease claimed to have had rheumatic fever, suggesting that a child with a heart murmur alone is very likely to be diagnosed as having rheumatic fever during the course of a febrile illness.

Management Aspirin is traditionally used to control the arthritis and fever; it is used in maximum doses. Where the patient is extremely ill, corticosteroids are commonly used, but there is no evidence that these reduce the incidence of endocarditis or subsequent development of rheumatic valvular disease. Prophylaxis Anyone who has had acute rheumatic fever is at risk of recurrence and is usually maintained on phenoxymethylpenicillin (250 mg orally daily, or an i.m. depot preparation of benzathine penicillin) or, if allergic to penicillin, oral sulphonamide, either until the age of 21 or for 5 years after the last attack of rheumatic fever, whichever comes later.

LIBMAN-SACKS ENDOCARDITIS

12

SLE (p. 1172) may lead to heart failure from hypertension and a myopathic process affecting the left ventricle. Involvement of the heart valves by a verrucous endocarditis is described as involving a significant proportion of postmortem specimens; however, valve disease is a clinical problem in only a few long-standing cases of SLE. The warty outgrowths occur at, and away from, the free edges of the valve cusps and over the mural endocardium. They involve the mitral valve in particular, and may lead to thickening of the chordae and subvalvular apparatus. Mitral regurgitation and aortic regurgitation are said to be the commonest lesions, but mixed valve lesions occur. Aortic stenosis has also been described in SLE. LibmanSacks endocarditis may become the site of infective endocarditis and, if haemodynamically important, is treated by prosthetic valve replacement.

RHEUMATOID ARTHRITIS A small percentage of patients with very active rheumatoid arthritis develop mitral and aortic valve disease, with exuberant nodular granulomatous lesions on the valve cusps and at other sites throughout the body. These lesions only occasionally cause significant valve disease, but very occasionally may cause significant stenosis or regurgitation in a patient who has very exuberant and severe rheumatoid arthritis.

REITER'S DISEASE AND ANKYLOSING SPONDYLITIS Reiter's disease and ankylosing spondylitis (p. 1148) can produce a degree of aortitis and aortic root dilatation and cusp retraction similar to that seen in syphilitic aortitis. There may be associated conduction abnormalities as well as aortic regurgitation, and occasionally these patients require aortic valve replacement and cardiac pacemakers.

CARDIAC TUMOURS Cardiac tumours (Table 12.38) are rare. They can present a variety of clinical features and mimic many other cardiac and systemic diseases. Benign tumours comprise 75% of primary cardiac tumours.

MYXOMAS The origin of myxomas is controversial. They appear as a gelatinous pedunculated mass, usually arising from the

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TABLE 12.38 Most frequent cardiac tumours Tumour

Frequency (%)

Prognosis

Myxoma Lipoma Papillary fibroelastoma Rhabdomyoma Angiosarcoma Rhabdomyosarcoma Other (including secondary)

30 10 10 8.5 9 6 26.5

Benign Benign Benign Benign Malignant Malignant -

Syncope and sudden death are also recorded, and recurrent emboli can lead to severe pulmonary hypertension and a paradoxical embolization to the left side through a patent foramen ovale. Constitutional symptoms are as common as on the left. Physical signs are more frequent than on the left side, with systolic and diastolic murmurs being audible in over 80%, and endocardial friction rub audible in 20%. Myxomas may arise in the ventricles, but these are less common. As with atrial myxomas, they are likely to embolize and cause obstruction.

Investigation fossa ovalis in the atria; 75% occur on the left, but occasionally the tumour invades both atria. About 75% are found in women. There is a slight familial tendency, and current theory suggests that myxomas arise from embryonic cells in the septum. Clinical presentation is in late middle age, when they reach sufficient size. The clinical features are haemodynamic obstruction, embolization and constitutional symptoms.

Left atrial myxoma In left atrial myxoma the large gelatinous mass obstructs the mitral valve and simulates mitral stenosis, producing left heart failure. A ball-valve mechanism can produce recurrent pulmonary oedema or syncope, which can lead to sudden death. Pulmonary hypertension with subsequent right heart failure mimics mitral valve disease. In one-third of patients there are systemic emboli, the brain being the most frequent site. Systemic symptoms are found in 90% of patients and mimic those of a collagen disease or infective endocarditis, with fever, anorexia, weight loss, myalgia, arthritis, Raynaud's phenomenon, petechiae and fingerclubbing. These features are thought to result from immunological reactions to necrosing tumour. Physical signs can mimic those of mitral stenosis, with a diastolic murmur in about 20% of patients. More common is a systolic murmur of mitral regurgitation and, classically, there is a 'tumour plop' instead of the opening snap of mitral stenosis. However, the tumour can be silent or give only intermittent ausculatory findings.

Right atrial myxoma Right atrial myxomas are less common than those on the left side; they can cause severe right heart failure, with oedema, hepatomegaly, ascites and pleural effusion.

Q Fig. 12.27

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Echocardiography has revolutionized the diagnosis of myxoma. Q The tumour can often be visualized popping backwards and forwards through the valve orifice. However, it can be missed, and a study from several windows may be needed to show small tumours and, particularly, right atrial myxomas. If satisfactory echo pictures are available there is now nothing to be gained from cardiac catheterization, which runs the risk of dislodging tumour and causing systemic emboli. Laboratory tests are frequently abnormal, especially in patients with systemic symptoms. Haemoglobin is low (with normochromic normocytic film), but may occasionally be high with right atrial myxoma, severe pulmonary hypertension and right-to-left shunting through a patent foramen ovale. A neutrophil leukocytosis occurs. The ESR is often raised, with an increase in plasma gammaglobulins.

Management Surgical excision of the tumour is essential but carries some risk of tumour embolization and recurrence, both from the site of excision, if incomplete, and from other sites in the heart. The tumour is therefore excised with its atrial attachment, and the atrial septum then patched. Many surgeons now inspect all four cardiac chambers, because of the high incidence of local recurrence and the occasional multiple tumour. Atrial myxomas are relatively easily treated and should be suspected wherever there is unexplained systemic embolism, particularly if there are features of a 'collagen disease', if a case of 'infective endocarditis' is persistently culture negative, and if features of mitral valve disease are accompanied by syncopal episodes. Right atrial myxoma should be suspected in unexplained right heart failure and recurrent pulmonary emboli.

CARDIAC DISEASE AND PREGNANCY Pregnancy places a sustained load on the heart which increases throughout the pregnancy and then peaks with labour. There is a considerable increase in cardiac output (30-50%), blood volume (40-50%) and extracellular

volume (about 7L), with an increase in heart rate of about lObpm and a slight fall in mean blood pressure. The circulation of the pregnant woman is as if she were vasodilated, with warm peripheries and an increase of up to 30% in resting oxygen uptake. The increase in cardiac output is accomplished by an increase in heart rate, stroke volume and ejection fraction. Venous pressure in the upper body increases marginally, if at all, whereas there can be an increase in lower body venous pressure when supine or standing, due in part to pressure of the gravid uterus on the inferior vena cava. This pressure increase, and the increase of up to 8.5 L in total body water, often leads to oedema of the ankles. The increase in plasma volume occurs earlier than a compensatory increase in total red blood cell volume, so that an apparent anaemia ensues.

Diagnosis Pregnancy makes the diagnosis of heart disease more difficult. The pregnancy may produce symptoms of fatigue, shortness of breath, ankle oedema and syncope. Physical examination may reveal flow murmurs, a mammary souffle, venous hum, a third heart sound, a raised a wave in the jugular venous pulse, displacement of the cardiac apex (by the elevated diaphragm) and basal rales (which clear on coughing) for the same reason, all of which may be taken to indicate heart disease. The above confounding symptoms and signs are unfortunate because of the increased risk posed by heart disease to both the mother and the fetus. Another reason for establishing whether heart disease is present, even if it appears to be asymptomatic, is the small risk of puerperal endocarditis. The murmur of pregnancy (Still's murmur} is a low-pitched, often vibratory murmur heard at the left sternal edge but usually loudest in the pulmonary area. It is extremely common, midsystolic and unaccompanied by any other signs of heart disease. High-pitched systolic murmurs, and all diastolic murmurs, indicate heart disease. The use of echocardiography and Doppler ultrasound will often be of great value in these cases. Chest X-ray is relatively contraindicated. If essential, the fetus can be shielded. The risk to the fetus late in pregnancy is much smaller than first thought. The ECG is usually normal but the axis may shift to the left, with T-wave inversion in lead 3, a small Q wave, and sometimes even ST and T-wave inversion in the limb and precordial leads; these ECG changes revert to normal at the end of pregnancy and recur in later pregnancies.

Management If the pregnant mother is known to have heart disease and is in functional class 3 or worse of the New York Heart Association classification (p. 468, Table 12.1), it is hazardous for the pregnancy to continue. Certain types of heart disease, e.g. coarctation of the aorta, severe hyper-

tension, severe aortic or mitral stenosis or cardiomyopathy, present particular hazards. Cyanotic congenital heart disease poses great risk to the mother if pulmonary hypertension is severe. Spontaneous abortion is frequent. Surgery during pregnancy may offer a solution to the mother who is anxious to continue with the pregnancy; closed mitral valvotomy, or open valvotomy and valve replacement under cardiac bypass, have been performed with a low maternal mortality and acceptable fetal risk. If valvular disease or a jet lesion (VSD etc.) is diagnosed, appropriate antibiotic cover is given at the time of labour, particularly if instrumentation (e.g. urinary catheterization) is used at the time of delivery.

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Anticoagulants A particular problem may be the need for anticoagulants. Discontinuation of anticoagulants is dangerous for a mother with a prosthetic heart valve, and possibly also for one who has had a pulmonary embolus. Warfarin is avoided during the first trimester, because of an increased risk of fetal abnormality. For a planned pregnancy, heparin can be given during the first trimester. Warfarin is then given until heparin is used to cover delivery by caesarean section.

Peripartum cardiomyopathy Pregnancy and labour may make occult heart disease manifest. Occasionally, catastrophic heart failure supervenes and appears to be associated with a progressive cardiomyopathy.

Hypertension Hypertension in pregnancy and pre-eclamptic toxaemia and eclampsia are discussed on page 592.

SECONDARY HEART DISEASE A wide variety of pathological conditions may also increase cardiac output and produce heart failure. These include thyrotoxicosis, anaemia, cor pulmonale, beriberi, arteriovenous fistulas, generalized Paget's disease of bone and exfoliative dermatitis.

Thyrotoxicosis Thyrotoxicosis dramatically increases metabolic rate, but the thyroid hormones also have a stimulant effect on the autonomic nervous system and the heart itself. There is usually a sinus tachycardia which is indicative of the severity of the disease, but in 15% of cases thyrotoxicosis triggers a supraventricular arrhythmia, most frequently AF. Pulse pressure and blood pressure rise slightly and the heart contracts more vigorously in thyrotoxicosis.

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Anaemia Severe anaemia makes a twofold demand on the heart. In order to supply the oxygen requirements of the body, the heart has to increase cardiac output, despite itself being perfused with anaemic blood. Mild anaemia is of marginal importance, but life-threatening anaemia may lead to cardiac dilatation and severe heart failure, with pathological changes in the myocardium of 'fatty heart'. As the myocardium extracts virtually all the oxygen from the blood in the coronary circulation, autoregulation of flow demands a dramatic increase in coronary flow to compensate for the extra myocardial work of severe anaemia. This cannot be accommodated if there is coronary disease of any severity, and continuous angina and heart failure may result.

TABLE 12.39 Inherited connective tissue diseases and the heart Condition

Cardiac condition

General features

Cutis laxa

Peripheral pulmonary stenosis Mitral regurgitation Arterial rupture Aortic dilatation, dissection, aortic and mitral regurgitation

General skin laxity, disrupted elastic fibres Hypermobile joints Hyperelastic skin Gracile habitus, arachnodactyly, lens subluxation, sternal abnormalities Fragile bones, blue sclera

Ehlers-Danlos Marfan's

Osteogenesis imperfecta Pseudoxanthoma elasticum

Aortic regurgitation Peripheral and coronary artery disease

Beriberi Beriberi is uncommon outside Asia, but minor forms may occur in some alcoholics and food faddists. Severe thiamine deficiency (classically due to subsistence on polished rice) results in autonomic and other nervous system damage, with profound vasodilatation and a high cardiac output. In its fulminant form the patient may die from pulmonary oedema within 48 hours of the onset of symptoms. Response to conventional heart failure therapy without thiamine is poor. Thiamine is given as soon as the diagnosis is suspected, and should be given to alcoholics in heart failure and in all cases of resistant heart failure where the nutritional background of the patient is doubtful.

Arteriovenous fistulas, Paget's disease of bone, exfoliative dermatitis If they are severe enough, arteriovenous fistulas, Paget's disease of bone and exfoliative dermatitis may all cause a considerable reduction in peripheral resistance leading to a large increase in resting cardiac output. The patient has a bounding pulse and hyperkinetic circulation, often with a third heart sound and systolic murmur. Heart failure may supervene if the heart is already damaged or if the stress is severe enough. Treatment of the condition will alleviate the strain on the heart.

Inborn errors of metabolism and connective tissue disorders Heart disease may complicate or be part of many other medical conditions (Tables 12.39-12.42). Marfan's syndrome is discussed in Chapter 3, page 71. (see also p. 601). O Aortic dissection is a frequent and lifethreatening complication.

Degeneration of elastin fibres leading to yellow pseudoxanthomas of skin, retinal angioid streaks, hypertension

TABLE 12.40 Inborn errors of metabolism and the heart Condition

Cardiac condition

Pompe's disease

Glycogen storage disease involving the heart muscle Aortic and pulmonary artery dilatation Multivalvular disease, coronary artery disease and cardiomyopathy

Homocystinuria Mucopolysaccharidoses: Hurler's and Hunter's syndromes (mental deficiency) Morquio's disease

Aortic regurgitation

TABLE 12.41 Chromosomal abnormalities and the heart Chromosomal defect

Cardiac abnormality

Trisomy 21 (Down's syndrome)

Endocardial cushion defects, ASD, VSD, pulmonary stenosis VSD, double-outlet right ventricle VSD, persistent ductus arteriosus, pulmonary stenosis VSD Coarctation Persistent ductus arteriosus

Trisomy 13 Trisomy 18 Cri du chat (short arm deletion 5) XO (Turner's syndrome) XXXY and XXXXX

ASD = atrial septal defect; VSD = ventricular septal defect

Athlete's heart O Fig. 12.28 584

Exercise training induces changes in the heart muscle similar to those in skeletal muscle. Power athletes who perform mostly isometric exercises (weight lifting, wrestling, tug-of-war) develop ventricular hypertrophy. The left ven-

TABLE 12.42 Skeletal syndromes and the heart Syndrome

Cardiac abnormality

Skeletal syndrome

Ellis van Creveld

Single atrium or ASD

TAR

ASD or tetralogy of Fallot ASD (and others)

Chondrodystrophic dwarfism Absent radius, thrombocytopenia Upper limb deformity, hypoplasia of clavicles Polydactyly, obesity

Holt-Dram Laurence-MoonBiedl-Bardet Noonan Tuberous sclerosis Leopard Cockayne Progeria Apert

Variable Pulmonary valve dysplasia Cardiomyopathy Pulmonary stenosis Accelerated atherosclerosis Accelerated atherosclerosis VSD

Pectus excavatum Bone lesions Broad fades, ribs abnormal Cachectic dwarfism Skeletal hypoplasia Craniosynostosis, syndactyly

ASD = atrial septal defect; VSD = ventricular septal defect; TAR = thrombocytopenia-absent radius syndrome

tricle has to generate high pressures to overcome increased impedance to flow during the isometric exercises. Continuous measurement of pressure indicates that the mean arterial pressure rises above 160mmHg during maximal isometric deadlifts. Remodelling of the heart occurs so that high intraventricular pressures can be generated. This objective can be achieved through augmented tension development in each myofibril, but as (without altering its constitution) each myofibril has a performance maximum, this limits the contractile reserve available during times of haemodynamic stress. An alternative mechanism is to increase the number of in-parallel myofibrils, which would increase wall thickness. Greater wall tension and intraventricular pressure can then be generated with each myofibril developing the same tension as before. The appearance of the LV that is induced by pressure overload is essentially that of increased wall thickness, commonly referred to as concentric hypertrophy, similar to the appearance in patients with chronic hypertension or aortic stenosis. Endurance athletes who perform mostly isotonic exercises (long-distance running, swimming, cross-country skiing, aerobics) develop dilatation of the ventricles. Remodelling of the heart occurs to ensure that large stroke volumes can be delivered. As each sarcomere has a maximum shortening distance, the stroke volume is increased by increasing the number of in-series sarcomeres. However, according to LaPlace's law, the resulting ventricular distension would result in greater wall tension being required to generate the same intraventricular pressure. Some increase in in-parallel myofibrils and hence wall thickening is therefore also necessary. The appearance of

the left ventricle induced by volume overload is chamber dilatation and eccentric hypertrophy, similar to that found in patients with 'high-output states' such as Paget's disease, beriberi and anaemia, or those with valvular regurgitation. In elite athletes, because of the marked ventricular dilatation, the cardiothoracic ratio on chest X-ray may exceed 0.5. Owing to the large stroke volumes, their heart rates at rest and during equivalent exercise workloads are significantly lower than those of normal sedentary subjects. Their peak exercise heart rates are not diminished and, combined with the enormous stroke volumes, their peak cardiac outputs are markedly augmented (up to 35L/min). They therefore have superior oxygen delivery, exercise capacity and performance. In certain types of endurance training, such as cycling, rowing and canoeing, the exercise contains not only isotonic but also resistance components. In these situations the observed hypertrophy is characteristically a combination of concentric and eccentric. It is important to note that the above remodelling processes are adaptive mechanisms to maintain or enhance the pumping capability of the heart in response to the physiological demands imposed upon it. Although the ventricular appearances of hypertrophy and dilatation are similar to those in pathological states of aortic stenosis or regurgitation, these changes observed in athletes should not be regarded as abnormal but as supranormal, as they are physiological and beneficial. If they need treatment, say for hypertension, drugs (e.g. (3-blockers, verapamil) that would impede these adaptive changes should be avoided. Diagnosis and management Clinically, apart from bradycardia, other commonly found features of athletes are sinus arrhythmia, benign systolic murmur usually due to pulmonary flow murmur, and occasional third or fourth heart sounds. The ECG may indicate left and/or right ventricular hypertrophy. A common abnormality is atrial or ventricular arrhythmia, but most of these do not cause symptoms. Confirmation that these are benign may be achieved by demonstrating the complete disappearance of the arrhythmia during exercise. Because of the high vagal tone some athletes are prone to develop heart block, which may require pacemaker insertion. Echocardiography indicates the types and extent of hypertrophy or dilatation. The left ventricular ejection fraction is invariably normal. To determine whether an athlete has supranormal cardiac function a cardiopulmonary exercise test can be performed. Achieving a supranormal maximal oxygen consumption is an indirect indication of superior cardiac reserve. If in doubt, direct measurement of cardiac reserve can be made noninvasively by measuring the cardiac output and blood pressure during maximal exercise. Athletes are also susceptible to cardiac disease. Detection may not be straightforward, because the same extent of damage (e.g. myocarditis) occurring in a normal subject

12

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would have resulted in obvious cardiac dysfunction or failure, but its occurrence in an elite athlete may be masked because the baseline cardiac performance may be so enhanced that the eventual cardiac function falls within the normal range. Symptomatically, however, the athletic subject would complain that exercise capacity is significantly reduced. Certain heart diseases are lethal when combined with vigorous or competitive sport. Subjects with hypertrophic cardiomyopathy, aortic stenosis, Marfan's syndrome involving the aorta and heart, and life-threatening arrhythmias should be dissuaded from taking part in such sport. Patients with suspected or confirmed viral myocarditis should be persuaded to stop training, because viral replication rates are enhanced with continued exercise, and the resultant damage to the myocardium may be worse than detraining. Apart from this, there is the potential danger of triggering serious arrhythmia during myocarditis, which may result in sudden death.

Sternal depression and straight back syndrome Abnormalities of the shape of the thorax are a common cause of systolic murmurs; they may also give rise to musculoskeletal chest pains, an abnormal X-ray appearance of the heart and, in severe cases, ECG changes. Sternal depression and an abnormally vertical dorsal spine (straight back syndrome) both allow very little room for the heart in the anterior-posterior axis; this is well shown on the lateral chest X-ray. There is often a systolic murmur arising from the distorted great vessels; respiratory function may be impaired because of restricted chest wall expansion on inspiration, giving rise to a poor effort tolerance; and there may be associated mitral valve prolapse as a congenital anomaly. The ECG commonly shows right bundle branch block, and there may be anterior T-wave inversion in the V leads in the most severe cases. Assessment includes careful clinical examination to exclude primary cardiac pathology, and echocardiography and Doppler ultrasound where doubt exists as to whether there is more than a 'flow murmur'. Mild forms of this condition are commonly seen in pregnancy, when the patients are referred because of the murmur. Reassurance often helps the chest pains, which usually have a musculoskeletal basis and become worse when the possibility of heart disease is raised. Simple back exercises may also help.

PERICARDIAL DISEASE

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The pericardium is a fibrous bag that supports and invests the heart. Like the pleura, it may be the site of inflammation, neoplastic infiltration and calcification, and may also be the site of fluid collection with or without inflammation.

TABLE 12,43 Causes of pericardial disease Infections Viral, e.g. Coxsackie, influenza Bacterial: pyogenic and tuberculosis Fungal Metabolic Uraemia Hypothyroidism Neoplastic Carcinoma of the bronchus Lymphomas Myocardial infarction

Autoimmune Collagen disease, rheumatoid arthritis, SLE Postpericardiotomy and postinfarction (Dressler's) syndromes Serum sickness and drug reactions Idiopathic (benign recurrent viral) relapsing pericarditis Rheumatic fever Haemopericardium Cardiac rupture Aortic dissection Trauma and surgery

Radiotherapy

Aetiology The causes of pericardial disease are shown in Table 12.43. All of these conditions can produce the clinical features of pericarditis with effusion. Heart failure can also cause a pericardial effusion, but these are small asymptomatic effusions, often discovered at routine echocardiography. Acute viral pericarditis The commonest viral causes are Coxsackie virus A or B, varicella, herpes simplex, influenza virus and echovirus (type 8). Frequently, a definite viral cause cannot be established. Typically, it occurs in young adults 1 or 2 weeks after an upper respiratory infection. The patient then develops fever, pericardial pain and malaise which may persist for a few weeks. Unfortunately, recurrences occur in about 25% of cases, possibly from an autoimmune mechanism. Tamponade is unusual. Acute pyogenic pericarditis Acute pyogenic pericarditis can follow pneumonia or a septicaemia and is treated with the appropriate antibiotics and repeated drainage, which may require surgical intervention. Staphylococcus and Haemophilus are the most common organisms involved. It may also occur in immunosuppressed patients and following cardiac surgery. Tuberculous pericarditis Tuberculous pericarditis may be asymptomatic until it presents as pericardial constriction (see below). It may present as a large pericardial effusion with enlargement of the cardiac silhouette on chest X-ray, or as a low-grade fever with weight loss, fatigue and features of pericarditis. Pericardial aspiration may reveal the organisms, but occasionally (as with pleural effusions) culture of the fluid or pericardial biopsy may be required before the diagnosis is established.

Malignant pericarditis Pericardial effusion fluid should always be sent for cytology, as malignancy may present with a pericardial effusion. The clinical features are similar to those of other types of pericarditis, but may be complicated by direct tumour extension into the pericardium, with a degree of constriction. Lung cancer is the commonest cause. Uraemic pericarditis Uraemic pericarditis develops with severe untreated uraemia and disappears with dialysis. It appears to be directly related to the blood urea level. Other types In most other types of pericarditis, such as in autoimmune disease, pericardial involvement is an incidental finding but may occasionally lead to constrictive pericarditis.

Clinical features The principal symptoms of pericarditis are pericardial pain, breathlessness (if the effusion becomes large enough) and, eventually, tamponade. There may be systemic symptoms related to infection, such as fever, rigors, weight loss and symptoms of the underlying cause (lung cancer, tuberculosis etc.). Pericardial pain Pericardial pain is a mediastinal pain that can be very similar to that of myocardial ischaemia, but differs in that it is more commonly referred to the shoulder and back and is often influenced by posture and mediastinal movements, such as coughing, sneezing and, particularly, swallowing. It is often relieved by leaning forward. The diagnosis may be difficult because of the occurrence of pericardial pain following myocardial infarction. There can also be a pleural element to the pain. Pericardial rub Pericardial rub - the main physical sign of pericarditis - is very variable and often absent. It is a rough scratching sound which seems nearer to the observer than the stethoscope headpiece. Typically, it has three components - systolic, diastolic and atrial-systolic. However, the atrialsystolic and diastolic components may not be present, and a purely systolic scratchy murmur may have other causes. The noise can sometimes be accentuated by leaning the patient forward or, if conditions allow, by putting them in the knee-elbow position. The sound conies and goes and does not necessarily disappear with the formation of an effusion; indeed, it may be found in up to 70% of patients with pericarditis and effusion. Pericardial effusion Pericardial effusion does not usually cause symptoms unless it is large, when there may be some breathlessness and, eventually, features of tamponade (see below). The

clinical signs of an effusion without tamponade (soft heart sounds, increased cardiac dullness etc.) are not as helpful as chest X-ray and ultrasound.

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Cardiac tamponade If the pericardial cavity fills with blood or pericardial fluid, the pericardial pressure may rise sufficiently to embarrass filling of the heart and lead to a form of cardiogenic shock (cardiac or pericardial tamponade), with very low cardiac output, cerebral confusion, and severe hypotension proceeding to death if the pericardium continues to fill. The pericardium is viscoelastic and can therefore stretch slowly to accept as much as 2 L of fluid over a period of time without the development of temponade, but much smaller amounts of fluid can be fatal if they accumulate quickly.

Aetiology Tamponade is usually caused by bleeding or effusion into the pericardial space. It can complicate aortic dissection and myocardial infarction with rupture into the pericardium. Bleeding can also follow surgery or trauma to the heart and mediastinum, and may follow perforation of the heart at cardiac catheterization, or injury after pericardial aspiration. Malignant disease is a common cause, but tamponade is an uncommon complication of other causes of pericardial effusion. Clinical features Severe hypotension with impalpable or very weak peripheral pulses may be present. Classically, careful palpation of the arterial pulses reveals pulsus paradoxus, in which the pulse pressure drops considerably on inspiration and the pulse may even become impalpable. The paradox is not that the pulse volume diminishes with inspiration (which happens normally to a small extent), but that the stroke volume of the left ventricle declines markedly while - paradoxically - the heart seems to be beating normally. The mechanism of pulsus paradoxus is related to the pericardial temponade dictating a small fixed volume to the heart. Normally, right ventricular filling is aided by inspiration but with tamponade (or pericardial constriction), this rightsided mechanism inhibits filling of the constricted left ventricle, whose stroke volume falls. The jugular venous pressure is usually markedly raised, may show a marked systolic drop (prominent x descent) and, sometimes, rises with inspiration (Kussmaul's sign). Chronic tamponade can mimic constriction, with hepatic enlargement and oedema. The heart sounds may be faint and there can be a pericardial rub.

Investigation of pericarditis The ECG changes of acute pericarditis are shown in Figure 12.66. The ST elevation remains concave upwards and is

587

FIG. 12.66 EGG of acute pericarditis illustrating widespread concave ST segment elevation

followed later by widespread T-wave inversion, probably indicating a degree of epicardial myocarditis. A large effusion can produce a diminution of ECG voltages; in extremely large effusions there can be 'electrical alternans', with the voltage being influenced by the heart swinging backwards and forwards in the effusion. Chest X-ray (if there is an effusion) shows increased cardiac silhouette, with a globular appearance to the heart but no evidence of raised pulmonary venous pressure. This appearance is not specific. Echocardiogram is the technique of choice in demonstrating a pericardial effusion, preferably with a 2D scan. A small effusion can be localized, and may be missed unless the operator is experienced. With a large effusion echocardiography will show the heart surrounded by a large bag of fluid, which is seen as an 'echo-free' space. Pericardial aspiration is described below. The fluid should be sent for bacteriological and cytological examination.

Pericardial pain often responds to anti-inflammatory agents. Infective pericarditis demands prompt diagnostic aspiration and identification of the infective agent, with appropriate chemotherapy. In viral pericarditis antiinflammatories alone are used, but where there is an autoimmune element, such as in postinfarction syndrome and recurrent 'viral' pericarditis, corticosteroids may help. A large effusion is drained as described below. If the patient suffers repeated attacks, a pericardial window can be made into the pleural space at operation.

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CONSTRICTIVE PERICARDITIS Constrictive pericarditis results from thickening and fibrosis of the pericardium with, in some cases, extensive calcification.

Management

O Case 12.8

Pericardial aspiration Pericardial aspiration can be both diagnostic and therapeutic. In an emergency, e.g. after a road traffic accident with trauma to the chest, if a patient is moribund with features suggesting tamponade (i.e. very high venous pressure), then aspiration from the apex of the heart with a needle of adequate length should not be delayed. Removal of even 50-100 mL of blood from the pericardium may reverse the state of shock. Elective aspiration is best performed in a coronary care unit with ECG, blood pressure and echo monitoring and a cardiac defibrillator available. After local analgesia of the chest wall, the pericardium is punctured either at the cardiac apex (which is free of major coronary vessels) or via a subxiphoid approach. The ECG monitor shows ventricular ectopics if the ventricles are touched. Using a metal needle connected to an ECG V lead, a current of injury (raised ST segment) is produced as soon as the myocardium is touched and, hopefully, before the ventricle is pierced. Ideally, a cannula, rather than a needle, is left in the pericardium, and aspiration or drainage follows. If the fluid looks like blood, pericardial blood from a haemopericardium can be distinguished from ventricular blood by the fact that it is defibrinated and will not clot. It also has a lower haemoglobin and haematocrit than venous blood, as it is almost always diluted with serous pericardial fluid. Diagnostic aspiration of a large effusion without subsequent drainage can lead to pericardial fluid draining into the pleural cavity. Drainage of a large effusion can take several hours, and recurrent effusion (e.g. in malignant disease) may require fenestration of the pericardium or insertion of a pericardioperitoneal drain by a cardiothoracic surgeon. O

Fig. 12.29

MCQ 12.23

Aetiology There may be an antecedent history of acute pericarditis or radiotherapy. Tuberculous pericarditis is now rare in western countries, but is the classic cause of calcific constrictive pericarditis.

Pathogenesis The heart is effectively encased in a rigid box, which eventually prevents it from filling. Haemodynamically, the diastolic pressures or filling pressures of the two sides of the heart become the same as the intrapericardial pressure; as this rises, the patient goes into bilateral heart failure, in which features of right-sided failure predominate.

Sometimes the constriction is selective, so that the left or the right side, inflow or even outflow, can be compromised most.

Clinical features Symptoms The major symptom is severe oedema, often with ascites, liver engorgement and progressive weight loss secondary to hepatic engorgement and low cardiac output. Patients with long-standing disease look cachectic, and with the liver enlargement and a degree of jaundice are easily thought to have carcinomatosis or cirrhosis of the liver. The absence of significant left-sided heart failure symptoms is characteristic. The patient can often lie flat without problems and does not have a history of paroxysmal nocturnal dyspnoea, but will always have a limited exercise tolerance and dyspnoea on exertion. Constriction may arise with no previous history of pericarditis. A previous history of pericarditis is a valuable clue to the diagnosis. Signs A very high venous pressure is invariable, as the enddiastolic pressure in both ventricles is about 25mmHg. The high venous pressure is interrupted by a rapid x and y descent or systolic collapse of the venous pressure. The pulse exhibits pulsus paradoxus, but this is not invariable and the presence of AF in about 30% of cases makes the sign difficult to elicit. The pulse will, in any case, be of small volume. The heart is not clinically enlarged and the rigid pericardium may impede palpation of the cardiac impulse. The heart sounds may be faint with a loud additional sound, the pericardial knock. This is a loud early third heart sound, resulting from the rapid filling of the ventricles being suddenly impeded by the rigid pericardium. Murmurs are uncommon.

Investigation The ECG is non-specific, showing low voltages and, usually, T-wave inversion; other changes may reflect epicardial myocardial damage resulting from pericardial impingement on the epicardial coronary arteries. Chest X-ray shows a normal-sized or slightly enlarged heart, often with an abnormal contour due to flattening of the atria. Calcification may be seen in the A-V groove on a lateral film. 0 Depending on the sites of constriction, there may be signs of left or right atrial hypertension. Pleural effusions are common. Screening of the heart reveals a typical 'diastolic shock', with lack of pulsatility of the atria. Echocardiography may demonstrate thickening of the pericardium. The ventricles fill rapidly in early diastole, but the differential diagnosis from restrictive cardiomyopathy is not easy. Cardiac catheterization would show elevation and equalization of diastolic pressures in all four chambers, with characteristic 'square root sign' of the early diastolic ventricular pressure waveform.

Management The only effective treatment is surgical decompression of the heart by removing enough of the pericardium to allow the heart to fill effectively. This means removing the adherent pericardium from around the great veins and atria, which are extremely thin-walled. Where the pericardium is adherent to the ventricles the coronary arteries are easily damaged, so considerable surgical skill and patience are required. ©

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SYSTEMIC BLOOD PRESSURE AND HYPERTENSION Cardiac performance and vascular resistance form part of an integrated system which controls arterial pressure and blood flow to the tissues. Despite our knowledge of many of the component mechanisms of pressure and flow control, many aspects remain unclear in both health and disease.

CONTROL OF BLOOD PRESSURE Neurosympathetic blood pressure control Activation of preganglionic sympathetic neurons to the heart produces an increased heart rate and increased strength of contraction. Vasomotor sympathetic outflow constricts vascular smooth muscle, producing arterial vasoconstriction. The supply to the veins is richer and more sensitive than to the arterial system. Increased vagal activity reduces the heart rate but, with the exception of the coronary and salivary gland vascular beds, there is no parasympathetic control of the blood vessels. Moment-to-moment reflex control of the circulation is via the arterial baroreceptors in the wall of the aorta and in the carotid arteries. The speed of this pressurecontrolling mechanism is illustrated by its important role in maintaining systemic pressure during abrupt changes in posture. Neurosympathetic influences on blood pressure and the circulation are rapid but tend to be transient; this is partly due to a tendency for the reflexes themselves to undergo accommodation, and partly because peripheral autoregulatory mechanisms may overcome neural constrictor effects.

Renin and angiotensin The renin-angiotensin-aldosterone system (Fig. 12.25) plays a major part in the control of blood pressure, regional blood flow and blood volume, via its control of sodium balance. Renin secretion from granules in the juxta-

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glomerular apparatus is stimulated by a fall in plasma volume, a drop in blood pressure and sodium depletion. The consequent rise in angiotensin II production and aldosterone secretion leads to sodium and water retention, and hence restoration of sodium balance and plasma volume. Under conditions of plasma volume reduction and sodium depletion (<50mmol Na+/day), angiotensin II contributes to the maintenance of blood pressure by both vasoconstriction and interaction with the sympathetic nervous system. In the kidney, angiotensin II has a preferential constrictor effect on efferent (postglomerular) arterioles, and thus maintains glomerular filtration pressure when the overall arterial pressure is diminished. The renin-angiotensin system plays a crucial role in the increased blood pressure seen with renal arterial constriction; the latter causes a rapid release of renin and angiotensin II and hence a rise in blood pressure. Angiotensin II causes changes in intrarenal flow patterns and stimulates aldosterone release. The combination of haemodynamic and direct effects on the renal tubules increases sodium reabsorption. An extrarenal local tissue renin-angiotensin system has been identified, and there is increasing evidence that abnormal function of this system may play a role in the pathogenesis of hypertension.

first sound (Kj) and diastolic pressure is usually within a few mmHg of sound muffling (K4). In many major trials of blood pressure treatment sound disappearance (K5) is used to define diastolic pressure. In some individuals K5 cannot be defined when peripheral vascular resistance is low, as sounds carry on to zero cuff pressure. The anauscultatory gap (K2-K3) is particularly prominent in the elderly; this is important, as mistaken identification of K3 as K] might lead to a serious underestimation of systolic pressure - by up to 15-20 mmHg in some cases. Its presence is accentuated by venous distension distal to the cuff. Accurate blood pressure measurement requires a cuff of adequate size: a small cuff will seriously overestimate pressures. The subject should be seated, with the manometer reservoir at the level of the sternal angle. The cuff bladder is arranged medially to overlap comfortably the medial aspect of the upper arm. Pressure in the cuff is inflated rapidly to 20-30 mmHg above that required to occlude the brachial or radial pulse. Pressure is then reduced slowly from the cuff while listening with a stethoscope over the previously located brachial pulse. The rate of pressure drop should not exceed 5 mmHg per second, and the line of sight should be such as to avoid parallax errors when reading the falling column of mercury.

Nitric oxide and endothelin

SYSTEMIC HYPERTENSION

More recent evidence suggests that nitric oxide (NO, previously known as endothelium-derived relaxant factor), endothelin, prostacyclin and other vasoactive factors that are locally produced by endothelial cells and vessel wall, play a role in the control of vascular tone and hence blood pressure. Suppression of NO production can result in hypertension, thus introducing the concept that blood pressure is controlled not only by vasoconstrictive neurohumoral factors, but also by paracrine vasodilators. Overproduction of NO, such as is seen in endotoxaemia, results in overvasodilatation leading to circulatory shock. Endothelin (first discovered in 1988), a peptide produced by endothelial cells and released abluminally towards the smooth muscle cells, is one of the most powerful vasoconstrictors. Its exact physiological role in the control of blood pressure is still unclear. Increased vascular synthesis and plasma concentrations of endothelin have been reported in hypertension, chronic renal failure and toxaemia of pregnancy. Hypertension has been reported to be due to a tumour overproducing endothelin. Endothelin receptor antagonists may have a role in the treatment of hypertension.

Definitions Blood pressure varies considerably, rising during exertion, and is subject to a circadian variation which may not be completely activity related. Ambient temperature and the degree of emotional or physical arousal will also affect systemic pressure levels. Systolic blood pressure rises with age

BLOOD PRESSURE MEASUREMENT

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Korotkoff defined the auscultatory features (Korotkoff sounds) over the brachial pulse as pressure was released from an inflatable cuff. Systolic pressure correlates with the

FIG. 12.67 Changes in blood pressure with age in three different communities: Londoners, urban Zulu and Kalahari Bushmen

therapy), it is very important to pay attention to other contributing risk factors as well.

Hypertension in special groups in the community

FIG. 12.68 Distribution of diastolic blood pressure in a western population (black line) Risk of death is shown by the blue line. The diastolic blood pressure levels are indicated at which treatment reduced mortality in two large trials (see text). VA = Veterans Administration; MRC = Medical Research Council.

in developed countries (Fig. 12.67). Within a community, blood pressure (systolic and diastolic) has a normal or Gaussian distribution, a factor that becomes very important when definitions of abnormalities of blood pressure are considered (Fig. 12.68). Insurance companies were among the first to note that a reduced lifespan was associated with recordings of elevated blood pressure. It was clear from their data that no cut-off pressure level could be identified at which no increased risk of premature death was present. Hypertension could therefore be defined as a blood pressure above a particular value, e.g. 160/90 mmHg. A more flexible definition - able to take into account new information derived from the results of therapeutic trials - might be preferable, for example 'the level of blood pressure above which investigation and treatment do more good than harm.' Figure 12.68 illustrates how successive treatment trials (the Veterans Administration in 1965, and the Medical Research Council in 1985) have lowered the blood pressure at which treatment has been shown to have benefits.

Risk stratification A small number of individuals have very high blood pressure and are at very high risk of complications of the disease and death. At lower levels the risk attributable to blood pressure is relatively less for the individual, but that low risk is shared by so many people that the associated complications and premature mortality pose a significant burden on the community. Blood pressure is not the only risk factor in these calculations. Because drug treatment of great numbers of the population tends to carry unwanted financial and medical consequences (owing to the requirement for lifelong

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There is a tendency to a high systolic blood pressure in old age and this carries with it the risks associated with hypertension at any age. Therapy is possible in older patients, and has been shown to reduce the risk of stroke and myocardial infarction. Urban black populations have a higher incidence of hypertension than their white neighbours. Both environmental and genetic factors are likely to be responsible. Hypertension is rare in some rural African communities but a very major problem in others. Stroke is the most common complication among black hypertensives, and myocardial infarction is relatively rare; the opposite is the case for white hypertensives. The effectiveness of treatment is similar among blacks and whites; however, there are minor differences in the response to certain drugs, with a slight resistance to the effects of B-adrenoreceptor blocking drugs being shown by black patients.

PRIMARY HYPERTENSION Borderline and labile hypertension About one-third of patients found to have an abnormal blood pressure at their first visit to the doctor will have lower blood pressure on subsequent visits. This borderline group may subsequently develop established hypertension. Some individuals appear to have wide swings in blood pressure, and have been called labile hypertensives. It seems likely that they do not form a pathologically distinct group, but manifest an accentuation of normal variability. As a group, they have a higher mortality than consistently normotensive individuals.

'White coat hypertension' Some patients have such a marked stress reaction when seeing a doctor (whether medical and whether wearing a white coat or not) that they raise their blood pressure to hypertensive levels. They appear calm externally and deny anxiety. This category of patients was first identified as a distinct subgroup on the introduction of ambulatory BP monitoring (see below). Whether patients with 'white coat hypertension' have a similar adverse prognosis as those with established chronic hypertension is unknown. There is a suggestion that some of them will eventually develop chronic hypertension later in life. These patients should be encouraged to undertake non-pharmacological methods of lowering blood pressure, such as avoiding obesity and increasing exercise. Some patients with essential hypertension may also have a component of 'white coat hypertension' superimposed.

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They are often given increasing numbers and doses of antihypertensive drugs. Repeated ambulatory blood pressure monitoring may be required to gauge their true response to treatment.

Because of arteriosclerotic changes in the major vessels of the elderly, the pulse pressure widens, with a greater rise in systolic than in diastolic pressure. Thus, isolated systolic hypertension may be observed. Even in isolation, systolic hypertension is associated with an excess risk of morbidity through stroke, myocardial infarction and congestive cardiac failure. Benefit of treatment in such cases is likely, and it is reasonable to aim for a systolic pressure reduction to <150mmHg.

not. This differentiation has no clinical or prognostic value as the conditions are identical, with an untreated mortality of about 80%. Patients may have a past history of hypertension, but in most this is the first manifestation of their disease. It is one of the few occasions when hypertension is associated with symptoms, which include visual disturbance, headache and breathlessness due to pulmonary oedema; with severe degrees of cerebral oedema blunting of consciousness, coma and epileptic seizures also occur. It is usually easy to treat and therapy is undoubtedly life-saving. Many factors have been implicated in the genesis of malignant hypertension. The rate of rise of pressure may be more important than absolute levels of hypertension and there may be associations with other factors that damage blood vessels, such as cigarette smoking.

Benign or essential hypertension

Hypertension in pregnancy

'Essential hypertension' is commonly used to mean idiopathic or primary hypertension. The majority of patients with hypertension (over 90%) have no known cause, and thus fall into the category of essential hypertension. This condition affects a vast proportion of the population - possibly as many as 20% of the middle-aged subjects in the UK, depending on the blood pressure levels adopted as the definition of hypertension. The diagnosis depends on an established elevated systemic pressure in the absence of changes in the ocular fundi and of proteinuria, and where no identifiable cause of pressure elevation has been demonstrated. Essential hypertension can affect any age group and can, when untreated, lead to many complications, including malignant and accelerated-phase hypertension.

During pregnancy cardiac output rises, but blood pressure normally falls owing to a decrease in vascular resistance. Obstetricians regard as abnormal a blood pressure greater than 140/90 (measured using Korotkoff 4 for diastolic pressure) in the first half of pregnancy, and by this criterion nearly one-quarter of the pregnant population will be hypertensive. About 2% will have a blood pressure greater than 160/105. Pre-eclampsia and eclampsia are placental syndromes which are limited to the duration of pregnancy, and of which elevated blood pressure is just one manifestation. Pre-eclampsia was previously defined as hypertension with proteinuria (>0.5 g/L per 24 hours) and oedema. However, the latter is a frequent finding in normal pregnancies and often absent in pre-eclampsia, so that it is no longer included as a diagnostic criterion. Proteinuria is a late manifestation of pre-eclamptic renal impairment. Impaired uric acid clearance, which occurs much earlier in the disease process, is more useful diagnostically. Evidence of disseminated intravascular coagulation occurs late in the disease. Eclampsia is defined as the development of convulsions in the above setting. The diagnosis of pre-eclampsia thus depends on the observations of an abnormal rise in blood pressure between the first and second halves of pregnancy of >30/20mmHg, associated with abnormal urate levels (>0.35 mmol/L at 32 weeks or >0.4mmol/L thereafter); proteinuria, impaired renal function and clotting disorders confirm the diagnosis, but occur very late in the disease. The consequences of pre-eclampsia are placental ischaemia and infarction and, in severe cases, maternal cerebral haemorrhage. Treatment is elective delivery, which confirms the diagnosis by effecting a rapid and complete cure. Medical management may reduce blood pressure but has not been shown to ameliorate other features of preeclampsia, which continue until delivery is effected. Pre-existing hypertension, low social class and the first pregnancy with a particular partner are risk factors for preeclampsia; interestingly, it appears to be less common in smokers.

Isolated systolic hypertension

Malignant and accelerated-phase hypertension Malignant or accelerated-phase hypertension is associated with vascular fibrinoid necrosis and loss of precapillary arteriolar autoregulation. The consequence is capillary vessel rupture and tissue necrosis through haemorrhage and ischaemia. The brunt of the damage is borne by renal, adrenal, cerebral, retinal, pancreatic and mesenteric vessels, for reasons that remain unclear. The clinical findings are elevated levels of blood pressure (which may be severe), associated with haemorrhages and exudates visible on the retina. Proteinuria due to similar vascular changes in the kidney is usual. Papilloedema (when present) O reflects cerebral oedema and was previously used to differentiate malignant hypertension, where it was present, from accelerated-phase hypertension, where it was

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Fig. 12.30

TABLE 12.44 Causes of secondary hypertension Type of cause Renal Parenchymal disease

Arterial disease

Endocrine disease Adrenal cortical overactivity Adrenal medullary overactivity Drug-induced

Congenital defects Miscellaneous

Examples Chronic renal failure of any cause Acute and chronic glomerulonephritis Polycystic disease Pyelonephritis Tumours, e.g. haemangiopericytoma; Wilms' tumour Diabetes Arteriosclerotic disease Fibromuscular dysplasia Embolism Polyarteritis nodosa Cushing's syndrome Conn's syndrome, adrenal hyperplasia Enzyme defects, e.g. congenital adrenal hyperplasia Phaeochromocytoma Contraceptive pill Liquorice-containing compounds Steroids Withdrawal of antihypertensives, esp. clonidine Cheese ingestion in patients taking monoamine oxidase inhibitors Sympathornimetic decongestant nasal sprays/appetite suppressants Coarctation of the aorta Porphyria (during acute attacks) Lead poisoning (during acute phase) Raised intracranial pressure

SECONDARY HYPERTENSION The causes of secondary hypertension are given in Table 12.44. As a general rule, the younger the patient with hypertension the greater is the likelihood that a cause will be found. In an adult hypertensive population less than 5% of patients will have a discernible cause. Although this proportion is small compared to those with essential hypertension, because many of the secondary causes are treatable by corrective surgery or specific therapy a high index of suspicion is required to avoid overlooking a treatable cause.

Renal disease The precise cause of high blood pressure in chronic renal failure is not clear. Adequate management of hypertension is important to prevent vascular complications due to hypertension and prevent further deterioration of renal function. There is no justification for surgical removal of

kidneys in unilateral renal disease, as medical treatment of hypertension is now likely to be more effective. Renal arterial stenosis activates the renin-angiotensin system, and restoration of the normal vascular supply may potentially cure the associated hypertension. Atheromatous disease is the commonest form of renovascular disease; it mainly affects middle-aged male smokers and is often part of a generalized degenerative disease of the arteries. Angioplasty may be useful, but the disease in smaller arteries limits the overall prognosis. In fibromuscular dysplasia (a disease of younger age groups), surgical reconstruction of renal arteries may be very effective. The importance of diagnosing renovascular hypertension has increased in recent years with the introduction of ACE inhibitors. These are to be avoided in renovascular hypertensives, as they can precipitate renal failure owing to the importance of angiotensin II in maintaining intrarenal haemodynamics in the underperfused kidney.

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Endocrine disease Hypertension, which may be severe, usually accompanies Cushing's syndrome (p. 932). Hypemldosteronism Overproduction of aldosterone may be due to single or multiple autonomous adrenal adenomas (Conn's syndrome) or bilateral micronodular hyperplasia of the zona glomerulosa. Clinical suspicion of primary hyperaldosteronism is raised when untreated hypertension is associated with hypokalaemia (K+ < 3.5mmol/L), alkalosis (HCCV > 30mmol/L), and a serum sodium which is high or at the upper limit of normality (Na+ > 145mmol/L). Investigation of primary hyperaldosteronism is aimed at differentiating adenomas from adrenal hyperplasia, as the former may be removed surgically. Radionucleotide adrenal scanning with labelled cholesterol, CT scanning and adrenal vein catheterization to measure the production of aldosterone offer the best methods of diagnosis. Explorative surgery may be necessary in some instances. Hyperplasia is treated successfully with antialdosterone drugs, such as spironolactone or amiloride.

Phaeochromocytomas Phaeochromocytomas are tumours, usually found in the adrenal, that secrete a mixture of catecholamines. They are responsible for clinical syndromes where hypertension may be episodic and alternate with episodes of postural hypotension. Paroxysms of hypertension are often associated with a constellation of symptoms, including headache, sweating, palpitations, feelings of apprehension and tremor. These symptoms are more sensitive in making the diagnosis than are most biochemical tests. The majority (90%) of the tumours are benign, and 10% arise outside the adrenals, most commonly at the bifurcation of the abdominal aorta. There are associated phaeochromocytomas in Sipple's syndrome (often a familial disorder with the combination of medullary carcinoma of thyroid and

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parathyroid adenoma) and in neurofibromatosis or von Recklinghausen's disease (p. 421). Investigation and management The diagnosis is confirmed by the detection of increased amounts of catecholamines and their breakdown products - normetadrenaline, metadrenaline and vanillylmandelic acid (VMA) - in urine or plasma. Localization of the tumour is by CT scanning and radionucleotide scans with MIBG (131I meta-iodobenzylguanidine). Treatment is surgical when possible, but can be hazardous owing to surges of catecholamine secretion during tumour manipulation. Preliminary treatment with a- and {3-blockade is essential, as are agents to raise blood pressure and prevent vascular collapse when the levels of these hormones fall rapidly as the tumour is removed.

Drug-induced hypertension Mineralocorticoid-induced hypertension with hypokalaemia and alkalosis accompanies the use of steroids, and may occur with carbenoxolone and excessive liquorice consumption. Hypertension induced by the contraceptive pill is generally mild and reversible on cessation of therapy, although this may take several months.

Coarctation of the aorta In coarctation of the aorta, children or young adults present with asymptomatic upper limb hypertension and are noted on physical examination to have characteristically late and low-volume femoral pulses compared with the radial pulses (radiofemoral delay). Hypertension may be difficult to treat medically and, if left until the patient is a teenager, is often only partially helped by surgical repair of the narrowed aortic segment. Those operated on late (after 20 years of age) frequently suffer the complications of uncontrolled hypertension, and about 12% may die in their 30s of cerebral haemorrhage or ruptured aortic aneurysm. Surgery is now recommended before the age of 6, but balloon angioplasty has recently been successfully used in this condition and may be used more frequently in the future if the initial good results are maintained. The hypertension of coarctation is not fully explained, but renal hypoperfusion, aortic baroreceptor activity and mechanical effects of aortic obstruction may all play a part. CLINICAL FEATURES OF HYPERTENSION

Until complications appear, essential hypertension has no symptoms and, by definition, no associated physical signs save the elevated blood pressure. Headaches (once widely

regarded as indicators of hypertension) are no more common in hypertension than in the general population, although very severe hypertension, associated with cerebral oedema, does produce headache. Breathlessness may be present, owing to elevated left ventricular and enddiastolic pressure and pulmonary venous congestion produced by left ventricular hypertrophy. Once the complications of essential hypertension are present, they are reflected in the symptoms and physical signs. Ventricular hypertrophy may lead to breathlessness, orthopnoea and frank cardiac failure; coronary disease to angina pectoris or myocardial infarction; cerebrovascular disease to stroke and dementia; and renal disease to all its associated symptoms. The presence of some symptoms (e.g. those associated with phaeochromocytoma) will suggest a secondary cause. Symptoms of renal impairment (e.g. nocturia and polyuria) may reflect the consequence of long-standing hypertension rather than its cause. Certain points in the examination of the hypertensive deserve emphasis, and require careful observation at diagnosis and during follow-up. Pulse Rate and rhythm. Atrial fibrillation is a late consequence of hypertension. A resting tachycardia might imply cardiac decompensation or a secondary cause, such as phaeochromocytoma or hyperthyroidism. Arterial wall. If thickened arteries are palpated in an under-50-year-old, aggressive treatment of blood pressure and other risk factors would be justifiable. Peripheral pulses. Radiofemoral delay is a sign of aortic coarctation, which may be a cause of hypertension in young patients. In older patients atherosclerotic disease may cause peripheral vascular bruits and absent distal pulses. Apex beat A displaced and thrusting apex beat indicates left ventricular hypertrophy (LVH) and therefore hypertension worthy of aggressive treatment. The absence of this sign does not exclude LVH. Abdomen Palpable kidneys might be found with polycystic renal disease. A systolic and diastolic abdominal or flank bruit raises the possibility of renal arterial stenosis. Optic fundus Haemorrhage, exudates and papilloedema (grades 3 and 4) are all signs of accelerated or malignant hypertension. Early signs of arterial wall thickening are narrowing of the arterial lumen (grade 1, which is difficult to identify) and arteriovenous nipping (grade 2). General aspects Other important general signs include:

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Fig. 12.31

• Signs of risk factors for vascular disease (xanthomata), which might tip the balance in favour of treatment because of the increase in vascular risk;

Signs suggesting Cushing's syndrome or neurofibromatosis (associated with phaeochromocytoma); Indications of congestive cardiac failure.

INVESTIGATION The aims of investigation are: • To establish the diagnosis • To identify a cause of the hypertension • To determine the presence and extent of complications from hypertension • To assess efficacy of treatment. The history and clinical examination provide clues as to which investigations are appropriate. Numerically, attempting to find an aetiology is far less rewarding, as only about 5% of all cases of hypertension have an identifiable cause. This proportion is higher in young adults, all of whom should be investigated accordingly.

Persistent proteinuria requires detailed testing of renal function (p. 1037). The discovery of haematuria should be followed by tests for inflammatory and neoplastic disease of the kidney. A 24-hour urine collection is required to quantify protein excretion; this may be helpful in hyperaldosteronism, Cushing's disease and phaeochromocytoma.

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Blood tests Routine haematological and biochemical tests are seldom rewarding. However, it is usual to obtain a full blood count and biochemical profile, which may occasionally provide useful information, for example: • An indication of renal function (urea and creatinine); • Electrolyte disturbances (low K+, raised HCO-3 and Na+) that might indicate hyperaldosteronism; • Other associated risk factors, such as hyperuricaemia or hyperlipidaemia; • Anaemia due to chronic renal disease, or polycythaemia secondary to renal disease.

ECG Ambulatory BP monitoring The difference between ambulatory BP (ABP) monitoring and clinic BP readings is similar to that between cinematography and snapshot photography. There are two ways of monitoring ambulatory BP: • With intra-arterial cannulation and direct pressure measurement • With indirect cuff manometry both of which record readings in a portable recorder which can subsequently be fed into a computer for display and analysis. The former method is now considered too invasive and is reserved for research purposes. Some patients with elevated blood pressure have 'white coat hypertension' (see above). The characteristic pattern is that they have significantly elevated blood pressure when the ambulatory BP monitor is first applied, and subsequent blood pressure readings at home or elsewhere show normal levels. A proportion of them show a further elevation of blood pressure as they make their way to hospital to return the equipment. Patients with essential hypertension possessing a 'white coat' component show elevated pressure at home, and further elevation during visits to hospital or clinic. The correlation between the effects of hypertension, such as left ventricular hypertrophy with isolated clinic BP reading, is much poorer than that with ABP. ABP provides information on diurnal variation in blood pressure. Blood pressure falls by about 20mmHg during sleep. The absence of nocturnal sleeptime falls in blood pressure is also associated with adverse prognosis. Urine testing Even though the yield of abnormal results by dipstick testing is not high, this simple test is essential in all cases.

An initial ECG may be helpful as a baseline for future changes, as well as in deciding whether to offer treatment. Features to be documented are signs of left atrial enlargement ('P mitrale', p. 477) and, with more severe levels of hypertension, evidence of LVH (Fig. 12.69) possibly associated with abnormalities in the ST segments and T waves that denote the 'strain' pattern. With effective blood pressure reduction these changes usually resolve. Chest X-ray The chest X-ray is helpful in establishing cardiac size and may reveal cardiac failure. 1 In most Caucasian patients it is normal, but cardiac enlargement is common in hypertensives of African descent. In young hypertensives, signs of a coarctation (p. 540) may be found.

FIG. 12.69 Typical ECG in severe hypertension showing left ventricular hypertrophy

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Ultrasound techniques The echocardiogram can determine the presence and extent of left ventricular hypertrophy. The presence of LV hypertrophy in a new patient without other causes for hypertrophy (e.g. athletism, aortic stenosis) is supportive of the diagnosis that the hypertension has been substantial and chronic. In epidemiological studies, left ventricular hypertrophy has been found to be an independent indicator of adverse prognosis. These patients benefit from more attentive management to achieve as normal a blood pressure level as possible. Abdominal ultrasound examination shows kidney size and ureteric anatomy and gives some information on the renal substance. Doppler study of the renal arteries can detect stenosis, the suspicion of which should lead to radionuclide renal scintigraphy to assess residual renal function, or to renal angiography. Renal artery stenosis is a contraindication for ACE inhibitor, renin inhibitor and angiotensin receptor antagonist therapy. Nuclear medicine techniques Nuclear medicine techniques are used to measure dynamic aspects of kidney and cardiac function. These specialized methods should be reserved for those in whom a specific problem has been identified. Renal angiography A renal arteriogram is the definitive test to determine renal artery stenosis. Angioplasty may be performed if the lesion is deemed suitable for intervention. Renal venous sampling may be performed to measure plasma renin activity, which provides complementary information about the extent and effects of arterial stenosis. Venous sampling may also be indicated to identify the locations of tumours producing vasoactive agents.

COMPLICATIONS OF HYPERTENSION

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The development of LVH in hypertension is an adaptive response, but the effects on diastolic function may give rise to pulmonary venous congestion and, with increasing hypertrophy, inner layers of myocardium become ischaemic. The associated acceleration of atheromatous coronary disease contributes to the progression to left ventricular dysfunction and cardiac failure. Atheroma deposition is accelerated by hypertension, and causes the most numerous of the complications of coronary artery disease; it also is responsible for most of the cases of stroke. Aortic dissection is a consequence of vessel wall degeneration and cystic medial necrosis. A pathologically distinct process affects smaller vessels, particularly of the renal and cerebral circulations; this consists of medial and intimal proliferation. Renal impairment may follow, although renal failure is usually a complication of the fibrinoid necrosis of the resistance

vessels, which characterizes malignant or acceleratedphase hypertension.

SUITABILITY FOR TREATMENT At the highest levels of blood pressure (diastolic greater than 115 mmHg) the risks to the individual patient are so high that treatment is mandatory. However, confirming that it is beneficial to treat patients with diastolic pressures between 90 and 114mmHg has been more difficult. The combined results of randomized trials suggest that treatment has decreased the odds of stroke significantly, by about 40%, but only managed to reduce the risk of heart attack by 10%. These large trials have provided no evidence to favour any one particular drug regimen over any other. Patients with diastolic blood pressures above 105 mmHg are recommended for treatment, particularly if they demonstrate any ventricular hypertrophy or renal impairment. For the 10-15% of the middle-aged population with diastolic pressures between 90 and 104 mmHg a more complex strategy is necessary. This is because halving the annual risk of a stroke, from 0.1 to 0.05% in an asymptomatic middle-aged man may not be worthwhile, particularly when set against the requirement for lifelong treatment. However, if the individual has already suffered a complication, such as a transient ischaemic attack, halving the annual stroke risk from 20 to 10% is a worthwhile goal. A strategy for patients with diastolic blood pressure between 90 and 104 mmHg should aim to identify those with the highest risk of complications. Treatment begins with measures to reduce associated risk factors, such as smoking, high blood lipids and obesity. Drug therapy of mild hypertension should therefore be reserved for those in whom all other measures have failed and those who carry the greatest risk of progression to severer forms of blood pressure or cardiovascular complications.

Systolic hypertension Although epidemiological studies have shown that systolic blood pressure is at least as good a predictor of subsequent complications as diastolic pressure, there is less information on the levels of systolic pressure that should be treated. In most cases, systolic and diastolic pressures follow each other closely. However, difficulties arise in elderly patients, where isolated systolic hypertension is more common. Precise guidelines are not available, but the fears that treatment might reduce cerebral blood flow and worsen cerebrovascular risks have not been borne out. Reduction of high systolic pressures (greater than 180 mmHg) might therefore be expected to accrue benefits by reducing the stroke rate, and this indeed has been the finding in the few studies of elderly hypertensive patients.

METHODS OF TREATMENT The importance of attention to associated risk factors, such as smoking and hyperlipidaemia, has already been emphasized, and is an important part of all treatment strategies. Blood pressure-lowering drugs may not be needed if other methods are successful.

Non-pharmacological methods Drug withdrawal. Withdrawal of drugs that may contribute to hypertension, e.g. NSAIDs, steroids and oestrogencontaining compounds such as the oral contraceptive pill, should be considered where possible. Patients with a high alcohol intake should be advised to abstain or reduce their intake. Dietary measures. For each kilogram loss of weight, blood pressure can be expected to fall by 2.5-3.0mmHg systolic and 1.5-2.3 mmHg diastolic. In general, salt restriction has not been found to be an effective treatment for hypertension at the levels of intake achievable with a tolerable western diet. However, high salt intakes can negate

the effectiveness of the thiazide diuretics used in treatment, so it is important to ensure patients moderate their intake. Relaxation. Teaching patients to relax - using formal programmes administered by non-medical personnel in general practices and continued at home by the patient has been shown to produce a modest sustained blood pressure reduction. Exercise. Aerobic exercise maintained for some 15-20 minutes will lower subsequent blood pressure readings by 5-10 mmHg for about 12 hours. Exercise may also improve associated cardiac risk factors, including obesity.

12

Drug treatment of essential hypertension The principles of drug treatment for hypertension are theoretically simple. Therapy with a single drug given once a day is the ideal, but combination treatment is frequently necessary. A step-by-step approach is frequently used, starting with a first-line preparation alone, and then in combination with another, before third- and fourth-line drugs are used (Table 12.45).

TABLE 12.45 Indications for specific antihypertensive drugs and their common side-effects Indication

Advantages

Symptomatic side-effects

Other side-effects

First line or adjunct to p-blockers or Ca antagonists

Effective, cheap, usually once-daily treatment

Gout, impotence

Spironolactone Amiloride Loop

First line in Conn's or adrenal hyperplasia In renal disease

Potassium-sparing

Gastrointestinal upset

Powerful diuretics

Urinary urgency

Hypokalaemia Glucose intolerance Lipids Hyperkalaemia in renal impairment As for thiazides

B-Adrenoreceptor blockers

First line

Antianginal and antiarrhythmic

Asthma in some subjects, tiredness, claudication and cold hands/feet

? lipid effect LDL HDL

Calcium antagonists

First or second line

Antianginal and antiarrhythmic

Flushing, oedema, gastrointestinal upset

Heart block and negative inotropy with some examples

Angiotensin-convertingenzyme inhibitors

First line in renal disease First line in heart failure

Well tolerated and very powerful; useful in heart failure

Cough, postural hypotension

Profound hypotension Renal impairment in renovascular disease

Angiotension II receptor antagonists

Second or third line

As ACEI, but no cough

Dizziness

As ACEI, hepatic impairment

a-Adrenoreceptor antagonists

First or second line

Largely superseded by Ca antagonists and ACE inhibitors

Postural hypotension

-

Can be used alone effectively

Sedation, impotence

Haemolytic anaemia

Hydralazine

Second/third line Methyldopa in pregnancy Third line

Headache

SLE-type reactions

Diazoxide

Third line

Oedema

Glucose intolerance

Minoxidil Bethanidine/guanethidine

Third and fourth line Fourth line

Largely superseded by Ca antagonists and ACE inhibitors Largely superseded by Ca antagonists and ACE inhibitors Extremely powerful vasodilator Rarely indicated

Hirsutism, oedema Postural hypotension/impotence

Fluid retention Hypotensive infarction

Type of drug Diuretics Long-acting thiazides

Others Methyldopa/clonidine

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Diuretics The long-acting thiazide diuretics such as chlorothiazide and bendroflumethiazide (bendrofluazide) are effective, although symptomatic side-effects such as impotence and gout can occur. They are less powerful in renal failure, when loop diuretics such as frusemide and bumetanide have an advantage. Thiazide diuretics cause biochemical changes which have given concern about their long-term safety. In particular, mild hypokalaemia is common and may be associated with a risk of cardiac arrhythmias. Hyperuricaemia may produce symptomatic gout and, in conjunction with glucose intolerance and increases in cholesterol and triglyceride concentration, an overall worsening of the cardiovascular 'risk factor profile' is produced by these drugs. It is not at all clear whether these concerns are justified, although the lack of improvement in the incidence of myocardial infarction in the vast majority of hypertension treatment trials has been attributed in part to these unwanted biochemical effects of the thiazide diuretics. B-Adrenoreceptor blockers Chance clinical observations led to the recognition that the B-adrenoreceptor blockers are effective antihypertensives. These drugs are specifically contraindicated in obstructive airways disease, because of the production of asthma even by drugs with supposed cardiac selectivity. Other troublesome side-effects are related to the B-receptor blocking action, with bradycardia, tiredness, claudication and cold limbs being prominent. The demonstration of their protective effect following myocardial infarction, as well as their antiarrhythmic and antianginal actions, make B-blockers a rational choice when CHD complicates hypertension. They have to be used with great caution, if at all, in heart failure. Plasma lipids are altered with B-blockade, potentially worsening the cardiovascular risk. However, whether these alterations are deleterious in the long term has not been clarified. B-Blockers with diuretics have become established as the mainstays of the management of hypertension. There are many examples of these drugs. In the UK, atenolol, metoprolol, propranolol, bisoprolol and pindolol are commonly used examples. Calcium antagonists The antihypertensive effectiveness of calcium antagonists is related to the fall in peripheral vascular resistance that follows resistance vessel vasodilatation. Side-effects of nifedipine can be attributed to its vasodilator activity and include flushing, headache and oedema; in contrast, verapamil has more gastrointestinal side-effects and ought not to be combined with B-blockade because of its propensity 1

598

MCQ 12.24

to produce heart block and impair ventricular contractility. Diltiazem fills an intermediate position, with fewer peripheral effects and more cardiac effects than nifedipine, but fewer myocardial effects than verapamil. Although these drugs have not been subjected to close analysis in large trials, there is no doubt of their efficacy and popularity, even as a first-line therapy. Angiotensin-converting-enzyme inhibitors The ACE inhibitors were specifically manufactured to inhibit the renin-angiotensin system by blocking the conversion of angiotensin I to its active form, angiotensin II. These drugs are subjectively very well tolerated, and their associated efficacy, in all but the groups of patients with renal arterial stenoses, has led to their adoption as the first of the second-line treatments to be used in the more severe degrees of hypertension. Cough is a common (>10%) sideeffect of ACE inhibitors, but at higher doses severe neutropenia, rashes and taste disturbance have been seen with captopril. Their hypotensive effect may be severe in relatively hypovolaemic patients and in those with hyponatraemia (which might occur in those taking diuretics). ACE inhibitors will cause a deterioration in function or renal failure in renal arterial stenosis. Methyldopa In pregnancy methyldopa still maintains a place in the treatment of hypertension, but the associated CNS sideeffects have made it less popular now that less sedative preparations are available. Sympathetic ganglion blocking drugs In the past, the sympathetic ganglion blocking drugs (guanethidine and bethanidine) were important as early effective treatments, but their use is now limited by their troublesome postural hypotensive effects, lack of supine blood pressure control and the sexual dysfunction that they produce in men. Drug selection in therapy Despite decades of antihypertensive drug therapy, the only drugs that have been shown to improve prognosis are thiazide diuretics and B-blockers. In newly diagnosed hypertensive patients without contraindications, these drugs should be considered as first-line therapy. Newer agents have numerous claimed advantages, but whether these will translate into improved prognosis is uncertain. Their use may be more sensibly reserved for patients with contraindications for, or intolerance of, diuretic or B-blocker usage, unless they can provide specific advantages, as shown in the following conditions: • Patients with angina benefit from antihypertensive drugs which are also antianginal. • Diabetic patients with proteinuria may benefit more with ACE inhibitors as an antihypertensive agent. • Patients with systolic heart failure have a better

• •

•

•

prognosis with ACE inhibitor or vasodilating B-blocker therapy. Patients with significant left ventricular hypertrophy or diastolic ventricular failure may benefit more from ACE inhibition as antihypertensive therapy. Thiazide diuretics may worsen diabetic control and (3blockers may blunt the sensation of hypoglycaemia, and so these drugs should be reserved as second- or thirdline antihypertensive therapy in diabetics. Thiazide diuretics may result in hypokalaemia and/or hypomagnesaemia, which exacerbate or precipitate serious cardiac arrhythmia, and should be avoided in susceptible patients. In black hypertensives, (3-blockers and ACE inhibitors are less effective as monotherapy than diuretics and calcium antagonists.

Combination therapy Adequate control of hypertension with monotherapy should be sought before any combination therapy is considered. Once it has been established that monotherapy is inadequate, then combination therapy may be required. The choice of combinations is largely empirical in order to attain acceptable blood pressure levels, but, from published trials, p-blockers plus dihydropyridine calcium antagonists, ACE inhibitors plus diuretics or calcium antagonists appear to offer advantages, whereas [3-blockers plus ACE inhibitors or diuretics plus calcium antagonists appear less efficacious. Combination of a (5-blocker and verapamil should be avoided as the combination is very negatively dromotropic and inotropic. Both diuretics and ACE inhibitors are liable to alter electrolyte balance, and there is no standard formula to calculate combination dosage - there is no substitute but to monitor serum electrolytes serially.

Drug treatment of hypertension in pregnancy Pre-eclampsia The treatment of pre-eclampsia (p. 592) requires delivery of the fetus. Nevertheless, drugs may be needed to control the blood pressure before delivery can be achieved. Methyldopa (250-500 mg, 6-hourly by mouth) is used and, if necessary, can be given parenterally. It has the advantage of being effective and harmless to the fetus, although its sedative side-effects can confuse neurological assessment and its onset of action is slow (1 hour). Hydralazine, orally (<300mg daily), by intramuscular injection (1020 mg, 3-6-hourly) or by constant infusion (5-10mg/h) is a suitable alternative, although flushing, tachycardia and vomiting may be side-effects at the higher doses. Given intravenously, it has a rapid onset of action which can be maintained by a constant infusion. p-Adrenoreceptor blockers and calcium antagonists have been found to be effective in the acute situation, although experience with these drugs and follow-up of the delivered neonates has been shorter than for methyldopa and hydralazine. Diuret-

ics are used only when cardiac failure complicates the picture.

12

Chronic hypertension in pregnancy Because of its known lack of effects on the fetus, methyldopa is the drug of choice; hydralazine is the usual alternative, although (5-adrenoreceptor blockers are being used increasingly without undue hazard. Mothers who are known moderate hypertensives may be advised to cease treatment at the time of conception, although no teratogenicity has been associated with any of the commonly used antihypertensive drugs. O

Drug treatment of hypertensive emergencies Malignant or accelerated-phase hypertension This previously rapidly fatal condition is now managed by bed rest with admission to hospital and oral treatment. Parenteral treatment is avoided unless coma, fits or severe heart failure are present. Under these circumstances an effective treatment is an intravenous infusion of labetalol, starting at 25mg/h and increasing to 120mg/h, with additional diuretic treatment for pulmonary oedema. Intravenous nitrates are also effective in this situation. Hydralazine given intramuscularly has been a popular treatment, but the 20-minute delay in onset of action may lead to additional doses or drugs being given, resulting in hypotension some hours later. Methyldopa, even when given intravenously, is also too slow to be used effectively. For cases caused by phaeochromocytoma, phentolamine (2.5-10mg i.v. bolus or Img/min by i.v. infusion) produces a rapid pressure reduction by cc-adrenoreceptor blockade, but such a response is not limited to this disease. Oral treatment is optimal in most cases of malignant and accelerated hypertension, and any of the usual antihypertensive drugs can be used successfully. Recent observations show that sublingual nifedipine (10-20 mg) produces a smooth blood pressure reduction beginning within 10 minutes, although the reflex tachycardia it produces may require treatment with a (3-adrenoreceptor blocker. Additional diuretic treatment is often given. The degree and rapidity of blood pressure reduction are important. In chronic hypertensives, cerebral autoregulation is lost at mean blood pressures above ISOITS mmHg and below 90-120 mmHg. Treatment should reduce mean blood pressure to 100-120 mmHg and no lower. This should be achieved over a 12-36-hour period to allow time for the relatively slow process of reestablishing normal cerebral autoregulation. Aortic dissection Aortic dissection is an emergency requiring prompt reduction of mean blood pressure to 100-110 mmHg; this is usually achieved with an infusion of sodium nitroprusside, starting at 12.5mg/min and titrating the dose against

599

blood pressure every 2-3 min. Infusion should not continue beyond 24 hours, but the resulting thiocyanate accumulation can be diminished by concomitant use of hydroxycobalamine by injection. There may be an advantage in reducing the systolic rate of change in aortic pressure as well as mean pressure. This can be achieved with Padrenoreceptor blockade, so that labetalol infusion with its mixed, though predominantly p-receptor, effects has been advocated for use in dissection.

Hypertension in chronic renal failure A proportion of patients with chronic renal failure have hypertension; in these, blood pressure may be controlled by dietary sodium restriction and fluid removal at haemodialysis. Drug treatment is necessary in some cases, and the excretory metabolism must be taken into account when dosages are calculated. Treatment is generally similar to that in essential hypertension.

Hypertension in phaeochromocytoma Hypertensive crises in phaeochromocytoma can be treated conventionally, but it is important to avoid (3adrenoreceptor blockade before full a-adrenoreceptor blockade has been achieved, in order to avoid unopposed a effects exacerbating hypertension. Parenteral phentolamine can be used acutely, and longer-term control gained with phenoxybenzamine (10-30mgt.d.s.), with the later addition of small doses of a [3-blocker, such as propranolol (40mgt.d.s.). If a surgical cure cannot be effected, longterm treatment with oc-methyltyrosine can be used, although side-effects are often troublesome.

Adrenocortical hyperplasia and Conn's syndrome

VASCULAR DISEASE AORTIC ANEURYSM Most intrathoracic aortic aneurysms are asymptomatic unless they become large enough to produce pressure on a main bronchus, on the phrenic nerve or if they produce aortic regurgitation. They may rupture and result in sudden death. They are frequently diagnosed on chest X-ray. They are a common manifestation of collagen diseases such as Marfan's syndrome, and are a complication of atherosclerosis and hypertension.

ACUTE AORTIC DISSECTION Dissection occurs when there is haemorrhage into the wall of the aorta, causing the media to separate from the other layers (Fig. 12.70). Most dissections are seen in middleaged or elderly men with arteriosclerosis and hypertension. More than 50% of patients who present with dissection die within 24 hours. It is a particular complication of Marfan's syndrome, where cystic medial necrosis is common. In this disorder progressive aortic dilatation leads to aortic incompetence and dissection with a high mortality. Dissections can be classified clinically according to the part of the aorta that is affected. When the ascending aorta is involved, it is termed a type A dissection (De Bakey types I and II), whereas those where only the aorta beyond the left subclavian origin is involved are called type B dissections (De Bakey type III).

Clinical features The most prominent symptom is a very sudden onset

Surgical removal of the adenomas in Conn's syndrome may not always cure the electrolyte disturbances and hypertension. In these circumstances, as in idiopathic hyperplasia, treatment with amiloride (20-70 mg daily) or spironolactone (200-400 mg daily) is effective.

FURTHER READING ON SYSTEMIC BLOOD PRESSURE AND HYPERTENSION Guidelines Subcommittee 1993 Guidelines for the management of mild hypertension: memorandum from a World Health Organization/International Society of Hypertension meeting. J Hypertens 11: 905-918.

600

1

Figs 12.32-12.34

3

MCQ 12.25 4

2

Fig. 12.35

Fig. 20.36

FIG. 12.70 Sites of dissection in aortic aneurysm

of excruciating pain, often described as tearing in nature. Unlike infarction pain, the pain is often totally unheralded and at its worst initially, but may uncommonly develop to a pulsating discomfort that persists. The pain may radiate through to the back and, in type B dissection, to the left shoulder. Typical myocardial infarction pain may also coexist if the coronary arteries are involved by the dissection.

Diagnosis and investigation The diagnosis can be difficult, and its importance has considerably increased with the emphasis on early acute treatment of myocardial infarction with thrombolytic drugs. Clearly, these may have terrible consequences in dissection. The patient is frequently hypertensive or has a history of hypertension, which may or may not have been treated. Patients with Marfan's syndrome are usually easy to identify but form only a small proportion of cases. In about 10% of patients a difference in blood pressure (20mmHg or more) in the two arms may be found, and in some a prominent pulsation is visible at the root of the neck. Auscultation may reveal aortic regurgitation in type A dissection, which is typically more obvious at the right sternal edge. The ECG may be normal except in those cases with associated coronary artery involvement. In some individuals the chest X-ray provides the first clue to the diagnosis, with mediastinal widening, left-sided pleural effusions and expansion of the aortic knuckle border beyond a calcified rim of endothelium. 1 The diagnosis is confirmed at cardial catheterization by contrast aortography. Coronary angiography is also performed to allow surgical repair. CT is helpful and less invasive, often being performed prior to catheterization but rarely supplanting it totally. 2 MRI is rapidly replacing CT. Echocardiography by the standard methods may demonstrate a proximal ascending aortic dissection, but transoesophageal echocardiography is the only ultrasound method able to adequately demonstrate the descending thoracic aorta. Transoesophageal colour Doppler is particularly useful, as the flow patterns make the intimal tear more obvious.

Complications Complications of the dissection include occlusion of arterial branches, including the coronary arteries, head and neck vessels, and indeed all distal arterial branches. Stretching of the aortic annulus in type A dissection is responsible for aortic regurgitation, which may be severe and lead to left ventricular failure and shock. Progressive dilatation of the aorta may obstruct the airways or oesophagus. Finally, rupture of the aortic wall may occur, producing pericardial or pleural effusion and, occasionally, intrabronchial haemorrhage. This complication frequently, but not always, causes death.

Management Treatment is usually surgical for type A dissection and many cases of type B. However, acute management includes blood pressure reduction by parenteral treatment, preferably with drugs reducing the inotropic force of the heart, such as labetalol by infusion. Pain control and sedation are also very important in this very distressing condition, where the outlook is often very poor. 3 4

12

ARTERITIS Arteritis is an inflammatory process involving the artery wall. It can occur in vessels of various sizes. If these are small, the condition is called necrotizing vasculitis and is found in a large number of 'autoimmune' conditions (discussed in Chapter 22). Involvement of the large arteries is much less common and occurs principally in Kawasaki's disease, Takayasu's (or pulseless) disease and giant cell (or temporal) arteritis.

KAWASAKI'S DISEASE Kawasaki's disease is a disease of children described originally in Japan but now reported from other parts of the world. The aetiological agent is unknown, but as the disease occurs in cyclical epidemics an infective agent is suspected. It was originally called 'mucocutaneous lymph node syndrome' because of the prolonged fever, skin rash and marked cervical lymphadenopathy. Later it was realized that there is a high incidence of coronary artery aneurysms, occlusions and myocardial infarction which, because many of the patients are infants, were originally missed. Diagnosis of these lesions can often be made noninvasively by ECG and 2D echocardiography. Management is based on the use of antithrombotic agents and steroids, but aspirin alone has been found to result in a lower incidence of coronary artery complications than some other regimens.

TAKAYASU'S ARTERITIS

Takayasu's arteritis - a disease which predominantly affects oriental women - was first described by an ophthalmologist whose first case was a young woman with cataracts and unusual arteriovenous anastomoses around the optic papillae. It was later realized that similar ophthalmic findings were seen in patients with absent radial pulses, hence its alternative name, 'pulseless disease'. The disease can be classified into three types: • Type I involves the aortic arch and its branches, producing diminished or absent pulses over the upper body (so-called 'reversed coarctation').

601

• Type II involves the descending aorta, particularly the renal arteries and vessels supplying the abdominal viscera. • Type III is a combination of I and II. Takayasu's arteritis has also been implicated in the development of primary pulmonary hypertension. The aetiology is unknown but the disease commonly starts in teenage girls, with a sex ratio of 8:1.

Clinical features There is often a systemic illness, with fever, arthralgia and fatigue. There may be pain and tenderness over the affected arteries. This systemic phase passes and is followed by a latent period. Some time later these patients, and others who had no systemic prodrome, present with the typical features of weak or absent pulses, low or unrecordable upper body blood pressure, hypertension, heart failure and ocular damage. The hypertension is produced by an increased aortic impedance secondary to major vessel occlusion or narrowing, and also from renal artery stenoses causing renal hypertension. Bruits over affected vessels are common. Heart failure is usually secondary to hypertension, but coronary artery ostial stenoses can occur, causing angina; aortic regurgitation has also been described.

Management and prognosis The acute systemic illness is alleviated by corticosteroids, which may reduce the incidence of sequelae. Antiplatelet agents, such as aspirin and dipyridamole, and warfarin have been used to reduce the frequency of cerebral transient ischaemic attacks and possibly retard the progression of arterial lesions. Morbidity is chiefly from heart failure and cerebrovascular events. Surgical treatment of severe vascular stenoses may become necessary.

GIANT CELL (TEMPORAL) ARTERITIS

602

Although predominantly affecting the cranial arteries, giant cell arteritis can, like Takayasu's arteritis, involve the aorta and its proximal branches. The disease is described more fully in Chapter 22, page 1183. Where major vessel arteritis occurs, it may complicate the more common presentation with cranial arteritis and polymyalgia rheumatica, or may occur alone. Symptoms are similar to those of Takayasu's arteritis, including angina and exercise-related ischaemia of the upper and lower limbs. Aortic regurgitation, aneurysm and dissection can complicate giant cell arteritis of the aorta. As for the commoner forms of the disease, treatment is with corticosteroids.

PERIPHERAL VASCULAR DISEASE ARTERIAL DISEASE Thoracic outlet syndromes In the past, the thoracic outlet syndromes were thought to be due principally to arterial compression of the subclavian artery but it is now appreciated that many of the symptoms are caused by compression of the brachial plexus as well. This is from an anomalous fibrous band that stretches from a cervical rib to the first rib and, in doing so, compresses the neurovascular bundle. The patient has symptoms in the hand, which appear promptly when the arm is abducted to 90° and externally rotated. A bruit can then be found over the supraclavicular fossa. These features disappear when the arm is returned to a relaxed position. Aneurysm of, and embolism from, the subclavian artery is a comparatively rare complication of this condition, which can lead to digital gangrene.

Peripheral arterial disease and arteriosclerosis Arteriosclerotic arterial disease can be from atheroma, focal calcific sclerosis (Monckeberg's arteriosclerosis) or arteriosclerosis. Monckeberg's sclerosis leads to calcification of the media without narrowing of the vessels, but is often associated with arteriosclerosis and luminal narrowing. Most symptomatic disease is due to atheromatous plaque formation, with subsequent stenosis, occlusion or embolization of the vessel. Haemorrhage into an atheromatous plaque may precipitate a sudden vessel occlusion. Emboli may arise from atheromatous plaques (as occurs frequently from the carotid); however, major emboli are more frequently from the heart, in such conditions as mitral valve disease, left ventricular aneurysm, mural thrombus following myocardial infarction, left atrial myxoma, endocarditis, and from any enlarged heart, particularly if there is atrial fibrillation. The sites of predilection for the atheroma are not fully explained, and any one patient may have principally coronary, cerebrovascular or peripheral vascular symptoms, with risk factors very similar to another patient whose symptoms are quite different. Atheroma tends to develop in the abdominal aorta and at the origins of major branches. These may be sites of mechanical stress or low shear.

Intermittent claudication Ischaemia of the lower limbs is usually accompanied by effort-related cramp in the calves, thighs and buttocks, which disappears with rest. The site of claudication indicates the probable site of stenosis or occlusion - the higher

the claudication the higher the atheroma is likely to be found. The walking distance on the flat is usually remarkably repeatable. Claudication is often accompanied by profound weakness as well as cramp in the affected muscles, which have become acidotic from anaerobic exercise. The combination of hip and thigh claudication with impotence in males (the Leriche syndrome) is due to severe atheromatous occlusion of the lower end of the aorta. More severe ischaemia produces a continuous pain at rest, particularly in bed. The pain is most frequently in the toes or foot, with some paraesthesia. The foot is often hung over the edge of the bed and may be subject to ulceration and gangrene. In diabetics with peripheral neuropathy there may be no pain but only ulceration and gangrene. Diagnosis and investigation Peripheral vascular disease is assessed by a careful history and clinical examination for signs of ischaemia, absent pulses, audible bruits over the proximal arteries, poor skin nutrition, low skin temperature and loss of hair, and then by blood pressure measurement. This is usually done using Doppler ultrasound on the ankle arteries with a proximal cuff. The normal ankle systolic pressure is usually higher than brachial (by about 20%) and should be maintained after exercise. The ischaemic leg often has an ankle pressure of about 50% of brachial at rest, which becomes unrecordable after exercise when the blood is diverted to areas of vasodilatation elsewhere. The severity of the hypotension is related to the degree of arterial disease. Management Most patients with claudication benefit from medical measures such as weight reduction, complete cessation of smoking and an energetic training regime that increases the claudication distance. Vasodilators and viscosityreducing drugs have a limited role. Surgical intervention after angiography now includes angioplasty, as well as endarterectomy and bypass grafting. It is reserved for more severe cases.

Gangrene Sudden ischaemia of a limb (from trauma, arterial thrombosis or embolism) leads to pain, pallor, coldness, and then numbness of the limb distal to the occlusion. If perfusion is not restored, sensation is severely diminished in an hour; within 6 hours ischaemic contracture of the muscles has started. This is followed by subcutaneous haemorrhage and focal gangrene. Fixed staining of the skin indicates death of the underlying tissues. Persistent pain and numbness without loss of sensation indicate a collateral flow. Managemenf This is an emergency and treatment is surgical, by embolectomy, emergency bypass grafting or eventual amputation.

Embolectomy under local anaesthetic can often save a limb. Heparin is used to prevent further clotting, particularly if there is an obvious embolic source.

12

Buerger's disease Buerger's disease was previously thought to be a distinct disease, but is now considered to be an accelerated form of atheroma affecting young men of 20-40 years of age who smoke (or chew) tobacco heavily. It affects the small arteries of the hands and feet, with an intense inflammatory response, and often involves the veins as well. Hand and instep claudication may occur, with loss of ankle and wrist pulses and gangrene of the toes and fingers. There is often an associated Raynaud's phenomenon (see below) and a migratory nodular phlebitis. Cessation of smoking or chewing tobacco is imperative. Prognosis For patients with symptoms of limb ischaemia, the rate of limb loss is about 2% per year for non-diabetics and 7% per year for diabetics.

Raynaud's syndrome and phenomenon Raynaud's syndrome and phenomenon are vasospastic conditions affecting mainly the hands; they are often precipitated by cold and sometimes by motion, although random spontaneous attacks are common. Attacks are characterized by episodes of arteriolar spasm; these produce cold pale fingers and hands, progressing over minutes or hours to cyanosis and ending with a red flushing phase. When the condition is not associated with any underlying disorders it is termed Raynaud's syndrome, and skin changes are not seen. This is commoner in young women. Raynaud's phenomenon occurs secondary to underlying systemic conditions, the most common being scleroderma. Other collagen diseases may be associated with Raynaud's phenomenon, as may thoracic outlet compression, arteriosclerotic vascular disease, vibration trauma in pneumatic drill users, and serum protein abnormalities.

Mesenteric ischaemia Mesenteric (or small bowel) ischaemia is described in Chapter 15, page 795.

VENOUS DISEASE Varicose veins are the commonest vascular disorder affecting the legs, and venous thrombosis is a frequent complication of many medical and surgical conditions.

Varicose veins Varicose veins are dilated and tortuous veins that vary in size from large palpable bunches to mere discoloured superficial spider bursts on the skin. They arise either

603

through primary abnormalities in the venous wall leading to dilatation and incompetence of the valves, or secondarily after damage caused by previous thrombosis. In either case, factors that impede venous flow or increase venous pressure in the legs contribute to their development, as does the prolonged standing required in certain occupations. Many patients suffer no symptoms but the veins can be responsible for discomfort, usually described as heaviness or pulling. Oedema may occur and, in chronic severe disease, pigmentation of the skin, a disfiguring dermatitis, ulceration or, at its severest, gangrene may follow. These complications are more prominent in the areas subject to the highest venous pressures, where skin nutrition is consequently poorest, namely in the lower third of the leg, often more marked medially. Management Elastic stocking support, injection of sclerosants and surgical removal (or stripping) of the veins are used to treat the varicose veins. Relief of exacerbating factors, such as obesity, ascites and right heart failure, is also important. Ulcers often heal slowly, and must be kept clean and uninfected. Elevation of the limb aids healing.

Venous thrombosis Occlusion of veins by thrombus is very common. It leads to considerable morbidity and, when the deep veins of the leg and pelvis are involved, to the risk of serious illness or death through pulmonary embolism. Superficial venous thrombosis Superficial venous thrombosis causes pain and swelling over the affected vessel, which is often palpable as a tender cord or small nodule. Unless complicated by progression to deep vein thrombosis (DVT), superficial venous thromboses are essentially benign and require only symptomatic treatment. NSAIDs, such as indomethacin or aspirin, plus local applied heat, are of help. Deep venous thrombosis The incidence of DVT is low in physically active subjects. The predisposing factors are divided into: • Transient/reversible factors - surgery, trauma, bed rest, prolonged immobility (e.g. long-haul airflights), pregnancy; • Chronic factors - venous disease, hypercoagulability of blood, active or occult malignant disease, pelvic masses and marked obesity; • Idiopathic - with no known risk factors.

1

604

MCQ 13.1

The risk of recurrence of DVT is lower in patients with a reversible risk factor than in those with chronic risk factors or idiopathic DVT. The risk of pulmonary embolism (PE) is low in patients with DVT confined to the calf veins. It is the proximal DVT involving veins in the thigh and pelvis that are potential sources of large pulmonary emboli. DVT of the axillary or internal jugular veins is much less common and rarely gives rise to PE. Superior vena caval thrombosis can lead to PE, and a known precipitating factor is the presence of indwelling central venous catheters (e.g. for parenteral nutrition). Clinical features and diagnosis The diagnosis of DVT is often difficult. The main features are pain and swelling of the affected limb. The symptoms vary with the extent and type of vein involved and are often absent. Dorsiflexion of the foot may produce calf tenderness (Homan's sign) in the extended leg, but this sign is often not very helpful. The most useful diagnostic test is the venogram which, when technically adequate, will usually establish the presence and extent of any thrombus. Doppler ultrasound velocity profiles can be useful, although only for DVT affecting veins above the knee. The major conditions which may mimic DVT include muscle trauma, rupture of a popliteal (Baker's) cyst (which resembles calf vein DVT) and sciatic nerve irritation. Complications The most serious complication in DVT is PE (Ch. 13, p. 675). This is usually a complication of thrombus above the knee, but sometimes occurs with calf vein thrombosis. Other complications include vein wall and valve damage leading to long-term venous insufficiency. Management Treatment of DVT is by intravenous heparin bolus (5000 U) followed by a constant infusion (24000^8000 U/24h) sufficient to maintain a partial thromboplastin time two to three times normal. Oral anticoagulation with warfarin is then instituted, with the heparin being discontinued once a prothrombin ratio of 2.5-3.0 is achieved. Oral anticoagulation is continued for 6 weeks in patients with transient/reversible predisposing factors, and for 6 months in those with idiopathic DVT. It may need to be indefinite in patients with known active malignancy, other bedridden conditions, recurrent DVT or haematological hypercoagulable states (e.g. thrombophilia). Recurrent subacute pulmonary embolism leading to chronic pulmonary hypertension is associated with a poor prognosis, and may require insertion of an inferior vena caval filter; such patients also need indefinite anticoagulation. It has become clear that prophylactic treatment with relatively low doses of anticoagulants (heparin by subcutaneous or intramuscular injection: 5000 U 8-hourly or enoxaparin 20mgs.c. o.d.) can prevent DVT, and hence PE, in patients at risk, such as those on prolonged bed rest after major surgery.

13

FURTHER READING British Thoracic Society 2002 The burden of lung disease (www.brit-thoracic.org.uk)

Respiratory

STRUCTURE AND FUNCTION OF THE RESPIRATORY SYSTEM 1

Disease John Moxham and John F Costello

Structure and function of the respiratory system 605 Symptoms and signs of respiratory disease 611 Examination of the respiratory system 619 Imaging the thorax 623 Bronchoscopy and lung biopsy

Respiratory failure 670 Lung transplantation 674 Pulmonary hypertension 674 Pulmonary Ihromboembolism 675 Sarcoidosis 682 Connective tissue and related diseases and the lung 689

627

Vasculitides and the lung 690

Respiratory infections 631

Pulmonary arteriovenous malformations and shunts 691

Lung abscess 647 Bronchiectasis 648 Cystic fibrosis 649

Pulmonary fibrosis and diffuse interstitial lung disease 692

Asthma 651

The acute respiratory distress syndrome 697

Pulmonary eosinophilia 659

Lung tumours 700

Chronic bronchitis and emphysema 661

Pleural disease 710

Respiration during sleep 668

Respiration can be defined as those processes concerned with gas exchange between an organism and its environment. In humans respiration begins with the uptake of O2 and ends with the elimination of CO2. The adequacy of gas exchange by the lungs depends on four closely integrated processes:

Neuromuscular and skeletal disorders 718

Respiratory diseases are responsible for a large proportion of premature mortality and serious morbidity among the population, and at the same time for a large amount of minor illness. In England and Wales respiratory diseases (including lung cancer) account for approximately a quarter of all deaths. They are the second most common cause of death after cardiovascular disease. Much morbidity and many deaths are smoking related. Unfortunately, despite an overall decline in numbers smoking, the prevalence of smoking in young people in the UK is on the increase, as is that in many developing countries.

• • • •

Ventilation Diffusion of gases Pulmonary capillary blood flow The carriage of gases by the blood.

In addition, breathing is regulated in accordance with the constantly changing metabolic needs of the body by an intricate control system. The anatomical organization of the human lung is eminently suited to its role as an exchanger of O2 and CO2. A series of branching airways conducts air into and out of the alveolar spaces. Similarly, the pulmonary circulation delivers blood to, and drains blood from, the pulmonary capillaries. Ninety per cent of the alveolar surface (80m2 in an adult lung) is covered with capillaries, providing a thin but large film of blood for exposure to the gases in the alveolar spaces. The respiratory system has other functions besides gas exchange: • The upper airways filter and humidify inspired air. • It provides an elaborate defence mechanism that protects the body against inhaled pathogenic microorganisms and toxic chemicals. • The pulmonary blood vessels serve as a reservoir for the left side of the heart. • It provides O2 and substrates for its own metabolic needs. • The lung modifies the pharmacological properties of a variety of drugs.

Ventilation Ventilation is the cyclical movement of ambient air into and out of the lungs, and the distribution and mixing of that air within the lungs. This cycle is accomplished by contraction and relaxation of the respiratory muscles and the elastic recoil of the lungs. During normal quiet breathing, about two-thirds of the inspired gas reaches perfused alveoli; this fraction is known as alveolar ventilation (VA). The rest of the inspired gas fills the conducting airways and

605

alveoli that may not be well perfused, and is known as physiological dead space (VD) or 'wasted ventilation'. Therefore, total ventilation (usually in L/min) = VA + VD. The commonly measured static lung volumes are shown in Figure 13.1. The static volumes depend on the distensibility (i.e. compliance) of both the lung and chest wall, and also the capacity of the respiratory muscles, often impaired in neurological disorders, such as motor neuron disease. The distensibility or compliance of the lung is affected by the elastic recoil due to the connective tissue elements in the parenchyma and the surfactant that lines the alveolar surface. Thus the compliance of the lung is decreased in diffuse pulmonary fibrosis (tissue changes) and neonatal respiratory distress syndrome (reduced surfactant), and increased in emphysema because of the destruction of lung elastic connective tissue. Reduced compliance of the chest wall (which includes the thoracic cage and the abdominal

wall) can be caused by bony ankylosis (ankylosing spondylitis), pleural thickening, obesity and ascites.

Diffusion of gases The term 'diffusion' describes the passive movement of O2 and CO2 between alveolar gas and pulmonary capillary blood (Fig. 13.2). It depends on three major factors: • The matching of ventilation and blood flow • The diffusion of gas from the alveolus to the red blood cell • The availability of haemoglobin and the chemical reactions within the red blood cell. Although O2 is the physiological gas that is most likely to be affected by abnormalities of diffusion, the diffusion capacity of the lung is usually measured with a nonphysiological gas, carbon monoxide (TLCO, or transfer factor). If the haemoglobin concentration is normal, a decreased transfer factor means either a reduction in the

Total lung capacity (L)

Vital capacity (L)

Residual volume (L)

3.4-5.9 2.4-4.3

1.1-2.3 1.0-2.0

4.8 -7.9

2.7-5.3 2.0-4.0

1.4-2.6 1,1-2.2

4.5-7.6 3.4-6.0

2.4-4.7 1.9-3.6

1.7-2.7 1.3-2.4

4.3-7.3 3.3-5.8

Age 20 -39

Male Female

3.6-6.1

Age 40 - 59

Male Female Age 60+

Male Female

FIG. 13.1 The subdivisions of lung volume Functional residual capacity (FRC) is the resting expiratory level. (TLC = total lung capacity; TV = tidal volume; IC = inspiratory capacity; VC = vital capacity; RV = residual volume; IRV = inspiratory reserve volume; ERV = expiratory reserve volume.) Normal values are also shown.

1

606

MCQ13.2

FIG. 13.2 The terminal respiratory unit In the terminal respiratory unit A blood from the pulmonary artery is in close proximity to alveolar gas, facilitating gas exchange B and thus the uptake of 02 and the elimination of C02.

effective alveolar-capillary surface available for diffusion (thickening, loss of membrane, or inability to inflate part or all of the lung to expose it to inspired air, as in lobar collapse or respiratory muscle weakness) or obstruction or destruction of capillaries (decrease in capillary blood volume).

Carbon dioxide is transported in the blood as HCO3 in solution, or in combination with haemoglobin. The chemical reactions are reversed as blood flows through pulmonary capillaries, thus allowing CO2 to evolve into alveolar gas. Carbon dioxide forms carbonic acid in the blood by the reaction:

Pulmonary capillary blood flow The adequacy of pulmonary capillary blood flow depends upon the volume and distribution of right ventricular output. Because distribution is gravity dependent, in the upright position there is more blood flow to the bases than to the apices of the lung; in addition, local mechanisms exist to divert blood from poorly ventilated regions of the lung.

13

CO2 + H2O -> H2CO3 catalysed by carbonic anhydrase, and the carbonic acid then dissociates by the reaction: H2CO3 - H+ + HCO3Accordingly, a rise in arterial Pco2 tends to increase H+ and decrease pH; this mechanism is of fundamental importance in acid-base balance and the regulation of ventilation (p. 1114).

Carriage of gases by the blood Oxygen is transported in the blood mainly in combination with haemoglobin; a small amount is present in solution. The relationship between the percentage saturation of haemoglobin and the partial pressure (or tension) of O2 (Po2) in the blood is shown in Figure 13.3. The shape of the curve is important: blood is nearly fully saturated when the Po2 is greater than 8kPa (60mmHg), as it usually is in arterial blood; furthermore, when the prevailing Po2 is low, 5.3kPa (40mmHg), as it is in the tissues, haemoglobin readily gives up its O2, which is then available for metabolic activities. The position of the curve is not fixed, and shifts occur to the right (decreased affinity) and left (increased affinity) in many common clinical conditions. Shifts of the curve to the right, resulting from an increase in Pco2, H+ concentration, temperature and organic phosphates (particularly 2,3-diphosphoglycerate), are beneficial because they facilitate O2 transfer to the tissues and thus serve to maintain tissue oxygenation (see also p. 1203).

Control of ventilation The rhythmic pattern of breathing is driven by the spontaneous discharge of neurons located chiefly in the medulla. The activity of these cells is modulated by signals from the pons, hypothalamus and cortex, and from central chemoreceptors and receptors in the lung. Although the physiological mechanisms involved are largely unknown, there is a remarkable matching of metabolic activities and ventilation.

PATHOPHYSIOLOGY

1

It is convenient to consider generalized lung disorders under the following headings: • • • •

Airflow obstruction Restrictive lung disease Abnormalities of diffusion Abnormalities of pulmonary blood vessels.

These functional categories often overlap and, of course, do not account for localized abnormalities such as those caused by tumours, pneumonia or pulmonary infarction.

Airflow obstruction Airflow obstruction is common and occurs in acute and chronic asthma, chronic bronchitis, emphysema, cystic fibrosis and bronchiectasis. Small peripheral airways are obstructed in patients with obliterative bronchiolitis and fibrosis, and inflammation can be demonstrated in the small airways of young smokers. Localized obstruction can be due to tumours, adenopathy, inhaled material, tracheal damage and pressure from an enlarged thyroid gland. FIG. 13.3 Oxygen dissociation curve In normal subjects a large fall in arterial oxygen tension causes a small reduction in oxyhaemoglobin saturation (and oxygen carriage). In a hypoxic patient (for example, with a PaO2 of 6 kPa/45 mmHg) a small fall in oxygen tension causes marked further desaturation.

Determinants of bronchial calibre The total cross-sectional area of the tracheobronchial tree increases progressively as each generation of airways branches because the sum of diameters of the daughter branches exceeds that of the parent branch. Therefore,

607

resistance to airflow, which depends on cross-sectional area, is greatest in the large or central airways and least in the small or peripheral airways. Airway calibre is influenced by the tone of bronchial smooth muscle, which in turn is regulated by a variety of neurohumoral mechanisms. Normally, there is a small amount of resting tone because parasympathetic-bronchoconstrictor impulses predominate over sympathetic-bronchodilator impulses. In addition to bronchoconstriction, airway calibre may be decreased by mucosal oedema, muscle hyperplasia, bronchial secretions and loss of elastic recoil. Bronchial calibre will also be reduced by external compression or intraluminal tumour. Tests of airflow obstruction There are simple tests to assess the severity of airflow obstruction that can be performed at the bedside, in the doctor's surgery or in the laboratory. A simple handheld meter is used to measure the maximum or peak expiratory flow rate (PEFR). PEFR measurements are widely used to assess the severity of asthma (see Fig. 13.33) A portable spirometer can be used to measure the forced expiratory volume in 1 second (FEVi - Fig. 13.4A) and the vital capacity (VC). Normally the lung can be rapidly deflated during a maximal expiratory effort and the FEV1 is >75% of the maximum volume that can be expelled (VC), but with airways obstruction expiratory flow rates are reduced and the FEV1 becomes a smaller percentage of VC. Both tests depend on patient cooperation and effort, and predominantly reflect the function of relatively large airways. Additional useful information on the calibre of smaller airways can be obtained by recording flow against volume during a forced expiratory manoeuvre, producing a maximal expiratory flow-volume curve (Fig. 13.4B). Maximum expiratory flows (PEFR) are achieved from close to full inspiration (total lung capacity) and flow becomes progressively less as the lung volume falls. This is partly due to the narrowing of normal airways that occurs as the lungs get smaller. In patients with widespread airways obstruction (e.g. chronic bronchitis) the narrowing of bronchi means that at low lung volumes there is a marked increase in airways resistance and a fall in maximum flows. The flow-volume curve is therefore convex. Diffuse airways obstruction causes an increased volume of gas to be trapped in the lung at the end of expiration. Hyperinflation is therefore an important feature of airways obstruction, and can be demonstrated in the laboratory as an increase in residual volume (RV) and an increase in the ratio of RV to total lung capacity (Fig. 13.5). In all patients with airways obstruction, reversibility in response to an inhaled (32 agonist should be assessed. Rapid improvement after inhalation of bronchodilators is characteristic of asthma (see Fig. 13.34) and may occur to a lesser degree in some patients with chronic bronchitis, emphysema and bronchiectasis.

608

Upper airway obstruction This may be caused, for example, by tumours of the larynx

A

B FIG. 13.4

A Forced expiratory spirogram Starting from a full inspiration, the volume expired during a forced expiration (forced vital capacity, FVC) is reduced in both obstructive and restrictive pulmonary disease. However, the volume expired in 1 second (FEV1) is disproportionately reduced in patients with airways obstruction, but not in those with restriction. B Expiratory flow-volume curves In patients with airways obstruction expiratory flow is strikingly reduced as residual volume is approached. In restrictive disorders the shape of the flow-volume curve (although not the magnitude) is normal. (TLC = total lung capacity; RV = residual volume; PEFR = peak expiratory flow rate.)

or trachea, by post-tracheostomy strictures or by inhaled foreign bodies. Clinically, it can be difficult to distinguish upper airway obstruction from other causes of airflow limitation (although severe narrowing of the upper airway causes stridor). The flow-volume loop is diagnostically helpful (Fig. 13.6). In patients with asthma or chronic bronchitis expiratory flow is more reduced than inspiratory flow; when upper airway obstruction is present, inspiratory flow may also be equally reduced.

Restrictive lung disease Limitation of lung expansion can result from diseases of

IB

FIG. 13.5 The effect of obstructive and restrictive disorders on lung volumes Both obstruction and restriction reduce vital capacity (VC). With obstruction, residual volume (RV) and functional residual capacity (FRC) increase due to airway narrowing and closure during expiration, and the patient becomes 'hyperinflated'. With restrictive disorders total lung capacity (TLC) and FRC are reduced due to reduced compliance, or reduced respiratory muscle strength. (TV = tidal volume; IC = inspiratory capacity; ERV = expiratory reserve volume.)

FIG. 13.6 Flow-volume curves with airways obstruction With obstruction of the upper airway (e.g. tracheal tumour) maximal flow rates are reduced, resulting in the characteristic 'plateau' shape of the flow-volume curve. When breathing out from full inspiration (total lung capacity: TLC), peak expiratory flow rate (PEFR) is reduced. Typically PEFR is reduced to a greater extent than the forced expiratory volume during the first second (FEV1). (RV = residual volume.)

the bony ribcage, pleura or lung parenchyma, and of the respiratory muscles. A restrictive defect is therefore a feature of disorders as diverse as kyphoscoliosis, the pneumoconioses and polyneuritis. Pleural thickening or effusion also limits lung expansion. The most common causes of restrictive lung disease, however, are diffuse infiltrative processes within the lung, such as pulmonary fibrosis or extensive sarcoidosis, which reduce pulmonary compliance. Regardless of the underlying cause, pulmonary function tests show small lung volumes (Figs 13.4 and 13.5) and, often, a reduced transfer factor. Airways resistance is not increased and the ratio of FEV1 to vital capacity (VC) is not reduced.

increased blood volume and haemoglobin content of the lungs, as in left-to-right intracardiac shunts, polycythaemia, early left heart failure and pulmonary haemorrhage. The TLCO is raised in asthma, perhaps reflecting the widespread inflammation of the small airways. Transfer factor may be expressed as the carbon monoxide transfer coefficient (KCO), which is the TLCO per litre of alveolar volume. When lung volume is reduced (e.g. pneumonectomy) but the remaining lung is normal, TLCO is reduced but KCO is normal. When lung volume is small because of an inability to expand the lung (e.g. weakness, obesity) TLCO is low but KCO is normal or increased.

Abnormalities of diffusion

Abnormalities of pulmonary blood vessels

Abnormality of any of the parameters that determine diffusion will reduce TLCO (see p. 606). Tests of diffusing capacity are affected by the concentration of haemoglobin; thus TLCO is low in patients with anaemia and high in those with polycythaemia. When corrected for changes in haemoglobin concentration, decreased TLCO values are found most commonly in patients with destruction or obliteration of pulmonary capillaries and/or maldistribution of alveolar ventilation (emphysema, pulmonary vascular disease, interstitial infiltrative diseases). Increased TLCO values are not common but are found in patients with

The function of the pulmonary vascular system is to expose mixed venous blood to adequately ventilated alveoli (Fig. 13.2). Local vasoconstriction in response to hypoxia acts to divert blood flow from poorly ventilated to betterventilated regions. Conversely, if blood flow to part of the lung is compromised, ventilation of that region is reduced. Both these compensatory mechanisms tend to preserve the normal balance between blood flow and ventilation that is essential for efficient gas exchange. The most common disorder of the pulmonary circulation

609

is pulmonary embolism. Chronic obliterative disease of pulmonary arteries may cause severe dyspnoea on exertion but is difficult to diagnose at an early stage because physical examination, chest X-rays and spirometry show no abnormalities. In such disorders, gas transfer is reduced and hypoxaemia intensifies, or may only be apparent, on exercise.

Arterial blood gases and pH Arterial blood gases and pH are also discussed in Chapter 21. The prime function of the lung is to add O2 and remove CO2 from blood. Thus the ultimate test of the adequacy of ventilation, diffusion, pulmonary capillary blood flow and control of ventilation is measurement of Po2, Pco2 and pH of arterial, or arterialized earlobe, blood. 1 'Arterial Po2 Arterial oxygen tension (Pao2) is normally between 11.3 and 13.3 kPa (85 and lOOmmHg) in healthy adults breathing air, at rest and at sea level. The main causes of hypoxia are ventilation-perfusion (V/Q) abnormalities (e.g. pneumonia), hypoventilation (e.g. narcotics or sedatives), impaired diffusion (e.g. interstitial lung disease) and right-to-left shunts (e.g. pulmonary arteriovenous malformation). V/Q abnormalities are the most common cause; hypoventilation is characterized by hypercapnia, and impaired diffusion is rarely an important mechanism except on exercise. Breathing at altitude causes hypoxia (see Ch. 2, p. 49). Reduced delivery of oxygen to tissues, and therefore cellular hypoxia, occurs in severe anaemia, poor tissue perfusion, and (rarely) with respiratory chain enzyme abnormalities (e.g. mitochondrial myopathies, cyanide poisoning). Patients may have significant arterial hypoxaemia without symptoms. Central cyanosis only occurs when the saturation of arterial blood is less than 85%. Thus the clinical signs and symptoms of mild to moderate, but nevertheless important, arterial hypoxia are unreliable, and the diagnosis must be made by analysis of arterial blood gases. With chronic hypoxia patients develop secondary polycythaemia and pulmonary hypertension. Arterial Pco2 The arterial CO2 tension (Paco2) at rest is 4.6-6.0 kPa (35-45 mmHg). Regulation of arterial Pco2 is determined according to the equation: Arterial Pco2 =Kx

CO2 production Alveolar ventilation

Only two variables, CO2 production and alveolar ventilation, are involved. Deviation from normal values of arter-

1

610

MCQ 13.3

ial Pco2 can be viewed as a failure of alveolar ventilation to increase or decrease in accordance with metabolic changes. Hyperventilation, an increase in ventilation in excess of metabolic need so that arterial Pco2 decreases, occurs in patients with a variety of common lung diseases (asthma, pneumonia, pulmonary embolism), presumably from reflexes arising from the chest wall or within the diseased lung. Hyperventilation also results from stimulation of the central nervous system by drugs (aspirin), irritative lesions (cerebral tumours, infections) or anxiety. When Paco2 falls below about 20 mmHg there may be a sudden onset of dramatic symptoms such as paraesthesiae, blackouts and chest pain (owing to vasoconstriction and increased nervous irritability). Some patients hyperventilate and have symptoms due to hypocapnia, without any demonstrable cause. Symptoms are often misattributed by both the patient and the attending doctors to serious organic disease. Correct early recognition and reassurance are helpful. Inappropriate breathlessness may be a separate syndrome which is often, but not invariably, associated with excessive breathing and hypocapnia during exercise. The causes are obscure, but about one-third of such patients are depressed. There are few management strategies and response to treatment is poor. It should be stressed that, following the documentation of hyperventilation (i.e. hypocapnia), recognized disorders that cause excessive ventilation should be excluded before attributing the condition to a psychological cause. Hypoventilation can result from disorders that involve the airways (chronic bronchitis), lung parenchyma (advanced diffuse interstitial fibrosis), chest wall (kyphoscoliosis), respiratory muscles (myasthenia gravis) or central nervous system (sedative drugs). Commonly, in chronic diseases that can eventually lead to hypoventilation, hypercapnia first occurs during sleep. Primary causes of sleep-disordered breathing (e.g. obstructive sleep apnoea) can lead to profound hypoxia by night and eventually persistent hypercapnia by day. Like arterial hypoxia, mild to moderate changes in arterial Pco2 produce no or few signs and symptoms. Thus, analysis of arterial blood gases is required to determine the presence and severity of disturbances in Pco2.

Arterial pH The arterial pH (Fig. 13.7) at rest is 7.38. It can also be expressed as H+ content, and the normal value is 3545 nmol/L. The arterial pH value represents the net effects of both respiratory and non-respiratory factors that regulate Pco2 and HCO3 (and other buffers). When ventilation increases acutely, Pco2 decreases and pH increases; conversely, when ventilation decreases acutely, Pco2 increases and pH decreases. If the ventilatory changes persist, pH gradually returns towards normal values as the kidney makes appropriate adjustments in blood concentration of HCO3-. Thus the pH value depends on both the magnitude of the change in Pco2 and whether or not compensation has had time to occur.

TABLE 13.1 Indications for lung function testing

ED

Diagnostic To evaluate symptoms, signs and abnormal laboratory tests Screening 'at-risk' individuals (smokers, occupational exposure) Assessing preoperative risk Assessing prognosis Monitoring To evaluate the effects of treatment (e.g. bronchodilators, corticosteroids) To assess progress in chronic disease (COPD, pulmonary fibrosis, drug-induced lung disease) Measurement of disability Assessment as part of rehabilitation programmes Medicoiegal issues, insurance claims Epidemiological surveys (Adapted from Crapo, R. N Engl J Med, 1994, 331: 25-30).

FIG. 13.7 Acid-base diagram The relationship of arterial pH [H+], Pco2 and bicarbonate with disturbances of acid-base balance. For example, acute ventilatory failure leads to a raised arterial Pco2 and a reduction in pH; compensatory renal mechanisms then increase bicarbonate and restore pH to normal. (Modified from Flenley D C 1971 Another non-logarithmic acid-base diagram? Lancet 1961.)

Lung function testing (Table 13.1) Patterns of lung function abnormality are easily identified (Table 13.2). Airflow limitation without reversibility and with a normal TLCO is compatible with chronic obstructive bronchitis; if emphysema is present, however, TLCO and KCO will be reduced. A more than 15% improvement in FEY1 or peak flow after inhaled bronchodilator is suggestive of asthma. Restrictive lung disease due to pulmonary fibrosis will show low lung volumes with a normal or high FEV1/VC ratio and a reduced TLCO, whereas if the restriction is due to chest wall disease the TLCO may be normal or slightly reduced and the KCO raised.

lessness. Patients with lung disease stop exercising before achieving their maximum predicted heart rate and have levels of ventilation that are disproportionately high for a given oxygen uptake. Assessment of respiratory muscle strength is useful in patients with neuromuscular diseases and when evaluating selected patients with unexplained breathlessness (see p. 615). Vital capacity is a particularly useful simple test. Maximum inspiratory and expiratory mouth pressures can be measured using simple hand-held pressure meters. Specialist laboratories can undertake more complex techniques (e.g. phrenic nerve stimulation and diaphragm strength measurements). Overnight pulse oximetry and, in selected cases, polysomnography, is required to properly investigate sleep-disordered breathing (see pp. 668-670).

FURTHER READING ON STRUCTURE AND FUNCTION OF THE RESPIRATORY SYSTEM Hughes J M B, Pride N B 1999 Lung function tests. Philadelphia: WB Saunders.

Exercise testing

Simple tests can be of great clinical value in patients limited by lung disease. The 6- or 12-minute walking distance, in which the patient walks as far as he can during the time allowed, gives an indication of overall exercise capability. In some patients it may not be certain that lung function is impaired, and in such instances the monitoring of oxygen saturation, by finger probe, during treadmill or cycle ergometer exercise, is a sensitive technique for detecting minor abnormalities of oxygenation. Formal laboratory exercise testing - measuring oxygen uptake, CO2 production, heart rate and ventilation during progressive treadmill or cycle ergometer exercise - can be helpful, particularly in patients with unexplained breath-

SYMPTOMS AND SIGNS OF RESPIRATORY DISEASE The most important symptoms of respiratory disease are: Cough Sputum Haemoptysis Breathlessness Wheeze Chest pain.

611

TABLE 13.2 Patterns of abnormality in lung function tests Feature

Asthma

Chronic bronchitis

Emphysema

Pulmonary fibrosis

Chest wall abnormalities*

Airflow obstruction Reversibility Hyperinflation Reduction of lung volumes TLCO KCO Lung compliance

Yes Yes Yes No Normal or increased Normal or increased Normal

Yes Slight Yes No Normal Normal Normal

Yes Slight Yes No Reduced Reduced Increased

No No No Yes Reduced Reduced Reduced

No No No Yes Normal or reduced+ Normal or increased Normal or reduced

* e.g. kyphoscoliosis, muscle weakness. + (See p. 609)

Cough

612

Cough is initiated when irritant receptors in the mucous membrane of the respiratory tract are stimulated. Cough is by far the most common respiratory symptom, and is characteristic in heavy smokers. Frequently, cough is triggered by the presence of sputum in the respiratory tract, and is useful in helping to clear infection from the bronchial tree. A wide variety of inhaled irritants in addition to cigarette smoke (e.g. noxious gases or cold air) may stimulate coughing, and this is more likely if the airways are already irritable because of inflammation as a consequence of infection. Similarly, the irritant receptors in the bronchial tree may be stimulated by tumours, inhaled foreign bodies, allergens and the asthmatic response, pulmonary oedema and external compression by lymph nodes. In non-smokers the most frequent causes of chronic cough are asthma, sinus disease and oesophageal reflux. With neurological disease laryngeal function may be impaired or oesophageal motility abnormal (e.g. achalasia), and cough may be due to repeated aspiration. Drugs can cause cough, by damaging the lung (p. 696) or causing asthma (p. 651). A characteristic persistent dry cough can occur with ACE inhibitors. Cough after drinking can also indicate an oesophagobronchial fistula. In some patients cough is worse at night, particularly in asthma or pulmonary oedema. Prolonged coughing reduces venous return, causes a transient fall in cardiac output and cerebral oxygenation, and leads to cough syncope. Damage to the recurrent laryngeal nerve, commonly at the left hilum due to bronchial carcinoma, leads to vocal cord paralysis and an inability to produce a normal explosive cough, which becomes 'bovine'. A dry cough, sometimes following an upper respiratory tract infection and often persisting for weeks or months, for which no cause can be found, is a common clinical problem. It can present a formidable management difficulty, especially as patients' expectations of 'cure' are high (Table 13.3, Figure 13.8).

TABLE 13.3 Investigation of chronic cough Chest X-ray/HRCT Pulmonary function testing Sinus X-ray/CT Skin prick testing Blood/sputum eosinophils Sputum culture/AFB Oesophageal function - Barium swallow, pH, manometry, Speech therapist evaluation Bronchoscopy (when occult endobronchial lesion suspected) Common causes of refractory cough Asthma Chronic bronchitis/smoking Post viral URTI Gastro-oesophageal reflux Chronic sinusitis/post nasal drip Bronchiectasis Endobronchial - tumours foreign body exposure to irritants Parenchymal - pulmonary fibrosis sarcoidosis Cardiac - left ventricular failure Drugs-ACE inhibitors Inhaled irritants Neuromuscular disorders Psychogenic

Sputum In healthy subjects the bronchial tree produces approximately 100 mL of mucus each day; this is carried upwards by ciliary action and is then unconsciously swallowed. This

TABLE 13.4 Important causes of haemoptysis Pulmonary infections Bronchiectasis (particularly upper lobe bronchiectasis from past pulmonary tuberculosis) Lung abscess Pneumonia Tuberculosis Aspergilloma Pulmonary infarction Tumours Carcinoma Adenoma (Haemoptysis is unusual with pulmonary metastases) Pulmonary oedema Particularly due to mitral stenosis Pulmonary haemorrhage Goodpasture's syndrome Idiopathic pulmonary haemosiderosis Systemic lupus erythematosus Pulmonary vasculitis

Trauma Needle biopsy Transbronchial biopsy Pulmonary contusion Vascular abnormalities Arteriovenous malformation Hereditary haemorrhagic telangiectasia Bleeding disorders Usually severe thrombocytopenia from any cause Miscellaneous Pulmonary endometriosis (catamenial haemoptysis)

13

Disorders of the upper airways Epistaxis Tumours

FIG. 13.8 Algorithm for investigation of chronic cough

'escalator' is a normal part of the mechanism for clearing debris and pathogens from the bronchial tree. In disease processes causing the production of excess mucus, irritant receptors are stimulated and sputum is coughed up. Sputum is not described reliably by patients and it is always best to inspect it. Sputum may be clear, white or mucoid, as in chronic bronchitis, or purulent, in which case pus is mixed with mucus and the sputum is yellow or green. Sputum may contain blood, which may be bright red (e.g. pulmonary infarction), a rusty colour (acute pneumonia) or pink (pulmonary oedema due to left heart failure). In asthma the sputum may contain mucus plugs. Microscopically, sputum may contain bacteria, pus cells, eosinophils (as in asthma and pulmonary eosinophilia) or malignant cells. It is helpful to know the volume of sputum produced each day, and this can be particularly large: greater than 20 mL in bronchiectasis, cystic fibrosis, and lung abscess when there is a bronchopulmonary fistula. Clinical progress can be monitored by documentation of sputum volume. Occasionally patients with alveolar cell carcinoma produce very large volumes of clear watery sputum

(bronchorrhoea). Anaerobic infection results in foulsmelling sputum.

Haemoptysis Patients may have difficulty in being sure that blood has been coughed rather than vomited. Coughed blood may be from a lesion of the nose, nasopharynx and vocal cords. When infection causes haemoptysis, blood will be mixed with purulent sputum, whereas in non-infective causes (e.g. pulmonary infarction) there is usually frank blood and no sputum. In patients with chronic bronchitis it is common for the sputum to contain occasional specks of blood, but more substantial haemoptysis is unusual (Table 13.4). A cause for haemoptysis should be carefully sought in all cases, but a definite diagnosis is only achieved in 60-70%. Occasionally haemoptysis can be severe and lifethreatening. This occurs most frequently in cavitating tuberculosis and bronchial carcinoma. In those patients in whom no definite cause for haemoptysis is found, careful follow-up is necessary, with repeated chest X-rays. The importance of haemoptysis as the presenting feature of lung cancer must be emphasized. In particular, frank haemoptysis in a smoker, even in the presence of a normal plain chest X-ray, may be the earliest warning of a

613

CASE STUDY: 13.1 PERSISTENT SEVERE HAEMOPTYSIS A 45-year-old Afro-Caribbean woman was admitted to hospital with persistent severe haemoptysis. She had originally attended the hospital 10 years previously with sharp central chest pain, bilateral hilar adenopathy, and enlargement of the mediastinal lymph nodes. At that time a lymph node biopsy, via a mediastinoscopy, demonstrated non-caseating granulomata, consistent with a diagnosis of sarcoidosis. Subsequently the patient developed bilateral pulmonary infiltrates and increasing breathlessness. She was treated with oral prednisolone, with substantial symptomatic improvement. Over the next few years, on varying doses of prednisolone, the adenopathy resolved but the interstitial lung disease persisted. The patient developed a moderately severe restrictive defect on lung function testing. She found the adverse effects of steroid therapy, particularly the weight gain and hirsutism, troublesome, and for a period of several years did not attend regularly for follow-up and took her steroid treatment intermittently. Eighteen months prior to her current admission she first experienced haemoptysis. At that time bronchoscopy showed blood throughout the bronchial tree, but probably originating from the left upper lobe bronchus. Chest X-rays and a CT scan showed extensive bilateral upper lobe fibrosis with spaces within the lung and cavity formation (Case Fig. 13.1.1).

Questions 1. Should the diagnosis of sarcoidosis be reconsidered? 2. What is the cause of the haemoptysis? 3. What would be the future management 01 this patient?

614

CASE FIG. 13.1.1 [70 Chest X-ray showing bilateral upper zone volume loss, fibrosis and cavitation (best seen on the right). B CT scan There are large spaces in the upper zones of both lungs.

The original presentation is typical of sarcoidosis. It is not uncommon for patients with extensive intrathoracic lymphadenopathy to experience chest pain, often with a sharp quality. The histology of the lymph node makes the diagnosis virtually certain. Tuberculosis was possible and culture of the biopsy material was essential. In this patient the culture did not yield mycobacteria and a certain diagnosis of sarcoidosis was therefore made. Although sarcoidosis can effect all racial and ethnic groups it can be particularly persistent and severe in Afro-Caribbeans. A reasonable question is whether the development

of upper zone spaces and cavitation should lead one to suspect an additional diagnosis, particularly tuberculosis. Occasionally patients with sarcoidosis do develop tuberculosis (and vice versa); however, extensive sarcoidosis also leads to cavity formation, usually in the mid and upper zones. The poor control of this patient's disease has led to extensive fibrosis and lung destruction, which can also cause a degree of bronchiectasis. Thus, although tuberculosis should be considered as a cause for the haemoptysis, so should bacterial infection within damaged and bronchiectatic lung. Crucial investigations would include sputum examination and culture to exclude tuberculosis and a tuberculin skin test, usually positive in TB and characteristically negative in sarcoidosis. This patient had bronchial lavage, which showed no evidence of TB, and a Heaf test which showed no reaction. She was treated with antibiotics and steroids and the bleeding settled. Over the next 18 months there were several episodes of substantial bleeding. Bronchial arteriograms showed abnormal bronchial artery circulations in both upper lobes, and on two occasions she was treated by bronchial artery embolization. This treatment produced only a temporary reduction in haemoptysis. In the months leading up to the current admission the patient had coughed blood during most weeks, often up to a cupful 'daily, and was highly symptomatic because of a persistent disabling cough for much of the day and night. Question 4. What other complication of her cavitatpry disease could explain her haemoptysis?

13

CASE STUDY 13.1 CONTINUED A repeat CT scan demonstrated soft tissue shadowing within the cavitatory systems in the upper lobes, particularly on the left, strongly suggesting aspergilloma formation (Case Fig 13.1.2). The patient underwent surgery and the complex mycetoma cavity in the left upper lobe was cleaned out and the space packed with intercostal muscle. She did well postoperatively, with resolution of both her cough and haemoptysis. If bleeding returns the management would be to operate to remove the mycetoma cavities within the right lung. Question 5. How should severe haemoptysis be managed? The main danger of severe haemoptysis is hypoxia, as the bronchial tree becomes flooded with

blood. Large-volume bleeding, combined with coughing, rapidly fills the large and small airways. It is helpful to identify which lung is bleeding and for the patient to lie on their side with the bleeding lung dependent, thereby limiting soiling of the good lung. If the PaCO2 is not raised mild sedation is appropriate. The patient should be discussed with anaesthetic colleagues because urgent intubation may be necessary. Intubation should be with a doublelumen tube to enable the bleeding lung to be isolated. Definitive treatment of haemoptysis will depend on the cause. For example, bleeding endobronchial tumour can be treated by laser therapy; bleeding from bronchiectatic lung by bronchial artery embolization; arteriovenous malformation by coil insertion; and, if necessary, refractory bleeding can be treated by lung resection.

CASE FIG. 13.1.2 IT] Chest X-ray. Note that compared with Figure 1 the left upper zone is more opaque, as a result of mycetoma formation. B CT scan. Note the large round opacity within a cavity in the left lung (arrowed). This is a large mycetoma.

tumour in a large airway which has not yet occluded the bronchus.

Breathlessness Breathlessness is an unpleasant awareness of the effort of breathing. This sense of effort usually reflects an increased ventilatory load (e.g. bronchoconstriction), a reduced breathing capacity (e.g. respiratory muscle weakness due to motor neuron disease) or both (e.g. severe COPD, in which respiratory muscle function is impaired because of hyperinflation and load is increased). The history should document severity: How far can the patient walk on the flat? How many steps can the patient climb without stopping? Breathlessness may have characteristic

features: in left heart failure breathlessness is worse when lying flat; in asthma it is frequently episodic, worse at night. With psychogenic breathlessness the patient complains of difficulty in taking air in, difficulty in fully filling the lungs with air and an inability to take a deep breath. These patients are often breathless at rest but not on exercise. Such 'behavioural breathlessness' causes a low arterial CO2, and symptoms of the hyperventilation syndrome (e.g. faintness, chest pains) can be reproduced by asking patients to breathe deeply for 20-30 seconds. The period over which breathlessness has developed is of great importance (Table 13.5). The patient with chronic bronchitis who continues to smoke has gradually progressive breathlessness; an acceleration in the pace of the symptom may reflect a bronchogenic

615

CASE STUDY 13.2 CHRONIC BREATHLESSNESS ON EXERTION IN A YOUNG PROFESSIONAL FOOTBALLER The patient was a 29-year-old man from Kenya who had come to the UK 4 years previously. He was a professional football player. For many years he had noted breathlessness on exertion, gradually becoming more severe, and despite his footballing talents he was now finding it difficult to complete a full game. Three months previously he had been admitted to hospital with cough, purulent sputum and fever. He was diagnosed as having a chest infection, treated with antibiotics, and made a full recovery, albeit slowly, after a period of 6-8 weeks. There was no relevant past medical history, and particularly no history of respiratory or cardiac illnesses. He was a non-smoker. On examination the patient was comfortable at rest; BP 125/80, heart rate 64, JVP not raised, apex beat not displaced, no murmurs or added sounds heard. There was no cyanosis, no clubbing, the trachea was central and the respiratory rate 14. Expansion of the lower chest on the left was reduced. The breath sounds were slightly reduced over the left lower zone anteriorly, laterally and posteriorly. Vocal resonance and tactile vocal fremitus were reduced at the left base. Occasional inspiratory crackles were audible at the left base.

Question 1. What is the likely explanation for the patient's physical signs and breathlessness?

Discussion There are no signs of cardiac or pericardial disease. The signs indicate chest pathology. The reduced expansion of the lower left hemithorax, combined with reduced breath sounds, tactile fremitus and vocal resonance, would be consistent

616

with pleural effusion, collapse or pleural thickening. The normally positioned apex beat and the easily audible breath sounds make a substantial pleural effusion unlikely. The central position of both the upper and lower mediastinum is against collapse. The pathology best explained by the physical signs is extensive pleural thickening. The chest X-ray is illustrated in Case Figure 13.2.1. What abnormalities are shown? Note the reduced transradiancy of

linear, mainly vertical opacities, typical of pleural thickening and calcification. There is dense calcification of the left diaphragmatic pleura. A CT scan of the thorax is shown in Case Figure 13.2.2 and demonstrates a rim of thickened

CASE FIG. 13.2.1 Chest X-ray. (See text for description).

the left lower zone compared to the right. The vascular pattern is nevertheless detectable, indicating that the abnormal shadowing is outside the lung (i.e. pleural). Pleural thickening is apparent, running down the inner border of the left chest wall and over the left hemidiaphragm, making the diaphragm indistinct. The mediastinum is central. Note the reduced space between the left lower ribs compared to the right, indicating that the changes are chronic. In the left lower zone, adjacent to the heart and behind it, are irregular

CASE FIG. 13.2.2 CT scan of thorax. A Scan through lower thorax, showing pleural thickening, calcification and reduction in volume on the left side. B Scan at the level of the diaphragm; on the left there is gross thickening, and calcification of the pleura. pleura with calcification, surrounding the left lung. Note the reduction in the area of the left hemithorax compared to the right. The cause of

this patient's chronic pleural thickening and calcification is almost certainly tuberculosis, which would have caused a tuberculous pleurisy when he was a child. Adult patients often have no knowledge of having been unwell when young. A traumatic haemothorax can cause a similar picture, but there was no history or signs of severe thoracic trauma. The lung function test results for this patient are shown in the table below. Measured

FEV! (L) VC (L) FEVj/VC % PEFR(L/min) TCO (mmol/ kPa/min) KCO

2.2 2.3 95% 455 7.8 2.3

Predicted

4.5 5.4 606 12.3 1.6

Question 2. What is the interpretation of these results?

The marked reduction of vital capacity, combined with the high FEV\/VC ratio, indicates a severe restrictive ventilatory defect. The small reduction in PEFR reflects the reduced TLC, and there is no airways obstruction. The difficulty in expanding the lung and recruiting alveoli for gas exchange causes the low overall gas transfer (TCO), but the lungs themselves are normal and relatively well perfused, and when TCO is corrected for the small lung volumes to derive the transfer coefficient (KCO) this is supranormal. A reduced TCO and normal or increased KCO is typical

13

of extrapulmonary restriction (e.g. pleural disease, obesity, muscle weakness).

Question 3. Why is the patient breathless?

The causes of breathlessness are multiple and poorly understood. Hypoxia and hypercapnia can contribute, but changes in blood gases per se are often not of great importance. Breathlessness is an unpleasant awareness of the difficulty of breathing and is most commonly the consequence of disproportionate respiratory effort. Whenever the load on the respiratory system is increased (e.g. lung fibrosis, airways obstruction) and/or ventilatory capacity is reduced (e.g. respiratory muscle weakness), neural respiratory drive is increased and becomes a larger proportion of maximum available respiratory drive. Thus, breathing is perceived as being a great effort. Pleural thickening encasing the lung, as in the present case, dramatically reduces chest wall compliance, imposes a high load on the respiratory system, and makes ventilation difficult despite great efforts. Case Figure 13.2.3 shows ventilation and perfusion lung scans of the patient. Note the marked reduction in ventilation of the left lung. Perfusion of the left lung is also reduced, but less so than ventilation, and such ventilation/perfusion mismatch contributes to hypoxia, especially on exercise. Treatment for chronic pleural thickening is limited. In selected cases it is possible for a thoracic

carcinoma, narrowing a bronchus or causing a pleural effusion. Most causes of breathlessness are relatively easily diagnosed by history, physical examination, chest X-ray, blood

ANT

VENT

CASE FIG. 13.2.3 Lung ventilation and perfusion scan. Both ventilation and perfusion are reduced in the left lung. The left lung is receiving 23% of total ventilation and 34% of perfusion.

surgeon to dissect the thickened pleura off the lung. This is a difficult operation, often only partially successful, and not appropriate in most cases. In the present case the patient was advised that surgery was not appropriate and he resolved to seek educational training for a different profession. The case emphasizes how important it is that acute pleural disease (particularly empyema) is correctly managed to avoid whenever possible the development of chronic extensive pleural thickening.

gas analysis and lung function tests. In difficult cases an exercise test may be helpful. Although orthopnoea and paroxysmal nocturnal dyspnoea suggest left heart failure, many patients with

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TABLE 13.5 Time course for the development of breathlessness Immediate Pneumothorax Pulmonary oedema due to cardiac arrhythmias Pulmonary embolism Inhalation of foreign body

Weeks Pleural effusion Anaemia Muscle weakness Months Tumours Pulmonary fibrosis Thyrotoxicosis Muscle weakness

Hours Asthma Left heart failure Pneumonia Laryngeal oedema Days Pneumonia Acute respiratory distress syndrome Left heart failure

Years Muscle weakness Chronic airways obstruction Pulmonary fibrosis Primary pulmonary hypertension Chest wall disorders

asthma are worse at night and many patients with severe airways obstruction are more comfortable sleeping with several pillows. Diaphragm weakness can cause profound orthopnoea.

Wheeze Wheeze is generated by increased turbulence of airflow through a narrowed airway. Patients with airways obstruction frequently complain of wheeze, which in asthma, chronic bronchitis and emphysema is predominantly expiratory. Patients may notice that a wheeze is inspiratory, indicating narrowing of the larynx, trachea or main bronchi, and occasionally they will remark that the wheezing sound is from only one side of the chest, as when a tumour narrows a major bronchus. Diffuse expiratory wheezes can occur in left heart failure.

Chest pain The many causes of chest pain can usually be distinguished by careful history taking, paying particular attention to the duration of the pain, its site and radiation, and the relationship to movement, breathing and exercise (see Ch. 12, p. 467). The quality of pain is also diagnostically important, especially if it is pleuritic in nature. Diseases within the

618

1

MCQ 13.4

3

Fig. 10.48

2

Figs 13.1-13.3

lung are usually painless, as there are no pain receptors in lung tissue. Pleural pain This usually indicates involvement of the parietal pleura by inflammation or malignancy, but is also a feature of pneumothorax. Inflammation of pleura can be caused by: • • • • • • •

Pneumonia Pulmonary infarction Lung abscess Tuberculosis Rheumatoid arthritis Systemic lupus erythematosus Uraemia.

Pleural pain is sharp, often well localized, worse on breathing, particularly with deep inspiration, and causes the patient to catch his breath. Pain from inflammation of the central diaphragm is referred to the shoulder; pain from inflammation of the lateral diaphragm is referred to the lower lateral chest wall and upper abdomen. Mediastinal pain Central chest pain may occur with primary carcinoma of the lung, particularly when there is involvement of mediastinal structures including lymph nodes. Adenopathy due to other disorders, such as sarcoidosis, can cause pain. The differential diagnosis will include angina, pericarditis, oesophagitis and bone pain. Severe sudden central chest pain can occur with pulmonary embolism (p. 682). Chest wall pain With rib fractures there is local pain and tenderness. Occasionally coughing leads to fracture, particularly of the middle ribs posterolaterally. Osteoporotic ribs and those involved by tumour fracture easily. Cough fractures in patients with chronic asthma treated with long-term oral steroids are relatively common, as are fractures in the elderly. Infiltration of the chest wall by tumour causes pain and is an important feature of pleural malignancy, particularly mesothelioma. Perichondritis causes pain and swelling of the costochondral junction, often of the second ribs bilaterally (Tietze's syndrome). Pain within the distribution of thoracic nerves occurs with herpes zoster, the pain frequently preceding the vesicular rash. Nerve root pain, often described as burning, also occurs with an intervertebral disc or malignant and inflammatory diseases of the spine. Local pain and tenderness of the muscles of the chest wall is caused by Coxsackie B viral infections (Bornholm's disease) which may sometimes involve the diaphragm. Upper chest wall and shoulder pain is a feature of neuralgic amyotrophy, and phrenic nerve involvement can lead to unilateral or bilateral diaphragm paralysis. Rib pain occurs in sickle cell crisis, and these patients are more likely to develop sickle lung. Localized muscle pain without an important underlying pathological process is common in breathless, coughing patients. 1

13

EXAMINATION OF THE RESPIRATORY SYSTEM In thoracic medicine the history, physical examination, chest X-ray and pulmonary function tests all contribute to diagnosis and assessment in a complementary manner. The chest X-ray gives accurate information on thoracic anatomy, whereas the clinical examination is much more useful in assessing pathophysiology. Before the clinical examination, many relevant observations will have been made while talking to the patient concerning breathlessness, pain, cough and general appearance. In addition, the history will have served to focus attention on particular diagnostic probabilities and possibilities that subsequent examination will confirm or refute. If already available, the information from the chest X-ray will similarly direct the physician's examination of the patient.

Examination of the hands Examination of the hands may give valuable information: • Finger and toe clubbing (Fig. 13.9) is an important physical sign. The four criteria for documenting finger clubbing are: increased sponginess of the nailbed; loss of the usual acute angle between the nail and the nailbed; increased nail curvature; and increased bulk of the soft tissues over the terminal phalanges. The majority of patients with clubbing have pulmonary disease (Table 13.6). Clubbing is occasionally familial in otherwise normal subjects. It can develop very rapidly, within a few weeks (e.g. with an empyema), but its onset is usually gradual. The mechanism of clubbing is not understood. The bones of the fingers and toes are normal. If the underlying cause is successfully treated clubbing usually resolves. • Hypertrophic pulmonary osteoarthropathy (HPOA). Virtually all patients with this unusual condition have clubbing, but only a few patients with clubbing have HPOA. There is arthralgia and joint swelling affecting particularly the wrists and ankles. X-rays show subperiosteal new bone formation in the long bones of the lower limbs and forearm, the bone scan demonstrates increased activity, and often the serum alkaline phosphatase is raised. Ninety per cent of cases are associated with bronchogenic carcinoma, particularly peripheral squamous cell tumours. • Examination of the nails. This may show that some or all of them are thickened and yellow or greenish in appearance. This occurs in the yellow nail syndrome, 3 in which clubbing is associated with lymphoedema, exudative pleural effusions, bronchiectasis and sinusitis. • Carbon dioxide retention. When there is carbon dioxide retention, peripheral vascular dilatation greatly

FIG. 13.9 Finger clubbing

TABLE 13.6 Important causes of clubbing Bronchial carcinoma (particularly squamous cell) Mesothelioma Benign intrathoracic tumours

Cyanotic congenital heart disease Bacterial endocarditis Atrial myxoma

Pulmonary arteriovenous fistula

Cirrhosis

Lung abscess Empyema Bronchiectasis Fibrosing alveolitis Asbestosis Advanced pulmonary fibrosis of any cause

Ulcerative colitis Crohn's disease

Familial

enhances blood flow and the hands are strikingly warm. With severe and acute carbon dioxide retention there may also be an irregular flapping tremor of the outstretched hands. The fingers may be blue (peripheral cyanosis), and if the limb is warm this is likely to reflect central cyanosis rather than poor peripheral perfusion.

Cyanosis In patients with a normal haemoglobin concentration, oxygen saturation must fall to 85%, corresponding to an arterial oxygen tension of 7-8 kPa (approximately 5560mmHg), before cyanosis can be clinically detected. As a consequence of the sigmoid shape of the oxygen dissociation curve (Fig. 13.3), further small falls in oxygen tension then produce large, dangerous falls in saturation. In anaemia, severe hypoxia is required to produce the quantity of reduced haemoglobin (about 1.5g/dL) necessary to cause cyanosis, whereas patients with polycythaemia become cyanosed at higher arterial oxygen tensions. The bluish colour of central cyanosis is best appreciated by examination of the tongue in adequate daylight.

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Cyanosis is a difficult physical sign, and estimates of severity are so unreliable that measurement of the arterial oxygen tension is the next logical step. Cyanosis cannot be reliably detected in many black and Asian patients, in whom severe hypoxaemia may go undetected. In most cases central cyanosis is due to lung disease. Right-to-left shunts within the heart or within the lungs (arteriovenous malformation) cause central cyanosis, as do pulmonary shunts in advanced cirrhosis. Rarely patients appear cyanosed due to methaemoglobinaemia or sulphaemoglobinaemia, most commonly caused by drugs.

Pulsus paradoxus The curious term 'pulsus paradoxus' is used to describe a greater than normal fall in blood pressure during inspiration. In normal subjects the systolic blood pressure falls by a few mmHg during inspiration. This fall is greater (not paradoxical) when venous return to the right heart is impaired, e.g. in patients with hypovolaemia, cardiac tamponade or massive pulmonary embolism. In respiratory disorders pulsus paradoxus is seen when there are large pressure swings within the thorax during the respiratory cycle. This is particularly likely to occur in severe acute asthma, when the extent of paradox is related to the severity of airways obstruction, and systolic blood pressure may fall by 40 mmHg on inspiration. The degree of paradox is best documented using a sphygmomanometer: as the pressure of the cuff is reduced, the systolic sound is initially only audible on expiration, but with a further reduction in cuff pressure it becomes audible throughout inspiration too. The pressure difference between the measurement taken when the systolic sound is first detected and the measurement taken when it is present throughout the breathing cycle is termed the degree of paradox (recorded in mmHg). In asthma, paradox is dependent on respiratory muscle contraction and is reduced when hyperinflation is so severe that the generation of large inspiratory pressures is no longer possible because of exhaustion, as well as with improvement in airways obstruction.

Jugular venous pressure The jugular venous pressure is raised in right heart failure, which is itself frequently due to pulmonary disorders such as chronic bronchitis. The venous pressure is also elevated if the resting pressure in the thorax is raised, as with a tension pneumothorax. When there is severe airways obstruction the pressure swings within the thorax are large; intrathoracic pressure is positive during expiration, owing

620

1 Fig. 13.4

2

Fig. 13.5

3

Fig. 13.6

4

5

Fig. 13.8

6

Fig. 13.9

Fig. 13.7

to active recruitment of the expiratory muscles and the positive recoil pressure of the respiratory system when expiration is halted by airway collapse at a lung volume well above normal FRC. This positive intrathoracic pressure elevates the jugular venous pressure, which then falls during inspiration. Thus, interpretation of the jugular venous pressure in the tachypnoeic patient, particularly with severe airways obstruction, is difficult. The jugular venous pressure is raised and not pulsatile in superior vena cava obstruction, most commonly due to malignant nodes or a tumour mass compressing the vein. 1 The most common cause is an extending bronchial carcinoma, but lymphoma, thymic tumours and metastases can all cause compression. Very rarely non-malignant lesions are responsible, e.g. mediastinal fibrosis, or aortic root aneurysm or dissection. Superior vena caval obstruction produces drowsiness, a sense of fullness in the head, swelling and cyanosis of the face, neck and arms, epistaxis, and sometimes papilloedema.

Peripheral oedema Peripheral oedema associated with severe pulmonary disease (cor pulmonale) is relatively common, and is most often seen with chronic bronchitis, in which there is hypercapnia as well as hypoxia. Patients with hypoxic normocapnic respiratory failure seldom have oedema. In some patients with oedema the jugular venous pressure is not elevated, the cardiac output is normal and fluid accumulation is related to factors other than right heart failure, perhaps mediated through the action of hypoxia and hypercapnia on renal blood flow and function.

Examination of the chest Examination of the chest (Fig. 13.10) may reveal that the chest wall shows an abnormality of shape (kyphoscoliosis, a barrel chest reflecting hyperinflation or pectus deformity) or an abnormality of symmetry (a reduction in the volume of one hemithorax reflecting underlying chronic fibrosis, or perhaps an increase in volume reflecting a pneumothorax). Much can be learned about respiratory function by observing the patient's breathing pattern. An increase in respiratory rate is a sensitive index of cardiorespiratory disorders and is not sustained above 14-20 breaths per minute in normal adults. Disorders that cause widespread functional impairment, such as asthma, pulmonary fibrosis and pulmonary oedema, invariably increase respiratory rate. Conversely, respiratory rate is reduced by central nervous system injury or central depressant drugs. Visible or palpable contraction of the accessory muscles is abnormal. Scalene and sternomastoid activity is particularly obvious in severely hyperinflated patients, whereas in patients who are not overinflated, accessory muscle activity is an indication of a greatly increased respiratory effort. In severely breathless patients abdominal muscle activity is vigorous.

Abnormality

Consolidation 2

Pleural effusion 3

Lobar collapse 4

Pneumothorax

5

Yes away from effusion

Yes towards collapse

No without tension Yes with tension

Pneural thickening 6

13

Chest radiograph

Mediastinal shift

No

Chest wall movements

Normal or

Breath sounds

(Bronchial)

Added sounds

Crackles

Percussion note duller =more resonant) Tactile fremitus Vocal resonance

No

Normal or

Occasional rub

No

Occasional click

No

Normal or

| most distinguishing sign FIG. 13.10 Signs of most important focal abnormalities

Chest wall movements Both sides of the thorax should be seen to expand equally during tidal and full inspiration. Hands placed flat on either side of the sternum can appreciate the predominantly forward movement of the sternum and upper ribs, whereas hands placed around the lower thorax can best detect the normal outward and upward movements of the mid and lower ribs. Overall movement of the ribcage is reduced by hyperinflation (e.g. emphysema), reduced pulmonary compliance (e.g. lung fibrosis), reduced chest wall compliance (e.g. ankylosing spondylitis) and weak inspiratory muscles (e.g. myasthenia gravis). Local chest wall movement is reduced in pleural effusion, pleural thickening, pulmonary collapse, and to a lesser degree in consolidation and pneumothorax. The pattern of breathing is altered by disease. For example, patients with stiff lungs, a poorly compliant ribcage or weak respiratory muscles breathe rapidly and shallowly. It must be stressed that clinical assessment of the depth of respiration is notoriously inaccurate. Patients with airflow obstruction have a prolonged expiratory phase and patients with left heart failure may have marked periodic respiration. With severe weakness or paralysis of the diaphragm the anterior abdominal wall moves paradoxically inwards during inspiration when supine (see Fig. 13.76).

Trachea and apex beat The trachea is an important anatomical landmark indicating the position of the upper mediastinum. It is best pal-

pated by one finger gently placed in the suprasternal notch. Loss of volume in one hemithorax, as with pulmonary flbrosis, pulls the trachea to the same side. Expansion of a hemithorax (as with tension pneumothorax) or local masses (e.g. an enlarged thyroid) pushes the trachea towards the opposite side. When examining the trachea, the distance between the suprasternal notch and the cricoid cartilage is noted and is normally 3-4 fingers, and a reduction in this distance is a reliable sign of hyperinflation. Assessment of tracheal shift is difficult in patients with hyperinflation because the displacement is within the thorax. A shift of the lower mediastinum displaces the cardiac apex. However, a displaced apex must be interpreted with caution because ventricular enlargement also moves the apex beat. In some patients the apex beat is not palpable, usually because of obesity or hyperinflation of the lungs. Less commonly the apex is difficult to palpate because of pericardial disease or poor left ventricular function, and the apex will be located on the right side with dextrocardia. Palpation at the left sternal edge may elicit the heave of right ventricular hypertrophy, common in patients with severe pulmonary disease causing pulmonary hypertension. In patients with hyperinflation heart sounds are much reduced at the apex, but are well heard over the lower sternum in the midline.

Percussion When percussing the chest, comparison should be made between corresponding areas on both sides in an attempt to detect differences in percussion note. The percussion note is resonant over aerated lung, and hyperresonant with emphysema, large bullae or pneumothorax. Percussion is

621

dull over solid organs such as the liver and heart (except with hyperinflation, when the aerated lung covers the heart). In the normal subject the upper level of liver dullness when supine is at the sixth rib in the midclavicular line. The percussion note becomes dull when there is fluid in the pleural space, when there is collapse of a lobe or lung, and when there is extensive consolidation. Less marked dullness occurs with pulmonary fibrosis, pleural thickening and large peripheral tumours. Basal dullness as a consequence of diaphragm elevation is easily confused with pleural fluid. When the palm or side of the examiner's hand is placed on the chest and the patient talks (e.g. says ninetynine) vibrations are easily felt (tactile fremitus); and if a stethoscope is used the voice sounds are well heard (vocal resonance). Tactile fremitus and vocal resonance are increased with pulmonary consolidation and decreased by pleural fluid, but are relatively crude physical signs.

Auscultation Listening to the chest is of the greatest clinical importance: a chest X-ray can subsequently provide detailed structural information, but auscultation is crucial for providing functional data. At the bedside the breathing of patients with airways obstruction is noisy, and this correlates well with the degree of obstruction documented by pulmonary function tests. This noisy breathing is particularly prominent in chronic bronchitis and asthma, but is less marked in emphysema because inspiratory resistance is not increased. On auscultation by contrast, breath sounds are generally reduced in patients with airways obstruction, particularly emphysema, and there may be local areas of greatly reduced breath sounds over bullae, a pneumothorax, pleural effusions, and when a lobe or lung is poorly ventilated, as when there is substantial bronchial obstruction due to tumour. Expiratory breath sounds are prolonged with airways obstruction, whereas expiration is rapid in patients with severe restrictive disease. In normal subjects expiration is followed by a pause before the next inspiration; this disappears as respiratory rate increases. Bronchial breathing is when the breath sounds become harsh and high-pitched, owing to enhanced transmission of sound through the abnormal lung. Whispered sounds are then easily heard as high-pitched 'whispering pectoriloquy'. Bronchial breathing is most commonly heard over areas of consolidated lung or over large peripheral cavities. In addition to alteration of the normal ('vesicular') breath sounds the stethoscope may detect additional sounds:

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Crackles Crackles (crepitations or rales) are short explosive sounds thought to represent the equalization of intraluminal pressure as collapsed small airways open during inspiration. Crackles therefore occur in disease processes causing small airway closure, whether due to airway damage (chronic bronchitis) or to increased interstitial volume (pulmonary oedema, pulmonary fibrosis). With diffuse disease the effect of gravity makes crackles more prominent in dependent parts of the lungs. In immobile patients small airways at the lung bases close, giving rise to crackles that clear once deep breaths are taken; the same also occurs postoperatively. The crackles of chronic bronchitis and emphysema are characteristically early in inspiration and are transmitted to the patient's mouth, where they can be easily heard by the unaided ear. In bronchiectasis the crackles are maximum in midinspiration, and in pulmonary fibrosis or oedema they occur during mid and late inspiration; in both circumstances the crackles are not transmitted to the mouth. Wheezes Wheezes are musical sounds reflecting airway narrowing, such that the airway oscillates between being open and closed like the reed of an oboe. In asthma, chronic bronchitis and emphysema, multiple polyphonic wheezes are heard in expiration. A localized area of narrowing due to tumour or foreign body produces a single monophonic wheeze. Wheezes caused by intraluminal secretions often disappear following coughing. The causes of wheeze are listed in Table 13.7. Narrowing of the upper airway (larynx and trachea) causes a wheeze in inspiration as well as on expiration, which may be audible at the bedside and is then described as stridor. Stridor is an important clinical sign that indicates severe, potentially critical, narrowing of the upper airway. Pleural rub A pleural rub is always pathological and is the sound produced when the two layers of pleura move over one another in a jerking motion, generating a creaking sound similar to that produced by bending stiff leather. Rubs are sometimes palpable, and the rubbing sensation is often appreciated by the patient. Pericardial sounds are discussed in Chapter 12.

SUMMARY 1 Common causes of crackles

• Crackles • Wheezes

1

• Pleural rub • Clicks.

MCQ 13.5

• • • • • • •

Bronchiectasis Pneumonia Left heart failure Acute respiratory distress syndrome Pulmonary fibrosis Chronic bronchitis and emphysema Bronchiolitis

TABLE 13.7 Causes of wheeze

Viewing the chest X-ray 1

Generalized

Localized

A normal chest X-ray is illustrated in Figure 13.11. The following points should be considered.

Asthma Chronic bronchitis Emphysema Pulmonary oedema

Tumour Extrinsic compression Foreign body Bronchial secretions

SUMMARY 2 Clinical examination: points to note • • • • • • • • •

Hands Cyanosis Respiratory rate Peripheral oedema Trachea and apex beat Jugular venous pressure Chest wall structure and movements Percussion note Breath sounds

Clicks A clicking sound with each heartbeat is occasionally heard with a small left pneumothorax.

FURTHER READING ON EXAMINATION OF THE RESPIRATORY SYSTEM Braman S S (ed). Pulmonary signs and symptoms. Clin Chest Med 1987; 8:2.

IMAGING THE THORAX THE CHEST X-RAY In respiratory medicine the chest X-ray is of fundamental importance in demonstrating anatomy and is a direct extension of the physical examination. Chest X-rays should be of good quality. Underexposure of films is a much greater problem than overexposure because it cannot be compensated for by any viewing conditions. Digital imaging systems have improved the quality of films, especially in difficult clinical situations (e.g. supine patients in ICU). Digital films can be viewed in depth and online, and may greatly change respiratory clinical practice. All available films should be studied in sequence: past films are frequently the most important in understanding the patient's clinical problems. The chest X-ray should be taken with the patient properly centred and the medial end of the clavicles equidistant from the spinous processes. The film should be taken in full inspiration, in which case the dome of the diaphragm will normally be at the level of the sixth rib anteriorly and the tenth rib posteriorly in the midclavicular line.

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Trachea The translucent tracheal air column is readily seen in the neck and superior mediastinum; it is placed centrally or slightly to the right. The tracheal air column may be narrowed by intraluminal disease (e.g. tumour), external compression (e.g. enlarged thyroid), or displaced to the right or left (e.g. upper lobe collapse or fibrosis). The paratracheal regions of the superior mediastinum are common sites of pathology (e.g. lymphadenopathy, apical pulmonary tumours). Diaphragm Downward displacement of the diaphragm indicates largevolume lungs (e.g. emphysema); upward displacement suggests small-volume lungs (e.g. pulmonary fibrosis), diaphragm dysfunction (commonly unilateral) or abdominal pathology. Both hemidiaphragms have a curved shape and a clear edge, and can be seen throughout their length. The right hemidiaphragm is 2 cm higher than the left. The level of the left hemidiaphragm, however, is influenced by the volume of gas in the bowel beneath it. The diaphragm becomes flattened by hyperinflation, best appreciated on the lateral chest X-ray. Costophrenic angle This sharp angle is obliterated and the lateral aspect of the diaphragm obscured by small pleural effusions. Chronic pleural abnormalities (e.g. from past infection) also blunt the costophrenic angle. Cardiophrenic angle The cardiophrenic angle is blunted by pleural effusion or thickening, and also obscured by pericardial fat pads. Sub diaphragmatic region Posteriorly the lung extends below the level of the diaphragm as viewed on the PA film, and pathology in this recess is easily missed; this area is best inspected on the lateral chest X-ray (see Fig. 13.13). On the left, gas in the stomach is commonly seen immediately below

SUMMARY 3 Viewing the chest X-ray Points to consider • Trachea (check the patient is not rotated). • Diaphragm • Costophrenic angle • Cardiophrenic angle • Subdiaphragmatic region • Cardiac silhouette • Behind the heart • Hilar shadows

• • • • • • • •

Horizontal (minor) fissure Vessels Lymphatics The lung fields Behind the clavicle, and lung apex Pleura Ribcage Soft tissues

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cardiac silhouette may be enlarged because of a pericardial effusion, as well as dilatation of cardiac chambers. The cardiac diameter is usually less than 50% of the transthoracic diameter, but this is a crude measure and absolute measurements are more valuable; the cardiac diameter is less than 14.5cm in females and less than 15.5cm in males on a standard size X-ray, and a change in diameter of more than 1.5cm between two X-rays is significant. Emergency chest X-rays taken in the AP plane magnify the cardiac silhouette, as do supine films. Behind the heart This is a notorious blind spot on the PA chest X-ray, particularly if the film is underpenetrated. Digital techniques have improved the imaging of this region. The retrocardiac space is well seen on the lateral chest X-ray. A retrocardiac shadow can be caused by a hiatus hernia, which may contain a fluid level.

Fig. 13.11 Normal chest X-ray Careful inspection will include: 1. Trachea; 2. Diaphragm; 3. Costophrenic angle; 4. Cardiophrenic angle; 5. Subdiaphragmatic region; 6. Cardiac silhouette; 7. Behind the heart; 8. Hilar shadows; 9. Horizontal (minor) fissure; 10. Vessels; 11. Lung fields; 12. Behind the clavicle, and lung apex; 13. Ribcage (Fig. 13.65); 14. Soft tissues (Fig. 13.65).

the diaphragm and provides some indication of the position of the diaphragm even when it is obscured by pleural or pulmonary pathology. Perforation of an abdominal viscus causes free gas below the diaphragm, as may abdominal surgery. Cardiac silhouette The mediastinum requires careful inspection to confirm that it is centrally placed and that the cardiac silhouette is of normal configuration and size (see Fig. 12.16, p. 481). The heart may be displaced by pleural effusions, collapse of a lung or lobe, extensive fibrosis or pneumothorax. The heart is displaced to the left by a depressed sternum, obvious on clinical examination and confirmed by lateral chest X-ray. Many disorders alter the configuration of the heart and mediastinum (e.g. cardiac and aortic disease, mediastinal tumour and lymphadenopathy) and the

1 Fig. 13.10 2 Fig. 13.11 624

Hilar shadows The left hilum is always higher than the right. The hilar shadows are vascular and the midpoint (the 'hilar point') is where the upper lobe veins appear to cross the basal pulmonary artery. The lateral border of the hilum is concave. Both hila are similar in size, shape and density. Adenopathy (e.g. tumour) is a common cause of hilar enlargement, with increased density and convexity of the lateral border. Volume loss in the lung (e.g. fibrotic shrinkage) distorts the hilum and moves the hilar point towards the loss of volume. Any rotation of the chest X-ray will make the hila asymmetrical. Horizontal (minor) fissure This fissure is visible in 60% of normal chest X-rays, running from the centre of the right hilum, laterally and horizontally, to meet the sixth rib in the mid-axilla. The fissure is more easily visible when there is increased pleural fluid (e.g. cardiac failure), and encysted pleural fluid, within any fissure, can mimic a mass lesion. Localized volume loss in the right lung (e.g. collapse of the right upper lobe) moves the fissure from its normal position, and the position of the fissure is therefore an important landmark when assessing the chest X-ray for possible obstructing lesions in the right bronchial tree. Vessels On the X-ray of normal lungs virtually all pulmonary shadows, apart from a few central bronchi, are vascular. Arteries can be traced back to the hilum, but this is more difficult with pulmonary veins. As expected, vessels branch asymmetrically and taper towards the periphery. In the erect posture blood flow to the base of the lungs is greater than to the upper zones, and vessels at the bases are therefore larger. Vessels in the second intercostal space are usually less than 3 mm in diameter on a standard size Xray. The right basal artery measures approximately 15mm. If vessels are enlarged, this implies that either pressure or flow is increased. Loss of vascularity (e.g. in emphysema) makes the affected area of lung abnormally transradiant. Following

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lobar collapse the remaining lobes of the lung enlarge, the vessels per unit volume of lung are reduced, and the chest X-ray shows increased transradiancy. The vascular pattern of the lung is therefore an excellent index of localized volume loss. It is not possible to see any vessels in a large bulla, cyst or pneumothorax (see Fig. 13.36). Lymphatics These are not normally visible on the chest X-ray, but when distended by fluid and surrounded by oedema (left heart failure) or infiltrated by tumour (lymphangitis carcinomatosa, see Fig. 13.64) they are seen as linear shadows. In left heart failure the distended lymphatics are seen as 1-2 cm horizontal lines extending inwards from the pleura, best seen just above the costophrenic angles (termed Kerley B lines, or septal lines). On the lateral film, septal lines are best seen immediately behind the sternum. The lung fields Pathological processes within the lung increase its density (with the exception of pulmonary embolism, emphysema and bullous disease). The abnormality may be localized (e.g. tumour mass, pneumonic consolidation) or generalized (e.g. diffuse fibrosis, pulmonary oedema). Abnormal shadowing is often characteristic of a particular condition or group of disorders, e.g. the bilateral apical shadowing with cavitation characteristic of pulmonary tuberculosis. Two particularly important radiological signs arise from increased pulmonary shadowing: the air bronchogram and the silhouette sign. • Air bronchogram. An air bronchogram (Fig. 13.12) is visible when alveoli are filled with exudate, transudate or other substance and the bronchi remain patent and filled with air. Important causes of an air bronchogram are pneumonia, cardiogenic pulmonary oedema, acute respiratory distress syndrome and alveolar cell carcinoma. • The silhouette sign. The outline of many structures on the chest X-ray is visible because of an interface between opaque tissue (e.g. heart or diaphragm) and air in the lung. If the lung adjacent to such structures also becomes opaque the 'silhouette' is lost (Fig. 13.13). Thus, collapse of the left lower lobe obscures the left or right hemidiaphragm and collapse of the lingula or right middle lobe obscures the left and right heart borders. 1

Fig. 13.12 Air bronchogram The chest X-ray shows bilateral air-space consolidation in a patient with pneumocystis pneumonia and the acute respiratory distress syndrome. Note that the major airways (arrowed) are seen as an 'air bronchogram' against the background pulmonary shadowing. 0

Behind the clavicle, and the lung apex The lung apex is an important site for pulmonary tumours and tuberculosis. If necessary, an apical view should be taken. Apical lesions are clearly demonstrated by CT scans. Pleura Pleural effusions usually obliterate the costophrenic angle, but loculated effusions and pleural thickening (e.g. mesothelioma, Fig. 13.74) are easily missed unless care is taken to look all around the inner aspect of the thoracic cage. In some cases the pleura may calcify (asbestos plaques, tuberculosis, past empyema). With pneumothorax the line of the visceral pleura is seen.

Fig. 13.13 Silhouette sign On the normal chest X-ray (Fig. 13.11) there is a clear silhouette of the structures making up the left mediastinum. Collapse of the left upper lobe (including the lingular division) causes an opacity adjacent to the mediastinum and the silhouette is lost. Note the volume loss of the left lung and shift to the left of the trachea.

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Ribcage The ribcage should be symmetrical. All bones should be inspected, looking particularly for fractures and destructive processes (Fig. 13.65). Destruction of ribs in the axillary line is easily missed unless care is taken to follow the curve of each bone - the 'skyline' - down the outer aspect of both sides of the thoracic cage. Soft tissues Inspection of the soft tissues not uncommonly provides valuable information which is helpful to the interpretation of lung field abnormalities. Thus, a mastectomy may be noted in a patient with a pleural effusion.

The lateral chest X-ray A lateral chest X-ray is necessary in many patients with cardiorespiratory problems in whom a comprehensive assessment of thoracic structure is required. On the lateral film some areas are better seen than on the PA view, and three-dimensional localization of pathology is possible (Fig. 13.14). Retrosternal area This area is transradiant and should be of the same density as the retrocardiac area. With hyperinflation (e.g. emphysema) there is an increase in the size and transradiancy of the retrosternal space. Conversely, there is increased retrosternal shadowing with anterior mediastinal masses (see Fig. 13.70).

SUMMARY 4 Viewing the lateral chest X-ray Points to consider • • • •

Retrosternal area Retrocardiac area Vertebral bodies Diaphragm

Greater (oblique) fissure Horizontal fissure Trachea Cardiac silhouette

Retrocardiac area Careful inspection of this area, which should be transradiant, is useful because much of the retrocardiac space is not easily visible on the PA chest X-ray. Vertebral bodies Superimposed structures make it difficult to visualize the upper thoracic vertebral bodies, but they are seen progressively more clearly towards the lower thoracic spine. If this is not the case this suggests that there is pathology (e.g. consolidation or tumour) overlying the spine (see Fig. 13.72). Diaphragm Both hemidiaphragms should be visible. The gastric gas bubble is beneath the left hemidiaphragm (see Fig. 13.72). Greater (oblique) fissure The greater fissure passes from where the anterior quarter of the diaphragm meets the posterior three-quarters, through the hilum, and up to the level of the fourth thoracic vertebral body. Displacement of the fissure is an important sign of volume changes within the lobes of the lungs. Horizontal fissure The horizontal fissure between the right upper and middle lobes passes anteriorly and horizontally from the level of the hilum. Its position is altered by volume loss, particularly of the right upper and middle lobes. Trachea The tracheal air column is frequently better visualized on the lateral chest X-ray than on the PA film. Cardiac silhouette Intracardiac, aortic and pericardial calcification is often better seen on the lateral than the PA chest X-ray.

Supplementary radiological examination of the chest

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FIG. 13.14 Lateral chest X-ray 1. Retrosternal area; 2. Retrocardiac area; 3. Vertebral bodies; 4. Diaphragm; 5. Greater (oblique) fissure; 6. Trachea; 7. Cardiac silhouette.

Films taken in expiration are useful for demonstrating small pneumothoraces not easily visible on the PA film at full inspiration and gas trapping in bullous disease or severe airways obstruction. Screening of diaphragm movement can detect paralysis (p. 718). For the differential diagnosis of pleural effusion from pleural thickening it can be useful to request a chest X-ray taken in the lateral decubitus position, in which free fluid will run along the lateral wall of the thorax.

CT scanning Many patients with cardiorespiratory disorders can be satisfactorily investigated with simple radiological techniques. However, CT scans of the thorax can provide remarkably detailed information of thoracic anatomy (Figs 13.15, 13.28, 13.35, 13.38, 13.53, 13.59, 13.70, 13.75). CT scanning is particularly useful for imaging the mediastinum and demonstrating pleural and chest wall disease. For many patients with bronchogenic carcinoma CT scanning is necessary to stage the disease adequately, particularly when surgery is being considered. Scanning is also valuable in the diagnosis and assessment of emphysema, bullous disease, bronchiectasis, lymphangitis carcinomatosis, alveolar proteinosis, interstitial lung disease, and pulmonary fibrosis. Spiral CT is often useful for the diagnosis of pulmonary emboli. Magnetic resonance scans are particularly good for

demonstrating lesions of bone lymphadenopathy.

and

for

detecting

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Ultrasound Ultrasound is not generally a suitable technique for visualizing the lung but it is a good method for imaging pleural disease, both pleural fluid and pleural thickening, subdiaphragmatic regions (particularly when investigating a subphrenic abscess), and for assessing diaphragm movement.

Positron emission tomography (PET) The key role of PET is in differentiating malignant from benign lesions, at presentation or following therapy with surgery or radiotherapy. PET can avoid alternative difficult and invasive procedures. Tumours are metabolically active and will take up an appropriate tracer, the most commonly used being fluorodeoxyglucose (FDG). The tracer emits positrons, and therefore tumour issue can be imaged by the PET technique. Clinical studies of PET in the diagnosis of pulmonary lesions, including the common problem of evaluating solitary pulmonary nodules, demonstrate near 100% sensitivity and high specificity for the detection of malignancy. Occasional false positive scans are because non-malignant processes can have high metabolic activity (e.g. tuberculous granulomas). Some tumour types (carcinoid, bronchoalveolar cell) can have a relatively low metabolic activity and are not always identified by PET. PET may not diagnose very small nodules. Overall, PET is probably superior to CT in staging nodal disease. It is useful for detecting distant metastases and identifying that some abnormalities demonstrated by CT are benign rather than malignant. It is a good technique for the follow-up of patients after surgery and radiotherapy, both to detect residual disease and to diagnose tumour recurrence early.

FURTHER READING ON IMAGING THE THORAX Armstrong P A, Wilson A G, Dee P, Hansell D M (eds) 2000 Imaging of diseases of the chest, 3rd edn. London: Mosby.

BRONCHOSCOPY AND LUNG BIOPSY Fibreoptic bronchoscopy FIG. 13.15 CT scans of the thorax [A] Scan demonstrating the normal pulmonary vascular pattern. B CT scan in arantitrypsin deficiency. Bullous air spaces occupy most of the left lung and much of the right posteriorly: the peripheral vascular markings are lost and the mediastinum is shifted to the right.

Fibreoptic bronchoscopy is an invaluable technique for diagnosis, assessment and therapy in respiratory medicine. For most patients the procedure is undertaken using local anaesthesia and on a day-case basis. As skills in the technique have increased, so the risks have become small and the indications for fibreoptic bronchoscopy have widened

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TABLE 13.8 Major indications for fibreoptic bronchoscopy • Investigation of symptoms, signs or radiological appearances suggesting pulmonary tumour (e.g. haemoptysis, hoarseness, mass, persistent consolidation, or volume loss on chest X-ray) • Diagnosis of pneumonias, tuberculosis and pulmonary shadowing in the immunocompromised host • Removal of mucus, pus and aspirated material from the bronchial tree (frequently on the intensive care unit) • Diagnosis and assessment of activity in diffuse interstitial lung disease (e.g. sarcoidosis)

(Table 13.8). Fibreoptic bronchoscopy is of great value in many patients with seemingly inexplicable respiratory problems. The development of video-assisted bronchoscopy has improved the views obtained, and the hardcopy colour images help in management (Fig. 13.16). Bronchogenic carcinoma Bronchogenic carcinoma is commonly visible as an obvious endobronchial tumour mass (Fig. 13.16B), in which case bronchial biopsy will confirm the diagnosis in 90% of cases. The flushing of saline over the surface of tumours and the subsequent aspiration of this fluid, or the brushing of the surface of tumours, provides cells for cytological examination, and these investigations have a diagnostic yield of 60-80% for visible endobronchial disease. In assessing the extent of malignant disease fibreoptic bronchoscopy is of great importance, allowing visualization of the proximal spread of the tumour, which is one of the factors that determines the feasibility and likely extent of any surgical resection. In patients with extrabronchial tumours situated adjacent to a large airway, a needle can be passed through the bronchial wall to acquire a cytological specimen. In selected patients endobronchial tumour can be partially destroyed by a laser beam, transmitted through a fibre passed down the biopsy channel of a fibreoptic bronchoscope. In patients with large central tumours causing breathlessness or haemoptysis that has not responded to radiotherapy, such palliative therapy can be of substantial benefit. In appropriate patients bronchoscopy can be used to introduce stents for the dilation of narrowed airways (usually caused by extrinsic compression by tumour) or treatment with local intrabronchial radiotherapy. Haemoptysis All patients with haemoptysis who are at risk of carcinoma of the bronchus should be bronchoscoped; approximately 10% of patients with a chest X-ray that does not obviously

1

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Fig. 13.12

2

Fig. 13.13-13.17

B FIG. 13.16 Bronchoscopy

1

A View of right and left main bronchi at fibreoptic bronchoscopy; the appearance is normal. B View of right main bronchus, occluded by bronchogenic carcinoma. ©

suggest tumour will nevertheless have malignancy. When bleeding is not due to tumour (for example in bronchiectasis) bronchoscopy is useful to determine the site of bleeding, which is important should bleeding become a serious problem and bronchial arterial embolization or thoracic surgery be considered. Interstitial lung disease Sarcoidosis is the most common cause of interstitial lung disease and in the majority of cases the diagnosis is easily confirmed by bronchoscopy. Overall, a bronchoscopic

antibiotics, bacterial culture is frequently negative and staining techniques give the most valuable information. Similarly, patients with pulmonary tuberculosis do not always have sputum, and in these cases bronchoscopy and lavage of the affected lobes is an efficient technique for confirming the diagnosis. In miliary tuberculosis BAL is commonly positive, and TBB will confirm the diagnosis in virtually all cases. Bronchoscopy with BAL and TBB is of great value in the investigation of pulmonary shadowing in the immunocompromised host (p. 638). The importance of these techniques has increased since the advent of AIDS (p. 638).

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Research indications for bronchoscopy Much important research data can be acquired through bronchoscopy. Bronchial biopsy and lavage can yield information on inflammatory changes in the airway and lung parenchyma and its response to treatment.

Bronchoscopy on the intensive care unit FIG. 13.17 Bronchoscopy Using the flexible fibreoptic bronchoscope, biopsy forceps can be passed into peripheral bronchi and samples of lung obtained by transbronchial biopsy.

transbronchial biopsy has a positive yield of 90% (p. 683). With the technique of transbronchial biopsy (TBB) a small fragment of lung tissue is obtained when the forceps removes the bronchial wall of the carina of two small peripheral bronchi (Fig. 13.17). In pulmonary fibrosis, including cryptogenic fibrosing alveolitis (p. 695), TBB is less helpful. The small samples obtained are often not representative, and if histological confirmation of the diagnosis is required, thoracoscopic or open lung biopsy is preferable. TBB can be diagnostic in the uncommon conditions of alveolar proteinosis, histiocytosis X and pulmonary disease due to inorganic dusts. Bronchoalveolar lavage At fibreoptic bronchoscopy saline is instilled into the periphery of the lung, with the tip of the bronchoscope wedged in the segmental or subsegmental bronchus, and the fluid is subsequently gently aspirated. The lavage fluid contains thousands of cells (macrophages, lymphocytes, neutrophils and eosinophils), the numbers of which, and their differential count, give information on the nature of the interstitial lung disease. In occasional circumstances bronchoalveolar lavage (BAL) can be diagnostic, as in alveolar proteinosis, pulmonary haemosiderosis and histiocytosis X. Pulmonary infections Some patients with pneumonia fail to show an adequate response to chemotherapy, yet do not have sputum for microbiological analysis. In such cases BAL provides helpful information, although in patients already receiving

Many patients on the intensive care unit, as well as other ill patients, often in the immediate postoperative period, develop sputum retention, basal atelectasis or pulmonary collapse. Bronchoscopy and BAL are effective at removing impacted secretions. BAL is frequently superior to conventional catheter suction in the diagnosis of intensive care unit pneumonias. Bronchoscopy is also valuable for the inspection of the bronchial tree, particularly the trachea, for catheter or endotracheal tube trauma, or stenosis.

Rigid bronchoscopy As a diagnostic technique, rigid bronchoscopy, which requires a general anaesthetic, has been largely superseded by fibreoptic bronchoscopy, but remains of great value in the following situations: • In the bronchoscopy of smaller children; • In patients who have a foreign body impacted in the bronchial tree; • For the biopsy of vascular tumours, particularly adenomas; • For obtaining a large biopsy sample to confirm submucosal malignancy not demonstrated by the small superficial biopsies that can be taken using the fibreoptic bronchoscope.

Transthoracic needle biopsy Several techniques are available to biopsy the lung and diagnose pathological processes, most commonly tumours, within it. The usual technique is fine needle aspiration or biopsy under radiological control. If it is performed using local anaesthesia, patients seldom experience pain and major complications are rare. A small pneumothorax is common (30%), particularly in patients with emphysema,

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and a few patients (<5%) will require tube drainage. The overall mortality is very low and the technique is now used extensively in the investigation of pulmonary disease. In practice, the most common indication is to provide confirmation of malignancy for tumours that are not visible at fibreoptic bronchoscopy. With experience and expert laboratory support a yield of 90% or more is obtained in malignant disease. A further important use of the technique is in the investigation of pulmonary infections not diagnosed by more conventional techniques, particularly fungal, protozoal and mycobacterial infections in the immunocompromised host.

Mediastinoscopy and mediastinotomy These techniques are mainly used to diagnose and stage bronchogenic carcinoma, but occasionally are required to confirm other malignancies (e.g. lymphoma) or to diagnose the causes of adenopathy (e.g. sarcoidosis or tuberculosis). At mediastinoscopy an incision is made above the suprasternal notch, the tissues anterior to the trachea are dissected and the mediastinoscope is inserted. Hilar, subcarinal and paratracheal nodes can be inspected, biopsied or removed. The involvement of mediastinal nodes in bronchogenic carcinoma is common (40% of all cases) and a positive diagnosis is achieved in sarcoidosis in more than 80% of cases. Mediastinotomy is occasionally required to evaluate areas of the mediastinum not accessible at mediastinoscopy, particularly the subaortic fossa on the left side, and most commonly the surgeon gains access through the second left costal cartilage. The development of CT scanning has reduced the need for mediastinoscopy and mediastinotomy. In carcinoma of the bronchus a CT scan which demonstrates a normal mediastinum obviates the need for surgical evaluation prior to thoracotomy. However, if the CT scan demonstrates adenopathy, such an evaluation may still be required to confirm that the nodes are involved by tumour and are not enlarged due to reactive hyperplasia.

RECENT ADVANCES IN THORACOSCOPY WITH VIDEOSCOPIC IMAGING Thoracoscopy allows direct inspection of the pleura overlying the lung and lining the chest wall (Fig. 13.18). Videoscopic imaging and the insertion of surgical instruments through additional small incisions greatly extends the thoracoscopic technique and allows 'keyhole' surgery in the thorax. Patients are treated under general anaesthesia and with a double-lumen endotracheal tube to allow controlled deflation of the appropriate lung. Common indications for this type of surgery include pleural biopsy (most often in the diagnosis of pleural effusion), lung biopsy, treatment of pneumothorax, fashioning of a pericardial window, sympathectomy, and biopsy of mediastinal masses. The indications continue to expand and the technique can be used for staging of lung cancer, lobectomy, management of bullous disease and volume reduction surgery for chronic obstructive pulmonary disease. Some surgeons have performed pneumonectomy and oesophagectomy via keyhole surgery. The advantage of minimally invasive thoracic surgery is reduced pain postoperatively. It remains to be clearly established whether time in hospital, time off work, morbidity and mortality are reduced. Disadvantages of the technique include longer operation times, high cost of equipment, and the need for specialist training.

Thoracoscopy The development of video-assisted thoracoscopy has resulted in a great increase in 'keyhole' thoracic surgery. FIG. 13.18 Thoracoscopy

Open lung biopsy Open lung biopsy is most commonly undertaken for diffuse interstitial lung disease, atypical tumours and, occasionally, serious pulmonary infections. A limited submammary thoracotomy allows biopsy of the anterior segments of all lobes, as well as inspection of the pleura and 1

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Fig. 13.18

2

MCQ13.6

1

View of lung (left) and parietal pleura (right) at thoracoscopy; there are multiple metastatic tumour deposits on the pleura.

mediastinum. Complications (approximately 5%) include infection and chronic pneumothorax, and there is a small mortality (less than 4%), reflecting for the most part the serious nature of the underlying illness in many of the patients. For peripheral lesions in the lung, or diffuse lung abnormalities, thoracoscopic minimally invasive techniques allow access not just to the pleura but to the underlying lung.

RESPIRATORY INFECTIONS UPPER RESPIRATORY TRACT INFECTIONS Most upper respiratory tract infections (URTIs) are viral and the majority of these are the results of infection with rhinoviruses of the picornavirus family. However, adenoviruses, coronaviruses, coxsackie viruses, echoviruses, influenza viruses, parainfluenza viruses and the respiratory syncytial virus (RSV) can all cause upper respiratory tract infections. URTIs represent the most common of all illnesses and are responsible for approximately half of all time lost from work. In addition to URTI the influenza viruses, parainfluenza viruses 1 and 2, adenoviruses and RSV can cause acute infection of the larynx, trachea and major bronchi, and are causes of croup. URTIs are most common in the late winter months and early spring. The most frequent manifestation of these viral infections is the common cold (acute coryza), which may be complicated by secondary bacterial infection and subsequently by sinusitis, otitis media, obstruction to the eustachian tubes and infection of the lower respiratory tract. Viral laryngotracheobronchitis, particularly in children, may be complicated by severe laryngeal oedema and life-threatening croup. Croup is also a feature of acute epiglottitis in children, and occasionally in adults, and is most commonly due to Haemophilus influenzae type B infection. The swelling of the epiglottis and surrounding soft tissues can rapidly produce respiratory distress. Unlike in laryngitis, the voice is not hoarse. The epiglottis is hugely swollen and attempts to examine the throat can precipitate total upper airway obstruction. In most patients with URTI the illness is self-limiting and symptoms subside after a few days. Antibiotics are not generally required unless there is acute epiglottitis due to H. influenzae, in which case intravenous chloramphenicol, or a cephalosporin such as cefotaxime or ceftriaxone, is indicated. However, in patients in whom secondary bacterial infection is both likely and potentially serious (e.g. in chronic bronchitis and emphysema) immediate treatment with antibiotics is justified. Oral amoxycillin, co-amoxiclav or tetracycline in standard doses are suitable. The development of stridor requires careful observation in hospital, with anaesthetic support for possible emergency intubation. Patients with stridor, particularly children with croup, adopt the posture that facilitates adequate ventilation and they should be allowed to do so. Inhalation of warm, humidified air is helpful. Given early, high-dose corticosteroids reduce the need for intubation, and in those who are intubated they shorten the time for which a tube is necessary. Nebulized corticsteroid therapy is helpful.

Sinusitis Sinusitis (infection of the paranasal sinuses) is a common complication of URTI and the bacteria most frequently

involved are H. influenzae and Streptococcus pneumoniae. Amoxycillin, trimethoprim or an oral cephalosporin in standard doses may be given. Facial pain and tenderness, headache, nasal discharge and a postnasal drip are the usual features. Radiology may demonstrate fluid levels within the maxillary sinuses or show sinus mucosal thickening. Sinusitis may complicate the nasal obstruction of allergic rhinitis, in which case topical steroid therapy is useful, in addition to oral antibiotics. Topical steroid can be administered by nasal spray (e.g. beclometasone or fluticasone) but if the nose is obstructed steroid nasal drops, incorporating an antibiotic, are usually more effective (e.g. betamethasone plus neomycin). Nasal drops are best instilled with the head held forward (between the knees) so that the fluid is retained within the nostril and the drugs able to be absorbed into the oedematous nasal mucosa. Persistent or recurrent sinusitis may require surgical drainage. Sinusitis is a common feature of patients with bronchiectasis (occasionally, both are manifestations of the immotile cilia syndromes) and it is equally important to control infection at both sites.

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LOWER RESPIRATORY TRACT INFECTIONS Acute bronchitis Acute bronchitis is common in smokers and in patients with asthma, chronic bronchitis and emphysema. However, it also occurs in otherwise healthy individuals, usually due to viral infections. In both groups, when bacterial infection occurs, the bacteria most often incriminated are Strep, pneumoniae or H. influenzae. These infections cause an acute inflammation of the trachea and major airways, and as a consequence of this there is chest pain, commonly experienced as a raw feeling maximal on deep inspiration, as well as chest tightness. The patient may wheeze. In patients with pre-existing chronic airflow limitation the development of acute bronchitis can cause severe breathlessness. Acute bronchitis causes an irritating, persistent dry cough, although after 1 or 2 days patients produce small amounts of mucoid thick sputum which subsequently becomes more plentiful and purulent. Appropriate antibiotic therapy is amoxycillin, erythromycin or tetracycline. In patients with chronic airflow limitation, aggressive therapy with bronchodilators is important, as acute bronchitis can precipitate a worsening of respiratory failure.

PNEUMONIA 2 Pneumonia remains an important clinical problem, causing many more deaths than any other infectious disease in the UK, both in the community and in hospitals. In recent years the aetiology of the pneumonias has changed with, for example, an increased incidence of opportunistic pneumonias in the immunocompromised host, particularly patients with HIV infection.

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TABLE

13.9 Differential diagnosis of a presumed pneumonia

Bronchial obstruction with distal collapse/consolidation Pulmonary infarction Empyema Pulmonary vasculitis or haemorrhage Alveolar cell carcinoma Leukaemia, lymphoma, Kaposi's sarcoma and other pulmonary tumours Pulmonary eosinophilia Allergic alveolitis Pulmonary drug reaction Radiation injury

TABLE 13.10 Important causes of community-acquired pneumonia Streptococcus pneumoniae Mycoplasma pneumoniae Haemophilus influenzae Staphylococcus aureus

Legionel/a pneumophila Viruses Mycobacterium tuberculosis

Although pneumonia is the most common cause of fever and pulmonary shadowing, other conditions must be considered in the differential diagnosis (Table 13.9). Having arrived at a clinical diagnosis of pneumonia, the next decision is what therapy to institute. For the adult patient, the clinical background of the pneumonia serves to reduce the range of possible pathogens. The most useful classification of the pneumonias is therefore a clinical one.

Community-acquired pneumonia Community-acquired pneumonia is commonly due to a limited and predictable group of pathogens (Table 13.10). Patients with pneumonia usually have fever, cough, breathlessness, abnormal chest signs and X-ray shadowing. Specific pneumonias may have additional features and Mycobacterium tuberculosis remains an important pathogen to consider (p. 645). Pneumococcal pneumonia Pneumococcal pneumonia is more common in the winter months and upper respiratory tract viral infections are a predisposing factor. Fever is often high and there may be rigors. Pleurisy is common and the cough, which is initially dry and painful, subsequently becomes productive of rusty sputum. Altered blood from the congested lung tissue gives

1

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Fig. 13.19

SUMMARY 5 Classification of pneumonia • • • • • •

Community-acquired pneumonia Hospital-acquired (nosocomial) pneumonia Recurrent pneumonia Aspiration pneumonia Pneumonia in the immunocompromised host Unusual pneumonias

SUMMARY 6 Typical features of pneumococcal pneumonia • • • • • •

More common in winter Rapid onset High fever/rigors Dry cough initially Pleurisy common Labial herpes common

the sputum its characteristic colour. Labial herpes simplex is common (30% of cases). In some cases the onset of symptoms in pneumococcal pneumonia can be very rapid and patients may be critically ill within a few hours. In the usual case clinical examination demonstrates crackles more than classic signs of consolidation, and a pleural rub is common. The chest X-ray shows hazy shadowing, often with an air bronchogram, in any lobe, although lower lobes are the most frequently involved. In the majority of cases the consolidation does not involve the whole lobe. 1 Mildly or moderately ill patients can be managed adequately at home and are satisfactorily treated with oral amoxycillin or erythromycin. Severely ill patients should be transferred to hospital for the adequate treatment of pain, dehydration and hypoxaemia. A Gram stain of the sputum will show typical Gram-positive diplococci, and blood cultures will be positive in 25-40% of untreated cases. If the specific diagnosis is established, benzylpenicillin is the treatment of choice, but patients also do well with amoxycillin. In the UK about 10% of pneumococci are partially or fully resistant to penicillin. Currently, penicillin or amoxycillin are adequate for mild to moderate infections, unless penicillin resistance is detected, in which case cefotaxime or ceftriaxone is required, especially in the more severely ill patient who requires hospitalization. Recovery from pneumococcal pneumonia is usually rapid, although the X-ray may take several weeks to return to normal, as is the case with most pneumonias. In patients who are more severely ill and who are bacteraemic, mortality may be as high as 25%. Of all pneumonias, pleural effusion is most common in association with pneumococcal infection. Empyema complicating the pleural effusion is now relatively rare and occurs in 3% of cases with positive blood cultures. In such blood culture-positive patients pneumococcal pneumonia can be complicated by pericarditis, endocarditis, septic arthritis, peritonitis, cellulitis and, on rare occasions, meningitis.

Haemophilus influenzae pneumonia It is unusual for H. influenzae to cause pneumonia in previously fit individuals. However, it is probably the most common cause of infection in patients with pre-existing lung disease, particularly in those with chronic bronchitis and emphysema. It is the organism most often responsible for the exacerbations that occur in chronic bronchitis, sometimes complicating an initial viral infection. The chest X-ray distinguishes haemophilus bronchopneumonia from simple infective bronchitis by showing shadowing, usually as nodules 0.5-3.0 cm in diameter at both bases, and on examination there may be bronchial breathing. The same picture of bronchopneumonia is sometimes seen with staphylococcal and pneumococcal infection. Bronchopneumonia is very common. Patients are often wheezy and progressively more breathless. There is usually fever, but in elderly and debilitated patients the temperature can be normal. Cough and purulent sputum are prominent features. As a consequence of diffuse airway inflammation and intraluminal sputum, patients with chronic bronchitis are frequently precipitated into respiratory failure and cor pulmonale. The first-line treatment of H. influenzae bronchopneumonia is intravenous cefuroxime unless the isolate is known to be sensitive to amoxycillin. Staphylococcal pneumonia Staphylococcal infection causes more necrosis than other organisms responsible for pneumonia, and there is a high incidence of abscess formation. In the community staphylococcal pneumonia is not common (about 1% of cases), but it is an important and serious complication of influenza and is therefore more common during influenza epidemics and during the winter months. Staphylococcal lobar pneumonia can be fulminant and rapidly fatal. In most cases the clinical picture is similar to that of pneumococcal pneumonia, but haemoptysis is more common. Cavitation is unusual in community-acquired pneumonias, with the exception of staphylococcal or particularly virulent serotype 3 pneumococcal infections. The chest X-ray typically shows bilateral consolidation, usually basal, with abscesses that are thin-walled and cyst-like. Staphylococcal lung abscesses may rupture into the pleural cavity, resulting in pneumothorax or pyopneumothorax. In the community, the development of pneumonia as a complication of influenza should be treated with flucloxacillin in addition to amoxycillin. Following admission to hospital, a Gram stain of the sputum is helpful in confirming the diagnosis and blood cultures are frequently positive. With a definite diagnosis treatment should be with intravenous flucloxacillin (l-2gqds) and fusidic acid. Although the majority of patients make a good recovery from staphylococcal pneumonia, the combination of influenza A infection and staphylococcal pneumonia still carries an appreciable mortality. Important complications include the haematogenous spread of infection to brain, bone and other organs, and occasionally patients can develop acute bacterial endocarditis.

Legionella pneumonia Legionella pneumonia was first recognized in 1976 after an outbreak of pneumonia with a high mortality at a Legionnaires' conference in Philadelphia. The pathogen is now known as Legionella pneumophila, a small Gramnegative coccobacillary organism. Infection is acquired from contaminated water, usually in air-conditioning systems and showers in hotels and hospitals, and transmission does not occur from person to person. Most cases have been in middle-aged or elderly males and have occurred in the summer months. Legionella is a cause of opportunistic chest infection in immunocompromised patients. Clinically, legionella pneumonia resembles viral or mycoplasma infection. There is a cough but little sputum, which is mucoid, not purulent. Patients are frequently severely ill, with high fever, rigors, confusion, myalgia, abdominal pain, vomiting and diarrhoea. Hyponatraemia, hypoalbuminaemia and haematuria (50% of cases) are common. The white cell count may be normal or modestly elevated, but is seldom above 15000 x 106/L. Gram stain of the mucoid sputum reveals no organisms. The chest X-ray most commonly shows patchy shadowing, which can be bilateral and which progresses to lobar consolidation. The diagnosis is usually retrospective and based on a greater than fourfold increase in the indirect fluorescent antibody titre. Legionella antigen can be detected in the urine, and this has proved to be a more useful test in the acute setting. The organism can be isolated from lung tissue, pleural fluid and blood. Treatment is with erythromycin (1 g 6-hourly) for a period of 3 weeks or clarithromycin (SOOmgbd). If the diagnosis is strongly suspected, or confirmed, and particularly in patients who fail to respond, or who are severely ill, rifampicin should be added. Ciprofloxacin may also be effective. The overall mortality is 15%, some patients dying despite appropriate antibiotic therapy.

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Viral and viral-like pneumonia Viral and viral-like pneumonias (Table 13.11) are characterized by fever, systemic symptoms (e.g. myalgia, headache) and a normal or near-normal white cell count. Respiratory syncytial virus infection is important in children. Influenza and measles are frequently complicated by serious bacterial infection, particularly staphylococcal. Cytomegalovirus is a cause of pneumonia in the immuno-

TABLE 13.11 Organisms causing viral and viral-like pneumonias Mycoplasma pneumonias Respiratory syncytial virus Influenza Measles Cytomegalovirus Adenoviruses

Parainfluenza virus Rhinovirus Varicella (chickenpox) Coxie/la bumetii (Q fever) Chlamydial pneumonias (psittacosis, ornithosis)

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compromised host (p. 638). Of the remaining causes, Mycoplasma pneumoniae, Chlamydia psittaci and Coxiella burnetii are the most important. Mycoplasma pneumonia M. pneumoniae is the most important agent causing the socalled 'atypical' pneumonias. In the past, this organism was the cause of major outbreaks of pneumonias in the armed forces; many cases still occur in clusters, and epidemics typically occur every 3 or 4 years. Infection is caused by an organism of the mycoplasma group, the smallest known free-living organism. Most patients are aged between 15 and 30 years. After an incubation period of between 1 and 3 weeks the patient develops symptoms suggestive of viral pneumonia, with systemic upset, arthralgia and myalgia being particularly common. Typically, the white cell count is not raised. The appearances on chest X-ray are very variable, and although segmental and subsegmental shadows are most common, a lobar pattern can also be seen. In mycoplasma pneumonia cold agglutinins are present in approximately 50% of cases and serological investigations demonstrate antibodies to mycoplasma in most instances. Mycoplasma titres may be raised for several years following infection. The most effective therapy for mycoplasma infection is erythromycin, tetracycline or doxycycline. Complications can include a haemolytic anaemia and renal failure, owing to the presence of cold agglutinins, as well as meningism, central nervous system involvement and myocarditis. For most patients the prognosis is excellent. Psittacosis and ornithosis Chlamydia psittaci infection is transmitted from parrots to humans (psittacosis) or from other birds to humans (ornithosis). The organism (intermediate between a virus and a rickettsial organism and an obligate intracellular bacterium) is in the dust derived from excreta and feathers. The birds do not always appear to be ill. There is usually a history of close contact with birds (e.g. pigeon racers). The ensuing illness is rather like influenza. There is a cough, mucoid sputum, and sometimes haemoptysis. The chest X-ray shows patchy consolidation. A complicating bacterial pneumonia is common. Diagnosis is best made by a rising titre for chlamydia antibodies, and effective treatment is tetracycline or doxycycline. Erythromycin may be used if these drugs are contraindicated. Chlamydia pneumoniae causes a pneumonia, usually in young adults within the community, similar to mycoplasma pneumonia. Diagnosis is serological and therapy is the same as for psittacosis.

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Rickettsial pneumonia (Q fever) The rickettsial organism (Coxiella burnetii) is transmitted from animals (most commonly cattle and sheep) to humans by dust inhalation. Slaughterhouse workers are most often infected. There is an abrupt onset of a viral-like illness with headache and meningism. Respiratory symptoms are less prominent. The chest X-ray shows patchy consolidation.

Diagnosis is confirmed by a rising antibody titre. A prolonged course of tetracycline (or erythromycin, combined with rifampicin in severe cases) is effective, as is chloramphenicol. Rickettsia can cause endocarditis (p. 574). Treatment of community acquired pneumonia Because of the likely pathogens, patients respond well to a macrolide antibiotic (e.g. erythromycin or clarithromycin) plus, if systemically unwell, amoxycillin.

Hospital-acquired (nosocomial) pneumonia Up to 5% of patients admitted to hospital for other causes subsequently develop a pneumonia; the mechanisms of infection are depicted in Figure 13.19. Particularly important predisposing factors are cigarette smoking, chronic lung disease, advanced age, obesity, the effects of anaesthesia and surgery, and prior use of broad-spectrum antibiotics. The causative organisms for hospital-acquired pneumonias are different from those responsible for communityacquired pneumonia and, in particular, Gram-negative organisms are responsible for 50% of cases. Anaerobic infections are also important (Table 13.12). The prior use of broad-spectrum antibiotics and the consequent colonization of the oropharynx with Gramnegative bacilli reduces the value of sputum culture and makes it difficult to find the cause of hospital-acquired pneumonias. The management of these pneumonias involves close collaboration between clinical staff and microbiologists. Gram stain of the sputum may be more useful than culture. Blood cultures will be positive in up to 25% of cases. For potentially serious pneumonias clinical management is helped by a precise diagnosis, and bron-

FIG. 13.19 Factors predisposing to hospital-acquired pneumonia

TABLE 13.12 Organisms responsible for hospital-acquired pneumonia Organism

% of cases

Gram-negative bacteria (especially Kiebsiel/a spp. and Pseudomonas spp.) Staphylococcus aureus Anaerobes Streptococcus pneumoniae Others (legionella, fungi etc.)

50 15 9 6 20

TABLE 13.13 Important causes of recurrent pneumonia Diffuse bronchopulmonary disease Bronchiectasis Cystic fibrosis Chronic bronchitis, emphysema and chronic asthma

Immotile cilia syndrome Immune deficiency states HIV infection Hypogammaglobulinaemia Myeloma

TABLE 13,14 Factors predisposing to aspiration pneumonia Altered consciousness Drug overdose Anaesthesia Epilepsy Cerebrovascular accident Alcoholism Dysphagia and oesophageal disease Stricture Achalasia Oesophageal pouch Fistula Hiatus hernia Reflux

13

Neurological disorders Pseudobulbar palsy Motor neuron disease etc. Nasogastric tubes Severe dental and upper airways sepsis Terminal illness

Local bronchial obstruction Tumour (benign or malignant) Adenopathy Foreign body

Local bronchopulmonary disease Bronchiectasis Congenital abnormalities (sequestration) Recurrent aspiration pneumonia

choscopy can yield useful information. The wide range of potential pathogens demands the use of broad-spectrum antibiotics, including good Gram-negative cover, in the initial therapy of hospital-acquired pneumonia. Mild to moderately ill patients can be treated with intravenous cefuroxime, with added metronidazole if aspiration is likely, with augmentin as an alternative. More severely ill cases require intravenous piperacillin-tazobactam plus gentamicin, or ceftazidime and amoxycillin. In the ICU appropriate treatment regimens would be: augmentin and clarithromycin ± rifampicin; cefuroxime (or cefotaxime, or ceftriaxone) and clarithromycin ± rifampicin; or a fluoroquinolone and gram-positive cover.

Recurrent pneumonia Prior to making a diagnosis of recurrent pneumonia, the possibility of a non-infective cause of recurrent pulmonary problems should be considered. Alternative diagnoses will include pulmonary infarction, pulmonary eosinophilia (including bronchopulmonary aspergillosis) and asthma. Recurrent pneumonia is unusual without a predisposing factor (Table 13.13). Any cause of obstruction to a bronchus can result in recurrent or persistent pneumonia, but malignant tumours are most important (p. 700). In elderly or debilitated patients, or those with impaired cough reflex or vocal cord

function, repeated episodes of pneumonia are commonly caused by aspiration of gastric contents (see below).

Aspiration pneumonia Many patients with aspiration pneumonia have dental sepsis, a predisposition to aspiration, or both (Table 13.14). Infection is usually with anaerobic organisms derived from the upper respiratory tract. Aspiration pneumonia may be acute, extensive and progressive, or it may run a more subacute course and progress to lung abscess formation. When cavitating anaerobic pneumonias communicate with the bronchial tree the sputum is both copious and foul-smelling. The site of the pneumonia or lung abscess will depend on the position of the patient at the time of aspiration. Aspirated material enters the right lung more easily than the left, and will enter the lower lobes when the subject is standing, and the apical segment of the lower lobes or the posterior segment of the upper lobes when supine. An important cause of anaerobic pneumonias and lung abscess is bronchial obstruction (e.g. with bronchogenic carcinoma), and if the diagnosis of aspiration is in doubt bronchoscopy is indicated. Radiological studies of swallowing will frequently be rewarding. Anaerobic infection causes considerable tissue destruction, with abscess formation, and empyema and metastatic abscesses can also occur. Prompt treatment avoids such problems. Most upper respirating tract anaerobes are sensitive to penicillin. Early aspiration pneumonias are adequately treated with amoxycillin, but more severe infections and lung abscesses require parenteral cefuroxime and metronidazole initially, followed by oral amoxycillin and metronidazole (depending on cultures). Postural drainage is important, and antibiotic therapy should be continued for 6 weeks or more to minimize lung destruction.

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CASE STUDY 13.3 PLEURITIC CHEST PAIN AND NIGHT SWEATS IN A 54-YEAR-OLD IRISH BUILDING LABOURER A 54-year-old Irishman was referred to hospital by his GP because of leftsided pleuritic chest pain and cough. The patient had become increasingly breathless over the previous week and had experienced drenching night sweats. He had lost 1 stone in weight. Although he had a cough, there was no sputum or haemoptysis. He had worked all his adult life as a building labourer, but was off work because of osteoarthritis of the left hip. A heavy smoker, he also drank 5-6 pints of beer on most days. On examination his weight was 80kg and temperature 37.7°C. There were extensive dental caries and poor oral hygiene. The hands were nicotine stained and there was equivocal finger clubbing. There was bronchial breathing and inspiratory crackles over the midzone of the left lung anterolaterally. The trachea was central, there was no lymphadenopathy, and neither liver nor spleen were palpable. Blood tests showed a white cell count of 7.9, Hb 10.9 and albumin 27. The chest X-ray was reported as showing air-space consolidation in the left lung, with a fluid level (Case Fig. 13.3.1).

Question 1. What is the most likely diagnosis, and what would you include in the differential? Discussion The differential diagnosis would include a cavitating pneumonia/lung abscess, tuberculosis, a cavitating tumour and vasculitic disorders (e.g. Wegener's granulomatosis). The development of a lung abscess seems most likely. The chest X-ray findings, fever and night sweats are consistent with this diagnosis.

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CASE FIG. 13.3.1 Note the extensive air-space shadowing in the left lung. There is increased density in the left upper and midzones, and loss of clarity of the left heart border, demonstrating extensive involvement of the left upper lobe. There is a fluid level within a large cavity in the left midzone. There is no volume loss and the right lung is clear.

Although most patients with a lung abscess and a fluid level have sputum - often copious - this is not invariably the case. Similarly, the white cell count is raised in most but not all cases. A lung abscess can occur as a result of primary infection or secondary to other conditions (see p. 647). The air-space consolidation in this case suggests the abscess is a complication of a pneumonia. Cavitating pneumonia leading to lung abscess formation can occur particularly with Klebsiella and staphylococcal infection. A common predisposing factor for a secondary lung abscess is bronchial obstruction, for example by a tumour. Infected pulmonary infarcts can also cavitate. In this case, where the lung abscess was almost certainly preceded by a pneumonia, this could have followed aspiration as a result either of excessive alcohol intake or poor

dental hygiene. Tuberculosis is a possibility, with the patient's ethnic origin, alcohol intake and normal white cell count making the diagnosis worth considering. The radiology, however, is not typical. In cavitatory TB the chest X-ray often shows bilateral abnormalities, and it is usually the apex of the upper or lower lobes that are most affected. Malignant disease must be considered. The patient is a smoker and in his work may have been exposed to asbestos. Cavitation is most common in squamous cell carcinoma, in which case finger clubbing might be expected. Although the fever and night sweats strongly suggest infection, it is possible that with a tumour there could be infection distal to obstruction. However, the radiology does not indicate volume loss. The patient has no clear

predisposing factors for pulmonary embolic disease or clinical features to suggest a vasculitic disorder such as Wegener's. Question 2. The patient had a CT scan of the thorax: how does this investigation help support a particular diagnosis (Case Fig. 13.3.2) The CT scan shows consolidation and cavitation (in keeping with lung abscess complicating a pneumonia), but no mass lesion, bronchial obstruction or volume loss. Nevertheless, because a tumour or tuberculosis were possible diagnoses, the patient was bronchoscoped. No endobronchial lesion was seen and bronchial lavage demonstrated no acid-fast bacilli. Question 3. Given the likely diagnosis of an acute pneumonia complicated by abscess formation and cavitation, what are the most likely pathogens? 4. Which antibiotics would you choose and for how long would you give them? 5. What is a rare but important complication of lung abscess?

CASE FIG. 13.3.2

lAl There is confluent consolidation with a well defined air bronchogram. [B] This scan, taken from just below scan A, shows the large cavity with its fluid level, and an air bronchogram. There is no mass lesion or evidence of bronchial obstruction.

Inhalation pneumonias Aspiration pneumonia is the term used to denote aspiration of organisms into the lower respiratory tract (usually anaerobes); inhalational pneumonias refer to the consequences of inhaling non-infected particulate matter, fluids and irritant gases. The inhalation of gastric contents during anaesthesia or other causes of reduced consciousness, or in childbirth (Mendelson's syndrome) produces a chemical pneumonitis and respiratory distress. When severe, the features are those of the acute respiratory distress syndrome (p. 697). Management includes antibiotics, and metronidazole provides good cover for anaerobic organisms, but corticosteroids are not helpful.

Common pathogens causing lunj abscess with pneumonia include Klebsiella, Pseudomonas, Staphylococcus and anaerobes, and therefore unless a specific organism can be identified broad-spectrum antibiotics are required. In this patient no organisms were identified from culture of blood or bronchial lavage fluid (perhaps because antibiotic therapy had been started by the GP prior to hospital admission). The possibility of aspiration when drunk, and the poor dental hygiene, suggested anaerobic infection was possible. The patient was treated with intravenous cefuroxime, metronidazole and flucloxacillin. Within days there was substantial symptomatic improvement, but it was 12 days before he became afebrile. It is not uncommon for resolution of fever and radiological changes to be slow with a lung abscess. After 2 weeks' therapy he was changed to oral antibiotic treatment, and in total he was treated for 6 weeks. Gradually, over a period of 2 months, the chest X-ray cleared. This patient made an excellent recovery, but a rare and serious complication of lung abscess is cerebral abscess.

Inhalation of food produces the clinical picture of a chronic, often recurrent pneumonia. The inflammatory infiltrate in the lung may progress to fibrosis. Lipoid pneumonia follows the aspiration of liquid paraffin laxatives, oily nosedrops or oily seawater. The lung pathology shows a foreign body giant cell reaction and fibrosis. Chronic pneumonias due to inhalation may mimic lung tumours and the diagnosis may only become evident following surgical resection. Repeated inhalation may eventually produce bilateral fibrosis and bronchiectasis. Hot smoke inhalation causes respiratory burns. There is oedema of the upper airways and bronchial tree, causing wheeze and croup. Severe injury is unlikely if there is no blistering of the mouth. Several hours or days after inhalation,

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pulmonary oedema may develop. Early corticosteroid therapy may be beneficial. Patients may progress to develop the acute respiratory distress syndrome (p. 697).

Pneumonia in the immunocompromised host The increased use of immunosuppressive agents and the emergence of HIV infection have greatly increased the prevalence of pneumonia in the immunocompromised host - so-called 'opportunistic' infections. These infections are particularly common in certain well-recognized groups (Table 13.15). In patients who are immunosuppressed, particularly following organ transplantation or cytotoxic therapy for malignancy, the development of fever and pulmonary infiltrates is not always due to infection (Table 13.16). Occasionally bleeding into the lung occurs in patients who are thrombocytopenic. Radiation pneumonitis is most intense between 4 and 6 weeks after treatment. In a small number of patients a non-specific pneumonitis develops for which no cause is found, even when the patient is submitted to open lung biopsy. Infection can be due to a wide variety of agents. Immunodeficiency facilitates infection with organisms seldom encountered in immunocompetent individuals and the clinical picture is often of a rapid, extensive and life-threatening pneumonia (Table 13.17). 1 TABLE 13.15 Groups at risk of opportunistic pneumonias Primary immunodeficiency B-cell deficiency (agammaglobulinaemia) T-cell deficiency (Di George syndrome) T-cell and B-cell deficiency (combined immunodeficiency)

Secondary immunodeficiency HIV infection (AIDS) Leukaemias and lymphomas Cytotoxic agents (particularly following organ transplantation and the treatment of haematological malignancies) Corticosteroid therapy Malnutrition, general debility, uraemia, liver failure etc.

TABLE 13.16 Fever and pulmonary infiltrates in immunocompromised patients Malignant infiltration (e.g. leukaemia, Kaposi's sarcoma) Pulmonary emboli Non-specific pneumonitis

Infection Pulmonary oedema Pulmonary haemorrhage Drug-induced pneumonitis Radiation pneumonitis

1

638

MCQ13.7

2

Fig. 13.20

TABLE 13.17 Important causes of pneumonia in the immunocompromised patient Bacterial Gram-negative organisms as well as Gram-positive Nocardia Mycobacteria Legionella Mycoplasma Ch/amydia

Viral Cytomegalovirus Herpes simplex Fungal Candida Aspergillus Cryptococcus Pneumocystis

Management of pneumonia in the immunocompromised patient Pneumonia in the immunocompromised host requires immediate investigation and treatment. All patients should have blood cultures and appropriate serological investigations for likely pathogens. The chest X-ray is of limited value, with the exception of pneumocystis pneumonia in patients with HIV infection. Any pleural fluid should be sampled. Localized shadows are more common in bacterial infection; diffuse infiltration suggests an opportunistic organism. In all patients the likely value (and the risks) of invasive techniques to establish a definite cause for pneumonia must be considered. Most patients with diffuse pulmonary infiltration do not have sputum, and invasive investigations are therefore required to demonstrate the infective agent. Transtracheal aspiration, percutaneous needle aspiration biopsy, sputum induction with nebulized hypertonic saline, bronchoscopy and open lung biopsy can all yield useful information. Bronchoscopy is the most widely available technique. Bronchoalveolar lavage is a valuable technique for diagnosing pneumocystis and cytomegalovirus infection and is safe in patients with thrombocytopenia and bleeding diatheses. Transbronchial biopsy, although effective, can produce dangerous haemorrhage in patients with bleeding problems (uraemic patients are particularly prone to haemorrhage) and pneumothorax is a complication, particularly hazardous in patients receiving positive-pressure ventilation. Specific pneumonias in immunocompromised patients Gram-negative pneumonias Bacterial pneumonias, particularly Gram-negative infections, are common in neutropenic patients (e.g. following bone marrow transplantation, or chemotherapy for leukaemia), particularly if the granulocyte count is less than 500 x 106/L, and may be associated with lifethreatening septicaemia. The chest X-ray usually shows localized shadowing, rather than diffuse infiltration. Following blood cultures empirical therapy should be started. Common organisms are Pseudomonas aeruginosa, Escherichia coli, Klebsiella, Enterobacter and Serratia spp.

The use of broad-spectrum antibiotics favours the emergence of resistant organisms and also the development of fungal infections. Treatment of Gram-negative infections commonly requires aminoglycosides, cephalosporins and antipseudomonal pencillins, for example either ceftazidime or piperacillin-tazobactam with gentamicin. Ciprofloxacin or a carbapenem (imipenem or meropenem) should be reserved for the treatment of resistant strains. Klebsiella pneumonia The most common clinical setting for this Gram-negative pneumonia is the elderly male patient, often with chronic lung disease, whose 'immunosuppression' is due to general debility, associated with chronic illnesses such as diabetes or alcoholism. The illness can be severe (mortality 20-50%), with high fever, rigors and pleuritic pain, and haemoptysis occurs more often than in most bacterial pneumonias. The upper lobes are commonly involved, with considerable necrosis and cavitation, often bilateral, and with bulging of the fissure adjacent to the consolidated lung. There may be diagnostic confusion with tuberculosis. Patients with klebsiella pneumonia can develop empyema. Treatment is most effective with gentamicin plus cefuroxime, but resolution is often slow and substantial residual pulmonary damage is not uncommon. Pneumocystis carinii pneumonia (PCP) Pneumocystis pneumonia occurs in patients receiving steroids and other immunosuppressive agents, and is particularly common in AIDS. The clinical picture is of fever, a dry cough and progressive breathlessness. On auscultation the lungs often sound remarkably normal. The chest X-ray is often clear when symptoms first develop, but there

FIG. 13.20 Pneumocystis carinii pneumonia (PCP) Note that the diffuse hazy consolidation is bilateral and maximal in the mid and lower zones. 2

is progressive bilateral pulmonary infiltration, commencing in the perihilar regions, without effusions or adenopathy (Fig. 13.20). PCP is often marked by profound hypoxaemia which is worse than might be suggested from the physical signs on chest X-ray. Untreated, all patients become incapacitated by dyspnoea and die of hypoxaemia. In patients with AIDS, pneumocystis pneumonia characteristically evolves over several weeks, whereas in other patients at risk the time course is more rapid. In AIDS, pneumocystis is the most common cause of diffuse pulmonary shadowing. Because pneumocystis pneumonia is so common in this group it is appropriate in some circumstances to initiate empirical therapy. Whenever there is doubt about the correct diagnosis, or if response to treatment for presumed pneumocystis infection is slow, a definite diagnosis is required; for this, bronchoscopy with BAL and, if lavage is negative, TBB, has a very high diagnostic yield. The diagnosis can also be achieved by inducing sputum production with nebulized hypertonic saline. When treated early, pneumocystis pneumonia responds well to therapy with high-dose co-trimoxazole (20 mg of trimethoprim and 100 mg of sulfamethoxazole per kg body weight per day) given for 3 weeks. Mortality has fallen from 30% to 5% in recent years. Trimethoprim and dapsone is an effective combination, as is clindamycin plus primaquine, whereas pentamidine, although effective, is more toxic. Progressive hypoxia may require CPAP therapy (p. 670), and in selected patients intubation and mechanical ventilation is appropriate. Unfortunately, recurrence is common. Co-trimoxazole and inhaled pentamidine provide effective prophylaxis. Because PCP is unusual in HIV until the CD4 lymphocyte count is less than 250, it is usual to initiate primary prophylaxis at that level. In AIDS patients with severe pneumocystis pneumonia and respiratory hypoxia (Pao2 < 9.0 kPa) corticosteroids, given early, improve survival. Aspergillus pneumonia Aspergillus fumigatus is a rare cause of pneumonia and patients usually have severe granulocytopenia or are on corticosteroid therapy, and have frequently received broad-spectrum antibiotics. Patients receiving therapy for leukaemia are particularly at risk. The clinical picture is of fever, dyspnoea, pulmonary infiltrates that resemble pulmonary infarction, sometimes with cavitation, and pleural involvement. There is frequently evidence of aspergillus infection at other sites, notably the brain, bones and endocardium. Diagnosis is most reliably achieved by open lung biopsy or transbronchial biopsy. Bronchoalveolar lavage in immunosuppressed patients frequently demonstrates aspergillus, but biopsy material is required to confirm invasive pulmonary infection. Treatment is with intravenous amphotericin, but mortality is high. High-dose lipid formulations of amphotericin B are commonly used in aspergillus pneumonia to reduce toxicity, but they are very expensive. Newer agents such as itrazonazole and voriconazole have activity against aspergillus, but their role in treating

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invasive aspergillosis, as an alternative to amphotericin, is not established. Some reports suggest that G-CSF in addition to amphotericin may improve outcome, but this has yet to be demonstrated unequivocally. Candida albicans is an unusual cause of pneumonia, occurring in the same high-risk group as those who develop aspergillus pneumonia and presenting a similar clinical picture. Blood cultures are frequently positive. Treatment is with amphotericin and flucytosine. Fluconazole may be an alternative. Nocardia pneumonia Nocardia asteroides can rarely cause a chronic suppurative pneumonia in otherwise normal individuals, but more commonly it is a cause of an acute pneumonia in the immunocompromised host. In addition to lung involvement, in which there may be a single lesion or extensive consolidation with cavitation, pleural disease, empyema and metastatic spread also occur. A CT head scan is an important investigation. The sputum shows Gram-positive hyphae which are acid fast and grow rapidly on aerobic culture. Co-trimoxazole (thrice normal dose) is effective; if there is no improvement in 4-5 days treatment can be changed to ciprofloxacin plus a cephalosporin such as cefotoxime or ceftriaxone. Other agents that have been successful include amitracin, imipenem and meropenem. Cytomegalovirus pneumonia CMV pneumonia is an important problem in immunosuppressed patients, particularly following transplantation (see p. 288).

Unusual pneumonias A number of unusual infections (bacterial, viral, fungal and protozoal) can cause pneumonia and are particularly important in certain parts of the world (Table 13.18). They are described in Chapter 9.

TUBERCULOSIS

TABLE 13.18 Unusual causes of pneumonia Bacterial Salmonella typhi and paratyphi (typhoid) Brucella abortus and melitensis (brucellosis) Pasteurella pestis (plague) Pasteurella tularensis (tularaemia) Bacillus anthracis (anthrax) Leptospira ictemhaemorrhagicae (leptospirosis) Rickettsial Typhus

Viral Varicella (chickenpox) Herpes zoster Epstein-Barr virus (infectious mononucleosis) Protozoal, yeast and fungal Actinomyces israelii (actinomycosis) Coccidioides immitis (coccidioidomycosis) Histoplasma capsulatum (histoplasmosis)

can infect anyone, but there are well-recognized 'at-risk' population groups in the UK, and these include the elderly, migrants and refugees from countries with a high incidence of the disease, as occurs in Africa and the Indian subcontinent, those in poor social circumstances, alcoholics, immunosuppressed patients and hospital employees. Tuberculosis is a common complication of HIV infection, and as a consequence the incidence has increased substantially in some areas of the world. Mycobacterium bovis was once a common cause of human infection but has now been almost eradicated in developed countries by pasteurization of milk and skin testing of cattle, with tuberculin-positive animals being slaughtered. Mycobacteria other than M. tuberculosis or M. bovis may cause infection in humans, for example M. kansasii, M. xenopi, M. avium and M. intracellulare. The source of infection, unlike the droplet route of M. tuberculosis, is generally thought to be exposure of susceptible individuals to organisms in water, soil, dust and animals (particularly pigs, chickens, birds and monkeys). The organisms are not transmitted between humans.

1

Infactivity, immunology and pathology Epidemiology In 19th-century England one person in five died of Mycobacterium tuberculosis infection. The dramatic decline in notifications and deaths reflects one of the great medical advances of that century. However, tuberculosis remains a common cause of death in the developing world. Eight million new clinical cases occur each year, leading to 2 million deaths. One-third of the world's population is infected with the bacterium that causes tuberculosis. TB

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1

MCQ13.8 2 Fig. 13.21

3

Figs 13.22,13.23

4

5

Figs 13.26-13.28

6

Figs 13.24-13.25 Fig.13-29

The response to a primary infection is shown in Figure 13.21. The usual result of this is a small subpleural lesion which heals with fibrosis; the glandular lesion also heals, and within about 18 months both may calcify. However, some lesions, especially in children, may erode a blood vessel (Fig. 13.22) and progress to 'miliary' tuberculosis, so named because of the 'millet'-sized lesions on the chest X-ray. Alternatively the lung lesion may progress, and cavitate or involve the pleura, causing a pleural effusion. Finally the lymph node involvement may progress, especially in Asians and Black Africans, and occasionally compress, obstruct or erode a bronchus, particularly that of the right middle lobe. Of those that heal, some subsequently develop postprimary tuberculosis (Fig. 13.21), often many years later,

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FIG. 13.21 Primary and postprimary (reinfection) tuberculosis In primary tuberculosis there is pneumonic consolidation (Ghon focus) which is usually subpleural and affects the mid or lower zones. [A] Subsequently, infection involves the draining hilar nodes [B] which may cause bronchial compression. Reinfection (post-primary) tuberculosis [C] is usually apical and progresses to cavitation, fibrosis, volume loss and pleural thickening [D].

sometimes referred to as reinfection adult tuberculosis. Whether the patients become reinfected exogenously or whether their existing lesions become active again is often not clear. Postprimary tuberculosis is usually apical, often bilateral, and can lead to cavitation, fibrosis, volume loss, bronchiectasis, and pleural thickening. Patients can develop a devastating tuberculous bronchopneumonia or miliary TB. In many countries children are immunized against TB using BCG vaccination (see below). Immunization confers only partial protection. Tuberculous infection in the immunized individual leads to postprimary disease.

Clinical features Some patients with tuberculosis are asymptomatic, their disease being noted on routine chest X-ray. Many patients have cough, often with sputum, haemoptysis, fever and weight loss. Tuberculosis may present insidiously, particularly in the elderly.

Investigation Tuberculin testing, in which protein derived from tuberculous bacilli is introduced into the skin, with either the Mantoux technique or the multiple puncture Heaf test, is useful in supporting the diagnosis, and for assessing contacts and children before BCG vaccination. A positive

FIG. 13.22 Miliary tuberculosis In miliary tuberculosis multiple organs are involved. The diagnosis is most commonly suggested by the chest X-ray. 4 Meningitis is relatively common.

Mantoux test should show 5 mm of induration using up to 10 tuberculin units. An alternative is the Heaf test. When performed correctly, a negative tuberculin test makes active tuberculosis infection relatively unlikely, except in patients who are profoundly immunosuppressed (e.g. those with advanced HIV disease). A normal chest X-ray is rare in active pulmonary tuberculosis. Characteristic appearances include: • Primary tuberculosis with hilar gland enlargement • Miliary tuberculosis (Fig. 13.23) 5 • Postprimary (reinfection) tuberculosis with cavitation (Fig. 13.24) 6 • Tuberculous bronchopneumonia. Fluorescent microscopic techniques and/or staining with the Ziehl-Neelsen stain are usually used to screen sputum to confirm that bacilli are present. Routine culture of the organism takes 2-8 weeks, and is important for excluding atypical mycobacteria and determining drug sensitivities. If the patient has no sputum, fibreoptic bronchoscopy with bronchial lavage is a useful diagnostic tool. In adults gastric washings or laryngeal swabs are seldom necessary when bronchoscopy is available. The sedimentation rate is usually raised, and in advanced disease there may be an anaemia with a raised white cell count, occasionally with a lymphocytosis. Liver function tests may be abnormal. Extrapulmonary tuberculosis can involve most organ systems (Table 13.19).

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CASE STUDY 13.4 COUGH AND WEIGHT LOSS IN A 39-YEAR-OLD WOMAN FROM AFRICA A 39-year-old female nurse presented to outpatients with reduced appetite, weight loss and cough of 4 months' duration. She had lost 3 stone in weight. The cough was productive of greenish sputum flecked with blood. Born in Tanzania, the patient had moved to the UK 18 months previously. She smoked 20 cigarettes daily. Preliminary investigations arranged by her family doctor had demonstrated an abnormal chest X-ray, a blood sugar of 22 mmol/L, albumin 34g/L, Hb 10.7 g/dL and WBC 9.4 (normal differential). Clinical examination showed a temperature of 37.8°C, respiratory rate 22 and reduced chest wall movements over the left upper chest, with bronchial breathing on auscultation. The chest X-ray showed extensive consolidation in the left mid and upper zones, with a large cavity. The lateral chest X-ray confirmed that the abnormalities were largely confined to the left upper lobe (Case Fig. 13.4.1).

Questions 1. What is the likely diagnoses? 2. What is the explanation of the weight loss? 3. What would be your first investigation?

Discussion The most likely diagnosis is pulmonary tuberculosis. The ethnic origin of the patient, the duration of symptoms, fever and X-ray appearances all favour this diagnosis. It is slightly unusual to have such extensive disease in the left upper lobe with no abnormalities at all in the right lung. The patient also has diabetes, probably exacerbated by her illness. Further questioning revealed that the patient had had transient gestational diabetes 15 years previously. It is likely that her

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CASE FIG. 13.4.1 [A] The PA chest X-ray shows extensive consolidation in the left lung, with a large cavity. [B] The lateral chest X-ray confirms that the disease is largely confined to the left upper lobe; note the large retrosternal cavity.

diabetes was contributing to the weight loss. Although tuberculosis is an important cause of weight loss, when this happens the patient is usually also hypoalbuminaemic. HIV requires consideration, although the white cell count is normal, without a lymphopenia. A key investigation is immediate examination of the patient's sputum, and this demonstrated numerous acid-fast bacilli.

Question 4. What would be your initial management? The patient has 'open' pulmonary tuberculosis and is infectious. Clearly, she should stop working as a nurse and the infection control team needs to be informed: TB is a notifiable disease and careful contact tracing will be needed.

The patient's TB requires treatment, as does her diabetes, and in view of the complexity and severity of her illness admission to hospital is appropriate. Drug resistance is an increasing problem in the therapy of tuberculosis, and resistance is relatively common in patients from some parts of Africa. Therefore, therapy is best started with four drugs, usually rifampicin, isoniazid, pyrazinamide and ethambutol. The patient was started on these four drugs and her diabetes was controlled with insulin. After appropriate counselling she was tested for HIV, and this proved negative. The patient responded rapidly to therapy. After a few weeks her diabetes was well controlled with oral hypoglycaemic agents. After 4 weeks of therapy the patient, who had been feeling much improved up to that point, developed nausea, tiredness and abdominal discomfort. She contacted the hospital and was immediately reviewed. On examination she was jaundiced and the liver was enlarged. Liver function tests showed a bilirubin of 84mmol/L, y-GT 564 U/L, aspartate aminotransferase 840 U/L and alkaline phosphatase 326 U/L.

incriminated. All drugs should be stopped and liver function monitored. This usually leads to improvement, but not always, and occasional patients develop established liver failure; a number of cases have been successfully managed with liver transplantation. When liver function tests have returned to normal, it is best to reintroduce therapy one drug at a time. The first-line drugs used in the treatment of tuberculosis are the best available, and it is desirable that as many of them as possible be used. Because rifampicin is the most likely to cause hepatitis, many physicians introduce either pyrazinamide or isoniazid first. If patients tolerate one drug for a week, the second drug is added, and subsequently an alternative third or fourth drug. If drug-induced problems are less severe than hepatitis (for example

skin rashes), and the treatment is crucial (for example in patients with extensive tuberculosis or TB meningitis), it may be possible to continue therapy with the addition of corticosteroids. In this patient the liver function tests improved off treatment, and therapy was continued with isoniazid, pyrazinamide and ethambutol. Sputum culture confirmed the diagnosis of mycobacterium tuberculosis. Because of the unconventional drug regimen treatment was for 9 months rather than 6.

13

Question 6. With therapy, what is the likely outcome for this patient in terms of lung function and chest radiology?

Question 5. What should be done?

Patients with TB commonly have minor abnormalities of liver function before starting therapy. They also often develop modest elevation of liver enzymes on rifampicin treatment. However, the development of jaundice and the markedly abnormal liver function tests indicate drug-induced liver disease. Rifampicin, isoniazid and pyrazinamide are all hepatotoxic, and rifampicin is the most commonly

CASE FIG. 13.4.2 Chest X-ray after 8 months' treatment. Cavitation is no longer visible and the consolidation has resolved, leaving some linear fibrotic change in the left upper zone.

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CASE STUDY 13.4 CONTINUED If treatment for tuberculosis is started early, patients usually do remarkably well. Consolidation clears completely and, perhaps surprisingly, cavities also disappear. Patients do less well if there is established fibrosis. Such fibrosis usually causes volume loss, and it is noteworthy that in this patient there was no evidence

of volume loss on her initial X-rays (Case Fig. 13.4.1). In this patient, after 6 months' therapy the large cavity had resolved and the extensive consolidation had largely disappeared, leaving relatively minor linear shadowing in the left upper zone (Case Fig. 13.4.2). The patient became symptom free and was not

FIG. 13.23 Miliary tuberculosis Thousands of small nodules, 'millet-size', all of similar size and distributed throughout the lungs.

Differential diagnosis In any febrile illness it may be relevant to consider tuberculosis, particularly if there is chest X-ray shadowing or lymph gland enlargement. It must be distinguished from simple pneumonia, and in such cases the usual clinical feature that raises suspicion of tuberculosis is the indolent nature of the illness.

Complications These may be due to dissemination of the disease, extensive lung damage or non-specific metabolic disturbances.

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644

Case 13.1

breathless. The FEVi and vital capacity were within the normal range and gas transfer was approximately 80% of normal. The Po2 of 10.4 and Pco2 of 4.7 demonstrated minor abnormalities of gas exchange. As a result of her illness, the patient managed to stop her cigarette smoking.

FIG. 13.24 Postprimary (reinfection) tuberculosis The widespread tuberculous consolidation involves predominantly the upper and mid zones. The translucent areas in the upper zones are cavities. There is calcification in the right upper zone of the right hemidiaphragm, suggesting that the patient has reactivation of old disease.

TABLE 13.19 Diagnosis of extrapulmonary tuberculosis' Three early morning urine specimens Liver biopsy Lymph node biopsy Bone marrow aspiration and trephine biopsy Lumbar puncture Laparoscopy and biopsy Joint aspiration Bone biopsy Stool specimens in immunosuppressed patients * All specimens should be cultured.

• Dissemination (extrapulmonary tuberculosis). Tuberculosis may involve lymph nodes, pleura, bones, joints, kidneys, adrenals, liver, peritoneum, bowel, epididymis, meninges and brain. 1 • Extensive lung damage. This may result in massive haemoptysis, bronchiectasis, breathlessness, and eventually respiratory failure with cor pulmonale. • Associated metabolic conditions. These can include hypokalaemia, hyponatraemia, hypercalcaemia and hypoalbuminaemia.

Identification of the organism is best achieved by culture from blood, bone marrow, liver and bronchi. In patients with advanced HIV disease the mycobacterial infection is usually disseminated. The organism is resistant to pyrazinamide and isoniazid, and treatment is difficult. Recommended drugs include ethambutol with rifampicin or rifabutin, quinolones, the newer macrolides, and amikacin. An in vivo response often occurs despite in vitro resistance, and is due to the synergistic action between combinations of drugs. However, prognosis is poor.

Atypical mycobacterial infections

Management of M. tuberculosis

Occasionally mycobacteria other than M. tuberculosis or M. bovis cause pulmonary disease. The most common of these 'atypical' mycobacterial pathogens are M. kansasii, M. xenopi, M. avium intracellulare (MAI) and M. malmoense. These are environmental organisms, found particularly in water and soil. In patients with HIV disease MAI is relatively common. In other patients M. kansasii infection is most frequent in the UK. Patients with atypical mycobacterial infection do not pose a significant infectious risk to their close contacts or carers. Except for patients with HIV disease, atypical mycobacterial infection occurs predominantly in middle-aged or elderly males. Often there is pre-existing lung disease. The onset of symptoms is gradual, most commonly with cough, sputum, haemoptysis and weight loss. The chest X-ray usually mimics classic postprimary M. tuberculosis infection. Treatment of these organisms is indicated only when it is clear that they are causing significant disease and is made on an empirical basis. M. kansasii is usually sensitive to rifampicin and ethambutol. M. xenopi is usually treated with rifampicin, isoniazid and ethambutol for 18-24 months; however, 9 months' therapy will eradicate the disease in 90% of cases.

Organisms in the walls of pulmonary cavities, exposed to a high oxygen tension, tend to replicate rapidly, whereas those in caseous areas or within macrophages, in which the pH is low, divide relatively slowly. There are therefore three populations of organisms to be treated:

Mycobacterial infection in HIV/AIDS Patients with the acquired immunodeficiency syndrome (AIDS) are frequently infected with mycobacteria, either typical M. tuberculosis or atypical mycobacteria, commonly Mycobacterium avium intracellulare. Infection may result in pulmonary or extrapulmonary disease, and unusual clinical presentations may occur. Although M. tuberculosis infection is usually a reactivation of previous tuberculosis, typical upper lobe disease is not so common in patients with AIDS. M. tuberculosis in AIDS is usually responsive to conventional antituberculous treatment. Prevention of tuberculosis is possible with isoniazid prophylaxis, and this should be considered in HIV-positive patients who also have a positive tuberculin skin test.

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• The rapidly dividing extracellular organisms • The slowly dividing extracellular organisms • The slowly dividing intracellular organisms (persisters). The immediate target for chemotherapy is to kill the large numbers of organisms in the 'rapidly dividing' group and to prevent the survival of 'mutant' strains. The slowgrowing intracellular and extracellular organisms will be completely eliminated only by a prolonged course of effective drugs, and if there are 'persisters' from these two groups they will cause late relapse of the disease.

Antituberculous drugs and treatment regimens The four most commonly used drugs in developed countries are listed in Table 13.20. With the use of isoniazid and rifampicin, both of which have activity against intracellular organisms, tuberculous lesions should be sterilized quickly. Effective chemotherapy of pulmonary tuberculosis is 6 months' isoniazid, and rifampicin, plus pyrazinamide and ethambutol given for the first 2 months. Ethambutol can be omitted in patients with a low risk of resistance to isoniazid.

'First-line' drugs for tuberculosis Drug

Daily dose

Side-effects

Rifampicin

10 mg/kg, usually 450-600 mg

Hepatitis, nausea, vomiting, fevers, thrombocytopenia, renal failure (on intermittent therapy), drug interactions (e.g. oestrogens)

Isoniazid (prescribed with pyridoxine 10 mg daily)

Children 6 mg/kg Adults usually 300 mg

Peripheral neuropathy, hepatotoxicity, hypersensitivity reactions

Mycobacterium avium intracellulare infection in AIDS

Pyrazinamide

20-30 mg/kg usually 1-2 g

Hepatotoxicity, hyperuricaemia, arthralgia

Infection with Mycobacterium avium intracellulare is the commonest atypical mycobacterial complication of AIDS.

Ethambutol

15-25 mg/kg

Optic neuritis, rashes

645

In patients with minor liver disease standard therapy can be given, but liver function should be closely monitored. In severe liver disease, second-line non-hepatotoxic drugs should be used (e.g. ciprofloxacin, streptomycin). In renal failure treatment of tuberculosis is with rifampicin, isoniazid and pyrazinamide, and if ethambutol or streptomycin is used the dosage should be reduced and drug levels monitored. Dialysis can greatly affect drug clearance. Rifampicin, isoniazid, pyrazinamide and ethambutol are safe in pregnancy, but streptomycin should be avoided. Rifampicin reduces the effectiveness of the combined oral contraceptive as well as other drugs, and approximately halves the pharmacological effect of concurrent oral prednisolone. Rifampicin makes urine a red-orange colour. Drug resistance Drug resistance is due to infection with an organism from an ineffectively treated patient (primary or initial resistance) or occurs during therapy (secondary or acquited resistance). Resistance to isoniazid is most common. Resistance to rifampicin and pyrazinamide is unusual, but in the Far East and Africa initial resistance to isoniazid or streptomycin, or both, is high. Multiple-drugresistant (MDR) TB is an increasingly important problem, usually in partially treated patients, for example from Africa and Russia. Such patients require isolation facilities for their treatment, and pose an important public health problem, not least for their medical carers. Immunosuppressed patients are at particular risk. In patients with resistant strains the use of 'second-line' drugs (e.g. streptomycin, capreomycin, cycloserine, quinolones, prothionamide), particularly in the first 2^4 months of treatment, may be necessary. Four or even five drugs may be required in this initial period, and to achieve cure a more prolonged, 18-24-month, regimen is necessary. Drug resistance can be determined using bacteriological or molecular tests on appropriate specimens. Drug resistance, for example to rifampicin, can be rapidly established using molecular techniques. Drug side-effects Short-course regimens are relatively non-toxic (Table 13.19), although rarely standard drug therapy can cause fulminant liver failure and liver function should be tested before starting therapy. If adverse reactions occur (most commonly skin rashes) all the drugs should be stopped and subsequently, when the reaction has subsided, one drug reintroduced. If all goes well, a second drug can then be started. Cost Rifampicin is an expensive drug and pyrazinamide is also costly. Cost limits their use in developing countries. Overall, however, short course chemotherapy remains one of the most cost-effective interventions worldwide. 646

Patient non-compliance with treatment The treatment of tuberculosis requires disciplined drug-

taking, usually on a daily basis, for 6-9 months in most drug regimens. This may be difficult to achieve, particularly in the rural populations of developing countries and in the vagrant populations of the inner cities of western countries. For this reason supervised twice-weekly regimens, ultrashort courses which accept less than 100% cure, or even supervision in a residential hostel, may have to be considered. An effective three-times-weekly treatment regimen is rifampicin, isoniazid and pyrazinamide, with either streptomycin or ethambutol, for 2 months, followed by rifampicin and isoniazid for 4 months. Supervision can include direct observations of pill-taking (directly observed therapy-DOT), urine tests for isoniazid, and urine inspection for the red discoloration of rifampicin. Combination tablets of rifampicin and isoniazid, with or without pyrazinamide, aid compliance. An advantage of combination tablets is that red urine or a positive urine test for isoniazid confirms that all drugs are being taken. Treatment of extrapulmonary tuberculosis Treatment of renal, bone and joint, lymph node, liver, pericardial, peritoneal and bowel tuberculosis is in general similar to that of pulmonary tuberculosis. The treatment of tuberculous meningitis deserves special mention, as treatment failure may be lethal. Treatment should include isoniazid, pyrazinamide and rifampicin, with a fourth drug such as streptomycin or ethambutol. Intrathecal drugs are rarely given. Treatment should be given for 12 months. Similarly, patients with miliary tuberculosis should be treated for 1 year. The use of corticosteroids in tuberculosis The administration of corticosteroids, in addition to antituberculous drugs, may sometimes be beneficial. Their use should be considered in the very wasted patient, in tuberculous meningitis and intracerebral tuberculomata, as well as in pleural and pericardial effusions. Where a patient develops hypersensitivity to a drug that essential and irreplaceable in a treatment regimen, steroids may allow therapy to continue.

Prevention The dramatic decline in tuberculosis in developed countries is due to several factors. Of great importance is the control of infection from human sources by effective chemotherapy. Isolation of infectious patients (those with smear-positive sputum) for 2 weeks is helpful. Contact tracing is crucial and immediate contacts, especially children, should have a tuberculin test and chest X-ray. Host defences are improved by better housing and social conditions and the use of Bacille Calmette-Guerin (BCG) vaccination. This vaccine, using an attenuated strain of tubercle bacillus, gives a harmless primary infection and therefore a large measure of immunity. It is given to teenage children in many developed countries and to infants elsewhere. To avoid the development of tuberculous disease, chemoprophylaxis (preventative therapy) is

commonly recommended for individuals with a strongly positive tuberculin skin test but without other evidence of infection who have not received BCG. Many are immigrants from parts of the world where tuberculosis is very common. Because of the increased risk of drug side-effects in older individuals, chemoprophylaxis is usually limited to children and young adults. A suitable drug regimen is isoniazid plus rifampicin in standard doses, for 3 months, or isoniazid alone for 6 months. In many developing countries the incidence of TB is high and rising because of HIV infection, and this poses a formidable public health problem.

FURTHER READING ON RESPIRATORY INFECTIONS American Thoracic Society 1994 Treatment of tuberculosis and tuberculosis infection in adults and children. Am J Respir Crit Care Med 149:1359-1374 Baughman R P 1994 Use of bronchoscopy in the diagnosis of infection in the immunocompromised host. Thorax 49:3-7 British Thoracic Society 2001 Guidelines for the management of community-acquired pneumonia in adults. Thorax 56 (suppl. iv) British Thoracic Society 2001 Management of opportunist mycobacterial infections. Thorax 55: 210-218 Fein A M, Niederman M S 1995 Guidelines for the initial management of community-acquired pneumonia: savory recipe or cookbook for disaster. Am J Respir Crit Care Med 152:1149-1153 Joint Tuberculosis Committee of the British Thoracic Society 1998 Chemotherapy and management of tuberculosis in the United Kingdom: recommendations 1998. Thorax 53:536-548 Joint Tuberculosis Committee of the British Thoracic Society 2000 Control and prevention of tuberculosis in the United Kingdom. Code of practice 2000. Thorax 55:887-901 Nunn P P, Elliott A M, McAdam K P W J 1994 Impact of human immunodeficiency virus on tuberculosis in developing countries. Thorax 49:511-518 Ormerod L P, Skinner C, Wales J 1996 On behalf of the Joint Tuberculosis Committee of the British Thoracic Society. Hepatotoxicity of antituberculous drugs. Thorax 51:111-113

LUNG ABSCESS

13

A lung abscess is an infected, cavitating lesion within the lung parenchyma. Abscesses can occur as a result of primary infection, or secondary to other conditions (Table 13.21). The two factors critical to the pathogenesis of lung abscesses are necrotic tissue and infection. Apart from septic emboli, infection is via the tracheobronchial tree and seeds in an area of necrotic lung tissue. This leads to further breakdown of lung tissue and communication with a bronchus. The presentation will vary with the cause: patients with acute lung abscesses secondary to bacterial pneumonia (e.g. Klebsieila) are acutely unwell, febrile and coughing foul, bloodstained sputum, whereas the presentation of a tuberculous abscess will be much more indolent. The patient's breath and sputum may smell faeculent in the presence of anaerobes. There may be finger clubbing. Lung abscesses are more common in alcoholics and elderly debilitated patients, who are prone to aspiration, and in intravenous drug abusers. Lung abscess may follow the aspiration of infected material in patients with dental sepsis and sinusitis, and may complicate bronchiectasis. The chest X-ray initially shows a homogeneous opacity, and only when bronchial drainage is established does an air-fluid level appear (Fig. 13.25). Sputum should be sent for Gram stain, culture and sensitivity and examined for acid-fast bacilli. Fibreoptic bronchoscopy will provide useful information, both for bacteriology (especially the

TABLE 13.21 Causes of lung abscess Necrotizing infection Pyogenic bacteria (Staphy/ococcus aureus, Klebsieila, anaerobes, Pseudomonas aeruginosa) Mycobacteria (M. tuberculosis or atypical mycobacteria) Fungi (Histoplasma capsulatum, Coccidioides immitis) Parasites (Entamoeba histolytica, Paragon ium wester mani) Secondary to bronchial occlusion Bronchial carcinoma or adenoma Foreign body aspiration Bronchial stenosis

Pulmonary infarction Pulmonary thromboembolism Pulmonary foreign body embolism (e.g. i.v. drug abusers) Septic pulmonary embolism Cavitation in malignant tumour Bronchogenic carcinoma (esp. squamous cell) Metastases Lymphoma Others Wegener's granulomatosis Infected cysts, bullae, sequestrations Pneumoconiosis (silica, coal)

FIG. 13.25 Cavitating lung abscess The abscess is in the lingular segment of the left upper lobe. The patient had a cough productive of large volumes of purulent sputum from the abscess cavity; note the fluid level.

647

isolation of anaerobes) and in identifying neoplasms or foreign bodies. Patients with staphylococcal or Klebsiella pneumonias tend to develop abscesses. The commonest radiological appearances with staphylococcus are of multiple, thinwalled cystic spaces with little fluid. Anaerobic abscesses due to Entamoeba histolytica usually involve the liver as well as the lung. The patient may have haemoptysis or cough up 'anchovy paste' or 'chocolate sauce' sputum. The treatment of lung abscess depends on the cause. Foreign bodies and some cavitating tumours can be surgically removed. When there is no surgically resectable lesion treatment centres on frequent physiotherapy and appropriate antibiotics, guided by the bacteriology of sputum, blood and bronchial washings, and given for 6 weeks or more. Needle aspiration to obtain samples of pus for microbiology may be helpful and percutaneous catheters positioned during radiological imaging can facilitate resolution. Surgical resection is occasionally necessary.

BRONCHIECTASIS

Bronchiectasis is chronic dilatation of bronchi, usually associated with deficient local clearance of secretions. The disease may be localized to a lobe or segment, or may be generalized throughout the bronchial tree. Clinically, bronchiectasis presents with intermittent or constant cough, and sputum with or without haemoptysis.

Aetiology Congenital factors • Cystic fibrosis (p. 649). This multisystem disorder is associated with bronchial obstruction due to inspissated mucus and thus recurrent infection, the consequence of which is bronchiectasis. • Immune deficiency syndromes. Bronchiectasis is particularly frequent in hypogammaglobulinaemia. • Kartagener's syndrome. This is the triad of dextrocardia, sinusitis and bronchiectasis. The sinusitis and bronchiectasis are due to disorders of ciliary function. The Chandra-Khetarpal syndrome is similar, but with laevocardia and no demonstrable ciliary abnormality. • Pulmonary sequestration. Bronchiectasis frequently occurs in congenitally sequestrated lung tissue. Inflammatory factors A variety of infective processes in the lung may produce bronchiectasis. These include infection with necrotizing

1

648

MCQ13.9

organisms such as Klebsiella pneumoniae, staphylococci, Pseudomonas aeruginosa and tuberculosis. The damage caused to the bronchial wall by these organisms may lead to dilatation and permanent ciliary dysfunction. Some viral infections, particularly adenovirus and influenza virus, may predispose to bronchiectasis, as may an episode of bronchiolitis or whooping cough in childhood. MacLeod's syndrome is a unilateral emphysema-like condition which follows early childhood infections and may be associated with bronchiectasis. The other major inflammatory process predisposing to bronchiectasis is immunological. This may be important in bronchiectasis of any aetiology, but the classic example is allergic bronchopulmonary aspergillosis (p. 660). It is likely that antigen/antibody complexes in the bronchial wall fix complement, causing an inflammatory reaction, tissue damage and bronchiectasis, characteristically in proximal large airways. Bronchial obstruction and retraction Proximal obstruction of an airway by foreign body, tumour, enlarged lymph gland or mucus plug causes secretions to accumulate distally; these then become infected, causing bronchial wall damage. The result of this process is often an area of bronchiectasis localized to a segment or lobe, which may be amenable to surgical resection. Retraction of lung tissue can occur with healing of tuberculosis or with extensive pulmonary fibrosis, causing distortion and widening of adjacent bronchi. Idiopathic Probably the largest single group of patients are those in whom a cause is never found. They usually have bilateral lower lobe disease.

Clinical features The usual presentation is with cough and sputum. In the advanced stage of the disease patients may produce up to 40-50 mL of sputum per day, most of it in the morning. Haemoptysis is common, usually as blood-streaking of the sputum. Massive haemoptysis does occur, often in association with a recurrence of infection, and is occasionally fatal. With widespread disease the patient is breathless, with malaise, weight loss and recurrent fevers. The physical signs depend on the extent and stage of the disease. In the patient with severe widespread bronchiectasis general health may be poor, finger clubbing is common, there are coarse crackles and wheezes, and there may be central cyanosis and cor pulmonale. Complications of bronchiectasis include pneumonia, lung abscess, pleural effusion, empyema, brain abscess and amyloidosis. With effective antibiotic therapy these complications are unusual. 1

Investigation The chest X-ray may be normal. However, the more characteristic radiographic changes (Fig. 13.26) include ring,

tive/restrictive defect develops, with variable response to bronchodilators. Younger bronchiectatic patients require a sweat test to exclude cystic fibrosis, and all patients should have a routine estimation of their serum immunoglobulins. A blood eosinophilia is common in allergic bronchopulmonary aspergillosis. Ciliary function may require investigation, including a nasal mucosal biopsy with motility studies.

13

Management

FIG. 13.26 Extensive bilateral basal bronchiectasis

FIG. 13.27 Bronchiectasis: CT scan There is extensive disease, with bronchial wall thickening and airway dilatation, easily seen in the left lower lobe (arrow).

line and parallel ('tramline') shadows - the appearances of thickened bronchial walls seen end-on or laterally. Thinsection CT scanning is a sensitive technique for demonstrating dilated bronchi (Fig. 13.27). If the disease is largely peripheral it usually has a cystic appearance, whereas when the major bronchi are affected they take on a fusiform or saccular appearance. Bronchography is seldom performed. The most common infecting organism is H. influenzae, but pneumococcus is also a frequent pathogen. Colonization with Ps. aeruginosa is not uncommon. Lung function tests reflect the extent and severity of disease. As the condition worsens a mixed obstruc-

The long-term management of bronchiectasis includes regular, effective physiotherapy. Patients and their relatives are taught postural drainage. In the majority of patients continuous long-term antibiotics are not appropriate and predispose to colonization with Ps. aeruginosa. Prompt treatment of intercurrent and symptomatic infection with appropriate antibiotics is essential. Regular inhaled antibiotics may be helpful (e.g. gentamicin, piperacillin, colomycin), especially in patients with cystic fibrosis. Severe episodes of infection require hospitalization. Antibiotic therapy should be guided by microbiological information whenever possible. If no organism can be identified, broad-spectrum cover, including activity against Pseudomanas, is required; for example, long-term venous access may be necessary in patients with frequent infective episodes (usually those with cystic fibrosis) and many such patients can be managed in the community. Patients with agammaglobulinaemia require regular intravenous replacement therapy and can be kept remarkably free of infection. Inhaled |3 agonists are useful in those patients with airways obstruction. Oral steroids are required in bronchopulmonary aspergillosis and can be helpful in some other bronchiectatic patients in whom bronchial damage is immunologically mediated. In severe cases patients eventually develop cor pulmonale and require diuretic and domiciliary oxygen therapy. A proportion of patients with cystic fibrosis have been successfully treated by heart-lung transplantation. Surgical resection for bronchiectasis is indicated in only a small number of cases, usually for localized disease caused by previous bronchial occlusion or lobar pneumonia. It may also be necessary to resect bronchiectatic lung for massive haemoptysis. Haemoptysis can sometimes be successfully treated by embolization of the relevant branch of the bronchial artery with foam. With the exception of patients with generalized disorders, such as cystic fibrosis or immune deficiency, the long-term outlook for the majority of patients with bronchiectasis is good.

CYSTIC FIBROSIS Cystic fibrosis is the most common potentially lethal genetic disease in Caucasians. It is an autosomal recessive

649

gene which is carried by 1: 20-25 of the Caucasian population and its incidence in Britain is about 1:2000-2500 live births. It affects more than 50000 people world wide. There have been important advances in the understanding of the genetics and pathogenesis of cystic fibrosis over the past 20 years and life expectancy has been greatly improved by a holistic approach to therapy. Mucus in cystic fibrosis patients is no more viscid than in chronic bronchitis. However, mucus-secreting glands throughout the body show morphological changes and the ducts of the glands are obstructed. The organs affected include the gut, pancreas, liver and reproductive tract. However, the most severe and life-threatening expression of the condition is within the lungs, which show evidence of small airway inflammatory change in infancy and subsequent susceptibility to infection with organisms such as Staphylococcus aureus and Haemophilus influenzas. Eventually most patients are infected with Pseudomonas aeruginosa. The cystic fibrosis gene was identified in 1989. It is located on the long 'arm' of chromosome 7 and encodes for the cystic fibrosis transmembrane conductants regulator (CFTR) protein. This protein is a member of the adenosine triphosphate (ATP)-binding cassette (ABC) family, which has two functions characteristic of this family of molecules: 1. It is a cyclic AMP-regulated chloride channel in the apical membrane of epithelial cells; mutations in the gene result in CFTR being either dysfunctional or wrongly localized; this impairs chloride transport across epithelial cells in the affected organs. CFTR mutations are amiloride-sensitive epithelium sodium channels causing increased sodium absorption. The epithelial cells of the respiratory tract and sweat ducts are relatively impermeable to chloride ions with a secondary increase in sodium transport; chloride transport in other cells such as erythrocytes, are normal. The ion transport abnormality leads to impaired local defence mechanisms in the respiratory tract and abnormal pancreatic secretions. The defect in the lung causes bacterial colonization, damage to the bronchial wall and bronchiectasis. Defective pancreatic secretion leads to a malabsorption syndrome, and blockage of the ducts with autodigestion of the pancreas results in diabetes mellitus in 10-20% of the adult patient population. The molecular mechanisms implicated in the lung disease are still a matter of debate. The 'high salt/defence' hypothesis suggests that missing or defective CFTR results in reduced transepithelial chloride conductants, allowing airway surface liquid (ASL) salt levels to remain close to plasma levels. The high salt concentrations may interfere with their epithelial cell-derived natural antibiotics, such as defensins, lactoferrin or 1

650

MCQ13.10

2

MCQ 13.11

TABLE 13,22 Clinical consequences of cystic fibrosis Neonates Meconium ileus Rectal prolapse Failure to thrive Recurrent bronchopulmonary infections

Older children and young adults Bronchiectasis Malabsorption Meconium ileus equivalent Infertility Cirrhosis and portal hypertension

lysozymes, and there is consequent bacterial colonization of the airway. 2. The low-volume hypothesis postulates that ASL is salt depleted because the abnormal CFTR is unable to inhibit EnaC. Therefore, there is depletion of the ASL volume leading to reduced mucociliary clearance and retention of mucus on the airway surface, which predisposes to chronic infection.

Clinical features and diagnosis The clinical presentation differs between neonates and older children and young adults (Table 13.22). Clinical examination of adolescents and adults usually shows finger clubbing secondary to chronic respiratory infection, retarded growth and development, and a hyperinflated chest with coarse crackles and wheezes. Gynaecomastia is occasionally seen, and there may be hepatosplenomegaly and other signs of chronic liver disease. The chest X-ray shows hyperinflated lungs and widespread bronchiectasis (parallel line and ring shadows, with multiple nodular opacities, mainly in the mid and upper zones; the hila are usually prominent). Lung function testing shows a progressive obstructive defect. The single most important diagnostic test is the sweat sodium, which is consistently greater than 70mmol/L in children with the disease and greater than 90mmol/L in affected adults, although the results in adults are less reliable. Sputum bacteriology will often yield S. aureus, and later in life Ps. aeruginosa becomes a major problem. Haemophilus may be an important pathogen, and patients occasionally develop tuberculosis. Prenatal diagnosis can be achieved by the measurement of elevated levels of enzymes such as alkaline phosphatase in the amniotic fluid or by DNA analysis of chorionic villus biopsies; these techniques are only of value for 'at-risk' pregnancies. Neonatal screening for immunoreactive trypsin in the blood is simple and inexpensive. The differential diagnosis includes hypogammaglobulinaemia, immotile cilia syndromes, asthma, coeliac disease and Schwachman's syndrome (pancreatic insufficiency, neutropenia, metaphyseal chondrodysplasia, growth retardation and frequent infections). 1

Management The outlook for patients with cystic fibrosis has improved, and predicted average survival for children born in the

1990s is now 40 years. These improvements have been achieved by aggressive physiotherapy, antibiotic treatment, pancreatic enzyme supplementation and dietary support. The cornerstone of treatment of respiratory disease is regular chest physiotherapy, particularly postural drainage. In the first year of life prophylactic antistaphylococcal drugs may be helpful. Severe infective exacerbations require intravenous antibiotics, usually antipseudomonal agents (e.g. gentamicin, ceftazidime, piperacillin, ciprofloxacin). As the disease progresses regular nebulized antibiotics are of value. To facilitate home care, some patients with repeated flare-up of infection have indwelling central venous lines and administer their own antibiotics. Bronchodilators, and occasionally oral corticosteroids, may be useful in patients with airflow obstruction. Pneumothoraces are not uncommon and should be treated conservatively whenever possible. Malabsorption is treated by oral pancreatic enzyme supplements. Abdominal emergencies occur, including adult meconium ileus equivalent, intussusception, acute pancreatitis and bleeding from oesophageal varices. Diabetes is common. Adult patients will need counselling about fertility, as 98% of the males are infertile (owing to maldevelopment of the vas deferens) and for females pregnancy can be hazardous. Patients and their family need constant moral, psychological and practical support. Genetic counselling of the parents of children with cystic fibrosis and of the patients themselves is essential. Gene therapy There are now many studies reporting gene therapy in cystic fibrosis patients. These have viral or non-viral vectors to deliver CFTR-cDNA topically to the nose or the lungs by aerosol or by liquid instillation. Although in theory the transfer of normal CFTR-cDNA into affected CF cells in early life should cause the production of enough normal CFTR to prevent the clinical manifestations of cystic fibrosis, technical problems with the vectors and the clinical response have meant that gene therapy is not yet curative. In particular, the target cell type, the target airways (large or small) and the barrier created by viscous mucus are proving difficult to overcome. Furthermore, it is not clear how much CFTR mRNA is necessary to get into cells to prevent disease. These topics are still the focus of intensive research and are likely to lead to important therapeutic advances in the relatively near future. The infected secretions in patients with cystic fibrosis contain abundant highly polymerized DNA released from dead and dying neutrophils. This contributes significantly to the increased viscosity of the secretions, and the development of recombinant human DNase (rhDNase) for inhalation helps to reduce sputum viscosity and assist clearance in selected patients.

Lung transplantation in cystic fibrosis Lung transplantation programmes around the world now

incorporate a significant number of patients with cystic fibrosis. Transplantation is reserved for those with the most advanced lung disease, and presents special difficulties. In particular because of the level of infection present the procedure is often complicated by postoperative sepsis, and this can be very difficult to manage. Furthermore, previous pleural disease or tracheostomies can either be contraindications or make the surgical techniques difficult. Live related lobar donor transplantation has also been carried out, with mixed success. Patients with cystic fibrosis who have advanced liver disease have had successful liver transplantations in recent years. Clearly, however, the best strategies for the treatment of cystic fibrosis and all its complications are preventative, and in the long term it is in this arena that the most success is likely.

13

FURTHER READING ON CYSTIC FIBROSIS AJRCCM 1995 Cystic fibrosis - from the gene to the cure. Am J Respir Crit Care Med 151(3) suppl. Range S P, Knox A J 1995 rhDNase in cystic fibrosis. Thorax 50:321-322. Wilmott R W, Fiedler M A 1994 Recent advances in the treatment of cystic fibrosis. Pediat Clin North Am 41:431-451.

ASTHMA

2

Bronchial asthma has been recognized since ancient times. Despite a recent improved understanding of its pathogenesis and consequent new treatments, morbidity and mortality from the condition remain a substantial clinical problem.

Definition The American Thoracic Society defines asthma as 'a disease characterized by increased responsiveness of the bronchi to various stimuli, manifested by widespread narrowing of the airways that changes in severity either spontaneously or as a result of treatment'. Asthmatics may be said to have 'twitchy' airways, and it is an essential feature of the resulting bronchoconstriction that it is usually reversible, at least in part, with the administration of inhaled bronchodilators. There are a number of non-specific trigger factors that can start an attack (Table 13.23).

TABLE 13.23 Non-specific 'trigger' factors in asthma Upper respiratory tract infection Exercise Cold air Laughter

Irritants: smoke, paint or chemical fumes Drugs, e.g. (3-blockers Industrial causes

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TABLE 13.24 Sensitizing chemicals and Industrial agents as a cause of asthma Material

Industry

Toluene diisocyonate (TDI) Soldering flux Cotton dust (byssinosis) Urine, serum, animal dander

Polyurethane industry Electrical, engineering industry Textiles Veterinary, agricultural and laboratory workers Bakers, millers Carpenters Chemical industry

Flour, grain Wood dust Sulphur dioxide, ozone, chloride

There are three components to asthma: the acute attack, the hyperresponsiveness of the airway to a heterogeneous variety of provocative stimuli, and persistent inflammation of the airways. Links between inflammation, hyperresponsiveness, and airflow obstruction are almost certainly central to the pathogenesis of asthma, but the mechanisms are not yet clearly defined. Much new information about the nature of the inflammatory infiltrate has been acquired from bronchial biopsies and lavage studies via the fibreoptic bronchoscope. Some late-onset asthmatics who have smoked may also have chronic bronchitis and are therefore difficult to classify, falling into the untidy category of 'asthmatic bronchitis'. Asthma caused by sensitizing chemicals and industrial agents is increasingly recognized (Table 13.24).

Epidemiology

652

Asthma is common, affecting between 5% and 7% of people in Europe and the United States. The peak age of onset is under 5 years, and in this age group it is more common in boys by a ratio of 3:2; over 5 years there is an equal sex ratio. There is an allergic component in one-third to half of all cases. About 2000 patients die from asthma in the UK each year, and it is likely that many of these deaths are preventable. There is a worldwide increase in the prevalence of allergy and asthma, especially in the developed countries. An international survey of asthma and allergy in childhood which assessed children aged 13-14 years demonstrated an over 20-fold difference in reported asthma symptoms worldwide. Symptoms were quite uncommon in eastern European countries and in Asia, and the highest prevalence was in the UK, Australia and New Zealand. There was a poor relationship between the incidence of allergic symptoms such as eczema and rhinitis and those of asthma, which might suggest that the risk factors are different or that they are following different time trends. Local environmental factors may play a part. In addition to the increasing prevalence there appears to be a trend towards increasing severity: in particular, in some countries such as New Zealand and Australia there is a

greatly increased hospital admission rate, and worldwide there is a steady increase in the use of anti-asthma medications. It is possible that environmental pollution and the consequent damage to protective epithelium may be contributing to this, allowing allergens to penetrate the airway lining. Furthermore, there have been disturbing epidemics of asthma deaths in recent years in England, New Zealand and elsewhere. It is possible that misuse and overreliance on inhaled (3-agonist bronchodilators may have played a part in these epidemics. Other risk factors for asthma mortality include cigarette smoking, previous hospital admission, and in particular admission to an intensive care unit, old age, social disturbance, ethnicity, dampness in the home environment, and the keeping of pets such as cats or dogs. Some of these factors may interact with and amplify other risk factors. There is one intriguing suggestion that lack of exposure to childhood viral infections (sometimes seen in single-child families) may actually predispose to the subsequent development of asthma.

Pathogenesis Cellular and molecular mechanisms in asthma About 70% of asthmatics have demonstrable atopy, with the production of specific IgE to environmental allergens, and positive skinprick tests with elevated serum IgE levels. Those who do not have atopy are labelled 'intrinsic'; they tend to have asthma that comes on later in life, are more commonly women, and may have aspirin sensitivity and nasal polyps. It is still a subject of speculation whether lowgrade allergy plays a part in intrinsic asthma. Inhaled allergens are critical to the initiation and perpetuation of airway inflammation in atopic individuals. Antigen-presenting cells are located in the bronchial epithelium and will present allergen to resident T cells, resulting in their activation and Th2 differentiation. Th2type cytokines (IL-4, IL-5, IL-10, IL-13 and GM-CSF) are derived from these activated T cells. The T cells also play an important part in the switching of B cells to IgE synthesis and mast cell survival, thus facilitating the inflammatory process by the activation and recruitment and stimulating survival of eosinophils in the airway. The hyperresponsiveness demonstrated in asthmatic airways correlates with severity, and these two factors in turn have been related to the numbers of activated eosinophils and T cells expressing IL-5 in asthmatic airways. Airway damage is one of the characteristics of asthma, and inflammatory mediators released by activated eosinophils such as MBP (major basic protein), ECP (eosinophil cationic protein) and LTC4 (leukotriene C4) play an important part in this. The role of the neutrophil is still being explored, but one important observation has been that in asthmatics dying suddenly from their disease, eosinophils are scarce in the airways but there is a marked neutrophil inflammation; in asthmatics whose death has been caused by a more indolent and slow downhill progression the eosinophil is the predominant inflammatory cell found in the airway at postmortem.

Bronchial 'hyperreactivity' appears to be the key to the asthmatic reaction. It is the unique property of asthmatic airways to react, by bronchoconstriction, inflammation and mucus production, to stimuli that would not elicit this reaction in normal airways. Possible mechanisms for bronchial hyperreactivity are listed in Table 13.25. There can be little doubt that immunological mechanisms (Ch. 4) play an important part in the asthmatic reaction (Fig. 13.28). Both immediate and delayed responses

TABLE 13.25 Mechanisms of bronchial hyperreactivity Inflammation, immunological liberation of bronchoconstrictor mediators Alterations in autonomic nervous control Abnormal ities of Ca 2+ flux Damage to epithelial 'tight junction'

are involved, and these can be demonstrated by the technique of bronchial provocation challenge testing. This is a method of provoking an asthmatic reaction in susceptible subjects by inhalation of antigens or chemicals. The immediate hypersensitivity reaction is mediated by degranulation of mast cells (Fig. 13.29). The mast cell degranulation is produced by the union of antigen with IgE antibody which is bound to the mast cell surface. Degranulation liberates a variety of substances, including preformed mediators and newly formed metabolites of arachidonic acid from the cell membrane (prostaglandins, leukotrienes etc.; see below). When asthmatic subjects are challenged with appropriate inhaled antigen and lung function is measured, they may show an immediate bronchoconstriction response within a few minutes. Lung function then returns towards baseline, but a further apparently unprovoked fall may occur 4-6 hours later.

FIG. 13.28 Interaction of inflammatory cells, inflammatory mediators and reflex mechanisms in the airway wall in asthma.

13

653

The early response is thought, in the main, to be due to the acute effect of histamine release from mast cells. The late response is more complex, mediated through the actions of inflammatory mediators such as leukotrienes and platelet-activating factor and the recruitment and activation of inflammatory cells. This highly complex pathogenic mechanism is the focus of much research, as it may represent a model for the ongoing inflammatory reaction in asthma and therefore be the target for antiinflammatory prophylactic drugs. Bronchial smooth muscle and secretions are regulated by neural mechanisms (Fig. 13.30). The balance of autonomic nervous control is important. The cholinergic vagal impulses have bronchoconstrictor and secretory actions. These effects are opposed by pYadrenergic receptors, which are bronchodilator and antisecretory. The (3adrenergic mechanism is supported by circulating cate-

cholamines. In patients with asthma, vagal reflexes may play an important part in bronchial hyperreactivity, particularly to stimuli such as cold air and exercise. Other mechanisms may play a part in bronchial hyperreactivity. Calcium flux across cell membranes is important for smooth muscle contraction and for mast cell degranulation, and agents that block this flux may prove to be useful in treatment. Finally, there is some evidence that the 'tight junction' between epithelial cells on the surface of the bronchial epithelium may be abnormally 'leaky', allowing antigen readier access to the mast cells underneath. It is therefore clear that no single mediator or mechanism is responsible for the asthmatic reaction, and research continues to elucidate this highly complex process. Pathology and pathophysiology The pathogenic mechanisms involved in asthma result in the histological changes shown in Figure 13.31. These changes can be acute or chronic. The sputum of asthmatics is often yellow and tenacious and contains many eosinophils, epithelial cells and bronchiolar casts ('plugs'). At postmortem in patients who die of acute asthma, many plugs are found in large and small airways.

Clinical features

FIG. 13.29 Mast cell mediators The release of preformed and newly formed mediators from mast cells involves calcium flux across the cell membrane, and in the case of the newly formed mediators, phospholipase A2 activation.

654

Asthma symptoms are episodic. Between attacks, patients, especially younger ones, may be asymptomatic and have no abnormal physical signs. The common symptoms of an asthma attack are cough, wheeze and breathlessness. Cough may be the only symptom, especially in children. Almost all asthmatics are worse at night and most will feel 'tight' in the morning. The fall in peak flow rate in the early hours of the morning is referred to as 'morning dipping' (Fig. 13.32). Acute asthma and sudden asthma deaths occur

FIG. 13.30 The control of airway calibre The balance of bronchodilatation from sympathomimetic p-receptor stimulation [A], and bronchoconstriction from parasympathetic vagal activity [B], is an important determinant of airway calibre.

TABLE 13.26 Clinical syndromes associated with asthma Eosinophilic syndromes Allergic bronchopulmonary aspergillosis Idiopathic pulmonary eosinophilia Tropical eosinophilia Churg-Strauss syndrome

13

Aspirin sensitivity and nasal polyposis Pericarditis Carcinoid syndrome

FIG. 13.31 The pathology of asthma Intense inflammation, with oedema and intraluminal mucous plugs, is the striking pathology of asthma.

contracting the accessory muscles of respiration. When the condition progresses despite active treatment, the patient is then said to have 'acute severe asthma' (p. 658). A number of clinical conditions are associated with asthma (Table 13.26). Allergic bronchopulmonary aspergillosis and other eosinophilic syndromes are discussed on page 660.

Investigation X-ray findings Most asthmatics have normal or hyperinflated lungs on chest X-ray. Mucus plugs can cause focal or segmental atelectasis, and sometimes collapse of a lobe or lung. Transient infiltrates are seen in association with eosinophilia. Spontaneous pneumothorax can complicate asthma in the acute phase.

FIG. 13.32 Peak expiratory flow rate (PEFR) in asthma The measurement of peak flow is essential for the management of asthma. PEFR is variable in asthmatics; it is lower in the early hours of the morning and on wakening ('morning dipping') and increases with p2 agonists (e.g. salbutamol). The chart is typical of a patient recovering from an episode of moderately severe asthma.

most frequently in the early hours of the morning. There is a personal or family history of allergy (rhinitis, conjunctivitis, eczema or urticaria) in up to 50% of patients. In many asthmatics, particularly in adult life, the airflow obstruction becomes persistent and somewhat resistant to treatment. This may be because 'remodelling' occurs in the asthmatic airway by the laying down of connective tissue inside and outside the airway wall and the proliferation of smooth muscle in the airways. Some of this may be related to epithelial damage activation and repair, but whatever the mechanism it does appear to be an important feature in the long-term pathogenesis of airflow obstruction. It is intriguing to speculate whether early treatment might prevent such morphological changes. In chronic asthma, particularly that which has persisted from childhood, there may be chest wall deformity. When asthma is severe the patient is distressed and vigorously

Other investigations Blood eosinophilia is common; it is usually greater in atopic asthma. Skinprick tests to common allergens may occasionally reveal an unsuspected source of allergy. Lung function tests may be normal between attacks. During episodes of asthma the PEFR, FEV1 and FEV1/VC ratio will be reduced and airways resistance increased. In addition to airflow obstruction the patient with acute or chronic asthma will have laboratory evidence of hyperinflation with increased total lung capacity (TLC), residual volume (RV), and ratio of RV to TLC. The transfer factor (diffusing capacity) for carbon monoxide is normal or increased in uncomplicated asthma. Hypoxaemia is common.

Diagnosis and management Recognition of asthma is not always straightforward. It is often missed in children who present with episodes of cough, wheeze and dyspnoea. Such 'wheezy bronchitis' in childhood is almost always asthma. The differential diagnosis of chronic asthma includes 'asthmatic' bronchitis, left heart failure, centrally obstructing tumour or foreign body, and recurrent pulmonary emboli. Asthma which repeatedly fails to respond symptomatically, or in terms of lung function improvement, to inhaled (3-agonists should

655

TABLE E 13.27

1. 2. 3. 4. 5. 6.

Six-part asthma management programme

Educate patients to develop a partnership in asthma management. Assess and monitor asthma severity with objective measures of lung function. Avoid or control asthma triggers. Establish medication plans for chronic management. Establish plans for managing exacerbations. Provide regular follow-up care.

always cause the diagnosis to be reconsidered. It may be difficult or impossible to distinguish late-onset asthma from chronic obstructive bronchitis in the elderly smoker. Many of them respond well to bronchodilators and have a better prognosis than patients with fixed airways obstruction. Supervision of chronic asthma is as important as in any serious chronic condition. Some hospitals run a very effective 'open-door' policy for asthmatics, allowing them to obtain immediate specialist advice whenever their asthma is severe. Education about the nature of the disease, the use of drugs and delivery systems, the avoidance of allergens and the recognition of deteriorating asthma are all important. Asthma can seldom be 'cured'. Long-term therapy is usually required, for prophylaxis or control, and it is critically important that this simple truth is appreciated by both the patient and the physician.

TABLE 13.28 Treatment of asthma Proven benefit

Dubious benefit

Potential benefit

Anticholinergics Disodium cromoglycate

Cough suppressants Potassium channel Mucolytics openers Phosphodiesterase Corticosteroids Vaccination inhibitors Calcium antagonists Sympathomimetics Antihistamines Ciclosporin A Prostaglandin analogues/ Tneophylline, aminopriylline Expectorants antagonists Leukotriene antagonists

Management

656

An international consensus report on the diagnosis and management of asthma recommended a six-part management programme (Table 13.27). Education includes the joint development of a treatment plan by the clinician and the patient, with guided self-management strategies. For the assessment and monitoring of severity, spirometry is recommended for the initial consultation and a period of home peak flow monitoring may also be useful. In advising the patient to avoid or control trigger factors, these must first be identified. Accurate identification and consequent avoidance may reduce symptoms, the need for medication and levels of airway hyperresponsiveness. Medication plans need to accommodate variability among patients, and a stepwise approach to drug therapy is now accepted worldwide (Fig. 13.33). It is important that patients are able to identify the symptoms of the onset of acute exacerbations and are given appropriate advice about what course to follow; following exacerbations, regular supervision and support by a clinician is essential. Treatment regimens (Table 13.28) can be broadly classified as long-term prophylactic treatment and treatment of exacerbations and acute severe asthma. Hyposensitization therapy (desensitization immunotherapy) is discouraged in the UK but widely practised throughout the world, despite little evidence of efficacy.

FIG. 13.33 The treatment of asthma

Drags of proven benefit Sympathomimetics (3-Agonists exert their action by stimulating the enzyme adenyl cyclase, which catalyses the formation of cyclicAMP within the bronchial smooth muscle cell (Fig. 13.30). All available pVagonists can be given by inhalation, which is the preferred route, and some by oral, i.v. and subcutaneous administration. Salbutamol and terbutaline are the two most commonly prescribed. Salbutamol is available in a metered dose inhaler (100 jig per dose), as a dry powder for inhalation ('Rotacap') for patients whose coordination is poor or for children, and as tablets, slow-release tablets, i.v. injection, a nebulizer solution and a syrup. Terbutaline is available in similar forms. Much research effort has been directed to the development of inhalers, such as 'turbohalers' that do not use fluorocarbon carriers, to comply with the proposed ban on the use of these chemicals.

Inhaler spacer devices can improve drug inhalation efficiency in patients unable to manage a conventional inhaler. With agonists, muscle tremor and tachycardia commonly occur, but tend to settle with prolonged usage. Longer-acting f^-agonists (e.g. salmeterol, formoterol) have been introduced, and may help control nocturnal symptoms. Leukotriene antagonists Leukotrienes are formed by the action of 5-lipoxygenase and 5-lipoxygenase activating protein (FLAP) on arachidonic acid to form leukotriene A4 (LTA4) which is in turn metabolized to leukotriene B4 or the cysteinyl leukotriene C4, leukotriene D4 and leukotriene E4 (LTC4, LTD4, LTE4). Leukotriene B4 is a powerful chemotactic agent, whereas the cysteinyl leukotrienes LTC4, LTD4 and LTE4 cause bronchoconstriction, increase mucous secretion, airway wall oedema, eosinophilia and increase bronchial hyperresponsiveness. These actions are of interest in the pathogenesis of chronic bronchitis and asthma; in particular, leukotriene B4 inhibition might reduce airway inflammation in chronic bronchitis and these studies are being pursued. However it was the role of the cysteinyl leukotrienes that generated most pharmacological interest and there are now specific cysteinyl leukotriene receptor antagonists such as montelukast, zafirlukast and pranlukast available for clinical use in asthma. There are data to show that they give good control of symptoms, inhibit exercise induced asthma, and are safe when given by the oral route. Additive effects to inhaled corticosteroids have also been demonstrated. Methyl xanthine derivatives (aminophylline and theophylline) Oral use is preferred in routine treatment, and intravenous use for acute asthma. Divided doses of slow-release theophyllines are effective and safe bronchodilators and they have prophylactic anti-inflammatory activity. These sustained-release formulations are useful when given at night for the prevention of nocturnal asthma and 'morning tightness'. Although 'therapeutic' serum theophylline levels of 10-20 mg/L have been targeted in the past, it is likely that levels as low as 3-5 mg/L have useful antiinflammatory actions. If excessive doses are given, or occasionally even when blood levels are in the therapeutic range, side-effects may occur. These include nausea, abdominal pain, headache, tremor, insomnia and palpitations, convulsions and cardiac arrhythmias. The dose administered should be reduced in elderly patients, those with liver disease, and those taking other drugs that increase theophylline blood levels (e.g. erythromycin). Anticholinergics Anticholinergic agents have proved to be of some value, particularly in older patients with late-onset asthma or 'asthmatic bronchitis'. Atropine can be delivered by inhalation in its methonitrate form from a nebulizer, although it is more convenient to administer the anticholinergics, ipratropium and oxitropium, as a metered-

dose aerosol. For patients optimally treated with inhaled pYagonists the additional benefit of anticholinergic drugs is seldom important.

13

Disodium cromoglycate It has been suggested that cromoglycate acts by 'stabilizing' the mast cell and preventing mediator release. However, modification of neural mechanisms may be equally important. Therapy is only effective when used on a regular prophylactic basis, and it has no intrinsic bronchodilator activity. Younger asthmatics tend to benefit most from its regular use, and it can also be used to 'block' exercise-induced asthma when administered about 20 minutes before planned exertion. Useful nasal and ophthalmic preparations are available for the treatment of hay fever. The drug has no serious side-effects. Corticosteroids Corticosteroids, probably by their anti-inflammatory action, are the most powerful drugs available for the treatment of asthma. Attitudes towards, and use of, Corticosteroids for the long-term management of asthma have been dramatically changed by the introduction of powerful, topically active fluorinated Corticosteroids for use by the inhaled route. Beclomethasone diproprionate, budesonide and fluticasone are most often prescribed. They enable asthmatics to be treated with low-dose inhaled corticosteroids, which are not absorbed in sufficient quantities to cause adrenal suppression or iatrogenic Cushing's syndrome, and are highly effective when used on a regular basis in the prophylaxis of asthma. Inhaled corticosteroid can also be delivered via a nebulizer. However, high doses for prolonged periods can cause side-effects, including osteoporosis. In some patients inhaled Corticosteroids predispose to oral Candida infection, but this can usually be easily controlled. If long-term oral Corticosteroids are essential for the control of asthma, patients should also be on maximum doses of inhaled Corticosteroids, thereby permitting the oral prednisolone dosage to be reduced by as much as 10 mg daily.

Inhaler therapy Many different inhaler devices are available. They include metered-dose inhalers (MDI), which traditionally used CFCs as a propellant, but which now, for environmental reasons, are being switched to CFC-free inhalers, using HFA (hydrofluoroalkane) carriers. MDI inhalers may be used with 'spacer' devices to facilitate use and improve airway deposition of the drugs. Breath-activated devices are useful aids to coordination. Many patients now use dry powder inhalers, which have the twin advantages of ease of use and being environmentally friendly. Nebulizer therapy Nebulizers can deliver pYagonists, anticholinergic drugs and, occasionally, Corticosteroids to the airways. They are increasingly used at home by patients with chronic airways obstruction, but in view of the large doses of drug used

657

(particularly pVagonists), such treatment requires careful assessment and supervision. It is important to document that nebulized bronchodilators confer a genuine advantage over maximal treatment with metered-dose inhalers. Summary of routine treatment of asthma Figure 13.33 illustrates the treatment strategy for asthma. Oral steroids are prescribed only when maximum therapy with all other drugs fails to control the disease. Selected patients with severe chronic asthma may be helped by immunosuppressive therapy (e.g. methotrexate). Treatment of acute severe asthma 1 The patient with acute severe asthma is distressed, dyspnoeic, and using accessory respiratory muscles; there are widespread inspiratory and expiratory wheezes and the chest is hyperinflated. When airways obstruction and bronchial plugging is severe and widespread, the flow of air through bronchi is greatly decreased and wheezing becomes less obvious, eventually resulting in the ominous 'silent chest' of advanced acute severe asthma. As the condition progresses, cyanosis, dehydration, exhaustion and ventilatory failure ensue. Indices of the severity of acute asthma are listed in Table 13.29. In the accident and emergency department, PEFR, heart rate and pulsus paradoxus (p. 620) are all related to asthma severity and should be documented with particular care. Arterial blood gas tensions should be measured in all patients whose asthma is sufficiently severe to require hospital assessment. Acute asthma requires immediate evaluation and treatment. Oxygen is necessary, and in almost all circumstances can be liberally administered without fear of CO2 narcosis. Salbutamol solution in a dose of 2.5-5.0mg can be given via a nebulizer and is usually very effective. This can be repeated 3-6-hourly as required. In addition, in very severe episodes, aminophylline is given in a dose of 5 mg/kg body weight intravenously over 20 minutes, to be followed by an infusion of 0.5mg/kg/h. In patients already taking theophyllines an infusion of aminophylline (0.5 mg/kg/h) can be started and the blood theophylline level checked. The dose of aminophylline is reduced if the patient is more than 55 years old, or if there is evidence of liver disease or cardiac failure. A theophylline blood level should be measured 18 hours after starting the infusion and the dose adjusted to remain within the therapeutic range of 10-20mg/L. If there are problems with venous access, subcutaneous terbutaline (0.25-0.5 mg) is helpful. Systemic corticosteroids must be given to all patients whose asthma is sufficiently severe to warrant hospital admission, and also to many less severe cases satisfactorily controlled in the emergency department. It is probably immaterial how corticosteroids are given; it may be as an i.v. bolus of hydrocortisone 3-6 mg/kg body weight fol-

TABLE 13.29 Indications of severe asthma Low PEFR (<150L/min, poor bronchodilator response) Associated with (one or more of): Vigorous accessory muscle activity Heart rate greater than 130 Pulsus paradoxus Arterial Po2 less than 8kPa (60mmHg) Arterial Pco2 greater than 5.5 kPa (41 mmHg) Gross overinflation (X-ray) Central cyanosis Disturbances of consciousness ECG abnormalities Pneumothorax/pneumomediastinum

lowed by an infusion of 3-6 mg/kg 6-hourly, or alternatively 60 mg of oral prednisolone for the average-sized adult. Supportive measures are also important. Patients with acute asthma become dehydrated. Physiotherapy is not helpful. Reassurance helps, but the best reassurance is improvement of the asthma. Sedatives should never be used unless intubation and mechanical ventilation are being contemplated. Antibiotics are prescribed if there is evidence of bacterial infection. Some patients fail to respond to treatment and become progressively more hypoxic. At the onset of an asthma attack patients hyperventilate and therefore have an acute respiratory alkalosis. As airways obstruction increases, exhaustion supervenes, ventilatory pump failure occurs, alveolar ventilation diminishes, CO2 rises and pH falls, leading to an acute respiratory acidosis. At this point the patient may require intubation and mechanical ventilation. Small tidal volumes should be used, and most asthmatics who need mechanical ventilation will need at least 48 hours on the ventilator to allow their asthma to respond to therapy. Bronchodilator and steroid therapy should be continued while the patient is being ventilated. Prognosis About 50% of children 'grow out of their asthma in early adult life. Late-onset asthma is almost always chronic, tends to be more severe, and usually needs more aggressive treatment. About 30% of asthma deaths occur within 2 hours of the onset of the acute attack, and these may be difficult to prevent. However, many of the remaining 70% of the 2000 deaths that occur annually in the UK should be preventable, by appropriate long-term therapy and the early recognition of deteriorating asthma.

ALLERGIC RHINITIS 1

658

MCQ 13.12

Allergic rhinitis (commonly known as 'hay fever', although it is not related to hay and there is no fever) is a condition

characterized by rhinorrhoea, nasal obstruction, sneezing, conjunctivitis, lacrimation, and nasal and pharyngeal itching. It is usually seasonal, with tree pollens being the allergen in the spring months and grass pollen in the summer. A perennial form occurs in those patients sensitive to allergens such as house dust, which are in the air all year round. Food allergy is an often quoted but clinically rare cause of rhinitis. Pathologically the mucosa of the nose is oedematous and inflamed, and the secretions are rich in eosinophils. Nasal polyps and sinus infection may be present, especially in the perennial type. The conjunctivae are congested and oedematous. The diagnosis is made by taking a careful history. Skinprick testing for a battery of common allergens is helpful. Serum IgE is usually elevated, and occasionally a radioallergoimmunosorbent test will help to define the allergen. The major differential diagnosis is from vasomotor rhinitis, which is a similar syndrome but with no documented allergic basis. Other conditions that may present in a similar fashion include exposure to irritants and repeated upper respiratory tract infections.

Management Although the symptoms of allergic rhinitis tend to improve as the subject gets older, they can, when active, be severe. Most of the relevant allergens are ubiquitous and therefore unavoidable. The first line of treatment is topical: nasal sprays or drops containing corticosteroids, such as beclometasone or budesonide, or disodium cromoglycate, are useful when used on a regular basis. Disodium cromoglycate eyedrops are also helpful for the conjunctivitis. These drugs can be supplemented by a non-sedating antihistamine by mouth, such as loratadine and fexofenadine or astemizole. The place of hyposensitization is debatable, and is usually reserved for isolated grass pollen allergy. Hyposensitization can be complicated by anaphylactic shock and should only be undertaken where resuscitation facilities are available. Occasionally a small dose of oral corticosteroids, e.g. prednisolone (10-15mg/day), or one or two injections of a depot corticosteroid during the season may be necessary.

FURTHER READING ON ASTHMA British Thoracic Society 1993 Guidelines on the management of asthma. Thorax 48 (2: suppl). The British Guidelines on Asthma Management 1995 Review and Position Statement. 1997 Thorax 52 (Suppl 1). Hall J B, Corbridge T C 1995 The assessment and management of adults with status asthmaticus. Am J Respir Crit Care Med 151:1296-1316. Holgate S 1993 Mediator and cytokine mechanisms in asthma. Thorax 48:103-109. Monson J P 1993 Systemic effects of inhaled corticosteroids. Thorax 48:955-956.

TABLE 13.30 Classification of pulmonary eosinophilia Known causes Fungal allergy Aspergillus fumigatus Candida albicans Stemphylium canugenosum Dresclera lawaiiensis Curvularia lunata Helminosporium Helminthic infections Ascaris lumbricoides (Lb'ffler's syndrome) Strongyloides Filaria ('tropical pulmonary eosinophilia') Ancylostoma

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Drugs and toxins Sulphonamides (including sulphasalazine) Nitrofurantoin Sodium aminosalicylate Penicillin Tetracycline Chlorpropamide 'Spanish toxic oil' syndrome Inorganic chemicals (e.g. nickel) Lymphangiography Blood transfusion

Unknown causes Simple pulmonary eosinophilia Chronic eosinophilic pneumonia Acute eosinophilic pneumonia Churg-Strauss syndrome Idiopathic hypereosinophilia syndrome

PULMONARY EOSINOPHILIA Pulmonary eosinophilia is a transient pulmonary infiltrate associated with an elevated blood eosinophil count. A cause can only be identified in some cases (Table 13.30). The blood eosinophil count is elevated above its normal upper level of 400/mm3 and may in some circumstances be as high as 50000/mm3. The serum IgE level is usually elevated in those cases with an identifiable cause, especially the allergic mycoses. Asthma is almost always present in cases of allergic bronchopulmonary aspergillosis, occurs in about half the patients with cryptogenic pulmonary eosinophilia, and is unusual with helminth infections apart from filariasis.

Pathogenesis The eosinophil has cytotoxic and anti-inflammatory properties. The cytotoxic properties act against parasites but may also damage host tissues. The pathological response to the various identifiable causes of pulmonary eosinophilia depends on the route by which they reach the lungs; if inhaled (e.g. allergic mycoses) the response is in the airways (bronchocentric), whereas if delivered to the lung via the pulmonary circulation the response is in the blood vessels (angiocentric).

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Allergic bronchopulmonary mycoses By far the commonest cause in developed countries is allergic bronchopulmonary aspergillosis (ABPA). This is due to sensitivity to the ubiquitous fungus Aspergillus fumigatus. This fungus thrives in warm, wet conditions, and symptoms therefore tend to occur in the autumn. The bronchial tree provides an ideal environment for colonization. When the fungus is inhaled there is an immediate hypersensitivity reaction, with eosinophils being drawn into the area. There may be several responses thereafter: • A simple asthmatic reaction with an eosinophilia but no radiological change; • Pulmonary eosinophilic infiltrates with consolidation and chest X-ray shadowing; • Mucus impaction with distal collapse and progressive airway damage due to the release of tissue-damaging factors; this in time may lead to a characteristic proximal bronchiectasis and upper zone fibrosis (Fig. 13.34), sometimes making it difficult to differentiate ABPA from old tuberculosis. Clinically, ABPA presents, often in early adult life, as worsening asthma. The patient may complain of coughing up rubbery brown or green plugs, and exacerbations of asthma are often accompanied by fever and fleeting pulmonary infiltrates. Almost all patients have a positive immediate-type hypersensitivity to Aspergillus fumigatus on skinprick testing, and about 90% have precipitating antibody. Treatment with oral prednisolone (30-40 mg/day) leads to rapid symptomatic and radiological improvement; whether or not it affects the long-term outcome is uncertain. Physiotherapy and occasionally bronchoscopy help to remove troublesome plugs, and the asthma responds to conventional treatment, usually including inhaled steroid. Many patients require a small maintenance dose of oral prednisolone to prevent relapse. Drugs and toxins There are a wide variety of drugs and toxins which can cause a pulmonary eosinophilic syndrome (Table 13.30). The drug reaches the lung via the pulmonary circulation and sets up an allergic reaction in the vessel wall. There is frequently an associated skin reaction. Patients may present with a pneumonia-like illness, with dyspnoea, cough, fever and pleuritic pain, or as a pulmonary vasculitis. Rarely, if the subject is exposed over a prolonged period, a type of fibrosing alveolitis develops. Whatever the progression, fleeting chest X-ray shadows and blood eosinophilia will be present. Almost all cases improve if the offending agent is stopped, and oral corticosteroids help speed recovery.

1

660

MCQ 13.13

2

MCQ 13.14

FIG. 13.34 [A] Chest X-ray of a patient with allergic bronchopulmonary aspergillosis and asthma, showing acute right upper zone shadowing. This shadowing resolved with steroid therapy. [B] A subsequent CT scan demonstrates right upper lobe bronchiectasis - dilated, thickened bronchi (arrow).

Helminthic infections Some helminths (Ascaris, Strongyloides, Toxocard) are borne to the lungs via the circulation, where they are attacked by eosinophils. During this phase the patient may be febrile and have pulmonary infiltrates, and the dying parasite may initiate an allergic response and thus an asthmatic attack. Filarial infection (e.g. with Wuchereria bancrofti) may cause asthma, and patients can also develop diffuse fibrosis and pulmonary hypertension. The chest X-ray in helminthic infections shows widespread nodular infiltrates which are at first transient but may become persistent. The diagnosis is confirmed by appropriate complement fixation tests and by finding ova in the stools (see also Ch. 9). 1

Unknown causes There is a spectrum of conditions of unknown aetiology that cause fleeting eosinophilic infiltrates in the lung and a blood eosinophilia. Pathologically, these range from a localized or generalized pulmonary eosinophilia to eosinophilic syndromes with vasculitis and granuloma formation. Classification is difficult; the most important distinction is between the clinical syndrome of cryptogenic pulmonary eosinophilia and those syndromes associated with vasculitis and granuloma formation. Cryptogenic pulmonary eosinophilia (eosinophilic pneumonia) Cryptogenic pulmonary eosinophilia is a syndrome of fever, weight loss, cough and breathlessness, with widespread, mainly peripheral, pulmonary infiltrates (Fig. 13.35) and a marked blood eosinophilia. The patient is usually non-atopic, but 10% have previous asthma. No cause can be identified. Some patients progress to a vasculitic/granulomatous type of disease. There is a rapid response to oral corticosteroids; treatment should be carefully tailed off, as recurrences are common, and usually corticosteroid treatment for up to 2 years is required. Allergic angiitis and granulomatosis This is a rare group of conditions in which allergic asthmatic patients present with symptoms similar to those of cryptogenic pulmonary eosinophilia. Radiologically they may show extensive transient pulmonary infiltrates, nodules, cavities, and occasionally pleural and pericardial

FIG. 13.35 Pulmonary eosinophilia Extensive, ill-defined peripheral consolidation in the left upper zone and less marked consolidation in the left lower zone in a patient with cryptogenic pulmonary eosinophilia. Characteristically, new shadows appear and previous ones resolve spontaneously.

effusions. There is a blood eosinophilia and a raised erythrocyte sedimentation rate and raised serum IgE, and about 50% of patients will have a positive ANCA. Lung biopsy shows a vasculitis, and if there is an allergic granulomatous reaction this is known as the Churg-Strauss syndrome, although there is probably a broad spectrum of pathological overlap in these syndromes. In many ways the syndrome is similar to polyarteritis nodosa, although lung involvement in typical polyarteritis nodosa is rare. There have been reports of the development of the ChurgStrauss syndrome in patients receiving treatment for asthma with leukothriene receptor antogonists; it is likely, however, that this is an 'unmasking' phenomenon caused by withdrawal of oral corticosteroid therapy. Other organs, such as the liver, spleen, heart, skin and central nervous system, may be affected by the vasculitis but, unlike in polyarteritis nodosa, renal involvement is uncommon. Treatment with prednisolone in high doses, with or without azathioprine or cyclophosphamide, significantly reduces mortality, although infective or cardiac complications may still be fatal. About half the patients with this condition will die within 3 months without corticosteroid therapy. Adequate treatment increases mean survival time to 2 years.

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CHRONIC BRONCHITIS AND EMPHYSEMA 2 Chronic bronchitis Chronic bronchitis is a clinical diagnosis in which there is cough productive of sputum on most days for 3 months of the year for 2 or more years, which is not due to a specific respiratory disease such as bronchiectasis. The disorder is characterized by excess mucus secretion. Pathologically there is hyperplasia and hypertrophy of the tracheal and bronchial mucus glands and an increase in the glandular elements of the bronchial wall. There is also inflammation, and eventually fibrosis, of small airways. The increase in intraluminal mucus and thickening of the bronchial wall produce airways narrowing and increased resistance, the fall in FEV1 correlating with the increase in mucous membrane thickness. Emphysema Emphysema is denned by its pathology and is characterized by the destruction of respiratory tissue and permanent enlargement of the unit of the lung distal to the terminal bronchiole (the acinus). The injury to alveolar septa is caused by proteolysis. Lung tissue is normally protected by a shield of proteinase inhibitors, derived from the blood but also synthesized locally. When the proteinase-antiproteinase balance is disturbed, favouring proteolytic activity, elastin destruction and septal digestion occur. The consequences of this are loss of the 'tethering' support of airways, leading to collapse on expiration and

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reduction of lung elastic recoil and pulmonary capillary bed. In the past much importance has been placed on the distinction between chronic bronchitis and emphysema. In the majority of patients both conditions coexist, usually in heavy cigarette smokers, and the physician therefore makes a clinical diagnosis of chronic bronchitis and emphysema.

Aetiology and prevalence Chronic bronchitis and emphysema are responsible for the personal disability and misery of tens of thousands of patients and impose a huge social and economic burden on society. Respiratory disorders are an important cause of death in the UK and, of these, chronic bronchitis and emphysema constitute a large proportion. In the UK 10% of absences from work are caused by chronic bronchitis and emphysema, and approximately 10% of occupancy of acute general medical hospital beds is the result of these diseases. Atmospheric pollution and occupational dust exposure are minor aetiological factors in chronic bronchitis; the dominant causal agent is cigarette smoke. For symptoms and physiological changes to be demonstrated it probably needs a smoking history of 20 pack years. Smoking also causes emphysema, probably damaging the lung by the release of proteolytic enzymes. Smoke-affected pulmonary alveolar macrophages, present in greater numbers than usual, release neutrophil chemotactic factor and the attracted neutrophils are damaged by smoke and release proteolytic enzymes, especially elastase, capable of lysing elastin, collagen and basement membranes. The effectiveness of oci-antitrypsin is impaired by smoking and the unchecked proteolysis results in centrilobular emphysema. This process is particularly rapid in patients who are deficient in aj-antitrypsin. Overall severity of airways obstruction is related to the number of cigarettes smoked.

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a-Antitrypsin deficiency This genetic disorder affects one in 5000 people, is equally common in men and women, and predisposes to the early development of emphysema, often before the age of 40. The emphysema is panlobular and basal (Fig. 13.14) and lung destruction is accelerated by cigarette smoke. Nonsmoking heterozygotes do not have emphysema, but it is possible that smoking heterozygotes develop emphysema more readily than smoking normals. Heterozygotes have about 60% of normal ocrantitrypsin values and homozygotes have values of < 10%. oci-Antitrypsin appears to inhibit neutrophil elastase, but more recent studies have suggested that several enzymes and inhibitors are involved in the proteinase-antiproteinase balance in the lung. The feasibility and clinical value of arantitrypsin replacement therapy is under investigation. Some patients with advanced disease have been managed by lung transplantation.

Mechanism of airflow obstruction In chronic bronchitis and emphysema the fundamental cause of reduced ventilatory capacity and breathlessness is the limitation of expiratory airflow (p. 608). Secondary to expiratory limitation, residual volume is increased, the thorax is hyperinflated and inspiratory capacity is markedly impaired, in part because of the compromised function of the inspiratory muscles. In chronic bronchitis airways resistance is increased and expiratory airflow reduced by the thickening of the bronchial wall and excessive intraluminal mucus. In emphysema a more important mechanism is the narrowing and collapse of airways during expiration, as a consequence of loss of the lung elastic recoil which normally keeps them open.

Clinical features Chronic bronchitis and emphysema develop over many years and patients are rarely symptomatic before middle age. Symptoms are initially minor, perhaps a morning cough productive of a little sputum. In some patients chronic bronchitis can remain a trivial problem, but in many smoking-related airways obstruction coexists and the patient then develops breathlessness. Initially breathlessness is on exertion, but exercise capacity progressively and slowly deteriorates and eventually patients become respiratory cripples, distressed by dyspnoea even at rest. Patients with predominant bronchitis are prone to periodic infections. Often the infective process remains confined to the bronchial tree, but sometimes infection involves the surrounding lung, with consequent pneumonia; thus, although some patients may have radiological changes of pneumonia in association with an infective exacerbation, the majority show no change on chest X-ray. Eventually patients with chronic bronchitis develop severe hypoxaemia, hypercapnia and peripheral oedema-cor pulmonale (the so-called 'blue bloater'). Patients with substantial emphysema tend to be very breathless, ventilating sufficiently to maintain normal arterial carbon dioxide and near-normal oxygen tensions. The development of cor pulmonale is a late and terminal event in these 'pink puffers'. These two clinical extremes overlap; many patients with a normal arterial carbon dioxide tension eventually become cyanosed, but the broad clinical distinction between the 'pink puffer' and the 'blue bloater' is useful. Oxygen therapy is much more difficult in the hypercapnic blue and bloated patient, sedation is more hazardous, and general anaesthesia poses greater risks because of postoperative sputum retention and difficulty in weaning such patients from assisted ventilation. Some patients have bronchial hyperreactivity, and exposure to cold air, acute temperature changes, dusts and cigarette smoke causes increasing breathlessness, respiratory distress and wheeze. The development of cor pulmonale indicates a poor prognosis, with a 30% 5-year survival. In association with severe hypoxia and hypercapnia, pulmonary arterial hypertension develops and some patients also have an ele-

vated jugular venous pressure. However, in many patients cor pulmonale is not simple cardiac failure, as cardiac output is frequently normal and there can be peripheral oedema without elevation of the jugular venous pressure. The mechanism of cor pulmonale remains obscure, but in part it reflects an increase in blood volume, perhaps due to hypercapnia and hypoxia causing sodium retention by the kidney. Cor pulmonale is unusual in the absence of hypercapnia. There is evidence that optimum therapy and careful follow-up of patients with cor pulmonale can produce good results. Physical signs In predominantly emphysematous patients, inspiratory airways resistance is not increased and inspiration is therefore quiet, whereas patients with predominantly chronic bronchitis have noisy breathing. To control airways collapse on expiration, patients with emphysema apply a positive pressure to the bronchial tree by the technique of purse-lipped breathing. As the diseases progress the physical signs may eventually include those of severe airways obstruction, hypoxia, hypercapnia and cor pulmonale. Severe hyperinflation is indicated by a reduction in the distance between the suprasternal notch and the cricoid cartilage, a barrel-shaped chest, and reduced abdominal outward movement during inspiration (reflecting limited

FIG. 13.36 Bullous emphysema The large bullae (right upper zone, right lower zone peripherally) display no vascular markings. Elsewhere the lung markings appear obvious, partly because of increased blood flow through relatively normal lung and partly because bullae compress adjacent lung tissue.

descent of the flattened diaphragm) coupled with pronounced movement of the upper chest. Patients with chronic airflow limitation often have early inspiratory crackles which can be heard at the mouth by the examining physician. Weight loss is common with advanced emphysema. Patients with emphysema have translucent lungs on chest X-ray, with few vascular markings, and bullae may also be present (Fig. 13.36). CT scanning is a sensitive technique for detecting emphysema (Fig. 13.37). Patients with predominantly chronic bronchitis may show bronchial wall thickening. Hyperinflation is more severe in emphysema. Commonly, radiological abnormality is most striking in the upper zones, but in cti-antitrypsin deficiency disease is predominantly basal.

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Respiratory function Many respiratory function tests designed to detect early COPD in the lung have been investigated. These include tests of 'small airways disease' which, although sensitive, have not been found to be useful in clinical practice. The forced expiratory volume in one second (FEV)) remains the single most useful indicator of airflow obstruction and correlates well with long-term prognosis. Furthermore, decline in FEV1 is significantly reduced by stopping smoking, although it never returns to normal predicted levels (Fig 13.40). In patients with chronic bronchitis and emphysema the FEV1 is reduced and the FEV1/VC% is low, indicating expiratory flow limitation (p. 608). VC for a relaxed manoeuvre is usually greater than for a forced effort. The PEFR, although low, is a less sensitive measure of the

FIG. 13.37 CT scan demonstrating diffuse emphysema, with multiple translucent areas (arrowed).

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severity of airways obstruction. Hyperinflation is confirmed by the increase in RV and TLC. Gas transfer is more dramatically reduced in the 'pink puffer' with a substantial element of emphysema. In the 'blue bloater' there is severe hypoxaemia, hypercapnia and sometimes secondary polycythaemia.

Management Restoration of normal function is not possible in chronic bronchitis and emphysema. The aim of therapy must therefore be to reduce disability by tackling the interrelated problems of airways obstruction, recurrent infections, breathlessness, hypoxia and poor exercise tolerance. Factors aggravating chronic bronchitis, particularly cigarette smoking, must be withdrawn.

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Airways obstruction Conventionally the airways obstruction of chronic bronchitis and emphysema is regarded as being irreversible. However, the majority of patients show some improvement in lung function with therapy directed at relaxing bronchial smooth muscle and, although small, this improvement can have an important impact on the disability of these patients. Prognosis in patients who respond well to bronchodilators is considerably better than for those with completely fixed obstruction. The most important bronchodilator agents are the selective pYadrenergic agonists (e.g. salbutamol and terbutaline), which are best administered by inhalation. For some patients maximal bronchodilatation requires a large drug dose and may be best administered by nebulizer (e.g. salbutamol 2.5-5 mg). Inhaled atropine analogues (ipratropium and oxitropium) can be helpful but, provided optimum doses of (32 agonists are administered, confer little additional benefit. Oral theophyllines available in slow-release formulation are of marginal use in chronic bronchitis and emphysema. It had been claimed that theophylline improved respiratory muscle contractility, but subsequent studies did not confirm this effect. Patients with severe airways obstruction should have a therapeutic trial of steroids - for example oral prednisolone (30 mg daily) for a period of 2-3 weeks - provided there are no contraindications. For patients in whom oral steroids pose problems (e.g. diabetes) a period of highdose inhaled steroid is appropriate. Long-term oral steroids will not be indicated in most patients but, when prescribed, require regular assessment; dosage should seldom exceed 7.5-10 mg daily, thereby minimizing drug complications. Steroid-responsive patients should be treated with inhaled steroid. Although inhaled corticosteroids are extensively prescribed for COPD, there are no data to suggest they affect the long term decline in lung function. When given systemically, they are valuable in acute exacerbations. There is some recent evidence to suggest that mucolytic agents such as acetyl cysteine may be beneficial in reducing the numbers of exacerbations of

chronic bronchitis. Early studies of leukotriene receptor antagonists and specific phosphodiesterase inhibitors are encouraging. Infection In acute exacerbations of chronic bronchitis an infective viral or bacterial pathogen is isolated in less than 50% of cases. However, viral infections are frequently complicated by bacterial overgrowth and the majority of patients develop purulent sputum. Severe exacerbations have a mortality of up to 25%, and prompt antibacterial therapy is of the greatest importance. Common infective organisms are Strep, pneumoniae and H. influenzae, and suitable antibiotics are amoxycillin, erythromycin, clarithromycin, azithromycin, macrolide antibiotics, ciprofloxacin and the cephalosporins. For most patients long-term chemoprophylaxis is not helpful, but if intermittent treatment fails a trial of continuous rotating antibiotic therapy is appropriate. Regular immunization against influenza is sensible, and pneumococcal vaccine should be administered every 3 years. Oxygen therapy During an acute exacerbation of chronic bronchitis and emphysema, oxygen therapy is necessary to avoid death from hypoxia. In patients with hypercapnia oxygen must be given at low and controlled concentrations (usually 24% or 28% O2). A more contentious question is the value of long-term domiciliary oxygen therapy. Studies suggest that long-term controlled oxygen therapy can benefit patients with airways obstruction who have severe hypoxia and who refrain from smoking cigarettes. It is necessary to administer oxygen virtually continuously, including during sleep. Long-term follow-up of domiciliary oxygen therapy in severe COPD demonstrates that the treatment can prolong mean survival by 5 years. The administration of continuous oxygen presents considerable practical and financial difficulties. Oxygen may be supplied in cylinders, as a liquid, or, preferably, generated by an oxygen concentrator. This therapy should be reserved for patients with severe disease who are well motivated. Oxygen therapy requires careful pretreatment assessment and long-term supervision. In practice, much oxygen used by patients in their homes is for a few minutes only and the main purpose is to relieve breathlessness. Oxygen is also available in small portable cylinders, and some patients find this helpful in reducing breathlessness on exercise, improving exercise capacity, and permitting excursions from the home. Many different techniques of delivering oxygen, including transtracheal catheters, are available. Patients with severe chronic bronchitis and associated hypoxia, hypercapnia, pulmonary hypertension and cor pulmonale have profound nocturnal hypoxaemia (Fig. 13.38). This hypoxaemia is much more a feature of the 'blue bloater' than of the 'pink puffer'. Much of the hypoxia is caused by hypoventilation and irregular breathing patterns during rapid eye movement (REM) sleep, and

6 weeks will also reduce the haematocrit. Whenever possible the first-line therapy for secondary polycythaemia is to improve lung function.

FIG. 13.38 Oxygen saturation during sleep in severe chronic bronchitis Patients who are already hypoxic can markedly desaturate during sleep, particularly REM sleep (vertical bars).

is not due to obstructive sleep apnoea (p. 668). Oxygen therapy during the night (2L/min by nasal cannulae) can alleviate hypoxaemia and make hypoxic periods less severe. The return of normal breathing patterns following REM sleep is impaired by sedatives, and these should therefore be avoided in patients with chronic bronchitis. The non-sedative tricyclic drug protriptyline reduces time spent in REM sleep, and can improve nocturnal hypoxaemia in some patients. Drug therapy for breathlessness In patients with airways obstruction it is the 'pink puffers' with normal CO2 values and mild or moderate hypoxia who are most breathless. In some patients reducing ventilation with diazepam, promethazine and dihydrocodeine can reduce breathlessness, and in patients without carbon dioxide retention a careful trial of such therapy is justified when symptoms are severe. For the devastating dyspnoea which is frequently a feature of terminal respiratory failure, diamorphine is helpful whatever the cause. Secondary polycythaemia Polycythaemia produces symptoms attributable to hyperviscosity, including somnolence, lethargy, poor concentration and headache. Venesection reduces these symptoms but does not affect lung function or blood gases. Venesection also improves cerebral blood flow, pulmonary hypertension and exercise tolerance. Patients with a haematocrit of 0.60 or more should benefit, and the haematocrit should be reduced to 0.50. This can be achieved either by simple venesection, exchange transfusion with dextran or plasma, or erythropheresis. Continuous oxygen therapy for

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Chest physiotherapy There have been few scientific studies of the long-term effect of chest physiotherapy techniques aimed at improving breathing patterns in patients with chronic bronchitis and emphysema; no benefit has been proven. Postural drainage is of undoubted benefit in patients with excessive bronchial secretions. Its effectiveness is increased by coughing or forced expiratory manoeuvres ('huffs'). Postural drainage has little place if patients do not have sputum. Vigorous physiotherapy, especially forced expiratory manoeuvres, can increase bronchoconstriction in asthma. During acute exacerbations of bronchitis and pneumonia several studies have, rather surprisingly, shown no benefit from physiotherapy. In the absence of excessive secretions physiotherapy is not justified in these patients. Mucociliary clearance is decreased and basal collapse is more common following general anaesthesia and surgery, particularly of the upper abdomen. The case for routine preoperative physiotherapy in chronic bronchitis patients is, however, not proven except for very high-risk patients. Pulmonary rehabilitation The evidence base for pulmonary rehabilitation in patients with chronic lung disease, especially COPD, is now strong. Rehabilitation can reduce breathlessness, improve quality of life and probably reduce overall requirements for health care (see Recent Advances). Assisted ventilation in chronic bronchitis Patients with severe progressive chronic bronchitis and emphysema eventually die of intractable ventilatory failure, having been breathless at rest and confined to their homes in the months before death. Their poor quality of life precludes such patients from being treated with mechanical ventilation to delay the inevitable outcome. Difficult decisions are posed by the less severely disabled, who require mechanical ventilation if they are not to die during an acute exacerbation of bronchitis. Many of these patients are difficult to wean from ventilation, particularly those with pre-existing hypercapnia and blunted ventilatory response to CO2. Before embarking on mechanical ventilation, every effort must be made to establish the background severity of respiratory disability, exercise tolerance and quality of life. For selected patients, non-invasive nasal positive-pressure ventilation is useful (p. 723). Cessation of cigarette smoking Tobacco smoke damages the bronchial tree and produces airflow limitation by a number of different actions. Smoke impairs mucociliary clearance and causes bronchial smooth muscle to contract by stimulating receptors and provoking the release of inflammatory mediators. In

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RECENT ADVANCES IN PULMONARY REHABILITATION Patients with chronic lung disease, most commonly COPD, are greatly limited by breathlessness and become locked into a downward spiral of deteriorating performance. As a consequence of their disease, any physical exertion causes breathlessness and patients therefore reduce their activities. This immobility leads to severe cardiorespiratory deconditioning and atrophy of skeletal muscle. As a consequence of these physiological changes, secondary to reduced mobility, any exercise invokes exaggerated production of lactate and CO2, which in turn increases ventilatory requirements and breathlessness. The excessive breathlessness further reduces mobility, and so on (Fig. 13.39). The abnormalities that develop in skeletal muscle, particularly the muscles of the legs, are striking and may reflect hypoxia, hypercapnia, poor nutrition and systemic factors, as well as disuse. A number of controlled clinical trials and metaanalyses have demonstrated that pulmonary rehabilitation can reduce breathlessness, increase exercise capacity and enhance quality of life. Rehabilitation programmes typically include education about the relevant disease and its therapy, and exercises (walking, cycling, leg and arm exercises). A usual programme would consist of 1-2 hours of exercise, two to three times a week for 8-12 weeks, delivered on an outpatient basis. The mechanisms underlying the undoubted benefits that most patients experience with pulmonary rehabilitation are not clear. Patients are unable to exercise with sufficient intensity to achieve large physiological improvements in respiratory or cardiac parameters. It is likely that the benefits are due in part to physiological improvements and in part to increased confidence and control of symptoms by patients. Ongoing clinical studies are seeking to identify those patients most likely to benefit, to define the most effective methods of rehabilitation, to determine the most cost-effective way of delivering programmes, and to determine the best way to maintain benefit. However, at present pulmonary rehabilitation is arguably the most effective intervention available for many patients with moderate/ severe COPD (and who have previously stopped smoking).

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addition, smoke increases mucus production and causes mucous gland hypertrophy. Smokers are predisposed to bronchial infection and consequent inflammation; the increase in elastase and the impairment of arantitrypsin, as well as impaired surfactant production, contribute to emphysema. It is therefore not surprising that chronic bronchitis and emphysema are found in 15% of middleaged males who smoke moderately or heavily but are rare

in non-smokers, and that deaths from bronchitis increase with the amount smoked. If patients with chronic bronchitis and emphysema stop smoking, the rate of decline in pulmonary function is reduced to that of non-smokers (Fig. 13.40). Indeed, if patients stop smoking early in their disease there is an improvement in pulmonary function. However severe the disease, stopping smoking will reduce cough. About half of regular long-term smokers die from smoking-related diseases. In middle age, smoking is responsible for 30% of all deaths in western countries: a tragic and avoidable epidemic. Deaths are from many

FIG. 13.39 The downward spiral of progressive disability in patients with chronic lung disease

FIG. 13.40 Airflow limitation and smoking FEV, declines with age. In smokers this decline is more marked, particularly in 'susceptible' smokers. Such patients, therefore, become breathless in middle or old age. When smokers stop the habit, the rate of decline in FEV! is markedly slowed. (From classic study of Fletcher C M, Peto R 1997 Br Med J; 1:1645.)

RECENT ADVANCES IN NON-INVASIVE POSITIVE-PRESSURE VENTILATION (NIPPV) Many patients with chronic ventilatory failure due to stable neuromuscular disease, for example kyphoscoliosis or weakness from past poliomyelitis, can be effectively treated by intermittent long-term mechanical ventilation, usually within their own homes. In the past such ventilatory assistance was provided by negativepressure devices, including tank ventilators (the 'iron lung') and cuirasses, or by positive-pressure ventilators via a tracheostomy. Now most of these patients are managed with nocturnal non-invasive positive-pressure ventilation, via a nasal mask. Nocturnal NIPPV is often highly successful. The technique is well accepted by patients, enhances their quality of life and improves ventilatory failure. Often patients lead normal active lives by day while receiving NIPPV by night. The key to success is that NIPPV controls the severe hypoventilation and hypercapnic acidosis that would otherwise occur during sleep, and this restores normal ventilatory control by day. The end result is that for many patients chronic respiratory failure is substantially or completely reversed, and this improvement can be sustained for many years. The success of NIPPV in the management of selected patients with chronic ventilatory failure has led to its use in other clinical settings. Increasingly, NIPPV is being used in the management of acute exacerbations of chronic obstructive pulmonary disease (COPD). Controlled clinical trials - performed in the UK, France and North America - have demonstrated that NIPPV can improve blood gases, reduce the need for intubation, and reduce mortality in patients admitted with severe acute COPD. NIPPV is a flexible treatment: hours spent on the ventilator can be varied from day to day and the therapy can be easily stopped and just as easily restarted. In those patients with COPD in whom it is felt that intubation and mechanical ventilation on the intensive care unit is not appropriate, because of age or severity of underlying disease, NIPPV should be considered: it may be life-saving. In those patients in whom intubation would be appropriate, NIPPV should also be considered as the first treatment option because it may avoid the need for intubation and ICU care. The success of NIPPV has resulted in increasing numbers of patients being treated by the technique, and this is a trend that is likely to continue.

TABLE 13.31 Smoking-related diseases • Cancer (lung, mouth, pharynx, larynx, oesophagus, bladder, renal pelvis, pancreas) • Chronic bronchitis and emphysema • Coronary heart disease • Peripheral vascular disease • Cerebrovascular disease • Gastric and duodenal ulceration • Crohn's disease • Osteoporosis • Fetal and neonatal death • Childhood disorders from passive smoking (respiratory infections, 'glue' ear)

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cian (and other medical staff) is effective and is most likely to work when the patient is unwell. In patients who are determined to stop smoking, nicotine replacement therapy by gum, nasal spray or transdermal patch can be helpful. Nicotine replacement therapy approximately doubles the chance of a patient stopping smoking. Clinical trials have also demonstrated the efficacy of bupropion, although its mechanism of action is not clear. Increased appreciation that the key problem is nicotine addiction will hopefully lead to better nicotine replacement therapies becoming available. In the UK nicotine replacement therapy is available on prescription, and services to support those seeking to stop are being strengthened. If patients are able to stop smoking, the health risks, particularly death from lung cancer, are greatly reduced (see Fig. 13.59, p. 701). Cigarette smokers who change to smoking a pipe or cigars inhale the smoke and this change is therefore not helpful. If patients are unable to stop smoking completely, they should smoke as few cigarettes as possible, change to lowtar brands, reduce the number of puffs, and smoke less of each cigarette. Lung surgery Surgical removal of bullae can help selected patients with severe bullous emphysema, particularly if they are compressing relatively normal adjacent lung. Selected patients with COPD can also be treated by lung transplantation. Lung volume reduction surgery is increasingly being considered in patients with severe emphysema (see Recent Advances).

FURTHER READING ON CHRONIC BRONCHITIS AND EMPHYSEMA

causes (Table 13.31), particularly coronary artery disease and lung cancer. Worldwide, four million people die each year from smoking. Patients with chronic bronchitis and emphysema have smoked for many years and have great difficulty in abstaining. Stopping smoking is particularly difficult if a spouse or cohabitee smokes. The firm advice of the patient's physi-

American Thoracic Society 1995 Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 152:577-5120. American Thoracic Society 1996 Cigarette smoking and health. Am J Respir Crit Care Med 153:861-865. Barnes P J 2000 Chronic obstructive pulmonary disease. N Engl J Med 343 (4): 269-280.

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RECENT ADVANCES IN LUNG VOLUME

REDUCTION SURGERY (LVRS) Some patients with severe emphysema can benefit from surgery that reduces the volume of the lungs. These patients are in addition to those who routinely benefit from removal of large bullae by bullectomy. Volume reduction surgery, whereby 20-30% of each lung is resected, has been carried out in many countries around the world over recent years. There have been few controlled clinical trials, but the data suggest that LVRS may well help carefully selected patients with disabling emphysema. If they are not suitable for lung transplantation these patients have few therapeutic strategies available. Furthermore, if patients who might otherwise be transplanted are treated with volume reduction surgery, scarce donor lungs are available for those with other fatal conditions. Lung transplantation for advanced COPD is, in most instances, not practicable because many of the patients are too old and infirm to be considered for the operation, particularly with the scarcity of donor organs. Surgical resection of parts of the lungs increases lung elastic recoil, which reduces the dynamic expiratory collapse of airways and therefore reduces expiratory airflow limitation. The reduction of lung volume lengthens the diaphragm, improves its mechanical advantage, and enables a given muscle tension to generate more transdiaphragmatic pressure; all of these changes improve the capacity of the diaphragm to achieve inspiration. The resection of badly diseased lung also decompresses relatively good-quality lung, allowing its function to improve. Volume reduction surgery therefore enhances expiratory flow, increases inspiratory capacity and improves the ventilation of relatively normal lung; emphysematous patients thereby become less breathless. To be considered for volume reduction surgery patients must have severe COPD with emphysema, be severely breathless, hyperinflated, with an FEV! of usually less than 0.7 L, and often requiring oxygen therapy. In major centres undertaking this surgery approximately 20% of referred patients are suitable, and in expert hands the results are encouraging with a significant improvement in FEV l5 arterial blood gases, breathlessness and quality of life. Improvements are often sustained for many months; long-term follow-up data show that benefits persist for about 3 years. The operative and postoperative mortality can be low. The results of further controlled clinical trials on mortality are awaited with interest, but it is likely that volume reduction surgery will be increasingly used to help symptoms in severely breathless patients with emphysema.

1

668

MCQ13.15

British Thoracic Society Statement 2001 Pulmonary rehabilitation. Thorax 56: 827-834. Bronchard L 2000 Non-invasive ventilation for acute exacerbations of COPD: a new standard of care. Thorax 55: 817-818. BTS guidelines for the management of chronic obstructive pulmonary disease 1997. Thorax, 52 (Suppl 5). Cooper J D, Lefrak S S 1996 Is volume reduction surgery appropriate in the treatment of emphysema? Yes. Am J Respir Crit Care Med 153:1201-1204. Geddes et al. 2000 Effect of lung-volume reduction surgery in patients with severe emphysema. N Engl J Med 343:239-245.

RESPIRATION DURING SLEEP SLEEP APNOEA SYNDROMES O Apnoea is defined as no gas flow at the nose or mouth for 10 seconds, and a sleep apnoea syndrome is conventionally, and rather arbitrarily, diagnosed if more than 30 such episodes occur during the night. Apnoea may be central, when there is no airflow and no chest wall movement; obstructive, when there is no airflow despite chest wall movement because of upper airways obstruction; or may result from both mechanisms. Obstructive sleep apnoeo Obstructive sleep apnoea is much more common than central apnoea, occurring perhaps to some degree in up to 1 % of the adult male population. The typical features are hypersomnolence by day and upper airways obstruction during sleep. Many (but not all) patients are obese and have thick necks; hypertension is common. In severe cases there is chronic alveolar hypoventilation at night, daytime hypoxia, secondary polycythaemia and cor pulmonale. Patients often have loud, persistent snoring, and the frequent arousals from apnoeic episodes greatly disturb sleep (although the patient may be unaware of this). Patients fall asleep by day and may have road and other accidents. There is difficulty in concentrating, particularly in the morning, intellectual impairment, personality change and irritability. Abnormal limb and body movements during arousals following apnoea (thrashing around in bed), sexual dysfunction and morning headaches are important features. During apnoea there are cardiovascular disturbances, particularly bradycardia. In some patients the upper airway is abnormally narrow (e.g. hypertrophy of tonsils and adenoids), but in most no

SUMMARY 8 Features of obstructive sleep apnoea Snoring Disturbed sleep Witnessed apnoeas Cardiac arrhythmias Excessive daytime sleepiness Morning headache

Intellectual deterioration Systemic hypertension Pulmonary hypertension Right heart failure Obesity/thick neck Small oropharynx

anatomical abnormality is found. In normals the upper airway narrows during sleep and this is more pronounced in individuals with thick necks. During obstruction the posterior and lateral walls of the pharynx collapse, occluding the oropharynx. The collapse of the upper airway is probably due to a failure to activate the upper airway musculature sufficiently during inspiration, and the negative pressures generated in the upper airway by the contraction of the respiratory muscles suck in the soft tissues of the oropharynx (Fig. 13.41). This negative pressure will be greater if the upper airway is narrowed, and nasal obstruction can be a contributory factor. Central sleep apnoea In central apnoea the patients snore less, are seldom obese, and complain of night-time wakening. The central drive to breathing is abnormal and inspiration may fail to be initiated. The syndrome may be primary or secondary to organic lesions of the brainstem. To document sleep apnoea, to determine whether it is central or obstructive and to assess the severity of nocturnal hypoxaemia, a formal sleep study in a specialist laboratory is required (Fig. 13.42). In patients with obvious obstructive sleep apnoea the assessment of nocturnal

Pathogenetic factors

Primary events

hypoxaemia by oximetry may be all that is necessary. However, it is possible to have severe symptoms due to disturbed sleep (arousal is due to the great efforts of breathing during obstruction) without significant hypoxaemia.

13

Sleep in other respiratory disorders Patients with airways obstruction and hypercapnia may become profoundly hypoxic at night as a result of hypoventilation (Fig. 13.39, p. 666). Nocturnal hypoxaemia is also a clinical problem in patients with advanced kyphoscoliosis or severe respiratory muscle weakness (p. 718). Sleepdisordered breathing in these conditions may cause daytime sleepiness and headache on waking.

Treatment of apnoea syndromes In the management of obstructive sleep apnoea (OSA) weight reduction is helpful but difficult to achieve. Nasal

Pathophysiological and clinical

consequences

FIG. 13.41 The mechanism of obstructive sleep apnoea (OSA) In severe cases, because sleep stops ventilation, sleep is grossly disturbed and daytime somnolence is very striking. (From Strading J R, Philipson E A Breathing disorders during sleep. Q J Med 1986; (new series) 58: 3-18).

FIG. 13.42 Sleep study in obstructive sleep apnoea The record shows a period when ventilation is obstructed and there is no airflow (V). At this time the diaphragm continues to contract (EMGdi); oesophageal (Pes) and gastric (Pga) pressure swings occur, and there is ribcage and abdominal movement (RC and AB). As obstruction continues arterial oxygen saturation (So2) falls. Eventually the activity of the upper airway muscles, including genioglossus (EMGge), increases, the upper airway becomes patent, and airflow is restored. Patients can have hundreds of similar episodes during the night. (From Onal et al Am Rev Respir Dis 1982; 125:167-174.)

669

continuous positive airway pressure (CPAP) is the standard therapy for symptomatic obstructive sleep apnoea, is very effective and remarkably well tolerated. A therapeutic trial of CPAP is often a useful diagnostic strategy: patients with obstructive sleep apnoea usually report dramatic improvement of their symptoms. CPAP has been shown conclusively to improve sleepiness in patients with OSA. Palatopharyngoplasty (PPP) - surgical reconstruction of the pharynx - can also be effective, but the site of obstruction may not be relieved in some patients and the long-term effects of surgery are not yet known. Anterior mandibular repositioning devices which can be fixed or titratable, may also be of use in some patients who are unable to tolerate CPAP. These are generally well tolerated and can significantly improve sleep quality in patients with mild-moderate OSA, probably by directly increasing the size of the upper airway. Drugs may sometimes be helpful, particularly protriptyline (a non-sedative tricyclic antidepressant); this reduces REM sleep, during which, as a consequence of reduced activity of upper airways musculature, obstruction is most likely. For many patients weight reduction and perhaps protriptyline are worthy of trial before considering CPAP or PPP. Troublesome snoring, without desaturation, can be treated by minor palatal surgery in selected cases, but it is important to document that the snoring really is a problem.

FURTHER READING ON RESPIRATION DURING SLEEP Engleman H M, Martin S E, Kingshott R N, MacKay T W, Deary I J, Douglas N J 1998 Randomized placebo controlled trial of daytime function after continuous positive airway pressure (CPAP) therapy for the sleep apnoea/hypopnoea syndrome. Thorax 53:341-345. McNamara S G, Grunstein R R, Sullivan C E 1993 Obstructive sleep apnoea. Thorax 48:754-764.

RESPIRATORY FAILURE 1

Definition There is no precise clinical definition of respiratory failure; the diagnosis rests on the interpretation of arterial blood gas measurements. A patient can be said to be in respiratory failure if the arterial oxygen tension (-Pao2) falls below 8.0 kPa/60 mmHg (normal range 11.3-13.3kPa or 85-100mmHg) or if the arterial carbon dioxide tension (Paco2) rises above 6.6kPa/50mmHg (normal range 4.6-6.0kPa or 35-45 mmHg), when the subject is at sea level, awake and breathing air. The condition may be acute or chronic; if the patient has arterial hypoxaemia with a

1 MCQ 13.16 670

TABLE 13.32 Causes of types I and II respiratory failure Type 1 (hypoxaemic) Pneumonia Emphysema Acute asthma Pulmonary oedema Pulmonary fibrosis Chronic bronchitis Pulmonary vascular disease Miscellaneous: lymphangitis, radiation pneumonitis etc. Type II (ventilatory) CNS

Trauma Cerebral tumour Raised intracranial pressure Drugs Hypoventilation syndromes Neuromuscular Cervical cord lesion Guillain-Barre syndrome Motor neuron disease Poliomyelitis Muscular dystrophies and myopathies Botulism Myasthenia gravis Muscle relaxant drugs Organophosphorus poisoning Status epilepticus

Thoracic cage and pleura Crushed chest Kyphoscoliosis Extensive thoracic surgery (thoracopiasty) Ankylosing spondylitis (rare) Lung and airways Severe acute asthma Pneumonia Upper airway obstruction, including obstructive sleep apnoea Chronic airflow limitation: chronic bronchitis, emphysema, bronchiectasis

normal or low Paco2 then he or she is said to have type I respiratory failure; and if the Paco2 is elevated, type II respiratory failure. Arterial hypoxaemia does not always imply respiratory failure: a low inspired O2 at altitude or an anatomical right-to-left shunt, as in congenital heart disease or arteriovenous malformation, can cause hypoxaemia despite normal lung function. The causes of types I and II respiratory failure are shown in Table 13.32. In general, the main disturbance in type I failure is ventilation-perfusion mismatch, and in type II it is inadequate ventilation. Chronic respiratory failure in the UK is most commonly due to chronic bronchitis and emphysema (p. 661). Measurement of the alveolar-arterial (A-a) gradient is useful in hypoxic patients, and may help to decide, for instance, whether the patient's hypoxaemia is secondary to central hypoventilation or to intrinsic lung disease. By calculating the A-a gradient the day-by-day progress of patients can be assessed even when they are being treated with varying concentrations of inspired oxygen. The A-a gradient indicates the contribution of venous admixture (i.e. true shunt or V/Qabnormality) to hypoxaemia. It can be calculated by using the concept of 'ideal alveolar air'

PAO2 = FiO2 -

Paco2 0.8

where FiO2 = inspired Po2 (20kPa in room air) and 0.8 = respiratory exchange ratio. Thus the normal alveolar oxygen tension is approximately 14 kPa, the normal arterial oxygen tension approximately 12.5 kPa, and the normal A-a gradient is therefore 1-2 kPa (see Ch. 14, p. 736). In the management of the hypoxic patient it should be remembered that tissue O2 delivery depends not just on Pao2 but also on the haemoglobin concentration and cardiac output. The most useful index of tissue oxygenation is the mixed venous (pulmonary arterial)/arterial O2 content difference. The normal oxygen combining capacity is 1.4mL O2/g haemoglobin (approximately 0.06mmol/g). The oxygen content of blood is the oxygen combining capacity x haemoglobin concentration x saturation (plus a small amount of dissolved oxygen in plasma, which is negligible at normal atmospheric pressure). Assuming the haemoglobin concentration is 15g/100mL, and the oxygen content of arterial blood is 1.4 x 15 x 0.95 = 20.58 mL/ 100 mL, and the oxygen content of mixed venous blood is 1.4 x 15 x 0.75 = 15.75, the arterial/mixed venous oxygen content difference is 4.83mL/100mL. If oxygen delivery is reduced (e.g. reduced cardiac output) the arterial/venous content difference widens. Type II hypercapnic ventilatory failure represents inadequacy of the respiratory muscle 'pump'. The concept of 'pump' failure leading to hypercapnia is a useful one, focusing attention on the importance of CNS output, neuromuscular function and chest wall movement in the maintenance of adequate ventilation (p. 718), although severe impairment of gas exchange can contribute to an elevated CO2.

Clinical features Acute hypoxaemia or hypercapnia is less well tolerated than chronic gradual alteration in blood gases. Virtually all patients with respiratory failure, with the exception of some with CNS dysfunction (e.g. drug overdose), are breathless. Acute hypoxaemia causes restlessness, confusion and sweating, with a tachycardia, poor peripheral perfusion and central cyanosis. Patients with acute severe hypercapnic ventilatory failure are breathless and cyanosed, and in addition may have confusion, flapping tremor of the hands, warm peripheries, bounding pulse and occasionally papilloedema. The mental state is probably the best clinical index to follow, as increasing confusion and restlessness often parallel a rising Paco2. When patients (for instance those with advanced chronic bronchitis) progress to severe chronic respiratory failure, with a compensated respiratory acidosis, symptoms may also include sleep disturbance with early morning headache and personality change. Such patients develop polycythaemia, pulmonary hypertension and cor pulmonale. Chronic hypercapnic respiratory failure can occur

despite normal lung function. Sleep apnoea syndromes, for example (p. 668), may be severe enough to produce pulmonary hypertension and cor pulmonale. Patients with neuromuscular disorders (e.g. myasthenia gravis or the Guillain-Barre syndrome) may also have life-threatening ventilatory failure despite normal lungs (p. 718).

13

Management Acufe respiratory failure The general principles for the management of acute respiratory failure are those of any other respiratory emergency. The airway should be kept clear of sputum and protected. Oxygen should be given in sufficient concentration to ensure a Pao2 of 8kPa (60mmHg). This can be delivered via a Venturi mask, which will give a fixed inspired oxygen concentration of 24, 28 or 35%, or a Hudson or MC mask which will deliver variable, but higher, inspired oxygen concentrations. In practice it is difficult to administer more than 40% O2 by conventional face masks. Higher concentrations can be given using a tight-fitting face mask; this also permits the application of continuous positive airway pressure (CPAP), which further increases Pao2. If an adequate Pao2 can only be achieved by a high FiO2 or CPAP, the patient is oxygen dependent and requires careful observation. In all patients with hypoxia the non-invasive monitoring of SaO2 is useful; however, in patients with ventilatory failure it is also crucial to monitor arterial pH and Pco2. If identifiable, the underlying cause should be treated: for example, antibiotics for acute bacterial pneumonias, or bronchodilators and corticosteroids for acute asthma. If the patient's condition is worsening, with deepening cyanosis, disturbance of consciousness, a rising Paco2, and progressive acidosis, then a decision whether to intubate and employ assisted mechanical ventilation must be made. This decision is based on a number of considerations, including the previous exercise capacity, the possibility of treating the underlying cause, the overall clinical state of the patient and serial arterial blood gas measurements. Chronic respiratory failure Patients with chronic respiratory disease who develop additional acute problems require a rather different pattern of management. Patients with long-standing hypoxaemia and hypercapnia are dependent on hypoxaemia to maintain ventilatory drive. High concentrations of inspired oxygen reduce respiratory drive and ventilation, resulting in a rise in Paco2 and a worsening respiratory acidosis. Oxygen must therefore be given in a controlled fashion, starting with an inspired concentration of 24% and with repeated monitoring of arterial blood gases. It should be emphasized that it is not necessary to raise the Pao2 into the physiological range: a Pao2 of more than 6 kPa (45 mmHg) is usually sufficient to maintain the patient in a reasonable clinical state. Although it is correct to exercise caution when administering oxygen to

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CASE STUDY 13.5 SEVERE VENTILATORY FAILURE IN A 71-YEAR-OLD WOMAN A 71-year-old woman, originally from the Caribbean, was referred to the Accident & Emergency department by her family doctor because of severe leg oedema, abdominal swelling and breathlessness on exertion. The patient had been unwell for 2 months, but previously she had been able to walk to the local shops and climb the stairs in her home. Hypertension had been diagnosed 6 years previously, and she was taking lisinopril 5 mg daily; more recently she had been started on frusemide 40 mg daily for her oedema. She had never smoked cigarettes and gave no history of respiratory problems. A married woman, she lived with her husband who was well. One week prior to admission, her GP had arranged an ultrasound scan which had shown substantial ascites. On examination, the patient was comfortable at rest. There was no fever. The blood pressure was 125/70, pulse 104, JVP elevated 8cm with prominent systolic venous waves present, the heart apex beat was displaced laterally and was forceful. The respiratory rate was 16, percussion and breath sounds were reduced at both bases, and there were a few basal crackles. There was severe pitting oedema of both legs, extending up to the anterior abdominal wall. Obvious ascites was present, but it was not possible to feel the liver. The patient was 5 ft tall and weighed 82 kg. The oxygen saturation measured by oximetry breathing air was 78%. The chest X-ray showed a large heart and clear lung fields (Case Fig. 13.5.1). The ECG demonstrated sinus rhythm, tall P waves and right axis deviation. The Hb was 13.6, WBC 6.2, urea and electrolytes normal. An echocardiogram showed grossly dilated right heart chambers, severe tricuspid regurgitation, and pulmonary artery systolic pressure of

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CASE FIG. 13.5.1 The cardiac silhouette is enlarged and the pulmonary arteries are prominent. The lung fields are clear, although there are small bilateral pleural effusions.

40 mmHg. There was pulmonary regurgitation, a dilated IVC, LVH and good left ventricular systolic function.

Questions

1. What is the differential diagnosis? 2. What further investigations are required? Discussion The most striking finding in this patient is the severe right heart failure. This could be due to primary cardiac disease, but the echocardiogram demonstrated no left heart problems: indeed, left ventricular function was good. Pericardial disease causing constriction can lead to high rightsided pressures, ascites and oedema, but the ECG showed no evidence of

a pericardial effusion or thickening. The right heart failure could be secondary to lung disease, but there was no history of respiratory problems, few abnormal lung signs and a clear chest X-ray. That the patient has never smoked is clearly important. One possibility could be that the pulmonary hypertension and . right heart failure were secondary to pulmonary vascular disease or pulmonary emboli. However, when pulmonary emboli cause such severe hypoxia (the oxygen saturation was 78%) and right heart failure, more severe breathlessness and circulatory disturbance might be expected. Urgent next investigations would include arterial blood gas analysis, lung function tests, and a ventilation/perfusion lung scan. The latter showed no substantial perfusion defects and no ventilation/perfusion mismatch, and was considered to indicate a low

probability of pulmonary emboli. The arterial blood gases, breathing air, showed a pH of 7.38, pco2 8.86, po2 5.85 and HCO3 39.1. On breathing 2 L of oxygen, the Po2 increased to 15.5 and the Pco2 rose to 10.4. The blood gas results confirmed severe hypoxia; it is striking that cyanosis was not noticed at the bedside, and illustrates how difficult this physical sign can be in dark-skinned patients. The results demonstrate type 2 respiratory failure (ventilatory failure) with a fully compensated respiratory acidosis. Despite the low Po2, the gas exchange function of the lung is clearly good, as evidenced by the high Po2 with 2 L of added oxygen. Lung function tests showed a predominantly restrictive ventilatory defect, with an FEVi l.OL (predicted 1.4), vital capacity 1.4 (1.8), gas transfer (TCO) 5.1 (5.8), transfer coefficient (KCO) 2.1 (2.0), TLC 2.8 (3.9), RV 1.7 (1.8). The flow-volume loop did not suggest airways obstruction. The investigations therefore demonstrated that the patient had severe hypercapnic ventilatory failure, pulmonary hypertension and right heart failure, with relatively normal lungs (on chest X-ray and in terms of gas transfer). Question 3. What is the most likely diagnosis?

Discussion There are many causes of chronic hypercapnic ventilatory failure (see Table 13.58). Most commonly there are severe abnormalities of lung function (e.g. COPD) or chest X-ray (e.g. kyphoscoliosis). There are relatively few causes of chronic ventilatory failure in the presence of a clear chest X-ray and relatively normal gas transfer. One such cause is respiratory muscle weakness (as in motor neuron disease), but the absence of symptoms and signs of neuromuscular disease makes this diagnosis unlikely in this patient. The most likely diagnosis is sleep apnoea. Such apnoea can be central, but in the majority of patients it is obstructive in nature (OSA, see p. 668). The patient had normal inspiratory muscle strength (as measured by maximum static inspiratory pressures - PImax and maximum sniff nasal pressure (SNIP)). A sleep study confirmed obstructive sleep apnoea (see p. 668). Subsequent questioning of the patient revealed that she had been sleepy during the day for many months, and that her family had thought her to be less mentally alert in recent years; she was also a loud snorer. The patient's ventilatory failure was initially treated with non-invasive ventilation and the blood gases rapidly improved. After a few weeks of nocturnal ventilation her obstructive sleep apnoea was treated with night-time nasal CPAP of

hypercapnic patients, it should be remembered that severe hypoxaemia - Pao2 less than 5kPa (38mmHg) - is lifethreatening and must be relieved, and hypoxaemic patients without CO2 retention (a common situation in fibrotic lung disease, for example) can receive high inspired oxygen concentrations without developing hypercapnia. If, with the proper use of oxygen supplements, the Paco2 continues to rise, and particularly if the respiratory acidosis worsens, a respiratory stimulant such as doxapram may, in the short term, occasionally be helpful. This may allow the use of a higher inspired oxygen concentration without precipitating a rise in Paco2. However, some patients will

15 cmH2O. Symptomatically she was much improved. With CPAP therapy and treatment with diuretics, her oedema resolved. Two weeks after starting CPAP therapy, daytime blood gas analysis, breathing air, showed a Po2 of 9.4 and a Pco2 of 6.1. The patient was discharged from hospital feeling well. She and her relatives considered that she was more alert, with much improved exercise tolerance and less breathlessness. With CPAP she was able to sleep well. The patient has remained well 3 years after admission, and when checked recently her daytime blood gases were Po211.4, Pco2 5.22 and HCO3 23.6. She has no signs of right-sided heart failure, the heart has reduced in size, and the ECG demonstrates a reduction in her pulmonary hypertension. Obstructive sleep apnoea (OSA) is discussed on page 668. Severe OSA is a recognized cause of ventilatory failure. In some patients there are additional contributory factors (e.g. severe obesity, COPD). To restore normal ventilatory control a period of noninvasive ventilation is often helpful and, once blood gases are normalized, ongoing treatment with CPAP is highly effective and known to improve quality of life. Hypertension is commonly associated with OSA (as in this patient) and may be more easily controlled when patients no longer have sleepdisordered breathing.

continue to deteriorate, and the point may come when a decision will have to be made about whether to offer assisted mechanical ventilation. In this group of patients, above all, their background in terms of respiratory function, exercise tolerance, and when they were last reasonably well, must be taken into consideration. Discussions should involve the patient's family and, very often, the patient. For selected patients with ventilatory failure, including those with chronic bronchitis, the technique of noninvasive intermittent nasal positive pressure ventilation may obviate the need for intubation and reduce mortality.

13

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LUNG TRANSPLANTATION For patients with end stage pulmonary disease, lung transplantation is now a realistic therapeutic option. The indications are listed in Table 13.33, and not all patients are suitable (Table 13.34). About 8000 procedures have been carried out to date. There is approximately a 70% one year survival rate, 54% 3 year survival rate and 42% 5 year survival rate with a median survival of 3.7 years; the procedure therefore offers longer survival and an improved quality of life. It is limited by the availability of donor organs and complications are common: these include primary graft failure, infection, airway complications and acute and chronic rejection; the chronic rejection is usually manifest as bronchiolitis obliterans. The technique of lung transplantation can be either single lung (e.g. for COPD or pulmonary fibrosis), sequential single lung, heart lung transplantation or lobar donation. The lobar donation technique can be either from living related donors or can be from a cadaveric source. As with any transplants the operation must be followed by treatment with irnmunosuppressive agents to avoid rejection, and prompt treatment of opportunistic infections. The commonly used drugs for immunosuppression include

TABLE 13.33 Clinical indications for lung transplantation End stage chronic obstructive pulmonary disease Idiopathic pulmonary fibrosis Cystic fibrosis Primary pulmonary hypertension Eisen monger's syndrome Sarcoidosis Collagen vascular lung disease Alveolar cell carcinoma

ciclosporin, tacrolimus, azathioprine, mycophenolate and corticosteroids.

FURTHER READING ON LUNG TRANSPLANTATION Arcasoy S M, Kotloff R M 1999 Lung transplantation. N Engl J Med 340:1081-1091. Maurer J, Frost A, Estenne M et al. 1999 International Guidelines for Selection of Lung Transplant Candidates. J Heart Lung Trans 17:70-709.

PULMONARY HYPERTENSION The normal resting pulmonary artery pressure is approximately 25/8 mmHg; values greater than 30/15mmHg indicate pulmonary hypertension (Table 13.35). More than one factor may operate in any particular patient: for example, patients with ventricular septal defects have increased pulmonary blood flow but eventually develop secondary obstructive and obliterative changes.

Clinical features Pulmonary hypertension leads to right ventricular hypertrophy and failure, low cardiac output, syncope, fatigue and breathlessness. Physical signs include a prominent 'a' wave in the jugular venous pulse, right ventricular hypertrophy and a loud pulmonary sound. The ECG confirms right atrial and right ventricular hypertrophy. The chest X-ray shows large central pulmonary arteries. Patients may also have signs of the particular underlying cause of pulmonary hypertension (e.g. airways obstruction, Fig. 13.43). The most important causes of pulmonary hypertension are listed in Table 13.36.

TABLE 13,35 Classification of pulmonary hypertension TABLE 13.34 Suitability for lung transplantation • Severe and progressive disease (but not moribund) with a poor prognosis (less than 2 years) • Age normally less than 50 years for heart-lung transplantation, less than 60 years for single lung transplantation • No significant renal, hepatic or other progressive systemic disease (no significant coronary artery disease in patients undergoing lung transplantation) • Psychologically stable

1 MCQ 13.17

674

Passive pulmonary hypertension Left heart failure Mitral stenosis LVF Hyperkinetic pulmonary hypertension Increased pulmonary blood flow ASD VSD Patent ductus

Increased pulmonary vascular resistance Vasoconstrictive e.g. response to hypoxia Obstructive Pulmonary emboli Veno-occlusive disease Obliterative Polyarteritis nodosa Systemic lupus erythematosus Systemic sclerosis Schistosomiasis Chronic bronchitis and emphysema Primary pulmonary hypertension

FIG. 13.43 Severe chronic bronchitis with marked hypoxaemia and pulmonary hypertension In keeping with airways obstruction the lungs are of large volume. The main pulmonary artery (see below the aortic knuckle) is massively enlarged, as are the branches of the left and right pulmonary arteries.

TABLE 13.36 important causes of pulmonary hypertension Diffuse lung disease Recurrent pulmonary embolism (p. 682) Chest wall abnormalities (p. 722) Sleep apnoea syndromes (p. 668) Mitral stenosis and congenital heart disease Primary pulmonary hypertension (Ch. 12)

monary veno-occlusive disease. Both conditions are rare. In the differential diagnosis it is important to consider silent recurrent thromboembolic disease, systemic lupus erythematosus and lupus-like syndromes (including the antiphospholipid syndrome). Primary pulmonary hypertension is of unknown cause and is seen most often in young women. Pulmonary function shows hypoxia due to ventilation-perfusion mismatch, and reduced gas transfer. Patients become increasingly breathless, have syncopal episodes, and develop right ventricular hypertrophy and eventually right ventricular failure. There is peripheral cyanosis, with a small-volume peripheral pulse and cold, blue hands. Central cyanosis is a late development. The jugular venous pulse has a giant 'a' wave and on auscultation there is a right atrial gallop, a tricuspid regurgitant murmur, a pulmonary systolic ejection click, a closely split second sound with a loud pulmonary component and a murmur (Graham Steell) of pulmonary regurgitation. The chest X-ray shows a dilated pulmonary artery. The signs are similar in pulmonary venoocclusive disease, with the important difference that there is pulmonary oedema and therefore more severe hypoxia as well as shadowing on the chest X-ray. The diagnosis of primary pulmonary hypertension is by exclusion of other causes of pulmonary hypertension, and the diagnosis of veno-occlusive disease requires a lung biopsy. The prognosis is poor, with a mean survival from diagnosis of about 3 years. In primary pulmonary hypertension pulmonary vasodilators (e.g. calcium antagonists, prostacycline) may be of value; some authorities also favour anticoagulation. In veno-occlusive disease anticoagulants and possibly azathioprine may be helpful. Patients with primary pulmonary hypertension can be successfully treated by heart-lung transplantation.

13

PULMONARY THROMBOEMBOLISM 1 Pulmonary hypertension due to diffuse lung disease Chronic bronchitis is the commonest cause of pulmonary hypertension, but it also occurs in severe tuberculosis, bronchiectasis, cystic fibrosis, cryptogenic fibrosing alveolitis and other respiratory diseases causing widespread lung destruction and hypoxaemia. Pulmonary hypertension is due to destruction of the capillary bed, a secondary arteritis, and also hypoxic vasoconstriction. In patients with airways obstruction continuous oxygen therapy can reduce pulmonary arterial hypertension and improve prognosis. Primary pulmonary hypertension This diagnosis includes classic primary pulmonary hypertension, in which the pulmonary arteries are diseased, and also a disorder localized to the pulmonary veins, pul-

Tumour, fat, amniotic fluid, parasites, air and injected material can all embolize to the lung, but most emboli are from venous thrombosis, particularly in the lower limbs and pelvis (p. 604). Although massive pulmonary embolism is an important cause of death, few patients with such large emboli survive to reach hospital. Most commonly the clinical picture is of less serious pulmonary emboli and pulmonary infarction. There is often a recent history of illness, trauma, anaesthesia or other factors known to predispose to deep venous thrombosis.

PULMONARY EMBOLISM AND INFARCTION Pulmonary infarction follows embolization to the peripheral branches of the pulmonary arteries. Emboli are

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CASE STUDY 13.6 BREATHLESSNESS AND COUGH IN A 64-YEAR-OLD MAN WITH CHRONIC LYMPHATIC LEUKAEMIA A 64-year-old male retired civil servant was seen in the outpatients' department having been referred by his GP because of cough and breathlessness. The breathlessness had started 3 months previously and had been progressive, such that he was now short of breath on minimal exertion and his exercise tolerance was reduced to approximately 100 yards on the flat at a slow pace. During the period over which the breathlessness had developed, there had been several occasions when there had been sharp deteriorations. The cough had started 2 months prior to the consultation, and was dry and particularly troublesome on exercise and at night. There had been occasional episodes of wheezing. On three occasions, after exercise, he had felt faint and on one occasion he had blacked out. Over a 3-month period the patient had lost about one and a half stones in weight. Shortly before the onset of breathlessness he had been investigated for a lymphocytosis and, following haematological investigations, including a bone marrow examination, he had been diagnosed as having early asymptomatic B-cell chronic lymphatic leukaemia. The total white cell count was 21000, with normal haemaglobin and platelets. The patient was a non-smoker, drank little alcohol, had no relevant past medical history and was taking no medication. Both his father and his only brother had died in their 60s of myocardial infarction. On examination the patient was comfortable at rest; blood pressure 140/80, heart rate 108, and the pulmonary second sound was loud. The chest was clinically clear, with no wheeze. The chest X-ray was normal, except for some prominence of the proximal pulmonary arteries.

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Questions 1. What could explain Ms symptoms? 2. What investigations would be helpful?

Discussion Possibilities to be considered as explanations for the patient's symptoms would include his lymphoma, a complicating opportunistic infection, asthma, left heart failure as a consequence of cardiac disease, and pulmonary embolic disease. Lymphoma can involve the lung, but usually in patients with extensive and aggressive disease. Lymphomatous infiltration can cause a restrictive ventilatory defect and severe breathlessness. Although the shortness of breath may be greater than expected from the chest X-ray (as is often the case in diseases that cause lymphatic infiltration), the X-ray is nevertheless invariably obviously abnormal. Opportunistic pulmonary infection should be considered, but the long history, the clear chest X-ray and the absence of fever make this unlikely. Breathlessness in a patient with a normal chest X-ray could be due to asthma, but little else supports this diagnosis. Patients with pulmonary emboli can develop bronchoconstriction immediately after embolization, and therefore have wheeze. Left heart failure requires consideration, although this is unlikely without cardiac enlargement or other abnormalities on the chest X-ray. Nevertheless, a left atrial myxoma, mitral stenosis and aortic stenosis need to be excluded. Useful investigations would be lung function tests, a ventilation/perfusion lung scan, an echocardiogram and

Doppler ultrasound examination of the lower limbs. Lung function tests demonstrated an FEV1 of 4.0 L, vital capacity of 5.4 and a peak flow of 555 L/min. These results were better than predicted for his age and sex, and demonstrate no evidence of airways obstruction (e.g. asthma) or of a significant restrictive defect (e.g. pulmonary infiltration). The echocardiogram demonstrated dilatation of both the right ventricle and right atrium, with minor tricuspid regurgitation. There was significant pulmonary hypertension. The ventilation/perfusion scan showed multiple abnormalities in both lungs, with reduced perfusion and relatively well preserved ventilation (ventilation/perfusion mismatch) (Case Fig. 13.6.1). The appearances were considered to indicate a high probability of pulmonary emboli. Doppler ultrasound demonstrated thrombus in the external iliac, common femoral, deep femoral, superficial femoral and popliteal veins on the left side. Following the confirmation of deep vein thrombosis and pulmonary embolic disease, the patient was treated with heparin by infusion and subsequently started on oral anticoagulation with warfarin. Within days there was marked improvement in symptoms, and after 10 days' treatment he was up and about, walking freely without breathlessness. At outpatient follow-up 2 months after his hospitalization the patient reported that he was well, not short of breath, with no cough, and able to play a full round of golf.

Question 3, What would be your anticoagulation strategy for this patient?

13

CASE FIG. 13.6.1 Ventilation/perfusion lung scan. The lung perfusion scans (top row) show multiple areas of reduced/absent perfusion. The ventilation scans (bottom row) are much less abnormal, and in many instances there is normal ventilation of poorly perfused areas of the lung. The scans indicate a high probability of pulmonary emboli. Seven months after his initial hospital presentation, and 10 days after having stopped his warfarin therapy, the patient developed breathlessness and chest pain. The breathlessness started acutely and deteriorated rapidly over a 4-day period. By the time of admission to hospital he was breathless at rest, and on the day of admission had an episode of collapse with loss of consciousness. He described his chest pain as a feeling of severe tightness. There had been no haemoptysis or pleuritic chest pain. On examination the patient looked ill, with cool pale peripheries. Blood pressure was 120/75, heart rate 119, and the oxygen saturation was 86% breathing air. The jugular venous pressure was not raised and there were no murmurs. Auscultation of the chest demonstrated no abnormalities. Questions 4. What is the explanation of the chest pain? 5. What would be your immediate management?

In severe pulmonary embolic disease the myocardium becomes ischaemic. Blood flow through the lung is substantially reduced because of widespread pulmonary emboli, and therefore cardiac output falls. The drop in cardiac output and arterial pressure reduces coronary artery blood flow. The patient's tachycardia reduces coronary perfusion during diastole. At the same time, the work of the heart is greatly increased because of the obstruction to the pulmonary vasculature. The combination of increased oxygen requirement of heart muscle combined with reduced oxygen delivery to the muscle results in ischaemic cardiac chest pain. Most patients with pulmonary emboli can be satisfactorily treated with heparin. However, if there is substantial cardiovascular impairment (as evidenced by hypotension, tachycardia, poor peripheral perfusion, reduced urine output or confusion) patients require treatment by thrombolysis. The most likely diagnosis was considered to be a recurrence of pulmonary emboli, and the patient had an urgent CT

CASE FIG. 13.6.2 CT scans. (A) Note the filling defect (due to thrombus) in the proximal left pulmonary artery (arrowed). (B) The distal branches of the pulmonary arteries are occluded by thrombus (arrows).

scan. This showed widespread pulmonary emboli affecting the pulmonary arteries to both lungs (Case Fig. 13.6.2). The patient was treated with a heparin infusion and subsequently with warfarin. Again, he made a rapid and complete recovery. Within 10 days he was discharged from hospital, and at outpatient follow-up he remained well. One year later his exercise tolerance was normal, he

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CASE STUDY 13.6 CONTINUED continued to play golf and had no symptoms. The white cell count had slowly but progressively risen and was 40 000. He continues on warfarin therapy. Question

Deep vein thrombosis is more likely in patients with acquired or inherited risk factors for thrombosis. Acquired risk factors include advanced age, immobilization, surgery, malignancy, oral contraceptive and hormone replacement therapy, antiphospholipid syndrome and

myeloproliferative diseases. Inherited predispositions include factor V Leiden, antithrombin deficiency, and protein C and S deficiency. Therefore, before deciding on long-term management, patients need to be screened for thrombotic factors.

6. What other investigations should have been performed?

frequently multiple, involving the lower zones more frequently than the upper part of the lungs, and only some cause infarction. In many instances of pulmonary embolism without infarction the distal lung remains viable because of adequate oxygenation via the bronchial arterial blood supply and the airways. Pulmonary infarction is much more likely to occur when there is coexisting disease affecting the airways or bronchial circulation. Pathologically, the lesions of pulmonary infarction are markedly haemorrhagic and involve the visceral pleural surface.

Clinical features The characteristic symptom of pulmonary embolism is sudden breathlessness. Indeed, relatively few processes cause such sudden dyspnoea (p. 615). Lateral, usually basal, pleuritic chest pain and haemoptysis develop some time after the onset of breathlessness, and are only clinical features if infarction has occurred. The haemoptysis consists of frank red blood without sputum. In addition to respiratory symptoms there may be pain or swelling of a leg, suggesting deep vein thrombosis, or a history indicating an increased risk of thrombosis. On examination there may be signs of deep vein thrombosis. The respiratory rate is usually raised, and if infarction has taken place there may be a pleural rub and a small pleural effusion. If embolization has been extensive there will be cyanosis and signs of cardiovascular stress. The most important cardiovascular sign is a tachycardia, and some patients will have an elevated jugular venous pressure and a fourth heart sound. With extensive embolism patients may have signs of pulmonary hypertension, and occasion-

1

678

Fig. 13.30

2

Fig. 13.31

3 Fig. 13.32

ally a systolic murmur can be heard over the lung fields, as a consequence of turbulent pulmonary blood flow past partial pulmonary arterial occlusion. Within a few hours of pulmonary infarction fever is the rule. Arterial blood gas analysis usually demonstrates hypoxaemia. However, not all patients are hypoxaemic and hypoxaemia is in itself a very non-specific abnormality. As a consequence of hyperventilation, there is hypocapnia. Patients with pulmonary embolic disease are frequently anxious as well as breathless, and their hypocapnia is not uncommonly taken to reflect anxiety. However, anxiety hyperventilation syndromes produce hyperoxaemia. Immediately following embolization there is often bronchoconstriction, there may even be wheeze, and later, a reduction in surfactant in the affected lung is a contributory factor to atelectasis. Symptomatic pulmonary embolism occurs in about 30% of patients with deep vein thrombosis in the leg or pelvis; if asymptomatic events are added to this figure about 50-60% of patients with deep venous thrombosis will have a pulmonary embolism at some stage. However, in patients with suspected deep venous thrombosis only 25% will actually prove to have the condition when fully investigated.

Diagnosis The clinical diagnosis (Fig. 13.44) of pulmonary embolism is difficult and clinical criteria alone are seldom sufficient. Accurate diagnosis is important, as without specific therapy there may be further, fatal, embolization. Furthermore, the institution of anticoagulation therapy has important consequences for the patient and is not justifiable without sound evidence. Important clinical factors in the diagnosis are a history of predisposing factors, a clinically obvious deep vein thrombosis, haemoptysis and a pleural rub. The chest X-ray in pulmonary embolic disease is frequently normal. When pulmonary infarction occurs, radio-

13

FIG. 13.44 Strategy for the diagnosis of pulmonary emboli (PE) The indication for venography to investigate patients with a matched ventilation-perfusion detect will depend on the degree of clinical suspicion of embolic disease. The same argument applies to a subsequent pulmonary arteriogram when venography is normal.

logical changes develop over the following 24 hours and may include peripheral shadows adjacent to the pleura, most often basal 1 and frequently multiple, an elevated hemidiaphragm, some segmental or lobar volume loss, and small pleural effusions (Fig. 13.45A). If pleural fluid is aspirated it is found to be an exudate and is frequently haemorrhagic. Secondary infection of infarcted lung causes cavitation. With resolution, the linear shadows of pulmonary infarction are characteristic and usually have a pleural component (Fig. 13.45B). The ECG is rarely helpful, except in the diagnosis of myocardial infarction or pericarditis, which may require consideration in the differential diagnosis of pulmonary embolic disease. Occasionally, the ECG changes are suggestive of pulmonary embolism in that they demonstrate right axis deviation, right bundle branch block or an S wave in lead I, a Q wave and an inverted T wave in lead III. However, non-specific abnormalities, particularly T-wave changes, are much more common. Severe or recurrent pulmonary emboli may be associated with pulmonary hypertension and the ECG changes of right ventricular and right atrial hypertrophy. Isotope lung scans are a useful investigation in many patients with pulmonary embolic disease. A normal perfusion lung scan largely excludes pulmonary embolic disease, but an abnormal scan is non-specific. Although an abnormal scan in conjunction with a normal chest X-ray may be taken to suggest pulmonary embolism, perfusion scans may be markedly abnormal in some

pulmonary disorders associated with a clear radiograph, as, for example, in asthma. Furthermore, pulmonary angiography demonstrates emboli in only 50% of patients with an abnormal perfusion lung scan and a normal chest X-ray. Thus, for many patients the confirmation of pulmonary emboli, rather than the exclusion of this diagnosis, necessitates a ventilation as well as a perfusion lung scan. Characteristically, the perfusion scan demonstrates a filling defect due to vascular obstruction, whereas ventilation to the affected area is relatively normal (Fig. 13.46). 2 In doubtful cases serial scans, during which the perfusion defects of pulmonary emboli resolve, are diagnostically helpful. Large or multiple ventilation-perfusion mismatched areas are highly likely to be due to pulmonary emboli (80-90% of cases). In a minority of patients - perhaps up to 20% of cases - matched defects can be due to pulmonary embolism confirmed angiographically. For patients with a matched defect and a normal chest X-ray the diagnosis of pulmonary embolism can only be confidently excluded by pulmonary arteriography. The importance of achieving a definite diagnosis in equivocal cases rests on the fact that, untreated, about 50% will have recurrent, sometimes fatal, thromboembolism. Spiral CT scan of the thorax is a rapidly evolving technique that can demonstrate intravascular clot in the pulmonary arterial circulation. 3 It has become one of the diagnostic methods of choice, often in combination with isotope lung scans and measurement of D-dimers in the

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FIG. 13.45 Pulmonary infarction: chest X-rays [A] Early changes. There is consolidation at both bases, particularly the left. The left hemidiaphragm is elevated. The patient has made a poor inspiratory effort due to pleuritic pain. [B] Resolving infarction. Linear basal shadows are characteristic.

blood. Normal levels of D-dimer make thromboembolisim unlikely (Fig. 13.44). In patients documented angiographically to have pulmonary emboli, 70% will have deep vein thrombosis, and therefore the demonstration or exclusion of deep vein thrombosis is helpful in determining the likelihood of pulmonary emboli. Venography has been helpful in the past in the management of patients with suspected deep venous thrombosis. However, more sophisticated duplex Doppler techniques, which are easier to perform and do not require the use of contrast media, are now and are reliable and reproducible methods of demonstrating venous thrombosis in leg and pelvic veins.

Management

680

The purpose of therapy is to halt the propagation of peripheral thrombus and avoid further pulmonary embolism, thereby allowing time for natural thrombolysis. The treatment of acute pulmonary embolism is intravenous heparin. Massive pulmonary embolism may require additional therapy (p. 681). An effective heparin treatment regimen is a continuous infusion, such that the partial thromboplastin time is prolonged to 1.5-2.0 times normal, commonly requiring 30 000-40 000 units of heparin daily. Heparin requirements tend to fall after 2 or 3 days. It is important to emphasize that the most critical period for aggressive treatment of deep venous thrombosis and

pulmonary embolism is in the first 48 hours after diagnosis; adequate heparinization during this period will greatly reduce the extension of clot and episodes of recurrence. Low molecular weight heparin treatment, with enoxaparin or dalteparin, which can be given subcutaneously once daily, has been studied for the treatment of deep venous thrombosis and has been found to be effective. It is likely that these drugs, as they are studied further, will replace intravenous heparin in the management of pulmonary embolism. If heparin treatment is complicated by bleeding, the action of heparin is rapidly reversed by the administration of protamine sulphate. Heparin therapy should be undertaken for 7-10 days. Thrombolytic therapy, most commonly used with massive pulmonary embolism (see below), is occasionally necessary when heparin treatment is inadequate, including cases with severe or extensive venous thrombosis, particularly when the inferior vena cava is involved. Long-term anticoagulant therapy with warfarin is initiated 3-4 days before heparin therapy is stopped, and is continued for 3-6 months unless a chronic predisposing factor for deep venous thrombosis (e.g. chronic venous insufficiency of the legs) indicates the need for prolonged therapy. If bleeding complicates warfarin therapy, treatment is with vitamin K1. In pregnancy, and in patients in whom intravenous heparin therapy is particularly hazardous, subcutaneous heparin is the treatment of choice. The resolution of pulmonary emboli is rapid, usually within 2-4 weeks. Heparin therapy is highly effective in preventing further thromboembolism.

13

FIG. 13.46 Pulmonary embolic disease: ventilation and perfusion lung scans Posterior scans demonstrate normal ventilation [Al. and numerous, mainly peripheral, defects of perfusion [B] characteristic of multiple pulmonary emboli. Such changes usually resolve over a period of several weeks.

MASSIVE PULMONARY EMBOLISM Massive pulmonary embolism is a relatively rare hospital emergency as most patients with fatal pulmonary emboli die within 2 hours, frequently before reaching medical help. For those who survive beyond 2 hours the outlook is good in most cases, provided they receive appropriate medical treatment. Surgical intervention is only rarely required.

Clinical features The clinical features of massive pulmonary embolism reflect the haemodynamic consequences of obstruction to a large proportion of the pulmonary arterial tree; more than 60% obstruction is necessary to produce serious consequences in a previously healthy individual. Less extensive embolism will be life-threatening in patients with severe pre-existing cardiorespiratory disease. Following embolism, some of the increase in pulmonary vascular resistance may be due to vasoconstriction, secondary to the release of agents such as serotonin from thrombus. The dominant symptom of massive embolism is severe breath lessness. In some patients there is central chest pain caused by myocardial ischaemia, reflecting the combination of a massive increase in right ventricular oxygen requirements and a reduction in coronary artery blood flow. Hypotension may cause syncope. Examination shows tachypnoea, tachycardia, hypotension and poor peripheral perfusion. Signs of pulmonary hypertension and right ventricular strain are not always present. The ECG is frequently unhelpful, with the most common abnormality, other than a tachycardia, being T-wave changes. The main importance of the ECG is in the differential diagnosis from massive myocardial infarction. Echocardiography is a very useful additional tool in the diagnosis of massive pulmonary embolism. During the acute phase it may show right ventricular dilatation and a reduction in right ventricular contractile function, in addition to elevated right heart

pressures. These will resolve when the embolic episode has passed. The chest X-ray is frequently normal or nonspecifically abnormal. Oligaemia of the lung fields is helpful when present, but can seldom be appreciated on emergency supine chest X-ray films.

Diagnosis and treatment Therapy is urgent and potentially life-saving. If the diagnosis of massive pulmonary embolism is probable and the ECG does not suggest myocardial infarction, urgent investigations are required, but immediate treatment with intravenous heparin (15000 units) is reasonable. When hypotension is severe, inotropic support to the right ventricle is needed. In patients who have collapsed with massive pulmonary embolism, external cardiac massage can move clot peripherally and restore part of the pulmonary circulation. Patients have and require high right heart filling pressures, and treatment with diuretics and vasodilators, including morphine, is deleterious. If the patient is capable of cooperation and facilities are immediately available, a ventilation-perfusion scan is performed. Indeed, a perfusion scan alone will be grossly abnormal and strongly support the diagnosis, provided the chest X-ray is clear. Patients who, for whatever reason, are unable to have isotope lung scans, require CT scanning or a pulmonary arteriogram, as do all patients for whom surgery is being considered. Pulmonary arteriograms and CT scans normally demonstrate large central filling defects (Figs 13.47,13.48). Most patients who survive long enough to reach hospital, and who are then treated with intravenous heparin and inotropic support, rapidly improve. Following confirmation of the diagnosis some are best treated with thrombolytic agents, which achieve more rapid and possibly more complete resolution than does intravenous heparin. Bleeding complications are, however, twice as likely as with heparin, and thrombolytics should not be given if patients have active haemorrhage, a history of a recent cerebrovascular accident or recent surgery, organ biopsy or childbirth.

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FIG. 13.47 Massive pulmonary embolism The pulmonary arteriogram shows a large filling delect in the right pulmonary artery, with almost no perfusion of the right lung and little perfusion of the left lower lobe peripherally.

Streptokinase is the thrombolytic agent most commonly used, but is antigenic. Urokinase is less antigenic but more costly. Thrombolytic agents are usually infused directly into the pulmonary artery. A small number of patients with severe haemodynamic disturbance fail to improve on medical therapy and require embolectomy. Surgery is performed with the patient on cardiac bypass. It is critically important that the definitive diagnosis of massive pulmonary embolism has been substantiated prior to surgery and, if so, the operative results are good (75% survival).

RECURRENT PULMONARY EMBOLISM With adequate anticoagulation therapy recurrent pulmonary emboli are uncommon. Rarely, anticoagulants are absolutely contraindicated, and in such patients, and those with recurrent emboli despite full anticoagulant therapy, inferior vena caval sieves can be used. Such surgical procedures are not always effective: the inserted devices may become dislodged, blocked or infected, and indeed may become a source of future emboli.

Repeated, often silent, pulmonary emboli can gradually obstruct a large proportion of the pulmonary vasculature and lead to pulmonary hypertension. Such patients may have a chronic low cardiac output state and intractable right heart failure. They have severe breathlessness, the cause of which is frequently not appreciated at first presentation. Any possibility of recurrent pulmonary emboli warrants comprehensive investigations including angiography or CT scanning. Anticoagulant therapy can prevent progression of the disease. When angiography or CT demonstrates central filling defects, some cardiothoracic centres have produced benefit to patients by surgical removal of organized clot. There is debate about the pathogenesis of pulmonary hypertension in relation to recurrent pulmonary emboli. It has been hypothesized that the raised pulmonary arterial pressures are not simply due to mechanical blockage of the pulmonary arterial tree, but may be caused by an intrinsic pulmonary arteriopathy associated with in situ thrombosis. New surgical techniques for pulmonary thromboendarterctomy often discover widespread hypertensive lesions throughout the pulmonary vasculature, without any visible thrombosis.

Prevention of venous thromboembolism The prevention of pulmonary embolism is possible if patients at high risk for the development of deep vein thrombosis and therefore pulmonary emboli are recognized and suitable prophylaxis undertaken (Ch. 12, p. 604).

FURTHER READING ON PULMONARY THROMBOEMBOLISM AND HYPERTENSION Hyers T M 1999 Venous thromboembolism. Am J Respir Crit Care Med 159:1-14. Recommendations on the management of pulmonary hypertension in clinical practice. Heart 2001; 86(suppl 1) il-i!3.

SARCOIDOSIS Sarcoidosis is a multisystem disorder of unknown aetiology. It can involve the liver, spleen, lymph nodes, heart, nervous system, salivary glands, muscles, bones and other organs. It usually affects young and middle-aged adults and the commonest presentation is with bilateral hilar gland enlargement. The diagnosis is made on the basis of the clinical and radiological findings, in combination with histological evidence of non-caseating granulomas.

Prevalence and distribution 1

682

MCQ 13.18

Sarcoidosis may present to all specialties and is relatively common. Worldwide, the prevalence is approximately 20 in 100000. It is more common in temperate climates, black

13

FIG. 13.48 Pathogenesis of sarcoidosis

Americans, and West Indian and Irish immigrants to the UK, and is less common in Chinese and peoples of the Indian subcontinent. However, differences in incidence may reflect, in part, a difference in the awareness of the disease and the availability of diagnostic facilities, particularly radiology, and in many parts of the world the disorder has been frequently misdiagnosed as tuberculosis. Sarcoidosis is unusual in children and in the elderly and is most common between the ages of 20 and 40, with a slight female preponderance. In general, the disease is more florid in Afro-Caribbeans than in Caucasians. There are occasional reports of familial and occupational 'clusters'.

Aetiology and pathogenesis (Fig. 13.48) The cause of sarcoidosis is unknown, but it is postulated that it results from the exposure of genetically susceptible individuals to environmental agents. The evidence for host reaction to environmental exposure includes epidemiological studies, the nature of the inflammatory response in sarcoidosis with the involvement of activated macrophages and CD4 T lymphocytes, and T-cell receptor studies in affected individuals. Inhalation is the most likely route for the causal agent and the sequence of events is probably one of alveolar injury and an influx of immune effector cells, followed by an inflammatory alveolitis. The alveolitis of sarcoidosis is predominantly lymphocytic (as shown by examination of lung tissue and bronchoalveolar lavage fluid), mostly acti-

vated T lymphocytes, with a reduction in circulating blood T lymphocytes. The increased lymphocytes in the lung are mostly T-helper cells, which are relatively depleted in peripheral blood. These changes may be responsible for the alveolitis, and partly explain the peripheral anergy of delayed-type hypersensitivity of sarcoidosis. Activated T lymphocytes secrete monocyte chemotactic factor, recruiting circulating monocytes and macrophages into the alveolitis, leading to granuloma formation. Lymphocytes also activate macrophages to form the epithelioid and giant cells of granulomas. The metabolic activity of macrophages is associated with increased levels of angiotensin-converting enzyme (ACE) in lung tissue, bronchoalveolar lavage fluid and serum. Whether the granulomas resolve or progress to fibrosis may be determined by the intensity of the alveolitis. The increase in T-cell activity stimulates B lymphocytes, which results in raised serum immunoglobulins, circulating antibodies and immune complexes. Heredity may play a part in the predisposition to sarcoidosis, and the condition is more common with some HLA groups. The characteristic pathological finding of sarcoidosis is therefore granulomas that consist of collections of large histiocytes (epithelioid cells) with occasional multinucleated giant cells and, more peripherally, lymphocytes (CDS-suppressor cells). There is no central necrosis, a point of contrast to many cases of tuberculosis, and the reticulin between the histiocytes is therefore intact. Non-caseating granulomas are not specific for sarcoidosis and can occur in

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TABLE 13.37 Causes of non-caseating granulomas Sarcoidosis Tuberculosis Primary biliary cirrhosis Leprosy Tertiary syphilis Brucellosis HypogammagIobuIinaemia Fungal infection

Berylliosis Foreign body reactions Cat-scratch disease Hypersensitivity pneumonitis Granulomatous arteritides Lymphomas Carcinoma (regional lymph node) Crohn's disease

other disorders (Table 13.37). Sarcoid granulomas are dynamic entities that develop, age and resolve. In chronic cases they are replaced by hyalinization and fibrosis.

Clinical features Because sarcoidosis can affect virtually all organs and tissues of the body, with the probable exception of the adrenal glands, the clinical features of this disorder are varied (Table 13.38). Non-specific constitutional symptoms are the presenting feature in about a third of patients; these include fatigue, fever and weight loss. Sarcoidosis is a cause of pyrexia of unknown origin. The lungs, liver, eyes and skin are most frequently involved, with more than 85% having some degree of pulmonary involvement, and many cases are diagnosed following a routine chest X-ray. Extensive sarcoidosis causes fever. Eye involvement can cause blindness. Respiratory, cardiac and renal failure are occasionally fatal.

TABLE 13.38 Clinical spectrum of sarcoidosis in the UK Clinical feature

% of cases

Abnormal chest X-ray (lung involvement ± hilar or mediastinal adenopathy) Erythema nodosum Lymphadenopathy Palpable splenomegaly Eye involvement Skin sarcoid Enlargement of parotid/lachrymal/other salivary glands Symptomatic nervous system involvement Bone cysts Symptomatic heart disease Symptomatic myopathy Liver biopsy positive*

>85 20-30 10-15 6 15-25 5-20 5-20 5 3-8 <5 <1 50-80

* Most patients with sarcoidosis can be diagnosed without the need for a liver biopsy.

Thoracic sarcoidosis The chest X-ray is abnormal in more than 85% of cases and the radiological appearances form the basis for the classification of thoracic sarcoid (Table 13.39). Stage I Hilar adenopathy is usually bilateral and symmetrical, 1 but can be unilateral. Adenopathy is the commonest manifestation of thoracic sarcoidosis, and more than half of patients have no symptoms. In addition to hilar gland enlargement the right paratracheal gland is frequently enlarged (Fig. 13.49). Bilateral hilar adenopathy can also occur in other disorders (Table 13.40). In up to 40% of stage I cases there is also erythema nodosum, and in the UK 80% of cases of erythema nodosum in young adults are due to sarcoidosis. 2 In association with bilateral hilar adenopathy and erythema nodosum there is commonly low-grade fever, polyarthralgia and a raised ESR.

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1

Fig. 13.33 2 Fig. 13.34 3 Fig. 13.35

4

Fig. 13.36

FIG. 13.49 Stage I sarcoidosis There is bilateral hilar lymphadenopathy (BHL) and also enlargement of the right paratracheal nodes (arrow), characteristic of sarcoidosis.

Although few patients have severe symptoms with stage I sarcoidosis a minority have cough and chest pain due to adenopathy. Bilateral hilar adenopathy is usually benign, with 80% of cases resolving in less than 12 months and 90% by 2 years. In 10% of cases glandular enlargement persists and eggshell calcification may develop, or patients may develop pulmonary opacities. Patients with bilateral hilar lymphadenopathy without erythema nodosum probably do rather less well, with up to 20% developing a pulmonary infiltrate.

TABLE 13.39 Classification of thoracic sarcoid Stage

Description of chest X-ray

0 I II

Normal Hilar adenopathy Hilar adenopathy plus parenchymal infiltrate Parenchymal infiltrate ± fibrosis

III

Stage at presentation (%)

Elevated ACE levels (%)

Positive transbronchial lung biopsy (%)

Positive Kveim test (%)

Positive liver biopsy (%)

8 51

-

50

-

65-80

29

30 56 71

75-100

70 80

85 65

12

56

75-85

40

60

TABLE 13.40 Differential diagnosis of bilateral hilar adenopathy

TABLE 13.41 Differential diagnosis of stage II and stage III sarcoidosis

Sarcoidosis* Tuberculosis Lymphoma Leukaemia Metastatic malignant disease

Cryptogenic fibrosing alveolitis Pulmonary tuberculosis Extrinsic allergic alveolitis Carcinoma Pneumoconiosis

Beryllium disease Hypogammaglobulinaemia Histoplasmosis Coccidioidomycosis Enlargement of pulmonary arteries

13

Bronchopulmonary aspergillosis Ankylosing spondylitis Berylliosis Histiocytosis X Pneumocystis carinii pneumonia

* Compared with sarcoidosis, all other causes of bilateral hilar adenopathy are uncommon.

prognosis for stage II sarcoidosis is less good than for stage I. Although 50% resolve spontaneously within 2 years, some take longer, 30-40% require steroid therapy, and in 10-15% long-term steroid therapy is required, despite which a small number develop progressive pulmonary fibrosis. The differential diagnosis of stage II and stage III sarcoidosis is shown in Table 13.41. Stage III With the development of pulmonary fibrosis, patients become breathless, hypoxic, and ultimately develop cor pulmonale. Pulmonary function tests demonstrate a severe restrictive ventilatory defect. In addition to fibrosis, which is characteristically most marked in the mid and upper zones, the chest X-ray may also show cavitation and bulla formation. 4 As would be expected, the prognosis for stage III sarcoidosis is less good, with about 30% showing significant improvement with steroid therapy. Extrathorocic sarcoidosis FIG. 13.50 Stage II sarcoidosis The X-ray shows florid stage II sarcoidosis, with bilateral hilar lymphadenopathy (BHL) and extensive pulmonary infiltrates. Pleural abnormalities in sarcoidosis are rare.

Stage II Pulmonary infiltrates coexist with adenopathy in about 30% of patients (Fig. 13.50). More severely affected patients have a restrictive ventilatory defect, with exertional breathlessness and a reduction in gas transfer. The chest X-ray appearances correlate poorly with physiological disturbances, the patient being frequently asymptomatic despite widespread pulmonary shadowing. The

Skin Erythema nodosum (see p. 407) is the most common skin abnormality, and is associated with acute, usually stage I, sarcoidosis. When there is erythema nodosum and BHL in a young adult a clinical diagnosis of sarcoidosis can be firmly made without resort to tissue biopsy. Erythema nodosum is an immunological response associated with sarcoidosis, and skin biopsy demonstrates a characteristic histology which is the same as for other causes of erythema nodosum. Sarcoid tissue itself can also infiltrate the skin: biopsy shows typical noncaseating granulomas. Small papules, plaques and subcutaneous nodules are common, and the skin of the nose may be involved (lupus pernio), as

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are scars and keloid tissue (Fig. 10.29, p. 408). When there is lupus pernio the upper respiratory tract is frequently involved by the disease and nasal mucosal biopsy is positive. Skin sarcoid more commonly affects females, and is more common, extensive and florid in Afro-Caribbeans.

between 2 and 10% of patients with sarcoidosis, and hypercalciuria in about three times that number. If undetected or untreated it may cause nephrocalcinosis, renal stones and eventually, renal failure.

Eyes Eye involvement is both common (up to 25% of cases) and potentially serious. Early eye involvement may be asymptomatic and many patients should be examined by an ophthalmologist. Uveitis, conjunctivitis and retinal involvement can all occur. Dry eyes (keratoconjunctivitis sicca) occurs in a Sjogren-like syndrome when the salivary glands are involved. The lachrymal, salivary and parotid glands may be enlarged. Eye involvement is an indication for steroid therapy, usually systemic.

Diagnosis

Hypercalciuria Hypercalciuria and hypercalcaemia can occur, but these disorders of calcium metabolism (p. 965) are not common. Lymphadenopathy Enlarged lymph nodes are present in 10-15% of patients and splenomegaly occurs in 6%, both abnormalities being more common in Afro-Caribbeans. Occasionally the spleen is very large and associated with anaemia, neutropenia and thrombocytopenia, which may improve following splenectomy. Cardiac sarcoid Involvement of the myocardium by granulomatous infiltration may be relatively common and is discussed on page 573. Nervous system Sarcoid affecting the nervous system is discussed on page 1431. Sarcoid involvement of muscle is usually asymptomatic, but occasionally patients have myopathic symptoms. Bone sarcoidosis Arthritis, acute and transient, is common with BHL and erythema nodosum, but chronic skeletal problems are unusual (3%), characteristically affecting the hands and feet in patients with skin sarcoidosis. Bone cysts, especially of the terminal phalanges, are most typical. Steroids have little effect and bone lesions are usually confined to cases of chronic sarcoidosis. Parotid glands Heerfordt's syndrome is fever, parotid gland enlargement, facial palsy and anterior uveitits, all due to sarcoidosis of the involved organs. Endocrine manifestations Abnormal production of calcitriol by activated macrophages and granulomas leads to hypercalcaemia in 1

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Fig. 13.37

Chest X-ray, CT scans and transbronchial biopsy give the diagnosis in the majority of patients. High-resolution CT scans can be particularly helpful, showing features characteristic of sarcoidosis. 1 It is noteworthy that even when the chest X-ray shows extensive parenchymal disease, auscultation is remarkably normal. Biopsy of any clinically involved tissue will confirm the diagnosis, and a liver biopsy will be positive in 50-80% of patients. Frequently, the most important differential diagnosis is between sarcoidosis and tuberculosis; tissue should therefore be stained for acid-fast bacilli and cultured for M. tuberculosis. Depression of delayed-type hypersensitivity in sarcoidosis reduces tuberculin reactivity. Two-thirds of patients do not react to 100 tuberculin units, and more than 90% fail to react to 10 tuberculin units. A depressed tuberculin reaction persists for many years, long after clinical resolution of sarcoidosis. In the differential diagnosis of sarcoidosis and tuberculosis, the tuberculin test is of considerable value. In cases where biopsy is relatively difficult (e.g. hilar adenopathy) or negative, a diagnosis of sarcoidosis can be substantiated by the Kveim test (Table 13.38). A suspension of particulate human sarcoid tissue is injected intradermally; in patients with active sarcoidosis epithelioid cell granulomas gradually develop and can be demonstrated following skin biopsy of the purplish-red nodule at 4 weeks. A positive Kveim test strongly suggests a diagnosis of sarcoidosis (false positives 1-2%). However, the Kveim test is not always positive in sarcoidosis and there is a relatively high false negative rate in chronic fibrotic disease. As a result of advances in radiology and biopsy techniques, Kveim tests are now seldom performed.

Management Assessment of the severity and activity of disease Although symptoms and signs are the main guide to management, further investigations are necessary and helpful in decision-making. Radiology Chest X-rays provide a crude index of the extent of thoracic sarcoidosis, and the correlation between radiological findings and functional impairment is poor. However, serial chest X-rays over months and years remain indispensable for documenting qualitative changes that occur either spontaneously or in response to therapy. Serum angiotensin-converting enzyme Serum angiotensin-converting enzyme (SACE) levels are high with acute granulomatous disease and correlate with

CASE STUDY 13.7 FEVER AND CHEST X-RAY ABNORMALITIES IN A 45-YEAR-OLD ASIAN WOMAN A 45-year-old Asian woman presented to her GP with a fever which she had noticed for 6 weeks. She had felt generally weak for 2 months and had experienced bilateral arthralgia in the lower limbs, particularly the knees. There had been 1 stone weight loss. The patient had not experienced shortness of breath and had no cough or sputum. Originally from India, she had been in the UK for 20 years and worked as a teacher. Soon after arriving in London she had developed pulmonary tuberculosis and had been treated with conventional therapy for 9 months. On examination the temperature was 37.6°C; there were no abnormal physical signs and, in particular, auscultation of the chest was normal. Routine blood tests were normal, except that the ESR was 38 mm/h. The chest X-ray showed bilateral pulmonary infiltrates, most severe in the midzones, and hilar lymphadenopathy (Case Fig. 13.7.1).

1,1 What is the difftirenflal .diagnosis?' 2, What should be the next investigations?

CASE FIG. 13.7.1 Chest X-ray. There is bilateral hilar lymphadenopathy and enlargement of the paratracheal nodes on the right. The bilateral pulmonary infiltrates are most marked in the mid and upper zones.

Discussion The two most likely diagnoses are tuberculosis and sarcoidosis. Tuberculosis is favoured by the past medical history, the ethnic origin and, to an extent, the fever. However, the radiology is more suggestive of sarcoidosis; the bilateral hilar lymphadenopathy and the bilateral mid and upper zone infiltrates being characteristic, as is the enlargement of the right paratracheal nodes. In sarcoidosis there may be no abnormal signs in the chest (e.g. crackles, bronchial breathing) despite substantial chest X-ray changes. Fever is not uncommon. Other infections should be considered, but the history is rather long. Lymphadenopathy occurs in lymphoma, as does fever, but the symmetrical pulmonary infiltrates would be unusual. Three helpful tests would be a tuberculin skin test, serum ACE and bronchoscopy with lavage (particularly seeking acid-fast bacilli), and transbronchial biopsy. The tuberculin skin test (Mantoux 1 in 1000) was negative. In a patient with active tuberculosis or past tuberculosis it would be expected that the skin test would be obviously positive. Skin anergy is characteristic of sarcoidosis, and the negative test in a patient known to have had tuberculosis in the past supports the diagnosis. Tuberculin skin testing is therefore a very useful, simple investigation when considering the differential diagnosis between tuberculosis and sarcoidosis. The ACE was raised at 118. A number of conditions cause a raised ACE, but sarcoidosis is the most common. Although some patients with tuberculosis can have a raised ACE, it is relatively unusual and therefore in this patient, the increase in the ACE favours the diagnosis of sarcoid. Bronchial lavage demonstrated no AFB and subsequent culture was negative. Transbronchial biopsy

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showed non-caseating granulomas consistent with a diagnosis of sarcoidosis. Because the histology of tuberculosis and sarcoidosis is granulomatous, histopathologists are often reluctant to make a definite diagnosis unless acid-fast bacilli are also seen. The granulomata of sarcoidosis do not caseate and, particularly given the other features supporting the diagnosis, the histology makes a diagnosis of sarcoidosis in this case certain.

Question 3. What treatment would you initiate?

In essence, the question is whether or not to treat with oral steroids. Steroids markedly reduce granuloma formation, reduce the serum ACE, reduce the extent of sarcoid tissue (e.g. lymph nodes or pulmonary infiltrates) and reduce systemic symptoms. It is less clear whether steroids alter the long-term outlook, but in patients with abnormalities in the lung that cause reduced lung function the use of steroids results in better long-term respiratory function. In this patient, with fever and bilateral pulmonary infiltrates, it is on balance reasonable for her to be treated with prednisolone.

Question 4. What are common extra-, if pulnjonary manifestations of sarcoidosis? Sarcoidosis can affect virtually any organ in the body (see p. 1431); after lung and lymph nodes, the tissues and organs most commonly involved are the liver, skin and eyes. Soon after the diagnosis of sarcoidosis was made, this patient developed a left lower motor neuron

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CASE STUDY 13.7 CONTINUED facial weakness and nodular changes in the skin on her face (Case Fig. 13.7.2). Although neurological involvement in sarcoidosis is relatively uncommon, the most frequent neurological manifestation is a facial nerve palsy. This complication should be treated with steroids, and if therapy is given early the outcome is usually good. However, in some patients the response is only partial and in a minority no improvement occurs. Skin lesions are relatively common in sarcoidosis. It is important to distinguish erythema nodosum, which is commonly associated with sarcoidosis, from infiltration with granulomatous tissue. Erythema nodosum is an immunological response to sarcoidosis rather than involvement by the disease. Sarcoidosis of the skin responds to steroid therapy, may also be helped by chloroquine, and particularly troublesome lesions can benefit from local injections of steroid. This patient was treated with prednisolone 40 mg daily. On this therapy there was rapid improvement of her facial palsy, the skin lesions disappeared, the chest X-ray improved with

CASE FIG. 13.7.2 The patient has been asked to close her eyes and complete lower motor neuron facial paralysis is apparent. Note also the multiple sarcoid skin nodules. substantial resolution of the pulmonary infiltrates, her fever subsided and she felt much stronger. The patient's progress was monitored in the outpatient clinic, with regular review of symptoms, signs, lung function, serum ACE and chest X-ray. Oral steroids were gradually reduced and eventually stopped altogether after 18 months. Soon after stopping the steroids the

chest X-ray abnormalities. However, not all patients with sarcoidosis have raised SACE levels and, conversely, some patients without sarcoid (perhaps up to 20%) can have high levels (Table 13.42). Tuberculosis and lymphoma seldom increase serum ACE. SACE is most useful in monitoring granulomatous activity and the response to steroid therapy. Bronchoalveolar lavage In normal subjects BAL usually shows less than 10% lymphocytes, whereas in sarcoidosis average figures for lymphocyte counts are 30%, with up to 50-60% in florid,

MCQ 13.19

688

patient developed erythema nodosum, the ACE was much elevated and her facial weakness became more pronounced. Her steroids were reintroduced and these problems responded quickly. She has now been followed up for 5 years and remains well. The ACE level fluctuates and she continues on 5 mg of prednisolone daily. There is minor residual facial weakness.

TABLE 13.42 Causes of a raised ACE Sarcoidosis Tuberculosis (occasionally) Liver disease Gaucher's disease Asbestos is Berylliosis

Silicosis Diabetes Hyperthyroidism Leprosy Histoplasmosis

acute disease. However, there is an overlap of the cell count in sarcoidosis with those in normal subjects, particularly smokers, as well as in patients with extrinsic allergic alveolitis, lymphomas and cryptogenic fibrosing alveolitis. BAL is not necessary for the clinical management of the disease.

Clinical Lung function tests

The correlation between chest X-ray appearances and pulmonary function is poor. Pulmonary sarcoidosis leads to a restrictive ventilatory defect with a reduction in lung volumes, pulmonary compliance and gas transfer. The most sensitive index of impaired pulmonary function is abnormal gas transfer, which may be reduced even in stage I disease. Some patients with sarcoidosis have an obstructive defect due to endobronchial disease (confirmed by bronchoscopy and bronchial biopsy and improved by steroid therapy) or to airway distortion from fibrosis. With moderate or severe disease patients may be hypoxic at rest, and in mild disease there is hypoxia on exertion. Pulmonary function testing is essential in the assessment of sarcoidosis, and repeated measurements are of great value in longterm management.

Treatment The known effects of steroids on immunological mechanisms suggest that these drugs should be helpful in suppressing the immunologically mediated alveolitis of sarcoidosis and, indeed, patients with acute florid disease appear to respond rapidly. In most patients the short-term effect of steroids is to improve symptoms, suppress inflammation and granuloma production and lower SACK levels. The chest X-ray can improve quickly, within 2 or 3 weeks. Prednisolone at a dosage of 30-40 mg daily, with a gradual reduction towards the minimum dose that controls disease activity, frequently 7.5-10mg daily, is normally prescribed. Treatment with steroids is indicated whenever vital organs are severely involved, including the lung, or when there is substantial systemic disturbance (Table 13.43). Treatment with systemic corticosteroids usually results in remission of granulomas in biopsies and substantial clearing of chest X-ray infiltrates and improvement in symptoms. Although data are limited, in patients with persistent pulmonary disease steroids do improve long-term lung function. Alternative immunosuppressive agents (i.e. methotrexate, azathioprine or ciclosporin) and chloraquine may be

TABLE 13.43 Indications for steroid treatment In sarcoidosis Eye involvement Severe chest X-ray changes (stage II and stage III disease) associated with a high serum angiotensin converting enzyme Intense alveolitis on bronchoalveolar lavage Breathlessness Hypercalcaemia and hypercalciuria Severe skin infiltration Severe involvement of the upper respiratory tract Cardiac involvement Nervous system involvement Salivary gland involvement

used for chronic disease, particularly chronic skin infiltration, but there is no evidence that these agents are superior to oral steroids. In severe intractable disease, and particularly CNS sarcoidosis, high-dose steroids (typically pulses of methylprednisolone) may be useful.

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Prognosis Approximately 60% of all patients with thoracic sarcoidosis resolve spontaneously and have a normal chest X-ray, mostly within 2 years. A further 20% will resolve with steroid therapy, which can then be discontinued. These patients have an acute or subacute type of the disease, clearly associated with a good prognosis. For the minority 10-20% with chronic disease, resolution, even with steroid therapy, is less likely, with radiographic clearing in about 50% who have stage II and 20% who have stage III disease. Patients with chronic pulmonary sarcoidosis may eventually develop pulmonary fibrosis and respiratory failure. With cavitary and bullous disease haemoptysis can be troublesome and mycetomas can occur. Although only a small percentage (2%) of patients with sarcoidosis die of the condition, most of these deaths are from pulmonary fibrosis and respiratory failure. Chronic extrathoracic sarcoidosis often responds poorly to treatment. Central nervous system involvement is particularly chronic and poorly responsive to steroid therapy.

FURTHER READING ON SARCOIDOSIS Gibson G J, Prescott R J, Muers M F et al. 1996 British Thoracic Society Sarcoidosis Study: effects of long term corticosteroid treatment. Thorax 51:238-247. American Thoracic Society 1999 Statement on sarcoidosis. Am J Respir Crit Care Med 160:238-247.

CONNECTIVE TISSUE AND RELATED DISEASES AND THE LUNG 1 Systemic lupus erythematosus (SLE) Pleurisy is common in SLE, affecting 50% of patients, with effusions in approximately 30%. An acute pulmonary vasculitis can cause widespread pneumonitis in about 10% of cases, sometimes leaving a residual basal atelectasis. Interstitial fibrosis is unusual. Patients may develop smallvolume lungs, the cause of which is unknown and which, in most cases, is not due to diaphragm weakness. In patients with the SLE-like syndrome characterized by the presence of anticardiolipin antibodies, thrombotic obliteration of the pulmonary vasculature can lead to pulmonary hypertension and severe breathlessness.

Mixed connective tissue disease Mixed connective tissue disease (MCTD) is a syndrome composed of features of SLE, polymyositis, rheumatoid

689

arthritis and scleroderma; it is not infrequently complicated by pulmonary involvement, including pleurisy, pulmonary fibrosis and pulmonary hypertension secondary to vascular involvement.

Rheumatoid arthritis The pulmonary manifestations of rheumatoid arthritis are described in Chapter 22, page 1136.

Systemic sclerosis The most common pulmonary manifestation of systemic sclerosis is pulmonary fibrosis, and pleurisy is unusual. Occasionally, pulmonary vascular disease occurs in the absence of parenchymal abnormalities, leading to pulmonary hypertension. Aspiration, with consequent pneumonitis, infection and bronchiectasis, is not uncommon in systemic sclerosis. Pneumonitis and fibrosing alveolitis can occur in Sjogren's syndrome and dermatomyositis. In dermatomyositis muscle weakness can be a major factor contributing to breathlessness and ventilatory failure.

Goodpasture's syndrome Goodpasture's syndrome consists of crescentic glomerulonephritis and pulmonary haemorrhage, associated with circulating antiglomerular basement membrane antibodies (see p. 1076). The onset of the syndrome frequently follows an upper respiratory tract infection, and is most common in young or middle-aged males. Haemoptysis is a key symptom, along with breathlessness. The chest X-ray shows diffuse alveolar shadowing (Fig. 13.51). The pulmonary haemorrhage causes an elevation in gas transfer, particularly KCO. Pulmonary bleeding is the most common cause of death. Prompt therapy with plasma exchange and immunosuppressive drugs has greatly improved the prognosis.

VASCULITIDES AND THE LUNG 1

Wegener's granulomatosis In Wegener's granulomatosis, described by Wegener in 1936, the characteristic pathology is a necrotizing granulomatous arteritis of the upper and lower respiratory tract and also of the kidney, where it causes a focal and segmental glomerulonephritis (p. 1076). Upper respiratory tract manifestations - particularly sinusitis, ulceration of the nasal mucosa and bleeding from the nose - are a

1 690

MCQ 13.19

FIG. 13.51 Chest X-ray showing extensive pulmonary haemorrhage in a patient with Goodpasture's syndrome.

common presentation, but unlike midline granuloniatous disease there is no facial ulceration. Middle-aged males are most frequently affected. Increasing breathlessness, haemoptysis and pleurisy occur with pulmonary involvement, which is present in 95% of cases. In most cases there is a low-grade pyrexia. In contrast to polyarteritis nodosa, hypertension is unusual. Wegener's granulomatosis is a multisystem disease and the widespread vasculitis may affect the eyes, skin, joints, heart and nervous system. In most instances it is the renal involvement, present in 85% of cases, that is critical. The chest X-ray shows nodules or masses which are commonly bilateral (Fig. 13.52), and which may be large and cavitate. Mediastinal or hilar adenopathy is rare. Endobronchial disease may be visible at bronchoscopy. In Wegener's, the ESR and CRP are usually raised and the platelet count may also be elevated. Eosinophilia is not a feature. The diagnosis is a clinical one (suggested by disease of the upper as well as the lower respiratory tract, and by renal involvement), supported by tissue biopsy demonstrating characteristic histology. Open lung biopsy gives the highest diagnostic yield, but diagnosis is often possible by biopsy of more accessible structures, such as the skin or upper airway mucosa. Renal biopsy confirms kidney involvement but the tissue obtained is commonly not diagnostic of Wegener's. A positive antineutrophil cytoplasmic antibody test (ANCA) strongly supports the diagnosis. Without treatment 80% of patients die within 1 year, the advancing renal disease being the major determinant of survival. Treatment with cyclophosphamide (l-2mg/kg/day), initially combined with steroids (prednisolone, 60mg daily), is often remarkably effective. Longterm remission is achieved by such therapy in up to 90% of patients, and in some cases with severe chronic renal impairment successful renal transplantation has been undertaken.

treatment of choice is local radiotherapy, and steroids are not helpful.

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Polyarteritis nodosa Pulmonary involvement in classic polyarteritis nodosa is unusual, but is a feature of the variant of polyarteritis known as allergic granulomatosis or the Churg-Strauss syndrome (p. 661), characterized by a necrotizing vasculitis, granuloma formation, eosinophilia and asthma. Treatment is with highdose steroids, and cyclophosphamide if necessary. Pulmonary involvement occurs in many other systemic vasculitides, including giant cell arteritis, Behcet's syndrome, Henoch-Schonlein purpura, hypersensitivity vasculitis (usually drug-induced) and lymphomatoid granulomatosis.

PULMONARY ARTERIOVENOUS MALFORMATIONS AND SHUNTS PULMONARY ARTERIOVENOUS MALFORMATIONS

FIG. 13.52 Wegener's granulomatosis A Chest X-ray showing typical appearance, with multiple irregular large opacities and cavitation. B CT scan demonstrating cavitation,

Arteriovenous malformations (AVMs) can be single or multiple and are usually in the lower lobes. Most are congenital and gradually increase in size as the individual becomes older. AVMs are fed by a branch of the pulmonary artery and drain into a pulmonary vein. A relatively common cause is hereditary haemorrhagic telangiectasia, an autosomal dominant condition associated with epistaxis and gastrointestinal bleeding. AVMs cause hypoxia through shunting. Severe shunting causes breathlessness and patients are clubbed; many patients, however, are asymptomatic. Haemoptysis is common. Auscultation may demonstrate a bruit. Emboli, sometimes cerebral, are an important complication. Because of the anatomical shunt, the hypoxia does not correct with 100% oxygen. Hypoxia also intensifies when the patient stands. In most patients the chest X-ray is abnormal, usually showing a peripheral nodule; AVMs can be well demonstrated by angiography, CT and MRI. Screening of relatives is advisable, to detect asymptomatic AVMs and, by appropriate intervention, to avoid the complications of paradoxical emboli. Treatment is by obstructing the AVMs, usually by coils, thereby relieving the hypoxia and preventing emboli. Lung resection is occasionally necessary.

Midline granuloma This is a rare disease, now thought to be a T-cell lymphoma, in which there is destruction of the tissues of the nose and upper respiratory tract. The characteristic pathology is of granulomas; patients are most often middle-aged females. Nasal involvement is the most striking feature, with the development of septal perforation and saddle nose deformity. The disease is localized (unlike Wegener's) and there is no arteritis. Without treatment the disease is fatal. The

HEPATOPULMONARY SYNDROME Many patients with cirrhosis are hypoxic, some severely so. Hypoxaemia intensifies with exercise and when the patient is upright. In most cases the hypoxia is due to abnormal pulmonary arterial vasodilatation, causing ventilationperfusion mismatch and intrapulmonary shunting. Shunting through the lungs can be demonstrated by lung

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scanning and echocardiography. The diagnosis is also supported by the worsening of hypoxia in the upright posture (orthodeoxia). Patients have a high resting cardiac output, low pulmonary vascular resistance and a mixed venous oxygen saturation. Some cases are greatly improved following liver transplantation.

PULMONARY FIBROSIS AND DIFFUSE INTERSTITIAL LUNG DISEASE

Clinical features of pulmonary fibrosis The conditions that cause diffuse pulmonary fibrosis (Table 13.44) share many clinical, radiological and pathophysiological features. The common presenting symptom is dyspnoea, which is mild at first but can progress to total incapacity. Often a persistent dry cough, particularly at night, is a feature. There may be symptoms of an associated systemic syndrome, including fever and weight loss during the acute phase. On examination the patient may have few physical signs outside the chest. However, when fibrosis is widespread there may be tachypnoea, cyanosis and, at a late stage, cor pulmonale. There may be finger clubbing, especially in patients with cryptogenic fibrosing alveolitis and asbestosis. Auscultation of the chest usually reveals predominantly basal inspiratory crackles, but there are exceptions (see below). The chest X-ray in the early stages shows a hazy, reticular and nodular infiltrate. As the lungs become more fibrotic, cystic spaces become evident and a 'honeycomb' pattern, sometimes with large bullae, develops. Lung function tests show a restrictive ventilatory defect (p. 608) with a reduced transfer factor and hypoxaemia.

OCCUPATIONAL LUNG DISEASE 1 The lung can be injured by the inhalation of dusts, fumes or other noxious substances at work in certain specific occupations. There are strict criteria for the diagnosis of these conditions and, in the UK, for determining the level of compensation. Pulmonary damage can occur in several ways: • • • • • •

Mechanical effects of dust retention Fibrogenesis (e.g. coal dust, silica) Granulomatous reactions (e.g. berylliosis) Toxicity (e.g. mercury vapour) Irritation of air passages (e.g. chlorine) Promotion of bronchial hyperreactivity (e.g. occupational asthma in laboratory workers who become hypersensitive to animal fur or urine). 1

692

MCQ 13.20

TABLE 13.44 Causes of pulmonary fibrosis Inhalation of dust or chemicals Organic dusts (e.g. avian proteins, moulds) Mineral dusts (e.g. asbestos, silica, coal dust) Chemicals (e.g. nitrogen dioxide, chlorine) Unknown causes Cryptogenic fibrosing alveolitis (syn. diffuse pulmonary fibrosis, idiopathic pulmonary fibrosis, usual or organizing interstitial pneumonia) Sarcoidosis Idiopathic haemosiderosis Histiocytosis X (Letterer-Siwe disease, Hand-Schuller-Christian disease, eosinophilic granuloma) latrogenic and poisoning Drugs (e.g. bleomycin, hydralazine, busulphan, amiodarone) Paraquat Radiation pneumonitis Oxygen toxicity Pulmonary involvement in systemic disease Rheumatoid arthritis Ankylosing spondylitis Systemic sclerosis Sjogren's syndrome Dermatomyositis Congenital Niemann-Pick disease Gaucher's disease Tuberous sclerosis Neurofibromatosis

Important occupational lung diseases include those due to inorganic dusts (e.g. silica, talc, asbestos, tin, iron), those due to organic dusts (e.g. cotton dust, maple bark dust) and those due to gases and fumes (e.g. chlorine, ammonia). Occupational exposure can also cause asthma, and lung and pleural malignancy.

Pneumoconioses due to inorganic dust inhalation The common pneumoconioses are listed in Table 13.45.

Coal miners' pneumoconiosis Inhalation of coal dust over a prolonged period damages the lung. The incidence varies with the type of coal being mined, occurring in about 12% of all miners but up to 50% in those who have mined anthracite for more than 20 years. For certification for compensation in the UK the diagnosis is radiological, not clinical. In the disease's early form these radiological changes consist of small nodules less than 1.5mm in diameter; this is termed simple pneumoconiosis.

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TABLE 13.45 The common pneumoconioses Disease

Occupation

Cause

Pathology

Coalminers' pneumoconiosis Silicosis

Coal mining Mining, quarrying, metal grinding, stone dressing, etc.

Coal dust Silica

Asbestosis

Demolition workers, shipbreaking, lagging and brake lining manufacture etc. Electronics, atomic energy reactors, aero engines Rubber industry Smelting Arc welding

Asbestos

Nodular and progressive massive fibrosis Focal fibrosis, centrilobular emphysema, progressive massive fibrosis, associated tuberculosis Focal fibrosis, pleural calcification, bronchial carcinoma, pleural and peritoneal mesothelioma Granulomas and interstitial fibrosis Focal fibrosis Mineral deposition Mineral deposition

Berylliosis Talcosis Stannosis Siderosis

Beryllium Magnesium silicate Tin oxide Iron oxide

In a proportion of cases the nodules grow up to 10mm in size, are irregular, and coalesce to form large masses which may cavitate, commonly in the upper lobes: this is referred to as complicated pneumoconiosis or progressive massive fibrosis.

About 15% of patients have positive antinuclear antibodies and, in a small number, active rheumatoid arthritis is present. This is Caplan 's syndrome, and the chest X-ray shows rounded peripheral nodules in the lung fields 0.55.0cm in diameter. First described in coal miners, the same appearances have since been seen in other forms of pneumoconiosis.

Silicosis Although now less common as a result of protective measures, silicosis is still a major occupational hazard because of the ubiquitous distribution of free silica. Silicosis results from the inhalation of fine particles of silicon dioxide crystals or quartz particles. Those involved in mining, quarrying, metal casting, sandblasting and the pottery industry are at risk. Rarely, inhalation can cause an acute febrile illness with rapidly progressive dyspnoea and cyanosis, which can occur after a short exposure and lead to death in a few weeks. The more common chronic form of the disease is due to the highly fibrogenic potential of silica and presents as slowly progressive dyspnoea and cough, occasionally with haemoptysis. Coexisting tuberculosis is not uncommon. The disease may progress even after exposure ceases. The radiological appearances are of upper zone fibrosis with characteristic hilar 'eggshell' calcification.

Asbestos-related disease Asbestos is the generic name for several silicates, including chrysolite (90% of all world asbestos), crocidolite (blue asbestos), osmosite and anthopyllate. Fibres persist in the lung long after inhalation and cause characteristic pathological changes. Those at high risk include demolition workers, pipe laggers, brake-lining industry workers and boiler makers. The respiratory effects of asbestos are a progressive pulmonary fibrosis (asbestosis), pleural plaques, and malignancy of the lung and pleura.

FIG. 13.53 Asbestosis Bilateral pulmonary fibrosis of asbestosis. There is also pleural thickening, best seen adjacent to the lateral chest wall on the left and diaphragmatic pleural calcification on the right.

Asbestosis presents as progressive dyspnoea and cough, with finger clubbing and basal crackles. Like the other pneumoconioses it may progress to respiratory failure. Asbestos fibres are inhaled and phagocytosed, causing damage to cell membranes and the release of lysosomal enzymes. Radiologically there may be basal linear and irregular shadows which in the later stages progress to 'honeycombing' throughout the lung fields, with the cardiac silhouette becoming indistinct (Fig. 13.53). Lung function tests show a restrictive defect with reduced transfer factor. There are usually 'asbestos bodies' in the sputum or bronchial washings. Pleural plaques are an indication of previous exposure to asbestos. They do not indicate lung disease or any increased risk over similarly exposed subjects of developing a tumour. They are usually basal or diaphragmatic and frequently calcify. CT scanning of the thorax is very useful in picking up early lesions, demonstrating the extent of pleural involvement, and distinguishing pleural from parenchymal disease.

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TABLE 13,46 Some causes of extrinsic allergic alveolitis Type

Disease

Source

Antigen

From fungi

Farmer's lung

Mouldy hay

Micmpolyspora faeni Thermoactinomycetes vulgaris Thermoactinomycetes sacherii

Mushroom worker's lung Bagassosis Ventilator pneumonitis Malt worker's lung Maple bark stripper's lung

Mushroom compost Mouldy bagasse Air conditioning and hot air systems Mouldy barley Mouldy maple bark

Aspergillus clavatus Cryptostroma (coniosporium corticale)

From birds

Bird fancier's lung

Pigeon/budgerigar/hen/parrot droppings

Avian serum proteins in droppings

From mammals

Pituitary snuff taker's lung Rat handler's lung

Porcine pituitary powder Rat droppings

Serum protein/pituitary antigens Rat serum protein

Bronchogenic carcinoma can be caused by asbestos exposure; cigarette smoking in asbestos workers greatly increases the risk, exerting a multiplicative rather than an additive effect. The tumours are usually adeno- or squamous cell carcinomas. Mesotheliomas of the pleura and peritoneum are associated with asbestos exposure (p. 717).

in some cases, by improvement. Patients with relatively acute disease can benefit from corticosteroid therapy, but such treatment is ineffective in the majority of cases. Lung transplantation is appropriate in selected patients. EXTRINSIC ALLERGIC ALVEOLITIS

Berylliosis Berylliosis differs from other pneumoconioses in that the initial pathological response to inhaling beryllium is a granulomatous one, which progresses to fibrosis. Histologically it may be difficult to distinguish from sarcoidosis. It can occasionally cause an acute pneumonic type of illness. Those at risk include workers in the atomic power and aero-engine industry.

Other inorganic dusts Other inorganic dusts vary in their ability to generate fibrosis; iron and iron oxides in arc welding and silver finishing (siderosis) and tin oxide in smelting (stannosis) are relatively non-fibrogenic, whereas magnesium silicate in the rubber industry (talcosis) can be a potent cause of fibrosis. Other dusts cause mucus hypersecretion and airway irritation with or without pneumonitis, e.g. cement, graphite, cadmium and many others.

Management In the management of lung disease caused by inorganic dusts, stopping further exposure is crucial and is followed,

1

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Case 13.2

2 Fig. 13.38

3

Fig. 13.39

1

This group of conditions is caused by the inhalation of organic dusts (Table 13.46). Chronic exposure to dusts that contain antigen sensitizes the individual, a precipitating antibody is produced, and granulomas appear in the lung which heal by fibrosis. Clinically, the patient may present with an acute illness 6-8 hours after heavy antigen exposure, with fever, 'flulike' symptoms, cough, dyspnoea and crackles. These resolve spontaneously in 24-48 hours if there is no further antigen exposure. The clinical features reflect the pathogenic mechanism, which is primarily an IgG-mediated 'late' type III hypersensitivity or Arthus' reaction to the antigen, although there is probably also a cell-mediated response. The result of repeated exposure is granuloma formation and eventually extensive fibrosis. More commonly the presentation is with established fibrosis, with dyspnoea and dry cough. Finger clubbing is uncommon, in marked contrast to cryptogenic fibrosing alveolitis. Inspiratory crackles and squeaks are characteristic. Radiologically, the changes are predominantly upper zone, with nodular and linear shadows and volume loss. 0 Lung function tests show reduction in lung volumes and transfer factor. Precipitating antibodies are present in the blood, and intrar dermal skin tests, read at 6 hours, are available for some of the causes and are especially useful in the diagnosis of bird fancier's lung. Bronchial challenge tests, with measurement of temperature, lung volumes and gas transfer, are occasionally valuable. The treatment of these conditions is first to stop exposure to the antigen. For the acute type of allergic

alveolitis this is usually sufficient. However, when chronic exposure has led to granulomatous change in the lung, treatment with corticosteroids is required. In advanced fibrotic disease, as with all end-stage fibrotic lung diseases, there is relatively little that can be done apart from considering lung transplantation.

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CRYPTOGENIC FIBROSING ALVEOLITIS Cryptogenic fibrosing alveolitis (CFA), a disorder of unknown aetiology, is characterized pathologically by migration of large mononuclear cells into the alveolar spaces with later thickening of alveolar walls, with fibrosis. The mononuclear cellular response is associated with acute symptoms, whereas the alveolar thickening and fibrosis are responsible for the more chronic clinical picture. CFA is an unusual disease but its incidence is increasing. Overall, deaths have increased threefold in the UK over a 20-year period. The pathogenesis of the condition is poorly understood. It is considered to be an altered state of host responsiveness to an as yet unknown stimulus. CFA is about twice as common in smokers, and is associated with exposure to metal and wood dust. An alteration of cell-mediated immunity has been proposed, as stimulated T lymphocytes increase fibroblastic activity. Activation of complement with consequent leukocyte aggregation may play a part. The pathological picture that emerges is, at first, an intraalveolar inflammatory response, with many mononuclear cells and an increase in reticulin, collagen and elastin. As the disease progresses there is fibrosis and destruction of lung architecture, with the formation of cystic spaces. Characteristically, CFA is a disease of late middle age and affects males twice as frequently as females. The acute variant may present with rapidly progressive dyspnoea and cough, widespread crackles and progressive respiratory failure within a few months. The chronic (and much more common) form presents with dyspnoea and dry cough, and in approximately 20% of cases polyarthralgia. About twothirds of the patients have finger clubbing and almost all have basal crackles. The condition may be associated with a variety of systemic diseases: rheumatoid arthritis, Sjogren's syndrome and systemic sclerosis. Other known causes of pulmonary fibrosis, such as the pneumoconioses or sarcoidosis, should be excluded, but with end-stage pulmonary fibrosis it is often difficult, even at postmortem, to determine the aetiology. The chest X-ray shows fine nodular and irregular shadowing (Fig. 13.54) and eventually 'honeycombing'. Lung function tests show a restrictive pattern with reduced transfer factor. Antinuclear antibodies are present in 45% of patients and rheumatoid factor in 20-25%. BAL usually yields a predominantly polymorphonuclear leukocyte pattern. To make a definitive diagnosis a lung biopsy may be necessary, by thoracoscopy or thoracotomy. However, the appearance of CFA on high-resolution CT scans is characteristic, 0 reducing the need for surgical biopsy.

FIG. 13.54 Cryptogenic fibrosing alveolitis (CFA) Diffuse pulmonary fibrosis, wifh linear and nodular opacities throughout both lungs. In less severe CFA the radiological abnormalities are commonly maximal at the bases, with differential volume loss of the lower lobes.

Patients who have a very active cellular histology respond better to treatment than those with established fibrosis.

Treatment The usual treatment is with oral corticosteroids and the response is variable, with only 10% improving substantially. Treatment may need to be continued over several years. Some patients respond to cyclophosphamide, which can also be used, as can azathioprine, as a steroid-sparing agent. It is unlikely that this treatment substantially affects the long-term prognosis. There is recent evidence that the subcutaneous administration of interferon-y1b over a period of a year may improve lung function and gas exchange. The progression of CFA is variable: some patients with very acute, severe disease (the 'Hamman-Rich' syndrome) may die within months. Overall, approximately 50% survive for 5 years and 25% for 10 years. There is a tenfold increase in the incidence of bronchogenic carcinoma. In appropriate patients fibrosing alveolitis can be successfully treated by lung transplantation.

Idiopathic interstitial pneumonia The term idiopathic interstitial pneumonia (IIP) embraces a group of diffuse parenchymal lung diseases which can be distinguished on the basis of clinical history, physical signs, pathology and chest radiology, particularly the recent use of high-resolution computerized tomography (HRCT). They can be described separately from other diffuse interstitial lung diseases, which include environmental and occupational lung disease and lung pathology associated with coronary and vascular disease, and those with dis-

695

tinctive pathology such as sarcoidosis. The recent development of minimally invasive surgery and thoracoscopic lung biopsy and its clinical correlations, along with the rapid development and sophistication of HRCT, has helped to further define and classify these conditions. Bronchiolitis

The bronchioles are the 'silent area' of the lung. Abnormalities in these airways may be primary or as a result of extension of diseases of the bronchi (such as chronic bronchitis or bronchiectasis) or of the lung parenchyma (such as cryptogenic organizing pneumonia). Diagnosis of these diseases is difficult because of the relative inaccessibility of the small airways and the nonspecificity of clinical and radiological features. Recent advances in HRCT and specific physiological tests of small airways disease have greatly added to our knowledge. As with idiopathic interstitial pneumonias, classification of diseases of the small airways has been confusing, with differences of emphasis from clinicians, pathologists and radiologists. The terms bronchiolitis/obliterative bronchiolitis/bronchiolitis obliterans have been used indiscriminately for what we now know are a wide range of different conditions. For simplicity bronchiolitis can be subdivided into 'proliferative' and 'constrictive' types, which can be accurately described in terms of the clinical presentation, radiology and pathology. Bronchiolitis obliterans, organizing pneumonia (BOOP)/cryptoqenic organizing pneumonitis (COP} Initially this condition was thought to be a disease of the small airways but is now recognized to be primarily a condition of the alveolar spaces. It is separate from obliterative bronchiolitis and has a characteristic histological pattern.

IATROGENIC LUNG DISEASE

There is a wide variety of drugs and physical agents, including oxygen and ionizing radiation, that can cause temporary or permanent lung damage. The drugs most commonly responsible are cytotoxic agents (Table 13.47; see also p. 161). Bleomycin toxicity is commonest, occurring in 3-6% of patients treated with the drug; it is dose dependent and there is increased toxicity in the elderly and in those who have received thoracic radiotherapy or combination chemotherapy. Likewise, the pulmonary side-effects of the nitrosoureas are more common in the elderly. The changes

Honeycomb lung

TABLE 13.47 Cytotoxic drugs causing pulmonary toxicity

This is a radiological description of a group of conditions that cause widespread cystic or 'honeycomb' appearances on chest X-ray. A 'honeycomb' appearance can be seen as the end stage of pulmonary fibrosis of any cause. Rare causes include Letterer-Siwe disease, tuberous sclerosis, Hand-Schuller-Christian disease, neurofibromatosis and eosinophilic granuloma. Patients with honeycomb lung tend to develop pneumothoraces. The long-term prognosis is poor, with respiratory and cardiac failure supervening.

Drug

Toxic effects

Bleomycin

Interstitial pneumonitis Pulmonary fibrosis

Nitrosoureas

Interstitial fibrosis

Mitomycin

Pneumonitis and fibrosis

Busulfan

Diffuse pulmonary fibrosis

Melhotrexate

Pneumonitis Blood eosinophilia

Idiopathic pulmonary haemosiderosis

Cyclophosphamide

Interstitial fibrosis

Idiopathic pulmonary haemosiderosis is a rare condition of unknown aetiology characterized by recurrent episodes of

Procarbazine

Pneumonitis Pleural effusion Blood eosinophilia

Chlorambucil

Pulmonary fibrosis

Melphalan

Pneumonitis Pulmonary fibrosis

1

696

intrapulmonary haemorrhage, pyrexia, haemoptysis, and a secondary iron deficiency anaemia. Most cases occur in childhood; patients may die during an acute episode, but more commonly recurrent episodes eventually cause severe pulmonary fibrosis and respiratory failure. Some authorities consider that there is an association with Goodpasture's syndrome (p. 1076). During acute episodes there may be crackles at the lung bases and occasionally hepatosplenomegaly. The chest X-ray during episodes of haemoptysis may show patchy, usually bilateral, shadowing in the middle zones. Following acute pulmonary haemorrhage (of any cause) the diffusion capacity of the lung (TLCO), measured in the lung function laboratory, is increased. Management consists of treatment of the iron deficiency and corticosteroids and/or azathioprine during acute episodes, although their value is as yet unproven. At 3 years from diagnosis one-third of patients will have died, one-third will have active symptomatic disease and onethird will be symptom-free.

MCQ 13.21

TABLE 13.48 Non-cytotoxic drugs which cause pulmonary toxicity Amiodarone Nitrofurantoin Penicillin Erythromycin Tetracycline Streptomycin

Neomycin Ethionamide Isoniazid Suiphonamides ACE inhibitors

in the lung induced by methotrexate may resolve despite continuing treatment with the drug. Cyclophosphamide causes a pneumonitis and fibrosis that can respond remarkably well to corticosteroid therapy. There are also a large number of non-cytotoxic drugs that can cause pulmonary toxicity (Table 13.48). The largest single group is antibiotics, and the most common of these is nitrofurantoin. The antiarrhythmic agent amiodarone is an increasingly important cause of pulmonary fibrosis; frequently the diagnosis is delayed because breathlessness is assumed to be due to cardiac disease rather than to lung damage. ACE inhibitors can cause a chronic dry cough. Some antibiotics (e.g. penicillin, erythromycin, etc.) can cause acute asthma. Pulmonary eosinophilia is associated with drugs such as isoniazid and sulphonamides.

Radiation injury Patients who receive radiation treatment to the thorax may sustain long-term lung injury. The acute injury is characterized pathologically by pulmonary vascular congestion, alveolar oedema and the formation of hyaline membranes. Patients become symptomatic at 4-8 weeks. This may progress, over a period of 6-12 months, to pulmonary fibrosis. Clinically, these processes cause a dry cough, chest wall pain and, depending on the extent of the damage, breathlessness. Radiation injury occurs most frequently in patients receiving treatment for carcinoma of the breast, lymphomas and carcinoma of the bronchus. The chest X-ray in the acute pneumonitis stage shows localized infiltration of the lung in the path of the radiation beam; when fibrosis has developed there is dense shadowing and volume loss. Symptoms and radiological appearances are poorly correlated: some patients with minor infiltrates may be severely dyspnoeic, whereas others with widespread X-ray changes may be asymptomatic. Treatment with corticosteroids may be useful in the acute phase, but once fibrosis is established no treatment is effective. Rarely, phrenic nerve damage causes diaphragm dysfunction. Oxygen toxicity The use of high levels of inspired oxygen causes lung injury indistinguishable from the acute respiratory distress syndrome (ARDS). The injury is related to both the inspired

oxygen fraction (FiO2) and the duration of exposure; a safe level has not yet been established, but an FiO2 of more than 0.7 over a period of more than several days may be associated with X-ray infiltrates and histological change. Toxic oxygen radicals (in particular superoxide anion, O2-) are thought to be important in oxygen-induced lung injury (see also ARDS below).

13

FURTHER READING ON PULMONARY FIBROSIS AND DIFFUSE INTERSTITIAL LUNG DISEASE British Thoracic Society 1999 The diagnosis, assessment and treatment of diffuse parenchymal lung disease in adults. Thorax 54 (suppl. 1). DuBois R M 1994 Diffuse lung disease: an approach to management. Br Med J 309:175-179. Kalica A R, Hunninghake G W 1995 Approaches to the treatment of pulmonary fibrosis. Am J Respir Crit Care Med 151:915-918. Pham S H 1995 New strategies for treatment of pulmonary fibrosis. Thorax 50:415-421. Raghu G 1995 Interstitial lung disease: a diagnostic approach. Am J Respir Crit Care Med 151:909-914. Ziesche R, Hofbaver E, Wittmann K, Petkov V, Block L-H 1999 A preliminary study of long-term treatment with interferon gammaIb and low-dose prednisolone in patients with idiopathic pulmonary fibrosis. N Engl J Med 341:1264-1269.

THE ACUTE RESPIRATORY DISTRESS SYNDROME 1 The term acute respiratory distress syndrome (ARDS) is used to describe a pulmonary condition characterized by progressive hypoxaemia, chest X-ray infiltrates and reduced lung compliance in the presence of a normal left atrial pressure. In many respects the clinical presentation resembles the respiratory distress syndrome of the newborn. The acute respiratory distress syndrome is sometimes called non-cardiogenic pulmonary oedema. It results from acute damage to the alveoli, in response to a wide and seemingly unrelated variety of initiating events (Table 13.49). The pathogenic mechanisms that produce the syndrome (Fig. 13.55) are due to diffuse damage to the pulmonary capillary endothelium, which results in increased 'leakiness' across the endothelial/epithelial barrier, resulting in the passage of plasma and red blood cells into the interstitial space and thence into the alveoli, causing alveolar flooding. The mechanisms responsible for the capillary endothelial damage are poorly understood. Activation of complement with leukocytosis and release of lysosomal enzymes, and interactions between mediators such as leukotrienes, prostaglandins, neuropeptides and superoxides, are all considered to contribute. Damage is therefore due to a complex series of events involving cellular, chemical, neural and vascular responses, all combining to produce the clinical syndrome. The clinical features are outlined in Table 13.50. A typical radiographic progression is shown in Figure 13.56.

697

TABLE 13.49 Conditions associated with the acute respiratory distress syndrome

TABLE 13.80 Clinical features of the acute respiratory distress syndrome

Shock (traumatic, septic etc.)

Initiating event

Infection Pneumonias (viral, bacterial, Pneumocystis carinii) Gram-negative sepsis

Dyspnoea and cough

Trauma (fat emboli, head injuries, lung contusion)

Crackles over lung fields Progressive hypoxaemia Chest X-ray infiltrates

'Stiff lungs' Normal left heart pressures With progression Sepsis Failure of other organs (kidneys, liver etc.)

Aspiration (gastric contents, fresh or salt water) Drug overdose (narcotics, barbiturates) Metabolic disorders (pancreatitis, uraemia) Inhaled toxins (02, smoke, corrosives) Blood disorders (disseminated intravascular coagulation, massive blood transfusion) Miscellaneous Paraquat ingestion Radiation Eclampsia Raised intracranial pressure Seizures High altitude

Management There are as yet no definite predictors as to which patients with the conditions listed in Table 13.48 will develop ARDS. However, the warning signs are deteriorating gas exchange, worsening chest X-ray, and, if the patient is being mechanically ventilated, increasing inflation pressures as the lungs become more 'stiff. Early diagnosis and effective treatment can shorten the course, minimize the long-term sequelae and improve the prognosis of ARDS. Unfortunately, early treatment cannot salvage all patients, many of whom die despite vigorous therapy. As measurements of pulmonary artery pressure, pulmonary artery wedge pressure and mixed venous O2 content are critical, a Swan-Ganz catheter should be passed into the pulmonary artery (p. 726). For the diagnosis of ARDS to be secure, the clinical features of the disorder are combined with a normal pulmonary artery wedge pressure (normal PAWP = 8-12 cm H2O). Once the diagnosis of ARDS has been made the patient is usually so hypoxic that endotracheal intubation and mechanical ventilation is required. The following aspects of the patient's therapy should be considered:

698

FIG. 13.55 Pathogenesis of the acute respiratory distress syndrome (ARDS) The many causes of ARDS have in common the damage to the alveolar-capillary membrane. The pathological changes that follow cause profound hypoxaemia. (FRC = functional residual capacity.)

• Fluid balance • Oxygenation • Drug therapy.

Excessive fluid administration may increase the pulmonary capillary hydrostatic pressure and thus cause further leakage of fluid into the lung interstitium and alveoli; if the patient is allowed to become fluid depleted, however, systemic and pulmonary perfusion may be inadequate, causing renal and other organ damage. A reasonable approach is to administer sufficient fluid to maintain a PAWP of 6-8 cm H2O, and if further circulatory support is required, to administer an inotropic agent such as dobutamine or isoprenaline. Fluid can be given in the form of 5% dextrose solution, or as a crystalloid, and if the patient is severely hypoalbuminaemic, intravenous salt-free albumin should be administered.

Fluid balance Fluid balance is illustrated in Figure 13.57. The physician treating the patient with ARDS is faced with a dilemma.

The first step in improving arterial hypoxaemia is to add supplementary O2. Very high concentrations of O2 may be

Oxygenation

13

FIG. 13.57 The relationship of pulmonary extravascular water and pulmonary capillary pressure In normal circumstances an increase in pulmonary extravascular water (and pulmonary oedema) does not occur until pulmonary artery 'wedge' pressure exceeds 3.3 kPa (25 mmHg). However, increased permeability (as in ARDS), and hypoalbuminaemia (common in intensive care unit patients) can cause pulmonary oedema at normal wedge pressures. (From Hopewell P C, Murray J F The adult respiratory distress syndrome. Ann Rev Med 1976; 27:243-356.)

FIG. 13.56 Acute respiratory distress syndrome The X-rays are of a young man who had sustained severe trauma and blood loss in a road traffic accident; the films cover a period of 5 days from a relatively normal X-ray A to bilateral infiltrates B to bilateral 'white-out' C accompanied by severe hypoxaemia. A Swan-Ganz catheter for measurement of pulmonary artery 'wedge' pressure (as a reflection of left atrial pressure) can be seen in situ on X-ray C. The patient died shortly after the last film.

used initially (up to 100%) but these levels should not be sustained, as they may of themselves cause pulmonary damage. Positive end-expiratory pressure (PEEP) has gained widespread acceptance as an effective method of ventilating patients with ARDS. Positive pressure (usually 5-15 cm H2O) is applied at the end of expiration, thereby preventing airway closure, limiting areas of atelectasis and reducing right-to-left shunting of blood through underventilated areas of lung. The net result of PEEP is usually an increase in Pao2 without increasing the inspired O2 concentration. However, PEEP is not without problems (see Ch. 14, p. 740). By increasing intrathoracic pressure it may reduce venous return to the heart and impair cardiac output. Inotropic support may be necessary, as is careful maintenance and monitoring of intravascular fluid volume. The higher the level of PEEP administered, the greater the risk of inducing trauma to the lung and pneumothorax. The optimum level of PEEP for individual patients can be determined by starting at low levels, say 5cm H2O, and working upwards in small increments, measuring at each level the effect of PEEP on gas exchange, lung compliance, cardiac output and mixed venous-arterial oxygen content difference (see p. 675). In ARDS the lung is 'stiff, a substantial proportion of alveoli are filled with fluid and the accessible lung volume is small. Attempts to deliver a large tidal volume therefore produce high peak inflation pressures, excessive stretching of parts of the lungs, and therefore severe damage. Patients are ventilated by techniques that keep inflation pressures as low as possible. A combination of a prolonged inspiratory phase (inverse inspiratory-expiratory ratio) and pressure-limited ventilation is commonly used. To keep airway pressures and tidal volumes down it is often necessary to allow the arterial CO2 to rise (permissive

699

TABLE 13.51 Relative frequency of primary pulmonary tumours

FIG. 13.58 CT scan in severe ARDS; prolonged mechanical ventilation has produced extensive barotrauma, with numerous bullae within the lungs and loculated pneumothoraces. 1

hypercapnia); provided this is gradual and not excessive it is well tolerated. Despite every effort it is sometimes impossible to ventilate patients with severe ARDS without causing severe lung trauma (Fig. 13.58). In ARDS, abnormalities are most severe in the dependent parts of the lungs, and oxygenation can be improved by periodically ventilating patients in the prone posture. Extracorporeal membrane oxygenation (ECMO) is a technique by which blood is continuously removed from the circulation, passed through a membrane oxygenator, and then returned. The results of controlled studies to date of ECMO in ARDS are discouraging and further technical advances are necessary before this can be considered a realistic option for treatment, except in a small number of selected patients. Drug therapy Sepsis, not respiratory failure, is now the commonest cause of death in patients with ARDS. Pulmonary and abdominal sepsis is particularly common. Steroids may be helpful in the proliferative phase of the illness, but have little effect on established disease. Inhaled nitric oxide is increasingly used as a pulmonary vasodilator, to improve ventilation-perfusion matching and cardiac function. Descriptive studies have shown improvements in oxygenation but controlled trials have yet to be reported, and caution is required when considering NO therapy. The outlook for patients with ARDS remains serious, although it has improved. There is a 40% mortality, and if

1

700

Fig. 13.40

2

MCQ 13.22

Tumour

%

Bronchial carcinoma Alveolar carcinoma Bronchial adenoma Hamartoma Other tumours

95 1-2 1-2 1 1

failure of an organ in addition to the lungs (e.g. the kidneys) supervenes most patients die. Of those who survive, most recover normal lung function; only a small proportion, usually those who have required ventilatory support for many weeks, develop bronchiectasis or pulmonary fibrosis.

FURTHER READING ON THE ACUTE RESPIRATORY DISTRESS SYNDROME Bernard G R et al. 1994 The American-European Consensus Conference on ARDS. Am J Respir Crit Care Med 149:818-824. Tobin M J 2000 Culmination of an era in research of the Acute Respiratory Distress Syndrome. N Engl J Med 342:1360-1361.

LUNG TUMOURS Carcinoma of the bronchus is one of the major causes of death in western countries. The 5-year survival for this common disease is 6-12%. In addition, the lungs and mediastinum are common sites for metastatic malignant disease, with about 30% of cancer patients developing lung secondaries, in half of whom metastases are limited to the lungs. Intrathoracic disease is relatively common in Kaposi's sarcoma. By far the most common primary lung tumour is bronchial carcinoma (Table 13.51).

BRONCHIAL CARCINOMA O In the 19th century bronchial carcinoma was unusual: by the mid-20th century, associated with the widespread habit of cigarette smoking, it had reached epidemic proportions. Lung cancer accounts for more than one-sixth of all cancer deaths worldwide. In the UK, carcinoma of the bronchus is the commonest malignancy in males and is approaching the importance of breast cancer in females; in all, 35 000 patients die each year from this disease (p. 145). The UK has a higher death rate from bronchial carcinoma than any other country in the world (p. 145). In America the incidence of the disease has reached a

plateau; in the UK deaths are starting to fall. Lung cancer rates in many developing countries are rising steeply, reflecting cigarette consumption. Screening programmes with routine chest radiographs or sputum cytology have not been shown to improve survival. There is, however, some recent evidence that early operable asymptomatic lung cancers can be picked up by the use of spiral CT scanning or by molecular genetic markers of cancer in sputum samples. If these reports are confirmed, screening of smokers may possibly produce a better outlook.

Aetiology Atmospheric pollution and industrial exposure to dusts, particularly asbestos, increase the incidence of lung cancer, but the dominant causative agent is tobacco smoke, which is responsible for 90% of cases. The disease is unusual in non-smokers and the increased incidence in smokers is related to the number of cigarettes consumed (Fig. 13.59). The incidence in ex-smokers slowly falls towards that of non-smokers. Passive smoking causes lung cancer in nonsmokers, and in the UK is responsible for approximately 300 deaths each year.

Pathology Bronchial carcinomas are conventionally classified into four main histological groups (Table 13.52). Squamous cell carcinoma Squamous cell carcinomas are most common. The neoplastic epithelial cells produce keratin and frequently arise

from major bronchi. The tumours are thought to originate in areas of squamous metaplasia which progress to carcinoma in situ and then to invasive carcinoma. Squamous tumours frequently cavitate; when peripheral they often invade the chest wall. Hypercalcaemia is a relatively common complication.

13

Adenocarcinomas Adenocarcinomas arise both centrally and peripherally, from the bronchial epithelium or submucosal glands. They do not cavitate and their histology is characterized by tubules and gland-like structures, often producing mucin. Adenocarcinomas are related to cigarette consumption but also occur in non-smokers. There can be diagnostic difficulty, as an apparent primary tumour may prove to be a metastasis from a tumour of the gastrointestinal tract, kidney, ovary, pancreas, thyroid or breast. Tumour markets may help to distinguish primary from secondary tumours. Small cell carcinoma Small cell (oat cell) carcinomas show differentiation into cells with amine-precursor uptake and decarboxylation (APUD) characteristics. Electron microscopy frequently shows neurosecretory granules. The malignant cells are small with little cytoplasm and dark, often oval nuclei. The tumours are usually central, highly invasive and disseminate rapidly. They may secrete a wide range of hormones, particularly ADH and ACTH. Large cell (undifferentiated) carcinoma Large cell undifferentiated tumours constitute a heterogeneous group, including giant cell and clear cell carcinomas, the cells of which show no evidence of maturation. They frequently arise centrally, invade the mediastinum and disseminate widely. Studies of the natural history of bronchial carcinoma and analysis of the time taken for tumours to double in size suggest that by the time a tumour can be diagnosed it may have been present for many years, and has frequently metastasized (Table 13.51).

Clinical features Symptoms of local disease Bronchial carcinomas frequently arise in major bronchi, and therefore common problems include cough, haemoptysis, breathlessness, wheeze and stridor. Some patients have diffuse, poorly localized chest pain, and many have chest infections. Of these symptoms, haemoptysis, progressive breathlessness and persistent respiratory infection are the most important.

FIG. 13.59 Mortality from lung cancer in doctors related to previously recorded smoking habits (Adapted from the classic paper Doll R, Hill A B 1964 Mortality in relation to smoking: 10 years observation of British doctors. Br Med J 1:1399-1414)

Haemoptysis There are many causes of haemoptysis (Table 13.2, p. 612), but in a middle-aged or elderly smoker carcinoma must always be excluded. A normal chest X-ray is unusual in bronchial carcinoma, but does not exclude a tumour.

701

TABLE 13.52 Natural history of untreated lung cancer Years from malignant change to: Doubling time (days)

Earliest diagnosis (1cm)

Usual diagnosis (3cm)

Death (10cm)

13.2

8.4 15,4

17.6

86

7.1

8.2

9.4

29

2.4

2.8

3.2

Histology

%

Squamous Adenocarcinoma Large cell undifferentiated Small (oat) cell

35

88

7,2

21 19

161

25

9.6

From Geddes D M 1979 The natural history of lung cancer: a review based on rates of tumour growth. BrJDisChest73:1-17.

FIG. 13.60 Symptoms and signs of intrathoracic tumour invasion and metastases

Breathlessness This is common in smokers who have developed generalized airways obstruction, but progression is usually gradual; accelerated breathlessness commonly occurs as a tumour narrows a major airway. Such narrowing may produce a localized wheeze, and occasionally stridor if the trachea or major bronchi are affected. Breathlessness may also be due to the accumulation of a malignant pleural effusion or the development of lymphangitis. Chest infections These are not uncommon in chronic heavy smokers and usually resolve quickly when treated with antibiotics. When infection occurs distal to a tumour, however, it frequently persists or relapses. For this reason failure of a pneumonia to resolve is a common presentation of bronchial carcinoma. Symptoms due to intrathoracic infiltration The common sites of local infiltration and associated clinical problems are shown in Figure 13.60.

702

Extrathoracic metastasis In bronchial carcinoma general symptoms such as lethargy,

anorexia and weight loss frequently signify disseminated disease. The most important sites of secondary spread are the liver, bone and brain, but virtually all parts of the body can be affected. In small cell carcinoma the bone marrow is involved in 10-20% of patients presenting with advanced disease, and can produce a leukoerythroblastic anaemia, but in most patients any anaemia is due to the non-specific effects of malignancy (Fig. 23.17, p. 1227). Non-metastatic manifestations Endocrine and metabolic changes occur in 10-15% of cases, but cause symptoms much less frequently. Hypercalcaemia Hypercalcaemia (p. 965) occurs in 6-7% of tumours. In many cases of squamous carcinoma this is due to the production of parathyroid hormone-related peptide elaborated by the tumour. In some patients hypercalcaemia is due to extensive bone metastases. Hyponatraemia The secretion of ADH-like peptides is nearly always associated with small cell cancer, and is a feature in 10% of such tumours (p. 1103). It results in a dilutional hyponatraemia.

Cusking's syndrome The ectopic production of ACTH-like peptides by small cell tumours is common but only occasionally causes symptoms (1% of all cases) (p. 932).

13

Clubbing Clubbing (Fig. 13.9, p. 619) is most frequently seen with squamous cell carcinoma (more than 50%) and is unusual in small cell tumours. Occasionally clubbed patients have hypertrophic pulmonary osteoarthropathy (HPOA) (p. 619). Neurological manifestations These are not common (less than 2%) and most frequently complicate small cell carcinoma. They are described on page 1434. Neurological manifestations can predate any obvious tumour. They may remit spontaneously, but usually progress and, except for rare cases, are little affected by treatment of the associated tumour.

Diagnosis Carcinoma of the bronchus is so common and has such a variety of symptoms and signs that it should be considered in most heavy smokers presenting to a general physician. Diagnosis is usually straightforward and the first important investigation is a chest X-ray. Indeed, 5% of cases are discovered when a chest X-ray has been taken for unrelated reasons. In a smoker, clubbing, haemoptysis, persistent chest infection or weight loss demand an immediate X-ray of the chest. Subsequent CT scanning often provides useful additional anatomical information, which can aid diagnosis and help in accurate staging.

FIG. 13.61 Carcinoma of the bronchus The left hilum is enlarged and more dense than the right. There are strands radiating from the hilum, and this spiculated appearance is typical of tumour.

Common radiological abnormalities Unilateral hilar enlargement Unilateral hilar enlargement (Fig. 13.61) is due to tumour and, frequently, involved lymph nodes. The hilum appears more dense than the opposite side, and the outer border of the hilum is frequently convex. Phrenic nerve invasion produces unilateral elevation of the diaphragm, and left recurrent laryngeal nerve involvement produces vocal cord paralysis with hoarseness. Peripheral solid tumour mass The tumour may be seen as a nodule, a large rounded mass or an irregular density (Fig. 13.62). Streaky shadows often extend into the surrounding lung, particularly towards the hilum, which may be abnormally bulky due to lymphadenopathy. Peripheral cavitating tumour mass A peripheral cavitating tumour mass is characteristic of squamous cell carcinomas. The cavitation is due to necrosis within the tumour, and the cavity wall is irregular and thick. However, a certain diagnosis is not possible on radiological criteria alone, and the differential diagnosis can include tuberculosis, lung abscess (Fig. 13.26), pulmonary infarction complicated by infection, vasculitic lesions and a rheumatoid nodule. Sometimes cavitation

FIG. 13.62 Carcinoma of the bronchus: peripheral (squamous cell) carcinoma The left hilum is enlarged due to adenopathy. Most pulmonary mass lesions more than 4cm diameter are malignant tumours.

703

SUMMARY 8 Common radiological abnormalities in bronchial carcinoma Unilateral hilar enlargement Peripheral solid tumour mass Peripheral cavitating tumour mass Volume loss/collapse affecting a lobe or lung

Abnormal mediastinum Lymphatic invasion Apical (Pancoast) tumour Pleural effusion

occurs in the consolidated lung distal to an obstructing tumour. Volume loss/collapse Bronchial carcinoma frequently arises in a major bronchus and gradually narrows the airway, leading to volume loss in a lung or lobe on the chest X-ray. Volume loss is therefore a critically important radiological sign, particularly if progressive. Eventually the tumour causes the collapse of a lobe or lung, producing an opacity on the chest X-ray (Fig. 13.12). Abnormal mediastinum Bronchial carcinoma frequently involves the mediastinum, and tumour infiltration as well as lymph node enlargement makes the mediastinal outline abnormal (Fig. 13.63). This is common in small cell tumours. Abnormalities of the mediastinum are well demonstrated by a CT scan.

FIG. 13.63 Carcinoma of the bronchus Central (small cell) carcinoma, lateral and inferior to the aortic knuckle. The usual outline of the aortic knuckle and configuration of the left hilar structures is lost. There is a secondary deposit in the left mid-zone.

Lymphatic invasion 1 2 The widespread involvement of the pulmonary lymphatics by tumour produces lymphangitis carcinomatosa (Fig. 13.64). This also occurs in malignant tumours of the stomach, pancreas and breast. Lymphatic invasion is well demonstrated by CT scans. 3 Apical (Pancoast's) tumour Apical tumours frequently invade the ribs, sympathetic chain (Homer's syndrome, p. 1295), brachial plexus and chest wall (Fig. 13.65). Apical tumours are well seen on CT scans or MRI. 4 Pleural effusion A common radiological manifestation of bronchial carcinoma at presentation is a pleural effusion, usually of large volume, which rapidly reaccumulates following aspiration, is commonly bloodstained, and often contains malignant cells. Positron emission tomography (PET) scanning PET scanning, which reflects metabolic activity in malignant tissues, accurately differentiates between benign and malignant nodules and is useful in staging lung cancer and identifying metastases (see p. 155).

704

1

Case 13.3

2

3

Figs 13.42-13.44

Fig. 13.41 4

Figs 13.45-13.47

FIG. 13.64 Carcinoma of the bronchus: lymphangitis carcinomatosa There are widespread linear and nodular opacities due to lymphatic infiltration. Basal septal lines are radiologically similar to those seen in left heart failure. Patients with lymphangitis usually have severe breathlessness.

Confirmation of diagnosis In addition to confirming the diagnosis, a knowledge of tumour cell type affects treatment; chemotherapy is frequently appropriate in small cell cancer but much less useful in non-small cell disease.

surgery, oncology, radiotherapy and palliative care. To achieve good results for patients a multidisciplinary team is therefore essential.

FIG. 13.65 Carcinoma of the bronchus: apical (Pancoast's) tumour The left first rib has been destroyed and there is a soft-tissue mass, due to nnetastatic nodes, in the supraclavicular fossa.

Bronchoscopy Fibreoptic bronchoscopy (p. 627) is the most important technique for confirming a diagnosis of bronchial carcinoma (as well as documenting the location of the tumour). A tumour is visible in about 70% of cases. Sputum cytology This simple, non-invasive technique can produce a positive result in up to 40% of patients. Sometimes the investigation confirms malignancy, but fails to determine the specific nature of the tumour. Similarly, cytology of pleural fluid will usually confirm a diagnosis of malignancy. Needle aspiration lung biopsy Percutaneous needle aspiration biopsy, with X-ray or CT screening to localize the tumour, is particularly effective for peripheral lesions not seen on bronchoscopy. A positive cytological diagnosis is achieved in 75-90% of patients with tumours. Surgical biopsy In a small number of patients surgical biopsy is necessary to establish a diagnosis. Mediastinoscopy and mediastinotomy allow biopsy of tumour within the mediastinum (see p. 630), and thoracoscopy or, occasionally, thoracotomy gives access for lung and pleural biopsy. Staging notation for lung cancer Following diagnosis, patients can be staged according to the extent of their disease (Table 6.6, p. 155). In general, only patients with stage I disease are suitable for surgery. The tumour, node, metastasis (TNM) system is useful when considering surgery for both small cell and non-small cell lung cancer. In small cell carcinoma a categorization into 'limited' disease (disease confined to one hemithorax) and extensive disease can be helpful when planning chemotherapy.

Management of lung cancer The management of lung cancer involves many disciplines: respiratory medicine, radiology, pathology, thoracic

13

Surgery The decision to resect a lung cancer should be made by a multidisciplinary lung cancer management team, and in these circumstances resection rates are often higher than when decisions are made by an individual clinician. The overall results of surgery are not good, with a 5-year survival of about 25%, but surgery represents almost the only possibility of cure in lung cancer. The critical question to be asked for each new patient with bronchial carcinoma is, 'Can this patient be cured by surgery?' The answer to the question of whether surgery is appropriate depends on the answer to several intermediate questions: 1. Is the patient's general health good? Coronary artery disease is common. Severe coexisting medical conditions may preclude surgery. 2. Is pulmonary function adequate to cope with major surgery and pulmonary resection? Most patients have airways obstruction. An FEVi of less than 1.5L usually precludes pneumonectomy. How much 'useful' lung is to be resected? 3. What is the site of the tumour: is surgery technically feasible? 4. What is the tumour histology? Small cell carcinoma is usually disseminated. Most favourable histology is well differentiated squamous cell carcinoma. 5. Is there evidence of local spread of tumour within the thorax? 6. Is there evidence of distant metastases? 7. Is the patient prepared to have surgery? In practice only 10-20% of patients are appropriate for surgical referral. Patients with pulmonary hypertension, hypoxia and hypercapnia should not be operated upon, and those with excessive sputum production often develop postoperative chest infections. Static lung function can be misleading and information on exercise tolerance is helpful. In most cases this information is as easily obtained by the physician walking up the stairs with the patient as by formal exercise testing. In addition to pulmonary function tests the contribution of the lung that will be resected can be obtained by perfusion and ventilation lung scans, and the postoperative FEV\ and VC can be predicted from such information. Recurrent laryngeal nerve invasion, malignant pleural effusion, superior vena caval obstruction, mediastinal lymph node spread and metastasis to the contralateral lung all preclude surgery. In considering surgery, assessment for mediastinal spread is critical. CT scanning can be helpful: a negative scan usually indicates that the mediastinum is clear, but a scan may demonstrate enlarged nodes that are subsequently found to be due to reactive hyperplasia

705

rather than tumour. These cases may require surgical assessment of the mediastinum. The relatively poor results of surgery in bronchial carcinoma reflect the widespread and early metastases so common in this disease. Prior to surgery, biochemical tests may reveal abnormal liver function, and liver secondaries can be confirmed by ultrasound or CT scan. Unfortunately, the available tests for detecting metastases, particularly those in the liver, frequently fail to pick up tumour deposits. A raised alkaline phosphatase may reflect bone secondaries, which can be confirmed by bone scan. CNS symptoms or signs indicate the need for a CT brain scan to exclude cerebral metastases. Results of surgical therapy The staging of disease, cell type, age of the patient and the operation performed all affect the results of surgery (Fig. 13.66). Although the overall survival rates of 25% at 5 years and 17% at 10 years are poor, some patient groups do relatively well. Young, fit patients who have a lobectomy for stage I squamous cell carcinoma have a 5-year survival of 55-60%. Chemotherapy Combination chemotherapy remains the mainstay of treatment of small cell lung cancer. The two most active regimens are etoposide and cisplatin, or cyclophosphamide, doxorubicin and vincristine. Treatment is given at 3-4-weekly intervals over a period of several months. A complete response to therapy with a return to normal of the chest X-ray and disappearance of tumour at bronchoscopy can be achieved in 25-50% of patients. Small cell tumours are rarely completely eradicated, however, and rapidly relapse. Chemotherapy

FIG. 13.66 Survival following surgical resection for non-small cell carcinoma of the bronchus

1 706

MCQ 13.23

increases the overall median survival from approximately 4 months without drug therapy, to 11 months with treatment (Fig. 6.12, p. 156). Approximately 10% of patients with limited disease will continue symptom- and diseasefree for 2 or 3 years. In general, patients with least tumour bulk and good general health have the best prognosis. The great reduction of tumour mass following treatment can produce dramatic symptomatic improvement, often following only two or three courses of drugs. Therapy can relieve breathlessness due to airways obstruction by tumour, bone pain due to metastatic disease, superior vena caval obstruction and haemoptysis. Chemotherapy is well tolerated by most patients, but avoiding the problems of nausea and infection due to marrow suppression requires careful attention to detail. A few more patients may achieve long-term survival if radiotherapy is combined with chemotherapy. However, the outlook for small cell carcinoma remains poor and is unlikely to be substantially improved until better chemotherapeutic agents become available. Combination platinum-based chemotherapy is increasingly being used as standard treatment for locally advanced and metastatic non-small cell lung cancer. Chemotherapy is used in conjunction with radiotherapy in stage III disease and increases survival compared with radiotherapy alone. Platinum-based chemotherapy may also be a useful palliative treatment. The increased use of active new drugs such as gemcitabine and the taxanes in conjunction with cisplatin is likely to result in further improvements in outcome in the next few years. Radiotherapy In bronchial carcinoma the principal purpose of radiotherapy is to produce symptomatic relief. Radiotherapy is particularly good at controlling bone pain, haemoptysis, superior vena caval obstruction and breathlessness due to narrowing of major airways. Following complete collapse of a lobe or lung, radiotherapy is less effective. Cerebral metastases often respond, albeit temporarily, to radiotherapy, with concomitant steroid therapy to control cerebral oedema. In patients with symptoms or signs of spinal cord compression urgent radiotherapy is indicated and can avert paraplegia. Back pain is often the first symptom in such patients. In carefully selected patients, radiotherapy can produce impressive results. For small, localized, well differentiated, particularly squamous cell, tumours in generally fit patients who are not suitable for surgery because of poor lung function, it is possible to achieve a 5-year survival of up to 17% following radical high-dose radiotherapy. Survival in localized small cell carcinoma is not greatly extended by radiotherapy alone, but tumour bulk can be dramatically reduced, with consequent excellent control of symptoms. In patients with small cell carcinoma who respond well to chemotherapy, prophylactic cranial irradiation can largely prevent the distressing development of symptomatic cerebral metastases. Mediastinal irradiation may also be used to prevent local relapse following induction of remission with chemotherapy.

A treatment regimen termed 'continuous hyperfractionated accelerated radiotherapy' (CHART), in which a small dose of radiotherapy is given three times a day over 12 days, may reduce tumour cell recovery between radiotherapy doses. Recent evidence suggests that this approach prolongs useful life. However, there are practical disadvantages, particularly as the treatment has to be given 7 days a week. Radiotherapy can cause a pneumonitis, the severity of which is related to the radiation dose. With radiation pneumonitis patients develop breathlessness and cough, often disproportionately severe relative to the chest X-ray abnormalities, usually about 6 weeks after therapy. Corticosteroids are helpful. Endobronchial therapy In carefully selected patients with obstruction of the major airways not amenable to chemotherapy or external irradiation, symptomatic relief can be achieved by a variety of endobronchial therapies, including endoscopic laser destruction of tumour, endobronchial radiotherapy and tracheobronchial stenting (see p. 628). Advanced bronchogenic carcinoma As with all malignant disease, patients with advanced bronchogenic carcinoma which is no longer responding to treatment require much medical nursing and social support during their last months of life. Support for the family is also important. The large number of patients dying of lung cancer represents an important challenge to hospitals, general practice, community terminal care teams and hospices. The future burden of lung cancer in countries that have only relatively recently adopted high levels of cigarette smoking will become a huge healthcare problem. Pain is a particularly troublesome symptom and radiotherapy may be required for its control. Pain may also require regular analgesics, particularly oral morphine. For intractable pain peripheral nerve blockade may be necessary. Morphine helps reduce the sensation of breathlessness. Poor appetite and lethargy can temporarily be alleviated by steroids, which may also improve the symptoms from cerebral secondaries for a few weeks or months. Weakness, immobility, poor food intake and analgesics all contribute to constipation. In the last weeks of life, pain, constipation, anxiety, breathlessness and weakness can greatly reduce the quality of life. Frequent assessment of the patient's needs is necessary. In this respect the family doctor's contribution is of great importance and the domiciliary terminal care team are able to provide a regular assessment in the patient's home. National guidelines generated by the Department of Health and the British Thoracic Society are now available in the UK and should help to deliver standard high quality management of lung cancer throughout the country. ALVEOLAR CARCINOMA

1

This is an unusual tumour with distinctive pathological and

clinical features. It constitutes 1-2% of primary pulmonary tumours. The sexes are equally affected and the tumour occurs in all races. Alveolar carcinoma is most common in patients above the age of 50, and is not related to smoking tobacco.

13

Pathology Alveolar carcinoma often arises within a damaged area of lung. Histologically the characteristic feature is malignant cells growing along the alveolar walls. On light microscopy it may be difficult to distinguish alveolar cell carcinoma from primary or secondary adenocarcinoma. The good prognosis for resection of early single nodule disease suggests that in most cases multinodular disease represents spread of tumour, rather than simultaneous multiple foci.

Clinical features The presenting symptoms of alveolar carcinoma are similar to other tumours although, because the tumour is not endobronchial, haemoptysis, bronchial obstruction and distal infection are less common. When the tumour mass is large or affecting both lungs, the patient becomes very breathless. In a few cases patients produce large volumes of clear, watery sputum (bronchorrhoea). The chest X-ray usually shows a single, irregular peripheral shadow sometimes resembling pneumonic consolidation, frequently with an air bronchogram within the tumour opacity. Cavitation is uncommon, but effusions occur. Multiple tumour opacities develop, initially within one, and then within both lungs (Fig. 13.67).

FIG. 13.67 Alveolar cell carcinoma of the lung The appearances of 'consolidation' are common with this carcinoma. Bilateral disease is also common.

707

Diagnosis

HAMARTOMA

Malignant cells can be detected in the sputum in some cases, but the distinction from adenocarcinoma is frequently not possible. Bronchoscopy and bronchial biopsy are usually negative, although transbronchial biopsy can provide a diagnosis. Diagnosis can be achieved by needle aspiration biopsy or, more frequently, by surgical biopsy at thoracoscopy or thoracotomy. Diffuse and multiple lesions are often initially thought to be infective, but failure to respond to antibiotic therapy raises suspicion of the true diagnosis.

Management Alveolar carcinoma is often relatively slow growing, and disseminated metastatic disease is less common than in other pulmonary tumours. Surgical resection is therefore the treatment of choice whenever possible, and good results can be achieved, with a 5-year survival of 50% for localized disease. More extensive disease has a poor prognosis and is difficult to treat, the tumour being resistant to chemotherapy and radiotherapy.

BRONCHIAL ADENOMA 1 The term 'adenoma' covers a variety of tumours, approximately 90% of which are carcinoid tumours arising from cells of the APUD series. The diagnosis is often made in young adults and the sexes are equally affected. These tumours are usually endobronchial, arising in larger airways, and causing airway narrowing, volume loss, collapse and distal infection. Common clinical features are cough, haemoptysis, breathlessness, unilateral wheeze and recurrent infections. Most tumours are of low-grade malignancy and symptoms may be present for a long time before a diagnosis is made. Wheezing and dyspnoea may lead to a mistaken diagnosis of asthma. Some tumours become malignant and occasionally (2% of cases) the patients develop the carcinoid syndrome (p. 796). It is important to note that tumour is not usually visible on the chest X-ray and the most common radiological abnormality is volume loss or lobar collapse. Diagnosis is frequently made at bronchoscopy, where 90% of these tumours are visible. The tumour is vascular and bleeds easily and profusely. Rigid bronchoscopy for biopsy is sensible if at fibreoptic bronchoscopy the appearances suggest an adenoma. The best treatment whenever possible is surgical resection, and the prognosis for these tumours is good unless there has been malignant change.

1 708

MCQ 13.23

Hamartomas are tumour-like malformations of disorganized tissue; in some the predominant tissue is cartilage, and in others smooth muscle. Unlike carcinoid tumours, hamartomas usually present over the age of 50. Males are three times more likely to be affected than females. Hamartomas are usually peripheral within the lung parenchyma and seldom within the bronchus. They grow slowly and are benign. Most are asymptomatic and are incidental findings on chest X-ray. The mass of the hamartoma is usually small, less than 4cm in diameter, rounded, well defined and sometimes calcified. Cavitation is rare. In most cases in the absence of typical calcification, and without the benefit of past chest X-rays, a malignant bronchial carcinoma will be part of the differential diagnosis and the correct treatment will be surgical excision. At surgery the hamartoma is felt to be hard, can be removed without resecting lung, and the prognosis is excellent.

THE SOLITARY PULMONARY NODULE

A common diagnostic and management problem arises when the chest X-ray, frequently a 'routine' investigation, shows a solitary pulmonary nodule (Table 13.53 and Fig. 13.68). The larger the lesion, the more likely it is to be malignant; lesions greater than 4 cm in diameter are usually malignant; those less than 8 mm are usually benign.

Management Resection of a single malignant nodule results in surgical cure in more than 60% of cases. Because 40% of all nodules are malignant, surgery should be considered in all patients who are fit for tumour resection, unless there is compelling evidence that the nodule is non-malignant. Nodules that have not grown in size for 2 years or which show calcification (especially central, diffuse or speckled) are likely to be benign. Solitary nodules in patients under the age of 35, especially non-smokers, are likely to be

TABLE 13.53 Causes of a solitary pulmonary nodule Malignant (40%) Bronchogenic carcinoma Alveolar carcinoma Bronchial adenoma Metastasis Benign (60%) Infectious granuloma Non-infective granuloma Benign tumour Other rare causes

25% 3% 2% 10% 50% 2% 2% 6%

13

FIG. 13.68 The 'solitary pulmonary nodule' A Small peripheral 'solitary pulmonary nodule' in the right lower lobe. B When there is doubt, calcification is best demonstrated by CT scan.

benign. The search for past X-rays is often the most rewarding investigation in these patients. A CT scan may demonstrate calcification more clearly or may show multiple pulmonary metastases. Positron emission tomography (PET) is useful to distinguish between malignant and benign pulmonary nodules, and a positive PET scan is strongly predictive of tumour. Fibreoptic bronchoscopy is seldom helpful because the lesion cannot be seen endoscopically. Needle aspiration biopsy is more useful, confirming malignancy in 75-90% of tumours, but a negative result is difficult to interpret. For some tumours and most benign lesions, the precise diagnosis is only revealed by surgical removal.

MEDIASTINAL TUMOURS 1 Mediastinal tumours are illustrated in Figure 13.69. Metastatic malignant disease is the most common cause of a mediastinal mass, most frequently at the hilum. Lym-

FIG. 13.69 Mediastinal mass lesions A The chest X-ray demonstrates a mediastinal mass: the preservation ot the silhouette of the descending aorta suggests'that the mass is placed anteriorly. B This is confirmed by the lateral chest X-ray: the retrosternal space, which is normally translucent, is opaque. The mass was a malignant thymoma. c Location of the more common mediastinal masses.

709

phoma and sarcoidosis are common, with anterior mediastinal adenopathy favouring the former. In addition to the lateral chest X-ray, CT scanning is crucial in elucidating the nature of mediastinal masses; contrast studies demonstrate vascular lesions, and cystic lesions (usually benign) can be identified. Thyroid isotope scans confirm a retrosternal goitre. Solid, non-vascular lesions usually require biopsy for diagnosis (for example, the differential diagnosis of carcinoma, lymphoma and sarcoidosis) by needle aspiration biopsy, mediastinoscopy, mediastinotomy, or thoracotomy. Neurogenic tumours are the most common cause of a posterior mediastinal mass. Symptoms arise from compression of local structures, a small proportion are malignant and treatment is surgical. Occasionally, a neurofibroma is associated with von Recklinghausen's disease. Dermoid cysts arise from ectodermal tissue, whereas teratomas are germ cell tumours that contain ectodermal, mesodermal and endodermal tissue. These teratodermoid tumours arise in the anterior mediastinum, commonly of young adults. Dermoids are usually cystic and benign, whereas teratomas are usually solid and malignant. Treatment is surgery to remove all or as much as possible of the tissue. In malignant cases, radiotherapy and chemotherapy may be necessary. Thymomas can be benign or malignant (about 25% of cases). Whereas many patients with thymoma have myasthenia gravis, only a minority with myasthenia have a thymic tumour. Treatment of all thymomas is surgical excision and, for malignant cases, postoperative radiotherapy.

FURTHER READING ON LUNG TUMOURS British Thoracic Society and Society of Cardiothoracic Surgeons of Great Britain and Ireland 2001 Guidelines on the selection of patients with lung cancer for surgery. Thorax 56:89-108. Doll R, Hill A B 1950 Smoking and carcinoma of the lung. British Med J 2:739-748. Matthay R A (ed) 1993 Lung cancer. Clin Chest Med 14 (1) Pieterman R M et al 2000 Preoperative staging of non-small cell lung cancer with positron-emission tomography. N Engl J Med 343 (4): 254-261. Report of a working group for the Standing Medical Advisory Committee 1994 Management of lung cancer; current clinical practices. London: HMSO.

PLEURAL DISEASE The visceral pleura, composed of a layer of mesothelial cells supported on connective tissue rich in lymphatics and blood vessels, covers the lung. The parietal pleura lines the

thoracic cavity, covers the diaphragm and meets the visceral pleura at the hilum. The visceral pleura has no pain fibres, whereas irritation of the parietal pleura induces the pain characteristic of pleurisy. Normally, the two pleural layers are adjacent to one another, separated by a thin film of fluid, continually formed at the parietal and drained at the visceral pleural surface. As a consequence of the elastic property of the lung, the pressure within the pleural space is negative, approximately -5cm H2O at resting endexpiration.

PLEURAL EFFUSION 1 Water and electrolytes from the pleural space are taken up by the visceral pleura and cleared by the pulmonary and systemic (bronchial) circulation, whereas the proteins of pleural fluid are mainly cleared via the lower mediastinal lymphatics. Excess fluid accumulates within the pleural space when visceral or parietal pleural capillary pressure is raised (e.g. left or right heart failure), when capillary permeability is increased (e.g. infection), and when lymphatic drainage is decreased (e.g. lymphatic invasion by tumour). The turnover of pleural water and electrolytes is rapid, even when a large effusion is present, hence the rapid response to diuretics of effusions due to cardiac failure. Protein turnover is less rapid, contributing to the slow clearance of effusions with high protein content. The accumulation of pleural fluid reduces the volume of the underlying lung, causing a restrictive ventilatory defect. Large effusions will lead to breathlessness, particularly if they develop rapidly, and, when unilateral, cause mediastinal shift.

Radiology The history, and particularly the clinical examination, may suggest pleural fluid, but the most helpful, simple investigation is a chest X-ray (Fig. 13.70). Radiology may suggest fluid but cannot determine its nature (e.g. a clear transudate, pus or blood). When there is doubt about pleural fluid a film taken in the lateral decubitus position will demonstrate pleural fluid adjacent to the lateral chest wall. Very small effusions are clearly seen on CT scanning. On occasion, pleural fluid becomes loculated, particularly when infected; ultrasound is a simple technique for confirming that fluid is present and locating its position. The collection of fluid in the pleural space beneath the inferior surface of the lung (subpulmonic effusion) can mimic an elevated hemidiaphragm. A lateral decubitus X-ray or ultrasound examination confirms the diagnosis of subpulmonic fluid.

Differential diagnosis 1

710

MCQ 13.24

2 Fig. 13.48

There are many causes of pleural effusion (Table The accumulated fluid may be a transudate, as a quence of alteration in the pressure relationships pleural space (as in cardiac failure), or it may

13.54). conseof the be an

TABLE 13.54 Causes of pleural effusion

13

Transudates (hydrothorax) Cardiac failure Hypoproteinaemia Constrictive pericarditis Myxoedema* Peritoneal dialysis and ascites (including Meigs' syndrome) Superior vena cava obstruction* Exudates Infections Malignancy Pulmonary infarction Rheumatoid arthritis Systemic lupus erythematosus Acute rheumatic fever Polyarteritis nodosa* Scleroderma* Dermatomyositis* Postmyocardial infarction syndrome Ovarian hyperstimulation Pancreatitis Subphrenic abscess Asbestosis* Familial Mediterranean fever Hepatic and pulmonary hydatid disease Hepatic amoebiasis Trauma Drugs Sarcoidosis* Yellow nail syndrome Radiotherapy* Chylous effusion Haemothorax latrogenic (e.g. misplaced subclavian infusion line) * Denotes that it is unusual for that disease.

FIG. 13.70 Pleural effusion A Small left effusion. The left hemidiaphragm cannot be visualized and the fluid appears to rise laterally and medially: on a lateral chest X-ray it rises anteriorly and posteriorly. (The patient had the yellow nail syndrome.) B Large effusion. Pleural fluid is homogeneous and without vascular markings or air bronchogram. The mediastinum is shifted to the right. Note the surgical clips in the left axilla. (The patient had metastatic pleural disease from breast carcinoma.) ©

exudate, as a result of increased capillary permeability (as in infection). Transudates have a protein content of less than 3 g/dL, are clear or light yellow, and often bilateral. Exudates have more than 3 g/dL of protein, are dark yellow or orange in

colour, often slightly cloudy, may clot on standing, and are usually unilateral. Trons udates Left heart failure, right heart failure, or a combination of both, are common causes of pleural effusion. Initially, the fluid may be unilateral, usually right-sided; when bilateral, the right effusion is usually larger than the left. In constrictive pericarditis the pleural effusions are less significant than the ascites. Any cause of hypoalbuminaemia may cause pleural effusion plus oedema and ascites; the nephrotic syndrome is often the cause. In Meigs' syndrome the pleural effusion is associated with ascites due to an ovarian tumour (usually a benign fibroma, occasionally

711

malignant disease), and resolution occurs if the tumour is removed. Effusions can occur with peritoneal dialysis and ascites. The mechanism of the hydrothorax is the direct passage of fluid through the diaphragm into the pleural space. Small communications have been observed at postmortem in patients with hydrothorax and cirrhosis.

712

Exudates Postinfective pleural effusions are most common with bacterial infections, particularly pneumococcal, and, if inadequately treated, may progress to an empyema. Even when not obviously purulent the fluid contains many polymorphonuclear leukocytes and is often associated with persistence of fever and leukocytosis. Mycoplasma is rarely responsible. Effusions following viral infections occasionally occur, particularly as part of the pleuropericardial involvement of Coxsackie B infections. Effusions have been described in glandular fever. Rarely, actinomycosis and other fungal infections can cause a pleural effusion. Tuberculosis, once a common cause of effusion, is now relatively unusual in the UK. An important aspect of diagnosis is pleural biopsy for histological examination and culture of the mycobacterium. Malignant pleural effusion may be due to primary pleural tumours, most commonly mesothelioma (see below) and rarely a benign pleural fibroma. However, the most common cause is metastatic pleural malignancy from carcinoma of the bronchus, as well as breast, ovary and other extrathoracic tumours. Effusions, usually bilateral, may complicate lymphangitis carcinomatosa (p. 704). Occasionally, lymphomas involve the pleura. Involvement of ribs and adjacent parietal pleura by myeloma may produce a pleural effusion. It is characteristic of malignant effusions that they develop rapidly and recur quickly after aspiration; they are also commonly, though not invariably, bloodstained. A pleural effusion is an important clinical feature of pulmonary infarction (p. 675). Pleural effusion is relatively common in some of the collagen vascular disorders (p. 690). In SLE and MCTD pleurisy and pericarditis are not uncommon, particularly in young and middle-aged women. Aspirated fluid contains lymphocytes, occasionally lupus erythematosus cells, and more often antinuclear factor and rheumatoid factor. In active rheumatoid arthritis 5% of patients have a pleural effusion (p. 1137). Pleural effusions are rather uncommon in polyarteritis nodosa, systemic sclerosis and dermatomyositis. Acute rheumatic fever is complicated by pleural effusions, usually small, in 10% of cases, most of which also have pericarditis. In the postmyo cardial infarction syndrome pericarditis and fever develop several days or weeks after acute infarction, and occasionally there is also a pleural effusion. Sarcoidosis is a rare cause of pleural effusions. Recurrent, self-limiting effusions can be a feature of familial Mediterranean fever (familial paroxysmal polyserositis). In the yellow nail syndrome effusions are associated with a yellow discoloration of nails, plus lymphoedema and occasionally

bronchiectasis and sinusitis. Lymphatic hypoplasia underlies the disorder, and this is thought to explain the effusions. Drugs can cause pleurisy with effusions: hydralazine (as part of a lupus syndrome), nitrofurantoin, sulphonamides, PAS, methotrexate, practolol and methysergide have all been incriminated. Radiotherapy to the lung can produce a radiation pneumonitis and small bilateral effusions. Following chest trauma and pulmonary contusion a pleural effusion occasionally collects. However, a haemothorax must first be excluded. Pathological processes below the diaphragm can cause pleural effusions, a common complication of acute pancreatitis, when it is usually painless, left-sided and haemorrhagic. The pleural fluid has a high amylase concentration, higher than in the blood. Occasionally similar effusions are seen in patients with chronic pancreatitis or pancreatic pseudocysts. Subphrenic abscess is frequently accompanied by a pleural effusion, most often on the right, with low lateral chest and shoulder pain as a consequence of diaphragm inflammation. On chest X-ray, in addition to the effusion, there may be elevation of the hemidiaphragm, below which there is sometimes a fluid level. If treatment is delayed, an empyema develops. Prior antibiotic therapy may produce a chronic clinical picture.

Investigation of pleural fluid Whenever there is doubt about the cause of an effusion, aspiration should be performed. Loculated or small effusions are best aspirated with ultrasound localization. Bloodstained effusions, rather than the frank blood of a haemothorax, are most common with malignancy, but also occur in pulmonary infarction and following chest trauma. Rare causes of a bloody effusion include cirrhosis, tuberculosis and leukaemia. Infected pleural fluid is turbid, and with advanced empyema becomes purulent. With a chylous effusion the fluid is a milky white colour. Analysis of pleural fluid protein concentration broadly separates transudates (less than 3g/dL) from exudates (more than 3g/dL), but in a large number of cases borderline, unhelpful values are obtained. Cytology is a key investigation, not simply for malignant cells. The presence of numerous polymorphonuclear leukocytes suggests bacterial infection; lymphocytes predominate in tuberculosis but are also common in any chronic effusion; eosinophils are numerous in the effusions of pulmonary eosinophilia, polyarteritis nodosa and Hodgkin's disease. Eosinophils can be the prominent cells following pulmonary infarction, and may also accumulate following bleeding into the pleural space from any cause. Pneumonias and rheumatoid arthritis are less usual causes for an eosinophilic effusion. Malignant cells are identified in up to half of patients with tumour involving the pleura. Bacteria may be demonstrated in postpneumonic effusions, particularly in those progressing to empyema. In tuberculosis acid-fast bacilli are only occasionally identified, but culture of pleural fluid for the mycobacteria is often useful.

In rheumatoid arthritis the pleural fluid contains a characteristically very low concentration of glucose. When pleural aspiration is not diagnostic pleural biopsy should be performed. Biopsy is particularly helpful in malignant disease of the pleura and in tuberculosis. Pleural biopsy An Abrams' biopsy needle is most commonly used and the investigation should not normally be undertaken when there is no fluid present, lest the biopsy needle puncture the visceral pleura. If the pleura is much thickened, biopsy with a cutting needle is safe even in the absence of fluid. Sometimes, diagnosis may require a large biopsy sample; for example, in mesothelioma a surgical biopsy is often indicated. Video-assisted thoracoscopy is very useful, and is increasingly used in the investigation of pleural disease (p. 630). Multiple biopsies increase the diagnostic yield, and one of the biopsy samples should be sent to the laboratory for culture if a diagnosis of tuberculosis is possible.

Management Infected pleural fluid should be promptly and completely drained; in many cases this is best done with an intercostal tube. Any pleural effusion causing breathlessness requires drainage. Malignant effusions may be large and recurrent, and therefore require pleurodesis. Re-expansion pulmonary oedema is rare, provided large volumes of fluid are not rapidly aspirated; passive drainage seldom causes problems. A variety of sclerosing agents can be introduced into the pleural space in an attempt to fuse the visceral and parietal layers, thereby avoiding the reaccumulation of fluid. Tetracycline, bleomycin and talc slurry can produce satisfactory results. If a large pleural effusion reaccumulates despite attempts at medical pleurodesis, surgical pleurodesis using talc powder or pleurectomy should be considered. This can be achieved by thoracoscopy or thoracotomy. Medical pleurodesis is successful in approximately 50% of patients, whereas surgery is effective in virtually all cases.

fluid. Fluid rapidly reaccumulates, and repeated drainage soon leads to severe wasting, hypoproteinaemia and lymphopenia. In up to 50% of patients with chylothorax there is spontaneous healing of the fistula, but if this does not occur the prognosis is poor unless the leak of chyle can be stopped. Following diagnosis a lymphangiogram is useful to determine the site of the fistula; if a leak is demonstrated the patient should be submitted to thoracotomy and ligation of the thoracic duct below the leak. If no leak can be demonstrated at lymphangiography, repeated aspiration is performed and the patient is supported by parenteral feeding, in the hope that the fistula will heal spontaneously. When healing does not take place, pleural drainage combined with pleurodesis is sometimes successful.

13

HAEMOTHORAX Haemothorax is usually the result of a penetrating injury or blunt trauma to the chest. Occasionally, a haemothorax develops without trauma. Such a spontaneous haemothorax, almost always left-sided, may occur with acute aortic dissection. Bleeding can occur with a pneumothorax, from the rupture of vessels within pleural adhesions, and in some cases the air may have been absorbed by the time of presentation. Bleeding disorders, heparin therapy, vascular pleural metastases and pleural endometriosis are rare causes of haemothorax. Haemothoraces, unless small and stable, should be drained by a wide-bore intercostal tube introduced in the midaxilla and connected to an underwater seal. If bleeding continues, the patient requires a thoracotomy. If blood is not removed from the pleural space, infection progressing to empyema can be a complication. In the long term an intense fibrous reaction to undrained blood can occasionally lead to a grossly thickened pleura and an encased lung, which then requires decortication if there is not to be substantial ventilatory impairment.

EMPYEMA CHYLOTHORAX Chylothorax most frequently follows rupture of the thoracic duct after trauma, particularly during thoracic surgery. Damage to the thoracic duct in the lower half of the mediastinum causes a right-sided chylothorax, whereas damage to the duct in the upper mediastinum produces a left chylothorax. When chylothorax is not due to trauma, malignancy involving the thoracic duct is the most common cause, particularly metastatic disease from carcinoma of the stomach, and lymphoma. Rarely chylothorax can complicate chylous ascites. Patients with chylothorax present with symptoms and signs of a large pleural effusion and the diagnosis is only apparent following aspiration of the milky white

Empyema refers to infected pleural fluid, whether a turbid effusion or frank pus. In many cases the diagnosis only becomes apparent on aspiration of the fluid. Most commonly, an acute empyema complicates a bacterial pneumonia, particularly pneumococcal, but other causes require consideration (Table 13.55). Staphylococcal pneumonia is an important cause in children. Anaerobic infection is sometimes difficult to diagnose, and it is likely that anaerobes are responsible for many 'sterile' empyemas. Tuberculous empyema is now unusual. It is not uncommon for empyema fluid to contain more than one organism. Empyema following thoracic surgery, and those associated with abdominal sepsis are frequently due to Gram-negative organisms. Amoebic liver abscess can rarely perforate the diaphragm and enter the

713

TABLE 13.55 Causes of acute empyema Thoracic surgery Penetrating chest injuries Sub-diaphragmatic infection Haematogenous spread of infection

Pneumonias Lung abscess Bronchiectasis Oesophageal perforation Pulmonary infarction

bronchus, thereby producing a bronchopleural fistula. Patients then cough large volumes of purulent sputum and on X-ray the empyema has fluid levels. Untreated, an empyema may discharge through the chest wall (empyema necessitatis). Empyema, particularly when due to staphylococcal infection, can be complicated by a pneumothorax (pyopneumothorax).

Management Antibiotic therapy will depend on the bacteriology of aspirated fluid, and regimens will often require metronidazole to cover anaerobic organisms. The pleural fluid must be completely drained as soon as possible. With early infection and freely moving fluid, needle aspiration can be successful. However, in most cases a large-bore intercostal drain should be inserted. The drainage of pleural fluid can be enhanced by instillation of intrapleural streptokinase (250 000IU daily for 3 days). If such treatment fails to produce rapid resolution of symptoms and complete drainage of the empyema, surgery is required. At surgery, the empyema is evacuated and the lung decorticated so that it may fully expand and thereby obliterate the pleural space.

Chronic empyema

FIG. 13.71 Empyema On the lateral chest X-ray the configuration of the posterior loculated pleural fluid is typical of empyema. The left hemidiaphragm is well seen, with the gastric bubble beneath it. The posterior curve of the right hemidiaphragm is obscured by the empyema.

pleural space, as can actinomycosis and hydatid disease. The empyema that occasionally complicates the mediastinitis of oesophageal rupture is usually left-sided. The clinical features of acute empyema include fever, night sweats and chest pain, with signs of a pleural effusion. The most common clinical setting is that of a pneumonia that has failed to respond to therapy. The white cell count is elevated (15000-20000) with a polymorphonuclear leukocytosis. Pleural fluid aspiration is essential and diagnostic; the fluid may be turbid, with numerous polymorphs or frank pus. Empyemas are usually posterior and lateral above the diaphragm. Initially, the pleural fluid moves freely in the pleural space and the chest X-ray demonstrates the appearances of a simple effusion, but the infected fluid rapidly becomes loculated and the chest X-ray then shows localized collections of fluid (Fig. 13.71). An acute empyema can breach the lung and enter a 1 714

MCQ 13.25

2

Fig. 13.8

Occasionally, the diagnosis of acute empyema is missed or the condition is inadequately treated and a stable chronic empyema develops. Infection is particularly likely to persist when there is an associated bronchogenic carcinoma or a bronchopleural fistula. Patients are usually not acutely ill. Fever is low-grade and there is likely to be clubbing, weight loss, anaemia, and the clinical signs of extensive pleural thickening. The chest X-ray shows dense pleural shadowing, perhaps fluid levels, and occasionally periosteal reaction in overlying ribs. A later radiological development is pleural calcification and a late clinical development is secondary amyloidosis. The treatment of chronic empyema is surgical, but in patients too frail for surgery drainage by a wide-bore drain, progressively shortened as the empyema cavity reduces, can produce satisfactory resolution.

PLEURITIC CHEST PAIN WITHOUT EFFUSION A variety of disorders can cause pleuritic chest pain, often with a pleural rub, but without a pleural effusion. Some of these conditions remain 'dry' but in most fluid may accumulate, and therefore many of the causes of a pleural effusion must be considered in the differential diagnosis of dry pleurisy. The most important causes of pleurisy without fluid are listed in Table 13.56. Pleuritic pain is a common feature of many radiologically obvious pneumonias, but can also occur with minor bacterial and viral pulmonary infections not radiologically

TABLE 13.56 Important causes of dry pleurisy Pneumonia (particularly pneumococcal pneumonia) Pulmonary infarction Bronchogenic carcinoma Lung abscess Bronchiectasis Tuberculosis Rheumatoid arthritis Systemic lupus erythematosus

Uraemia Coxsackie B virus (Bornholm's disease) Familial Mediterranean fever Trauma Asbestos pleural disease, including mesothelioma

apparent. Epidemic myalgia (Bornholm's disease), most commonly due to the Coxsackie B virus, is primarily an infection of intercostal muscle but occasionally the pleura is involved. The intercostal muscles are tender. There may be associated pericarditis, myocarditis or orchitis. Pain may relapse and remit several times before finally settling.

TABLE 13.57 Conditions predisposing to spontaneous pneumolhorax

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Chronic bronchitis and emphysema Asthma Cystic fibrosis Tuberculosis Marfan's syndrome, Ehlers-Danlos syndrome Congenital cysts Honeycomb lung

pneumothorax). Most commonly, spontaneous pneumothorax develops in an otherwise fit person as a result of the rupture of a small apical pleural bleb, probably congenital in origin. Young men are most frequently affected and are often tall and of slim build.

Clinical features PNEUMOTHORAX 1 Pneumothorax is air in the pleural space, as a consequence of which there is partial or complete collapse of the lung. Owing to the recoil of the chest wall and the lung, the pressure within the pleural space is normally negative. When the pleural membrane (visceral or parietal) is breached, air is sucked into the pleural cavity and the lung collapses. When the defect in the pleura seals, the pneumothorax is closed and there is no movement of air in or out of the pleural cavity. When there is a persistent defect in the pleura the pneumothorax is open. When this defect is of the visceral pleura there is then a bronchopleural fistula, and air moves in and out of the pleural space during breathing. Occasionally the damaged visceral pleura acts as a valve, permitting air to enter the pleural space on inspiration but not to leave it on expiration, leading to a tension pneumothorax. A pneumothorax may be spontaneous, or follow chest trauma, mechanical ventilation, ruptured oesophagus, or artificial induction. Causes of traumatic pneumothorax include blunt trauma to the chest, commonly external cardiac massage, and penetrating chest injuries (e.g. stab wounds or needle aspiration biopsies that breach the visceral pleura from without) and transbronchial biopsy and positive-pressure ventilation that breach the visceral pleura from within. A spontaneous pneumothorax may be primary, in which case the patient is otherwise healthy, or may be secondary to some other disorder (Table 13.57). Of these, airways obstruction, particularly with associated bullous emphysema, is the most common predisposing cause. Rarely, in young women, pneumothorax may follow the passage of air from the abdominal cavity into the pleural space (usually the right) through fenestrations in the diaphragm. The air enters the abdominal cavity from the fallopian tubes at the time of menstruation (catamenial

Characteristically, there is a sudden onset of chest pain laterally, sometimes radiating to the shoulder. With substantial collapse of the lung there is associated breathlessness, and a dry, irritating cough is common. Sometimes the patient is aware of the partially collapsed lung flopping about within the thorax. On examination the most striking findings are of reduced breath sounds and hyperresonant percussion. A small left-sided pneumothorax may be associated with a clicking noise with each heartbeat, noted by the patient and on occasions loud enough to be heard by others. A large pneumothorax in a normal person causes breathlessness, and in the presence of pre-existing pulmonary disease a small one may cause severe respiratory distress. Tension pneumothorax is a medical emergency. The valve action of the pleural tear results in a progressive increase in the size and pressure of the pneumothorax. The underlying lung is totally collapsed. The mediastinum is shifted to the contralateral side, compromising the function of the opposite lung, and the high intrathoracic pressure elevates the jugular venous pressure, reduces venous return and causes tachycardia, low cardiac output, and eventually circulatory collapse and death. With the exception of a tension pneumothorax, when action may be required immediately, a chest X-ray is necessary in all patients in whom the diagnosis of pneumothorax is a possibility. © Small apical pneumothoraces may be difficult to see and an expiratory chest X-ray, which enhances the contrast between lung tissue and air in the pleural space, is helpful. For small pneumothoraces the edge of the visceral pleura is often easier to see when the chest X-ray is viewed on its side. The X-ray allows an assessment of the size and position of the pneumothorax (the air may be loculated if there are pleural adhesions), any abnormality in the underlying lung, and the presence of mediastinal or subcutaneous air. A loculated pneumothorax can be difficult to distinguish from a bulla, in

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which case a CT scan is helpful. CT can also detect pneumothoraces too small to be visible on chest X-ray. A small volume of pleural fluid is commonly seen, but when there is a larger collection it should be sampled to exclude bleeding and, occasionally, infection (pyopneumothorax). Recurrence of pneumothorax is common; a young person with spontaneous pneumothorax has a 20-30% chance of a second one, usually on the same side; with each pneumothorax the probability of further episodes increases. The longer the time that elapses following a pneumothorax, the less chance there is of a recurrence.

Management

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Any pneumothorax sufficient to cause or increase breathlessness requires drainage. Many patients, particularly young, otherwise fit males, present with a small or moderate pneumothorax, and whatever breathlessness was experienced acutely has settled. Such closed pneumothoraces do not require therapy and the patient can be monitored as an outpatient, provided he is instructed to seek medical advice if breathlessness returns. A 20-30% collapse of a lung normally takes several weeks to expand fully. Simple aspiration is an effective treatment for many pneumothoraces. If aspiration is not effective (because of a bronchopleural fistula) an intercostal drain is required. In a tension pneumothorax, if necessary, prior to the insertion of an intercostal drain, tension can be released by inserting an intravenous cannula into the pleural space in the second interspace in the midclavicular line. Unless a pneumothorax is loculated, the best site for a drain is in the midaxilla at the level of the sixth intercostal space. When the catheter is connected to the underwater sealed drainage bottle, any pleural air under positive pressure bubbles out. Careful and regular inspection of the level and movement of the water meniscus in the draining tube provides important information in the management of a pneumothorax (Fig. 13.72). In a closed pneumothorax, coughing or other manoeuvres that produce a positive intrathoracic pressure drain the air and the pneumothorax rapidly resolves. When there is a large defect in the visceral pleura, producing an open pneumothorax and a bronchopleural fistula, any manoeuvre producing positive intrathoracic pressure causes much bubbling, but because the pleural defect remains the pneumothorax does not resolve. The chest drain is kept in situ in the expectation that the pleural defect will close and the pneumothorax convert from an open to a closed type and then resolve. If resolution does not occur within a few days, it is common practice to apply suction to the pneumothorax. In practice, only a minority of open pneumothoraces - usually those in which the pleural leak is small - can be treated in this way. Frequently, the application of suction simply serves to hold the pleural defect open. When air no longer bubbles from the catheter even when the patient coughs, a chest X-ray should be taken to confirm that the lung has expanded fully. If this is the case,

FIG. 13.72 Pneumothorax [A] In a closed pneumothorax the meniscus in the drain rises and falls with breathing, and at resting end-expiration the small negative intrathoracic pressure supports a column of water. B In an open pneumothorax air bubbles into the drainage bottle, with each breath, during active expiration, c If pleural fluid blocks the drainage tube the bubbling of air ceases and there is little movement of the meniscus with breathing. This situation can therefore mimic that of a resolved pneumothorax.

the drain should be clamped for several hours, and if the lung remains fully inflated the drain can be removed. Where a drain has been inserted for a recurrent pneumothorax a medical pleurodesis should be undertaken prior to removal of the catheter, most commonly with tetracycline, bleomycin or talc slurry. If an open pneumothorax persists for a week despite a period of suction the patient should be referred for thoracoscopy or thoracotomy, closure of the bronchopleural fistula, and parietal pleural abrasion or pleurectomy.

MediasHnal emphysema (pneumomediastinum) Air can enter the mediastinum following penetrating neck injuries, and after oesophageal or bronchial rupture, but the most common cause is rupture of alveoli. Air enters the interstitial tissues and tracks to the mediastinum. High intrapulmonary pressures, for example due to vomiting, are frequently the cause. In asthma, gas trapping, alveolar distension and high intrapulmonary pressures during coughing make mediastinal emphysema a relatively common complication. Positive-pressure mechanical ventilation can produce mediastinal emphysema as well as pneumothorax. Mediastinal emphysema is usually asymptomatic but can cause chest pain, which may be worse on swallowing or breathing. There may also be a crunching sound coincident with each heartbeat. Radiology may show air in the upper mediastinum, around the heart, within the soft tissues of the neck, and in 30% of cases an associated pneumothorax. Treatment is of the predisposing cause, following which the mediastinal emphysema rapidly resolves. Resolution can be hastened by breathing a high oxygen concentration, during which the more soluble oxygen replaces the insoluble nitrogen.

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TUMOURS OF THE PLEURA The pleura can be the primary site of benign or malignant tumours or, more commonly, the site of metastatic malignant disease.

Fibroma The pleura - usually the visceral surface - may be the site of a single benign fibrous tumour (localized fibrous mesothelioma). The tumour, which is well encapsulated and often pedunculated, is frequently first noted as a peripheral pleural mass on routine chest X-ray. A pleural effusion is uncommon. These tumours are not associated with asbestos exposure. Fibromas can become large and thereby cause breathlessness as well as chest pain. Patients are generally middle-aged or elderly, and clubbing, as well as hypertrophic pulmonary osteoarthropathy, is a frequent association. A definite diagnosis is seldom possible without thoracoscopy or thoracotomy and biopsy, and surgical resection is the correct management. If left untreated, these tumours may eventually become locally invasive.

Diffuse mesothelioma Diffuse mesothelioma, a highly malignant tumour, is related to asbestos exposure in most - perhaps all - cases. The patient's exposure to asbestos is, on average, 40 years prior to the malignancy becoming apparent. Most commonly, exposure to asbestos is in the shipbuilding, construction and demolition industries. Crocidolite (blue asbestos) is most commonly incriminated. In the UK 1300 patients each year are diagnosed as having malignant mesothelioma and the number is likely to rise to 3000. The tumour spreads over the pleural surface, causing great thickening of the pleura by malignant tissue, and the lung becomes encased. The tumour spreads into the mediastinum, through the diaphragm to involve the peritoneum, and invades the chest wall. An effusion is characteristic and is often bloodstained. Distant metastases occur, although relatively infrequently, and cause major clinical problems. The histology is pleomorphic and a definite diagnosis, is often difficult on a small biopsy sample. Malignant mesothelioma can be divided into three subtypes: epithelioid, sarcomatoid and biphasic. Differentiation between epithelioid and metastatic adenocarcinoma can be difficult. The use of adenocarcinoma and mesothelioma markers can facilitate immunohistochemical discrimination. Patients with malignant mesothelioma present at an average age of 60, most commonly with persistent dull chest pain. There is progressive breathlessness because of pleural thickening and the accumulation of fluid. Finger clubbing occurs but is relatively unusual. The chest X-ray commonly shows a large effusion, with the pleural tumour often only apparent following aspiration. CT scanning clearly demonstrates the extent of pleural disease, and

FIG. 13.73 Mesothelioma [A] The chest X-ray shows bilateral pleural thickening and fluid, B The CT scan shows extensive pleural thickening, plus fluid, and pleural calcification posteriorly on the right (arrow).

when pleural calcification is also present the appearances are highly suggestive of the diagnosis (Fig. 13.73). Although cytology of aspirated fluid may demonstrate malignant cells, and Abrams' or cutting needle pleural biopsy may also show malignancy, a large surgical biopsy is sometimes needed to confirm the diagnosis. However, surgical biopsy can be followed by infiltration of the thoracotomy scar by tumour. The diagnosis is commonly achieved by thoracoscopic biopsy. A very small number of patients with localized disease can be cured by surgery; for most, treatment is palliative. Overall, no therapy, whether surgery, cytotoxic drugs or radiotherapy, has been demonstrated to prolong life. Recurrent symptomatic pleural effusions can be managed by talc pleurodesis or thoracoscopic pleurectomy. Chest wall pain, but not breathless-

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ness, can often be helped by palliative radiotherapy. Life expectancy is 1-2 years following presentation. In the UK patients with a history of asbestos exposure are eligible for industrial injuries benefit.

Metastatic malignant pleural disease Pleural metastases with an associated effusion are common, particularly with bronchial carcinoma. The effusion is usually painless, but causes breathlessness and may require pleurodesis (p. 713). Pleural involvement is also common following malignant disease of the breast and ovary. Less commonly, pleural involvement occurs in other carcinomas, lymphangitis carcinomatosa, multiple myeloma, malignant lymphoma (particularly Hodgkin's disease), Kaposi's sarcoma and Waldenstrom's macroglobulinaemia.

TABLE 13.58 Neuromuscular disorders which cause respiratory muscle weakness Neurogenic Motor neuron disease Surgical trauma of phrenic nerves Polyneuropathy Neuralgic amyotrophy Poliomyelitis Multiple sclerosis Traumatic tetraplegia Acute porphyria Charcot-Marie-Tooth disease Following radiotherapy

Myopathic Muscular dystrophy/atrophy Inflammatory myopathies Myotonic dystrophy Acid maltase deficiency Thyroid myopathy Metabolic disturbance (e.g. hypophosphataemia)

Neuromuscular junction Myasthenia gravis Lambert-Eaton syndrome

FURTHER READING ON PLEURAL DISEASE British Thoracic Society 2001 Statement on malignant mesothelioma in the United Kingdom. Thorax 56:250-265. Davies R J O, Traill Z C, Gleeson F V 1997 Randomised controlled trial of intrapleural steptokinase in community acquired pleural infection. Thorax 52:416-421. Miller A C, Harvey J E on behalf of the Standards of Care Committee of the British Thoracic Society 1993 Guidelines for the management of spontaneous pneumothorax. Br Med J 307:114-116. Peto J, Hodgson J T, Matthews F E, Jones J R 1995 Continuing increase in mesothelioma mortality in Britain. Lancet 345:535-539. Reid P T, Rudd R M 1993 Management of malignant pleural effusion. Thorax 48:779-780.

NEUROMUSCULAR AND SKELETAL DISORDERS NEUROMUSCULAR DISORDERS Ventilation depends on adequate central respiratory drive, and depression of central nervous system function can therefore cause ventilatory failure. In such patients the diagnosis is usually self-evident and the resulting hypercapnia easily documented. Central nervous system dysfunction may also cause sleep apnoea syndromes (p. 668). In addition, a wide range of neurological and muscular disorders can cause ventilatory impairment on the basis of respiratory muscle weakness (Table 13.58).

The respiratory muscles

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In a normal person at rest inspiration is active, whereas expiration is a passive process; most of the respiratory muscles are therefore inspiratory in their action. The diaphragm is the principal muscle of inspiration and is responsible for 80% of ventilation at rest. Diaphragm

contraction causes descent of the diaphragmatic dome, anterior displacement of the abdominal wall, elevation of the lower ribs and expansion of the lower thorax. At resting lung volume (functional residual capacity) the external intercostal muscles are inspiratory and the internal intercostal muscles are expiratory. The abdominal muscles are the most powerful muscles of expiration. The accessory muscles of respiration are conventionally considered to be the sternomastoid, scalene and pectoral muscles, which act mainly to fix or elevate the upper ribcage. However, many other muscles contract vigorously during maximum respiratory efforts.

The respiratory muscles in neuromuscular disease Clinical assessment Isolated involvement of the respiratory muscles by neuromuscular disease is unusual, and most patients will have evidence of more widespread involvement, with, for example, weakness of other muscle groups, bulbar problems and impaired cough, as well as breathlessness. On examination there may be muscle wasting, weakness and fasciculation. Patients with bilateral severe diaphragm weakness or complete diaphragm paralysis present an unusual and striking clinical picture (Fig. 13.74). Severe weakness of the inspiratory muscles reduces the lung volume on the chest radiograph, but this can be an unreliable sign; unless the radiologist is already aware of the diagnosis, it is likely that it will be assumed that the patient has chosen not to take a full inspiration rather than that he or she is incapable of doing so. Diaphragm paralysis elevates the hemidiaphragm involved. Radiological screening, which should be performed with the patient supine, will demonstrate the upward movement of a paralysed hemidiaphragm during

FIG. 13.74 Paralysis or severe weakness of the diaphragm In patients with severe diaphragm weakness, when supine the contraction of the intercostal muscles lowers intrathoracic pressure, sucks the diaphragm into the chest and the anterior abdominal wall moves inwards. Patients with diaphragm paralysis therefore have severe orthopnoea.

FIG. 13.75 The effect of respiratory muscle weakness on lung volumes The principal effect of substantial weakness is to reduce vital capacity. (TLC = total lung capacity; TV = tidal volume; VC = vital capacity; RV = residual volume.)

a sharp sniff. Diaphragm movement can also be assessed by ultrasound. Lung function Respiratory muscle weakness reduces both inspiratory and expiratory capacity (Fig. 13.75). Total lung capacity is reduced, residual volume (RV) is increased, and both of these changes decrease vital capacity (VC); this simple measurement is therefore excellent for the detection of respiratory muscle weakness. VC is an ideal measurement in the follow-up of patients with weakness and in muscular dystrophy; for example, the VC correlates well with both the clinical staging of disease and the assessment of prognosis. In neuromuscular disorders that can cause rapid profound weakness (e.g. Guillain-Barre syndrome) large falls in VC warn that assisted ventilation may be required. The measurement of VC is particularly useful when assessing diaphragm weakness. In the upright posture VC is reduced, but when the patient lies flat there is a further marked fall in VC, characteristically by 50% with total paralysis of the diaphragm. Lung function in patients with respiratory muscle weakness shows no evidence of airways obstruction and the ratio of FEVj to FVC is normal. Although overall gas transfer may be reduced, when corrected for the reduction in lung volume, gas transfer coef-

ficient (KCO) is normal or raised. With the progression of neuromuscular disease patients gradually develop hypoxaemia, but hypercapnia is a late development associated with a poor prognosis. Hypercapnic ventilatory failure is unusual before the VC has fallen to below 50% of normal. With generalized respiratory muscle weakness, particularly when the diaphragm is severely involved, ventilatory failure is more pronounced when supine, and may be particularly severe during sleep. Sleep studies are therefore very useful in the assessment of such patients.

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Respiratory pressures A normal supine VC excludes severe inspiratory muscle weakness, but a reduced VC is not specific for weakness and must be assessed in the context of possible coexisting lung disease. A more specific and sensitive index of global respiratory muscle strength is provided by measurement of maximum static mouth pressures. Pressures are measured by a transducer or gauge; expiratory mouth pressures are recorded during a maximum expiratory effort at TLC against an obstructed airway, and inspiratory mouth pressures are measured during a maximum inspiratory effort from RV. In patients with generalized neuromuscular diseases respiratory pressures are commonly reduced to 50% of normal, even though patients are often not particularly breathless. Hypercapnia is unusual unless inspiratory mouth pressures are reduced to below 30% of normal. Diaphragm weakness The phrenic nerves are commonly invaded by tumour, particularly carcinoma of the bronchus. Viral infections, including herpes zoster, can cause a phrenic neuropathy, as can the neurological disorders of motor neuron disease, poliomyelitis, neuralgic amyotrophy, Charcot-Marie-Tooth disease and many peripheral neuropathies. Trauma, particularly surgical, is important, and phrenic nerve dysfunction is quite common following cardiac surgery. In the past, phrenic crush and phrenic avulsion for the treatment of tuberculosis was a common cause of phrenic neuropathy. Unilateral phrenic nerve palsy causes a 20% reduction in ventilatory capacity and a reduction in maximum transdiaphragmatic pressures, but patients have few symptoms: perhaps transient breathlessness, in the absence of additional pathology. Bilateral phrenic nerve paresis, on the other hand, causes shortness of breath on exertion and severe orthopnoea; indeed, patients are quite unable to remain flat for more than a few seconds. Many patients sleep propped up or on their sides to assist ventilation. Diaphragm strength can be specifically and accurately measured by recording transdiaphragmatic pressure with oesophageal and gastric balloon catheters during a maximum sniff effort. A non-volitional assessment of phrenic nerve and diaphragm function is achieved by electrical or magnetic phrenic nerve stimulation in the neck and measurement

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CASE STUDY 13.8 DIFFICULTY IN SLEEPING IN A PATIENT WITH MOTOR NEURON DISEASE A 55-year-old woman was referred for a neurological opinion with a history of progressive pseudobulbar palsy developing over a 6-month period. She had difficulty with speaking and swallowing. She had not noticed weakness in her limbs. On examination there was facial weakness and a brisk jaw jerk, a brisk gag reflex and reduced tongue movements. The movements of the tongue were slow and spastic, and the tongue was wasted with fasciculation. There were also widespread fasciculations in all muscle groups of the upper limbs. In the lower limbs occasional fasciculation was noted, but the power was normal. Neck flexion was weak. There were no sensory abnormalities. Reflexes were brisk in the upper limbs and normal in the lower limbs, and the plantar responses were flexor. An MRI scan of the brain was normal and neurophysiological studies demonstrated denervation in all four limbs and the facial muscles. A diagnosis of motor neuron disease was made.

Questions

1. From a respiratory point of view, wiiat tests are useful at this stage? 2. What ire the most common causes of death in MND?

Discussion Most patients with motor neuron disease die because of ventilatory failure caused by weakness of the respiratory muscles. In some patients aspiration and chest infections are important causes of morbidity and mortality. Abdominal muscle weakness reduces cough effectiveness. Inspiratory muscle

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weakness reduces inspiratory capacity and expiratory muscle weakness reduces expiratory capacity, and therefore vital capacity reflects overall respiratory muscle weakness and is a predictor of survival. Some patients have difficulty with the vital capacity test and alternative measurements may be required. However, for many patients with motor neuron disease (and other neuromuscular disorders) the measurement and monitoring of vital capacity is an essential part of assessment. The vital capacity in this patient was 98% of predicted, indicating that at this stage there was no substantial weakness of the respiratory muscles. Over a period of 4 months the patient's speech progressively deteriorated and she became virtually unintelligible. She also had severe problems with pooling of saliva and with swallowing. A feeding gastrostomy (PEG) was inserted. Nine months after referral the vital capacity was reduced to 40% of predicted. Although her limbs remained reasonably strong and she was able to walk unaided, there was breathlessness after 500 yards. The patient was sleeping poorly, waking frequently at night, and in the morning felt tired. First thing in the morning there were headaches, which cleared over a period of approximately half an hour. The patient was uncomfortable with breathlessness when lying flat on her back, and preferred to sleep at 45°. Throughout the day she felt lethargic and tired, and frequently fell asleep. Questions

3. Why is the patient's sleep disturbed? 4. What is the significance of her ofthopnoea?

Patients with respiratory muscle weakness eventually hypoventilate during sleep. Initially this is episodic, occurring first in REM sleep. The hypoventilation causes hypoxia and hypercapnia and leads to arousal. Sleep is therefore fragmented and of poor quality. As a result of sleepdisordered breathing, patients are excessively tired and sleepy during the day. The hypercapnia causes headache on wakening, which persists until the CO2 is reduced as ventilation increases. As weakness progresses, ventilatory failure becomes established during the day as well as the night. The orthopnoea in this patient signifies diaphragm weakness. When supine, the weak diaphragm is unable to descend and displace the abdominal contents against gravitational forces. When upright it is much easier for the diaphragm to descend. The diaphragm is the most important muscle of inspiration, and therefore orthopnoea is an important symptom. In general, orthopnoea develops when diaphragm strength is reduced to approximately one-third of normal. Lung function tests and respiratory muscle strength tests showed FEVi 0.4 L (predicted 2.4), VC 0.7 L (2.8); the patient had difficulty in performing these tests and therefore more detailed studies of respiratory muscle strength were undertaken, involving the measurement of oesophageal, gastric and transdiaphragmatic pressures during inspiratory efforts and following stimulation of the phrenic nerves. In addition, the pressure generated at the nostril during a maximum sniff effort (sniff nasal inspiratory pressure) was measured. These measurements confirmed that the inspiratory muscles, including the diaphragm, were profoundly weak approximately 20% of normal strength. Expiratory muscle strength

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CASE STUDY 13.8 CONTINUED was also reduced to about 20% of normal. Blood gas analysis showed a Pao2 7.0 kPa, Paco2 9.2 kPa, pH 7.38 and bicarbonate 40.4.

Question 5. What do these blood gases indicate? The patient has chronic ventilatory failure with a compensated respiratory acidosis. The chronicity and severity of the ventilatory failure make oxygen therapy (and sleep) hazardous. The patient was instructed in techniques to augment coughing by the physiotherapists. Treatment was initiated with non-invasive positivepressure ventilation delivered via a nasal mask (Case Fig. 13.8.1). The patient tolerated this therapy well, and over the next few days the Pao2, when off the ventilator, increased to 9.09 kPa and the CO2 fell to 7.0 kPa. The patient was discharged from

CASE FIG. 13.8.1 Patient receiving non-invasive ventilation, via a nasal mask, from a small bed-side ventilator. Nocturnal domiciliary non-invasive ventilation improves the quality of sleep and enhances quality of life in many patients with neuromuscular disease.

hospital and continued non-invasive ventilation at home at night. The quality of her sleep improved dramatically and she felt much better, with resolution of her tiredness by day and no further headaches. The Paco2 and bicarbonate progressively fell. The patient and her carers were

of diaphragm electromyogram, phrenic nerve conduction time, and twitch transdiaphragmatic pressures.

Management Respiratory muscle weakness due to neuromuscular disease may improve spontaneously, as in the GuillainBarre syndrome, or may respond to appropriate therapy, as in myasthenia gravis. Prior to improvement, some patients may require a period of mechanical ventilation. In most patients, however, deterioration is relentless, particularly in those with muscular dystrophy or motor neuron disease, and these patients die of respiratory infection and ventilatory failure. In some patients deterioration may be relatively slow or a plateau may be reached, with respiratory muscle weakness causing ventilatory failure and disabling breathlessness. For carefully selected patients assisted ventilation may be appropriate, particularly at night. Non-invasive positive-pressure ventilation (via a nasal mask) and, less commonly, negative-pressure ventilation (with tank ventilators, cuirasses and jackets) can both be used, usually in the patient's home, and long-

in no doubt that the quality of her life was improved by nocturnal ventilation. Gradually the patient developed limb weakness and increasing immobility, and eventually, 1 year after starting ventilatory support therapy, she died.

term survival and/or improved quality of life can make this treatment worthwhile. In patients with quadriplegia from high cervical cord lesions, the diaphragm and other respiratory muscles are paralysed and the patient is dependent on mechanical ventilation. If the phrenic nerves are intact, as shown by adequate diaphragm contraction with percutaneous phrenic nerve stimulation, diaphragm pacing via the phrenic nerves can sustain ventilation and mechanical ventilation is no longer required. A common disorder affecting diaphragm function is hiccup: usually this is transient, but can occasionally be a chronic and disabling problem. Many therapies have been tried, but the most effective is baclofen.

Metabolic disorders causing weakness Acidosis impairs the contractility of both skeletal and cardiac muscle. Hypercapnia, perhaps mediated through acidosis, adversely affects muscle function and it is probable that the interaction of hypercapnic acidosis and hypoventilation contributes to the rapid deterioration of patients with ventilatory failure and a low pH. Hypophos-

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phataemia is a well-recognized cause of ventilatory failure due to respiratory muscle weakness and is an important factor on the intensive care unit. Reversible weakness of the respiratory muscles also occurs with thyroid disease, hypokalaemia and disorders of magnesium and calcium metabolism.

Weight loss and muscle weakness Patients with a wide variety of medical and surgical illnesses have profound weight loss and muscle atrophy, with consequent weakness. This loss of muscle bulk can involve the respiratory muscles, which therefore also become weak. Adequate nutrition (p. 748), particularly in hospitalized patients, can minimize wasting, as will the reversal of catabolic factors such as sepsis, fever, protein-losing states and steroid therapy. Immobilization leads to rapid atrophy of skeletal muscle, and it is possible that prolonged mechanical ventilation causes disuse atrophy of the respiratory muscles.

Respiratory muscle function in patients with airways obstruction

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Chronic bronchitis, emphysema and asthma cause airways obstruction and hyperinflation, both of which require the patient to generate greater than normal pressures during tidal breathing. The capacity of the respiratory muscles to produce the required large negative intrapleural pressure is compromised by muscle shortening, decreased diaphragm curvature, increased velocity of shortening and abnormal ribcage geometry. Respiratory muscle contractility may also be impaired by reduced oxygen delivery to the muscle, as a consequence of hypoxaemia and cardiovascular disease, and also by the respiratory acidosis associated with acute hypercapnia. The increased work of breathing combined with the reduced capacity of the respiratory muscles to generate tensions limits ventilatory reserve, causes breathlessness, and may predispose to the development of respiratory muscle fatigue and hypercapnic ventilatory failure as, for example, in severe acute asthma. Patients with airflow limitation require a high respiratory centre output to maintain ventilation, and depression of neural output (for example by sedatives) can markedly impair breathing. The work of breathing is reduced and the function of the respiratory muscles improved by therapy that reduces airflow limitation and lung volume. In patients with chronic lung diseases, specific respiratory muscle training has been undertaken with a view to improving both the strength and endurance of the respiratory muscles. Although some studies have reported a modest benefit from training, the overall value of such programmes remains a matter of debate. Attempts have also been made to improve respiratory muscle contractility with drugs. It has been postulated that theophylline may have a very small inotropic effect, but it is doubtful

whether under most circumstances this is of any clinical importance.

Respiratory muscle fatigue All skeletal muscles fatigue when subjected to sufficiently high load, and the respiratory muscles are no exception. Careful studies of the stressed respiratory muscles of normal subjects have demonstrated fatigue in terms of electromyographic changes, slowing of relaxation rate, and reduced contractile response to nerve stimulation. However, these complex techniques have not easily been applied to patients with ventilatory failure, and the clinical importance of respiratory muscle fatigue remains to be established. Data from patients on ICU failing to wean from mechanical ventilation indicate that muscle fatigue may play a part. Some authorities, particularly in North America, advocate the 'resting' of the respiratory muscles by assisted ventilation to allow fatigue to resolve. More clinical studies on the detection of respiratory muscle fatigue and its clinical importance are necessary before widespread use of this approach could be advocated.

THORACIC DEFORMITY Adequate ventilation requires that the thoracic cage be of adequate volume, rigidity and mobility. Many of the disorders causing thoracic deformity are now rare (for example rickets), and the most common problems are flail chest (a surgical and anaesthetic emergency), ankylosing spondylitis, scoliosis, thoracoplasty and fibrothorax.

Ankylosing spondylitis Ankylosis of the ribs is characteristic of ankylosing spondylitis (p. 1148) and chest expansion is frequently reduced. Respiratory problems occur relatively late in the course of the disease and most patients are 50-70 years old before developing symptoms. In addition to the classic radiological changes affecting the spine (p. 1150), patients can also develop upper zone pulmonary fibrosis with cavitation and occasionally an aspergillus fungal ball (mycetoma). Despite the reduced expansion of the ribcage, ventilation is relatively little impaired because of good diaphragm function and, in the absence of lung involvement or coexisting cardiac disease, ventilatory failure does not occur. As a consequence of the importance of diaphragm function, patients tolerate badly upper abdominal surgery or any other factors impairing diaphragm movement.

Scoliosis Scoliosis refers to a lateral curve of the spine (Fig. 13.76) and in most cases, perhaps three-quarters, it has no known cause. A wide variety of disorders are responsible for the remaining cases (Table 13.59). Although a congenital

13

TABLE 13.59 Disorders causing chronic scoliosis Idiopathic Disorders of bone (e.g. osteogenesis imperfecta) Neurological diseases (e.g. cerebral palsy, poliomyelitis) Muscle disease (e.g. muscular dystrophy) Connective tissue disorders (e.g. Marfan's syndrome, Ehlers-Danlos syndrome) Thoracic surgery (e.g. pneumonectomy, thoracoplasty) Chronic infection (e.g. empyema)

vertebral abnormality produces scoliosis in childhood, most scolioses develop in adolescence during the rapid growth spurt. Congenital heart disease is common in scoliotic patients. Scoliosis makes the thoracic cage stiff. The deformity also reduces the volume of the lungs and adversely affects the mechanical advantage of the respiratory muscles. Lung function tests show a restrictive ventilatory defect, the severity of which is related to the angle of scoliosis, with high thoracic curves causing the greatest impairment. Patients with moderate or severe scoliosis are breathless, and with more severe deformity they eventually develop hypoxaemia, hypercapnia, pulmonary hypertension and cor pulmonale. Patients with scoliosis secondary to neurological disorders are frequently the most severely affected, particularly if diaphragm function is impaired. Ventilatory failure first becomes apparent during the night, particularly as a consequence of the hypoventilation associated with REM sleep. With the onset of ventilatory failure, the patients require assisted ventilation. Positivepressure ventilation, via a nasal mask, is very effective. Negative-pressure devices, such as a purpose-built cuirass, a Tunnicliffe jacket, pneumosuit or body wrap, can also be used. Such domiciliary ventilation is usually only needed at night and can produce remarkable long-term wellbeing, with control of respiratory failure by day, reversal of pulmonary hypertension and resolution of cor pulmonale. During acute episodes of deterioration more prolonged ventilatory support may be required. From a respiratory point of view the role of surgery to straighten a scoliosis is controversial. Most surgery is undertaken in adolescence, with the aim of avoiding deterioration of the curvature and ventilatory function that otherwise occurs at this time. Thoracoplasty, surgical collapse of the ribcage to compress the cavities of tuberculosis, was a relatively common surgical procedure in the treatment of pulmonary tuberculosis prior to modern drug management. It produces a similar ventilatory defect to scoliosis. Many patients with

FIG. 13.76 Chest X-ray showing severe kyphoscoliosis Eventually such patients commonly develop ventilatory failure.

thoracoplasty develop breathlessness and eventually ventilatory failure in later life. Some of these patients have been treated with nocturnal domiciliary ventilation, with excellent long-term results comparable to those for scoliosis. Such is the success of assisted ventilation programmes that all patients with severe or progressive chest wall deformity (and some with neuromuscular disease) require careful specialist long-term follow-up.

FURTHER READING ON NEUROMUSCULAR AND SKELETAL DISORDERS Guelaud C, Similowski T, Bizec J-L, Cabane J, Whitelaw W A, Derenne J-P 1995 Baclofen therapy for chronic hiccup. Eur Respir J 8:235-237. Hill N S 1995 Long term nasal ventilation. Editorial. Thorax 50:595-596. Lyall R A et al 2001 A prospective study of quality of life in ALS patients treated with non-invasive ventilation. Neurology 57: 153-156. Polkey M I, Green M, Moxham J 1995 Measurement of respiratory muscle strength. Thorax 50:1131-1135. Shneerson J M 1995 Disorders of the thoracic skeleton. In: Brewis R A L, Corrin B, Geddes D M, Gibson G J (eds) Respiratory medicine, 2nd edn. London: W B Saunders 1537-1546.

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14 Critical Care

Medicine John Goldstone, Geoffrey Bellingan and Martin Smith

Introduction 725

Organ donation 747

Cardiovascular system 725

General care of the critically ill 749

Sepsis 733 Respiratory problems 736 Central nervous system problems 742

nial pressure or jugular venous bulb saturation, is undertaken as required. Infusions, urine output and total fluid balance can be measured over periods of minutes, hours or days. Routine laboratory investigations are often performed on the ward itself, enabling sequential analysis of arterial blood gases, electrolytes and other biochemical data. Many hospitals have developed high-dependency units (HDUs) that allow detailed monitoring, either as part of the ICU or run as a separate ward in close liaison with ICU, often with the same clinical team. Patients requiring close observation rather than organ support can be admitted to the HDU, and if they deteriorate they can then transfer to full ICU care. Central to this process of monitoring and adjustment of the patient's physiology are the intensive care nurses, who are highly trained and usually allocated one per patient on the ICU (1:2 on HDU, depending on the patient mix).

CARDIOVASCULAR SYSTEM

Sedation 749 Outcome 750

INTRODUCTION Critical care medicine has its origins in the treatment of failing organ systems; it began with respiratory support, using techniques developed in anaesthesia, and was accelerated in the 1950s by the need to ventilate large numbers of patients with paralytic polio. Patients are now admitted to the intensive care unit (ICU) not only to receive mechanical ventilation, but also for the management of a wide variety of severe illnesses. Thus the critical care team will care for medical, surgical, obstetric or paediatric patients, or indeed any patient who has a failing organ that needs treatment or simply close monitoring. The most common causes for admission to the ICU are listed in Table 14.1. The skills required by an 'intensivist' are thus extensive and the work demands the expertise of a team of medical staff, nursing staff and others, including physiotherapists, pharmacists and speech therapists. This team functions most effectively when led by an enthusiastic and committed critical care specialist. By necessity, the ICU concentrates facilities in one area, with an array of technology. Facilities are available for immediate resuscitation. Many physiological variables are monitored continuously with the aid of electronic monitors at each bedside, including oxygen saturation, respiratory rate, pulse rate, ECG, continuous intra-arterial blood pressue monitoring and central venous pressure (Fig. 14.1). More detailed monitoring, such as cardiac output, intracra-

Patients admitted to the ICU frequently require assessment, monitoring and therapy directed at the cardiovascular system (CVS). Cardiovascular failure may be due primarily to a cardiac event, e.g. myocardial infarction, or secondary to other organ failure. The function of the heart is to deliver oxygenated blood and nutrients to peripheral organs and tissues, and when perfusion is reduced, secondary effects such as renal failure ensue. Indeed, normal cerbral function, urine output and blood pH remain the most basic indices of a functioning circulation. The aim of management is to determine the nature of the cardiovascular problem, monitor the effect of treatment and make adjustments to therapy as appropriate.

ASSESSMENT Whether assessment is by clinical examination or complex monitoring, the approach to the circulation should involve an evaluation of filling status, cardiac output and peripheral perfusion. The optimization of the cardiovascular system may be urgent, to avoid organ damage. In uncomplicated cases that respond rapidly to treatment, invasive measurements may not be required, but in many patients the need for physiological information to guide treatment requires invasive techniques. Traditionally, disorders characterized by hypotension are termed 'shock' (hypovolaemic, cardiogenic or septic). The clinical picture of reduced peripheral perfusion (cold, vasoconstricted limbs), reduced vital organ blood flow (oliguria or anuria, mental confusion) and compensatory tachycardia due to sympathetic overactivity are common to cardiogenic and hypovolaemic shock. In sepsis, peripheral vasodilation causes warm limbs with bounding pulses, making the clinical

725

FIG. 14.1 A typical bedside in ICU The patient is surrounded by monitoring equipment but central to his care is the careful charting of observations and constant adjustment of treatment by the intensive care nurse.

assessment misleading; however, the blood pressure is low and can lead to end-organ dysfunction (Fig. 14.2). As peripheral perfusion fails oxygen delivery to the tissues is reduced, and as respiration continues an oxygen debt builds up. Anaerobic respiration leads to the production of lactic acid. If this process continues the chances of survival decrease as the oxygen debt and serum lactate rise (Fig. 14.3). In these complicated cases, cardiovascular performance is optimized by manipulating filling pressures (intravascular infusions), systemic and pulmonary vasoconstriction (nitrates, ACE inhibitors, calcium antagonists, oxygen, nitric oxide) and cardiac contractility (inotropes, chronotropes), all of which may require continual adjustment and intervention. In addition, cardiac function can be manipulated by reducing workload (mechanical ventilation and paralysis) and by improving coronary perfusion, by using an intra-aortic balloon pump or surgically (with angioplasty or vein grafting).

Filling pressures The force of contraction of cardiac muscle is determined by its length:tension relationship, and force generation falls if the muscle is excessively stretched (increased preload). Function is also impaired by excessive afterload,

1

726

MCQ 14.1

TABU 14.1 Common causes of admission to ICU, UCLH Diagnosis

Incidence (%)

Postoperative care Pneumonia Chronic obstructive lung disease Sepsis Myocardial infarction and heart failure ARDS

46 16 10 6.5 5 3

which prevents cardiac muscle shortening (see Ch. 12). For a given preload and afterload, contractility is also influenced by ionic and hormonal factors (e.g. acidosis, hyperkalaemia, hypocalcaemia). It is not possible to measure fibre length directly on the ICU, but it is possible to measure pressure within the heart during cardiac filling. During diastole, atrial pressure is related to fibre length, and the filling pressure rises as the heart muscle fibres stretch. Initially the response to a rise in filling pressure (increased preload) is an increased stroke volume, but excessive pressures cause a fall in output. Pressure in the right atrium can be simply measured through a central venous catheter and a manometer; the height of the column of water is measured above the level of the right atrium, taken as being the midaxillary line when supine. Electromanometers convert the pressure signal into an electrical output, and this can be visualized

14

FIG.

14.3

When perfusion fails, outcome is related to its severity. This is indicated by an oxygen deficit and the arterial lactate concentration.

TABLE 14.2 Requirements for accurate measurement of CVP • • • •

FIG. 14.2 Management of hypotension

on the bedside monitor. Requirements for accurate measurement of central venous pressure (CVP) are shown in Table 14.2. Central venous access can be achieved from many sites. The most common method is to cannulate the internal jugular vein. To reduce the incidence of trauma during the procedure, a guidewire is passed through a small-gauge needle and the central venous catheter is threaded over the wire. Most catheters are multilumen, allowing several infusions to be administered simultaneously and safely. The position of the line and the possibility of a pneumothorax should be checked with a chest X-ray after insertion. The CVP is influenced by circulating blood volume and vascular tone. In the hypovolaemic patient filling pressures

Freely falling meniscus when connected to the patient Meniscus has fallen to steady baseline Meniscus swings with respiration/ventilation Reference point and body position are standardized between measurements

may initially be maintained by an increase in smooth muscle tone within the venous circulation. Under these circumstances a normal CVP may be misleading. Further blood loss or vasodilation (e.g. administration of opiates) will lead to low filling pressures and hypotension. A single estimate of central venous pressure is unreliable in indicating blood volume status, as are many commonly measured indices of haemodynamics (blood pressure, heart rate, mean arterial pressure). Volume status is more adequately assessed by measuring the haemodynamic response to a dynamic change. A key manoeuvre on the ICU is thus the fluid challenge. During continuous CVP monitoring, the impact of a rapidly administered bolus of fluid (200-400 mL of colloid) is observed. In the hypovolaemic patient the response to fluid challenge is a transient rise in pressure, but this is not sustained and CVP falls rapidly back to the baseline value (Fig. 14.4, line A). As fluid replacement continues, further volume challenges result in more gradual rises and falls in filling pressure until the point is reached where an increase in filling pressure is sustained (Fig. 14.4, line C). At this stage fluid replacement is adequate. 1 Volume status can also be assessed by observing the effect of either a volume load induced by leg elevation or the effects of vasodilatation induced by a bolus of a vasodilator (e.g. nitrates). Stroke volume can be continuously assessed during both these manoeuvres from the velocity profile of blood flowing in the descending aorta measured with an oesophageal Doppler ultrasound probe. With these techniques it is possible to demonstrate whether or not further venous filling is appropriate in

727

FIG. 14.4 The effect of a fluid challenge on central venous pressure (CVP) Line A occurs when CVP is unaffected by a bolus of colloid, and represents hypovolaemia. In line B a transient rise in filling pressure occurs, but is not sustained. In line C , filling pressure rises after the fluid challenge and is sustained.

rapidly changing circumstances, e.g. when inotropic agents are being used. Volume loading may enable inotropic support to be reduced, especially if vasoconstriction is a prominent feature. There is now excellent evidence that maintaining appropriate volume loading in high-risk patients prevents further complications and improves outcome. In health, right and left atrial pressures change in parallel, allowing assessment of left ventricular function from right-sided filling pressures. This relationship may be altered in disease (Table 14.3), requiring the more direct assessment of left atrial pressures. Left heart filling pressure can be measured by the insertion of a pulmonary artery catheter (see below), which can also be used to determine cardiac output and therefore the construction of filling pressure/cardiac output curves.

Pulmonary artery catheters

728

Pulmonary artery (PA) catheters are introduced via a great vein and advanced into the right atrium. Passage of the catheter into the right ventricle and out through the pulmonary valve into the pulmonary artery is enhanced by an air-filled balloon at the tip of the catheter. The flow of blood into the right atrium and out into the pulmonary artery carries the catheter into smaller arteries until it becomes wedged in a narrow vessel. When the balloon is deflated the catheter recoils proximally, restoring perfusion to the distal lung segment. Running through the catheter is a lumen that emerges at the tip. The pressure at the catheter tip is displayed continuously, and as the catheter is advanced the characteristic pressures of the right atrium, right ventricle and pulmonary artery are observed (Fig. 14.5). The occluded

FIG. 14.5 Pulmonary artery (Swan-Ganz) catheter in position in a patient with severe pneumonia As the catheter is advanced through the great veins into the right atrium (RA), right ventricle (RV) and pulmonary artery (PA), the characteristic pressure waves are displayed. The catheter is sited in the PA, and when measurement of pulmonary artery wedge pressure (PAWP) is required, the balloon at the tip of the catheter is inflated.

TABLE 14.3 Common circumstances where left- and right-sided filling pressures do not agree • Valvular heart disease (e.g. mitral stenosis) • Myocardial infarction • Pulmonary hypertension (e.g. secondary to lung disease, pulmonary embolus)

pressure is termed the pulmonary artery wedge pressure (PAWP) and is related to the filling pressure of the left side of the heart. Pulmonary artery catheters commonly have several lumina, so that cardiac output can be measured. Specialized fibreoptic catheters measure oxygen saturation at the tip, giving a continuous output of mixed venous oxygen saturation (SVo2). There is currently great debate as to the role of PA catheters, arising from a study demonstrating that certain groups of patients in whom the catheters were inserted had a worse outcome than those who did not have PA catheters. Despite ongoing debate about this report it is clear that great attention needs to be focused on who inserts the catheter, the clinical indications, the quality of the measurements made and, most importantly, the therapeutic responses made to the information derived.

Cardiac output Cardiac output can be determined in patients on the ICU by measuring the rate of disappearance of a dye introduced into the right atrium (dye dilution technique). The 'dye' conventionally used is cold saline and the fall and recovery in temperature is sensed at the tip of the catheter (in the pulmonary artery) by a miniature temperature

14

FIG. 14.6 Filling pressure versus cardiac output

FIG. 14.7 Poor contractility

Patients are normally in the middle of the filling curve. In the hypovolaemic state, the response to fluids is to move the filling pressure from point 1 to point 2, increasing the cardiac output.

Relationship between cardiac index (Cl) and filling pressure (PAWP) for the normal (solid line) and poorly contracting (dashed line) heart. Compared with normal the PAWP/CI curve (dashed line) is almost flat over a wide range of filling pressures.

gauge. In patients with a low cardiac output the rate of disappearance of the 'dye' is slow, and the resultant curve of dye concentration against time is low and flat. If the cardiac output is high, dye is quickly washed away from the heart and the curve is peaked and narrow. With sophisticated computer technology employing fuzzy logic, cardiac output can be measured continuously from right heart catheters, which slightly heat blood passing over the catheter and detect the temperature of the blood at the tip in the pulmonary artery. Cardiac output can also be determined using the oesophageal Doppler, by a lithium dilution technique, and clinically with reasonable accuracy by determining peripheral perfusion (warm to the fingers and toes, to the hands and feet or to the knees and arms, allied to an assessment of the strength of the arterial pulse). Disorders of the circulation can be considered by constructing a graph of filling pressure versus cardiac output (Fig. 14.6). To allow for differing sizes of patients, cardiac output is normalized by dividing by the body surface area, producing a cardiac index (CI) which is expressed in litres/minute/m2. The normal heart responds to a raised filling pressure (increased preload) by a rapid increase in CI. At the upper limits, further stretching or dilatation of the heart results in a reduction in cardiac output. When cardiovascular function is abnormal, the position of the curve is shifted (Fig. 14.7). The graph can be used to define the problem, monitor the effect of treatment and predict outcome. The filling pressure of the heart can be reduced either by a reduction in circulating blood volume due to haemorrhage or severe dehydration, or by loss of venous return

if the circulation is suddenly vasodilated, as would occur with sepsis. Baroreceptors detect the fall in filling pressure, stimulating the release of catecholamines from the adrenal gland and sympathetic nervous system. Catecholamines act on the myocardium to increase the heart rate and force of contraction (positive inotropic effect), and on the peripheral vessels to maintain venous return by venoconstriction and blood pressure by vasoconstriction (increased systemic vascular resistance). Other neurohormonal reflexes are also stimulated. Fluid loss from the kidney falls initially because of a reduction in glomerular filtration rate (GFR). Aldosterone is released, and salt and water reabsorbed, leading to the production of small urine volumes (<750mL/day) with low urinary sodium concentrations (<20mmol/L).

Peripheral perfusion When peripheral perfusion is poor, blood flow to skin, subcutaneous tissue and muscle is reduced, leading to cold clammy extremities. Blood flow is also diverted from mesenteric organs, such as the kidney, leading to oliguria. This response is mediated by baroreceptors and catecholamine production is stimulated. Peripheral perfusion may also be compromised during sepsis-induced vasodilatation, despite an often elevated cardiac output. In this circumstance perfusion is limited not by a failure of stroke volume or cardiac output, but by hypotension and preferential blood flow through arterial venous shunts in peripheral organs; the exact mechanisms leading to organ failure in sepsis are, however, not clear.

729

A metabolic acidosis is the fundamentally important observation common to all causes of poor peripheral perfusion. Sequential measurement of acid-base status is crucial; continuing acidosis or a worsening base deficit indicates continuing haemodynamic problems. Such sequential measurements are facilitated on the ICU by the use of an intra-arterial catheter, commonly in the radial or dorsalis pedis artery, from which arterial blood gas samples can be taken quickly and simply. With effective treatment and optimization of the circulation metabolic acid is cleared from the circulation, although frequently this process does not occur as readily as its accumulation, leading to a delay in the restoration of a normal pH. Several attempts have been made to measure tissue hypoperfusion directly, most successfully for the gut and brain. Measurements of gut mucosal pH can be made with balloon tonometers passed nasogastrically, and intracellular pH can be calculated to assess the perfusion defect at the tissue level. Although this and other methods of directly measuring tissue oxygen consumption are helpful, they have not yet replaced the more general measurement of acidosis in the arterial circulation. During anaerobic metabolism glucose is metabolized to pyruvate, but this substrate cannot enter the oxidative pathways and is converted to lactate. Lactate concentration in the circulation can be measured directly. Raised lactate levels indicate a decompensating circulation. Serial measurements of lactate greatly enhance the diagnosis of peripheral hypoperfusion. Lactate measurement is especially useful to exclude other causes of arterial acidosis, such as renal failure. As cardiac output declines, more oxygen is removed from arterial blood in order to maintain tissue consumption. In health, 25% of the available oxygen that is delivered to the tissues is removed, and the venous blood is 75% saturated when it returns to the heart. In hypoperfusion more oxygen is extracted, and the blood returning to the heart therefore has a lower saturation. Global venous oxygen saturation can be measured from samples of blood drawn from the pulmonary artery. Using specialized pulmonary artery catheters, mixed venous saturation (Svo2) can be measured continuously in the pulmonary artery. When cardiac output is low, oxygen extraction reaches a maximum and the mixed venous saturation falls. An Svo2 of <50% indicates a very poor prognosis. Cold peripheries can be assessed by measuring the temperature gradient between the core and the periphery (great toe) with two simple electrical thermometers. As perfusion falls the peripheries cool and the temperature gradient increases. A gradient greater than 4°C indicates hypoperfusion, and this measurement can be used to guide treatment, especially in the hypovolaemic patient.

1

730

MCQ 14.2, 14.3

SUMMARY 1 Non-circulatory causes of metabolic acidosis • • • •

Ketoacidosis Renal failure Drugs, e.g. salicylates Poisons, e.g. ethylene glycol

Fluid replacement Restoration of blood volume should be rapid to avoid organ damage. The speed of transfusion is often inadequate, especially in the elderly, where there is a fear of precipitating heart failure. As a guide to the adequacy of fluid replacement, a fluid challenge or other dynamic test of blood volume adequacy should be employed (Fig. 14.4). The ICU allows the rapid restoration of circulation because patients can be closely monitored. Choice of replacement fluid (Table 14.4) The choice of replacement fluid depends on the cause of the decreased filling pressure. In haemorrhage, replacement with blood is essential, although blood substitutes may be used until blood is available. Severe dehydration requires predominantly salt and water replacement. Reduction in filling pressure due to vasodilatation can be corrected with a plasma substitute. If the circulation is restored quickly the metabolic effects of an inadequate circulation will reverse spontaneously, but acidosis, hyperkalaemia and hyperglycaemia require careful management in patients in whom hypovolaemia has been prolonged.

Fluid overload Critically ill patients often retain fluid because of renal dysfunction, excess antidiuretic hormone (ADH) secretion or drug therapy (e.g. steroids). Volume overload may occur as a result of injudicious intravenous fluid therapy in patients who cannot produce a compensatory diuresis. The filling pressure is raised, stretching cardiac muscle to the point where contractility declines, at the plateau of the PAWP/CI graph. The clinical signs can be similar to those of the poorly contracting ventricle (see below), both right- and left-sided filling pressures being raised. Treatment is to reduce filling pressures rather than to infuse inotropes. Diuretic therapy reduces the volume of the circulation and promptly relieves oedema. If filling pressures are critically high, vasodilator therapy can reduce them acutely. Diuretic therapy will only be successful if cardiac output is sufficient to perfuse the kidneys and renal function is not impaired. If renal function is inadequate, volume reduction can be achieved by haemofiltration or venovenous dialysis (p. 1059).

14

TABLE 14,4 Replacement fluids

Solution

Stability

Half-life in circulation

Crystalloid

Good

10-15 min

Only a quarter to a third will remain intravascular

Haemaccel

Good

2-4 hours

Hespan

Good

6-12 hours

Fresh frozen plasma

Once thawed, clotting factor activity diminishes after 2 hours. Good

Several hours

Initially intravascular. As metabolism and excretion occurs, oncotic pressure declines and the original gain in intravascular volume diminishes With increased permeability, Hespan redistributes and can remain in tissues. As a result, colloid and tissue oncotic pressure can rise substantially. Intravascular

Albumin

1 hour

Redistribution

Mainly intravascular but low molecular weight results in tendency to dissipate within tissues and this is enhanced if permeability is increased

Poor contractility The relationship between filling pressure and CI when left ventricular function is depressed is shown in Figure 14.7. As filling pressure rises, the response of the ventricle is reduced and the CI is low. This typically occurs after myocardial infarction (cardiogenic shock). The crucial point is that rises in the filling pressure do not improve the CI. Pulmonary oedema occurs when the filling pressure is raised. The pressure at which fluid extravasates into the lung is determined by the balance of forces driving the fluid out of the circulation (hydrostatic pressure) and the osmotic pressure of the plasma, acting to retain fluid within the vasculature. As the filling pressures rise, this point is exceeded and oedema fluid develops (p. 699, Fig. 13.57). Oedema develops at low pressure if plasma proteins are reduced or capillary permeability is increased. Patients with pump failure have a low-volume pulse, raised jugular venous pressure, a third heart sound, and sometimes signs of pulmonary oedema. As a result of the low CI, urine output may be reduced. In such patients monitoring of the circulation is necessarily invasive, and includes continuous arterial pressure monitoring through a cannula inserted into a peripheral artery, cardiac output monitoring (PA catheter or oesophageal Doppler) and measurement of urinary output via a urinary catheter as an index of renal perfusion.

Management In pump failure the aim of management is to increase the

Colloid osmotic pressure

Clotting factors

Zero

None

None

28mmHg

None

25mmHg

High in most clotting factors

25mmHg

None

Comment Very good with long shelf-life, mainly used in USA for volume expansion Often used for initial volume replacement Stable in solution with a long shelf life With large transfusion volume a coagulopathy may occur. This colloid has advantages when capillary leak due to inflammation occurs Needs to be stored as frozen and therefore requires thawing

Not recommended for use on the ITU as its molecular weight is low and in inflammation it quickly leaks from the circulation

output of the heart for a given filling pressure, thereby altering the slope of the PAWP/CI curve. Positive inotropic agents The naturally occurring inotropic agents are adrenaline (epinephrine), secreted by the adrenal medulla, and noradrenaline (norepinephrine), produced by the sympathetic nervous system. Other inotropic drugs include the adrenaline precursor dopamine and the synthetic dobutamine. These drugs increase the force of cardiac contraction by stimulation of (3 receptors. A further category of drugs, the phosphodiesterase inhibitors (enoximone and milrinone), produce an inotropic response by increasing intracellular cyclic AMP. These drugs are also vasodilators, leading to a reduction in peripheral vascular resistance. These newer agents are more expensive and, unlike the catecholamines, their half-life is measured in hours, making it difficult to finely adjust their effect. Positive inotropes are detailed in Table 14.5. Preload reduction with vasodilators is most effective when the filling pressure/cardiac output curve is flat, and changes in filling pressure produce a reversal of pulmonary oedema without large decreases in the CI. Careful monitoring of the circulation is essential, as slight alterations in vasodilating dose may produce large reductions in cardiac output. All vasoactive drugs should be given by volumetric pumps, and the shorter-acting drugs are an advantage. Alterations in peripheral vascular resistance can be particularly effective if combined with inotropic support, improving forward flow while maintaining myocardial perfusion pressure. 1

731

TABLE 14.5 Positive inotropes (dosages shown are an initial guide) Agent

Receptors

Dose range ( /kg/min)

Actions

Comments

Adrenaline (epinephrine)

a and

1-10

Noradrenaline (norepdinephrine) Dopamine

a

0.1-4.0

Low dose: HR ++, contractility ++ Increasing dose: vasoconstriction, SVR++ Vasoconstriction ++

Dopaminergic, , -nergic

Isoprenaline

3 (low dose) 5-10 (intermediate) 10-40 (high dose) 1-10

Low dose: renal and mesenteric vasodilation Intermediate dose: HR and contractility raised High dose: vasoconstriction HR++, contractility ++

Useful alternative to dobutamine, but vasoconstriction may reduce peripheral perfusion Increased blood pressure at expense of perfusion, not an inotrope Used to promote renal perfusion. Often used in conjunction with dobutamine

Dobutamine

1-10

HR and contractility increased

1-10

Inodilator

Dopexamine

DA, P, NA reuptake inhibitor

SUMMARY 2 Factors that reduce 02 delivery to the myocardium • • • • •

732

Diastolic pressure <60mmHg Overdistension of ventricles Tachycardia Vasoconstriction Hypovolaemia

Negative inotropes The force of contraction of the myocardium is depressed by acidosis, hypokalaemia, hypoxaemia and hypercapnia. These negative inotropes, particularly acidosis, offset the effectiveness of treatment. The dose response of catecholamines is adversely affected by acidosis. Correction of these disturbances may depend on restoration of peripheral circulation, although in the short term reversal of acidosis by hyperventilation (in patients receiving mechanical ventilation) and bicarbonate may be necessary. Another group of negative inotropes used on the ICU are sedative drugs, commonly continuously infused in mechanically ventilated patients. It is important that these drugs are infused at the minimum dose necessary to keep the patient comfortable. Oversedation has many serious consequences, particularly reduction of cardiac performance and airway protection. The major determinant of oxygen delivery to heart muscle is coronary blood flow which, if reduced, impairs contractility. Myocardial blood flow, especially to the subendocardial layer, is reduced by an increase in ventricular wall tension. This is the case in the dilated heart and in one contracting against a raised peripheral vascular resistance. Flow to all layers of the myocardium is crucially dependent on diastolic pressure and duration, and both are reduced by tachycardia. Improvement of coronary

Improves contractility but increases myocardial 02 consumption Preferred initially as vasodilatation enhances cardiac output Action limited by tachycardia; possible preferential splanchnic vasodilator

blood flow can be effected by a reduction in afterload (reducing ventricular wall tension), if it is achieved without markedly decreasing diastolic pressure or causing a tachycardia. Mechanical support Myocardial function may remain depressed despite conventional therapy. Mechanical devices have been developed to enhance heart action by decreasing left ventricular work and improving coronary blood flow. One such is the intra-aortic balloon pump (LABP). The pump is connected to a sausage-shaped balloon that is introduced percutaneously into the femoral artery and placed in the descending aorta. The gas-filled balloon is inflated during diastole, and blood flow in the aorta away from the heart is reversed, increasing coronary blood flow. The balloon collapses at the start of systole, decreasing peripheral vascular resistance. The IABP therefore reduces afterload but maintains coronary perfusion. It has had considerable success in the management of pump failure immediately before or after cardiac surgery, but much less success in patients with a low CI, for example after myocardial infarction. New techniques, including artificial hearts, may in the future allow time to prepare selected patients for cardiac transplantation, although these are only available in a few centres. With severe pulmonary oedema the work of breathing is greatly increased. Overall oxygen consumption (and myocardial work) is reduced by mechanical ventilation. Although mechanical ventilation may depress the CI when patients are hypovolaemic, positive-pressure breaths may enhance cardiac function in the failing heart. Improvements in cardiac function may also occur by controlling pulmonary oedema, reducing the work of breathing and allowing for a stable period during which other therapies can be pursued.

SEPSIS Sepsis is now the 13th most common cause of death in the USA but, with the associated sepsis-induced multiorgan failure, is the most common cause of death on the ICU. It is thus a great challenge in modern critical care medicine. As our understanding of the clinical syndrome has been illuminated by basic science research, the need for stricter definitions has led to a series of terms: • Systemic inflammatory response syndrome, SIRS. This is a clinical condition with at least two of the following: temperature >38°C or <36°C; heart rate >90 beats/min; respiratory rate >20 breaths/min or a low Paco2; WCC >12 x 109 or <4 x 109, or >10% immature forms. Note that in 50% of patients SIRS is initiated from a noninfective cause, such as pancreatitis, haemorrhage or burns. • Sepsis. SIRS and a positive blood culture. • Severe sepsis (this has had many other names, such as multiple organ dysfunction syndrome, MODS). This is sepsis associated with organ dysfunction, hypoperfusion abnormalities (e.g. raised creatinine, low platelet count, DIC, mental confusion, hypoxaemia and cyanosis) or hypotension. • Septic shock. This is sepsis-induced hypotension, despite fluid resuscitation.

Clinical presentation The clinical appearance of sepsis may be a progression of the entities described above, with the illness beginning with SIRS. In aggressive cases the illness may present at a later stage. There is increasing recognition of the importance of Gram-positive infections in the aetiology of sepis in the ICU and these, together with mixed infections and fungal infections (which are also increasing in incidence), account for more cases of sepsis than the traditionally recognized Gram-negative infections. Many cases of sepsis occur without positive blood cultures, and other severe illnesses may initiate the inflammatory response. These may all result in clinically indistinguishable conditions.

Tissue hypoperfusion Within the terms used to describe sepsis, tissue hypoperfusion is an important clinical stage. It may be manifested by oliguria or by a metabolic acidosis, and serum lactate levels may be elevated (>2.0mmol/L). In contrast to other forms of hypoperfusion, tissue oxygen uptake is limited and oxygen extraction decreases. As a result, more oxygen is present in blood returning to the heart and mixed venous O2 levels are elevated. The relationship between oxygen supply to the tissue and uptake changes. Oxygen uptake may be linearly related to supply, and no 'plateau' exists as supply is increased. This has been interpreted as an oxygen handling problem at the level of the cell, although there

RECENT ADVANCES IN THERAPEUTIC INITIATIVES IN SEPSIS

14

The manipulation of individual mediators released during sepsis has been an attractive concept, especially as manufacture of monoclonal antibodies is possible. Unfortunately, initial enthusiasm has been tempered by lack of clinical success. It is possible that NO acts as a final pathway during sepsis, especially inducing hypotension. Although L-arginine analogues have been used clinically, no large studies are available describing a beneficial effect of such novel drugs on outcome. Plasmapheresis is now being more widely applied in adult medicine, and in fulminant infection (e.g. meningitis) this may be of value, especially acutely. Surface cooling during fever often results in vasoconstriction and a decrease in drug therapy, as well as decreasing peripheral oxygen consumption. Despite negative trials for steroids in early sepsis, they may be beneficial in fulminant cases.

may also be a microcirculatory component, with shunting through some capillaries and reduced perfusion through others. Cardiac output may be raised as initially myocardial contractility is maintained. With organ dysfunction cardiac output will decline, and perfusion often requires inotropic support.

Therapeutic strategies Throughout the 1980s investigators sought to manipulate the effects of sepsis, and several therapeutic initiatives have been extensively studied. Basic support of the cardiovascular system involves optimization of fluid administration, as the patient is often functionally hypovolaemic with a vasodilated and leaky circulation. Fluid therapy needs to be aggressive, large quantities are required, and the ICU is the ideal environment for monitoring filling status (changes in stroke volume or central venous pressures in response to filling) along with close monitoring of blood pressure and end-organ effects, such as arterial pH and urine output. The choice of fluid is often debated, but colloids are generally used in the UK. Synthetic colloids have much to commend them, as albumin often leaks away from the circulation, dissipating its effect.

Optimization of the circulation It is now widely accepted that simple measurements such as vital signs and urine output do not predict survivors from non-survivors in the critically ill. Studies in highrisk surgical patients demonstrated that data obtained from Swan-Ganz catheters describing cardiac output, the amount of oxygen delivered to and consumed by the tissues, do predict survivors. It is possible to describe the

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lowest level of these parameters associated with survival, and these parameters were then used as a target for patients to achieve - so-called 'goal-directed therapy'. Three typical patterns emerged from these studies. First, a group of patients who naturally respond to critical illness by raising oxygenation indices: these patients tended to survive. Second, patients who had suboptimal indices but in whom it was possible to achieve the target oxygen delivery by raising the cardiac output with either fluid therapy or inotropic support, or increasing transport capacity by blood transfusion. Lastly, some patients were never able to achieve the target, and this group had a very poor prognosis. Much of this information has been derived from studies in high-risk surgical cases whose haemodynamics were studied in a controlled theatre environment. When this approach was applied to the general population of critically ill on the ICU, many workers found that the 'goals' that predict survival could not be achieved, often because cardiac output could not be raised sufficiently. It is now recognized that the distinction lies between those who can be optimized prior to a major inflammatory insult (e.g. major surgery) and those in whom the inflammatory processes are already established (e.g. SIRS, severe sepsis and septic shock). In these latter patients attempts at achieving goals were often associated with a worsening prognosis. Nevertheless, the importance of filling to maintain the cardiac output, and attention to treatment of the circulation (especially when patients are acidotic), should be emphasized. Many patients with sepsis will require intropic support in addition to fluid therapy, although aggressive cooling of septic patients with a pyrexia may prevent or reduce the need for inotropes. The choice of inotrope depends on cardiac output, with noradrenaline (norepinephrine) being the agent of choice for hyperdynamic sepsis and adrenaline (epinephrine), with or without intravenous nitrates, being a suitable option for those with a low cardiac output.

Inflammatory mediators The inflammatory response seen in sepsis is frequently initiated by endotoxin derived from surface molecules of Gram-negative bacteria. The binding of endotoxin complexes to cell surface receptors begins mediator release, characterized by production, amplification and numerous positive feedback loops between the mediators. This cascade can often continue when the precipitating agent (infection) appears to be controlled. One group of mediators involved are metabolites of arachidonic acid, the eicosanoid family, and they share a similar hairpin-shaped molecule with two fatty acid side

1

734

MCQ 14.4

arms and a central ring structure. Arachidonic acid is broken down by cyclooxygenase or lipoxygenase pathways. They include the prostaglandin, thromboxane and leukotriene groups. Many of the clinical signs of sepsis can be induced by these molecules, and their synthesis is increased in septic animals and humans. It is possible to ameliorate the effect of sepsis by altering eicosainoid production or by the use of anti-inflammatory drugs, strengthening the suggestion that this group of agents is of central importance. Further effects during sepsis come from neutrophils, macrophages and the B and T lymphocytes. Many cytokines are released from these cells, including tumour necrosis factor (TNF), interleukins, especially IL-1, IL-4, IL-6, IL-8, IL-10 and IL-13, interferon, and the colonystimulating factors G-CSF, GM-CSF and M-CSF. These cytokines have multiple roles in the inflammatory response, including increasing inflammatory cell numbers through increased bone marrow production and release; many also delay leukocyte apoptosis. These mediators also prime and activate inflammatory cells, regulate adhesion molecule expression and stimulate the production of other mediators, such as free radicals, the eicosanoids and platelet-activating factor (PAF) (Fig. 14.8A). Numerous attempts have been made to block specific mediators and thus to alter the course of the septic process, including antiendotoxin antibodies, anti-TNF therapy, the use of natural inhibitors such as IL-1 receptor antagonist and antagonists against PAF, although so far these approaches have not been successful. This failure is due partly to the enormous redundancy of the inflammatory cytokine network, with huge overlap in the effects of many cytokines such that no single mediator occupies a pivotal role that cannot be replaced by other cytokines. 1

Nitric oxide Many patients present with hypotension, and indeed the term septic shock was used to describe this ominous development. Hypotension is associated with a worse prognosis and over 50% of patients may not survive. Nitric oxide (NO) is a ubiquitous molecule produced from L-arginine by nitric oxide synthetase (NOS), of which there are several isoforms, distinguished by the cells that synthesize them and by whether enzyme levels can be induced by proinflammatory mediators. NO is produced constitutively by the endothelial enzyme eNOS (also termed NOS III), where it is central to regulation of normal vascular tone. Another NOS is produced by neuronal cells and called nNOS or NOS I, but the most important NOS in sepsis is believed to be an inducible NOS produced by macrophages and other cells and called iNOS or NOS II. It is believed that this leads to excessive production of NO in inflammatory conditions, where it contributes to the severe hypotension so characteristic of sepsis. NO functions as an intracellular messenger, involved in many subcellular signalling functions, and can directly inhibit

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FIG. 14.8 Mediator response to sepsis A Many mediators are produced after an insult, leading to an inflammatory response, B The response to sepsis falls into three types. Little response or overwhelming response may both result in death. C eNOS is constitutive and requires Ca2+ to be activated, allowing it to be turned on and off quickly, whereas iNOS needs to be transcribed, and this process happens 2-4 hours after activation or injury. When activated, the amount of iNOS is substantially higher, leading to a many-fold amplification of activity.

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cellular function, for example acting as a competitive inhibitor of the mitochondrial electron transfer chain. It is also cytotoxic and is part of the normal armoury of the neutrophil and macrophage for killing phagocytosed bacteria. Its cytotoxic actions may, however, also contribute to the organ damage seen in severe sepsis. Of great therapeutic interest is the finding that refractory severe hypotension has been treated with NOS inhibitors, analogues of Larginine, which block NO production and enable the blood pressure to rise (Fig. 14.8B). However, a recent multicentre trial of an NOS inhibitor in severe sepsis failed, with an excess mortality in certain subgroups, although this may have been due to reductions in cardiac output in the highdose groups. Paradoxically there are circumstances where it may be advantageous to deliver NO rather than to block it. In acute lung injury, hypoxaemia is often associated with patchy collapse and atelectasis, and perfusion to many parts of the lung is reduced. NO (a gas) can be administered mixed with the gas from the ventilator and acts to vasodilate the pulmonary circulation, but only the blood vessels associated with ventilated alveoli. This leads to a rapid increase in the Pao2, although it is unclear whether this (transient) rise in oxygenation translates into a persisting clinical benefit. The inhaled NO is rapidly bound to haemoglobin, clearing it from the circulation and preventing systemic hypotension. The effect of NO in terms of mortality in acute lung injury is the subject of current clinical studies.

RESPIRATORY PROBLEMS Respiratory failure has many causes (p. 670, Table 13.32). Severe hypoxaemia with or without hypercapnia is a common indication for transferring a patient to the ICU for monitoring and, where necessary, mechanical ventilation. A particularly common error leading to poor management is restricting the amount of oxygen delivered to patients in respiratory distress. Loss of hypoxic drive to breathe does exist but affects only a small minority of patients. Despite this, it is common to find patients with low saturations being given restricted oxygen therapy. Far more appropriate is to give higher levels of oxygen to patients in respiratory distress and observe them closely for any signs of hypoventilation. It should be recognized that elevations in Paco2 are not usually due to loss of hypoxic drive to breathe but to many other factors, of which exhaustion, with small tidal volumes, is particularly common. These patients will benefit from unrestricted

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736

MCQ14.5

2

MCQ14.6

SUMMARY 3 Tissue oxygenation - important

measurements

Tissue perfusion - cardiac output Oxygen carriage in blood - Pao2, Sao2, Hb Tissue uptake of oxygen - mixed venous oxygen tension and saturation Metabolic acidosis and lactic acid accumulation

oxygen therapy, with good physiotherapy and correct positioning (sitting up), and restricting their oxygen to 24 or 28% will not correct their tissue hypoxia and will thus not help in correcting the underlying problem. Another common error is to take a blood gas on air rather than on oxygen. There is no need to take the patient off oxygen just to see how low the Pao2 falls, as this can be detrimental and is unnecessary, as the Pao2/Fio2 (see below) provides a clear indication of the oxygenation.

Assessment of ventilation and tissue oxygen delivery During steady-state conditions, when the amount of CO2 from the tissues is constant, arterial CO2 tension is dependent on alveolar ventilation. The adequency of ventilation can therefore be judged by Paco2. As ventilation becomes inadequate, CO2 is retained and eventually the patient becomes acidotic. Over a number of days acclimatization to hypercapnia may occur, and the respiratory acidosis is compensated for by a metabolic alkalosis (p. 1115). Despite the undoubted value of CO2 measurements in the assessment of ventilation, it should be emphasized that in some patients (e.g. those with severe asthma) there can be acute respiratory distress with CO2 levels that are normal or reduced. Adequacy of oxygenation is more difficult to assess. Arterial oxygen tension should be judged against the added oxygen the patient is breathing. In disease, as gas exchange deteriorates so the difference between the inspired oxygen tension and that of arterial blood increases (the A-ao2 gradient widens; p. 670). The size of the A-ao2 difference indicates the failure of the lung to perform gas exchange (see Table 14.6). An indication of this deficit is easily assessed by calculating the Pao2/Ho2 ratio. In health, if the blood gas is measured in kPa this ratio is greater than 65 (450 when blood gas is measured as mmHg) (e.g. 13.3/0.21 = 66.5), and severe disease is indicated when the ratio falls, with the Pao2/Fio2 for acute lung injury being less than 40kPa (300 mmHg) and for acute respiratory distress syndrome (ARDS) less than 26.7kPa (200mmHg). Reduction in the ratio may be due to impaired diffusion or ventilation/perfusion (V/Q) mismatch, and added oxygen can correct these defects. However, if the hypoxaemia is due to blood bypassing ventilated alveoli (physiological shunt), then increasing the oxygen fraction will not dramatically improve blood gases. Both the level of added oxygen that is required and the rate at which it is neces-

TABLE 14.6 Assessment of oxygen uptake by the lung The difference between alveolar and arterial oxygen tension is normally small. The extent of the alveolar-arterial (A-ao2) gradient provides a useful measure of the severity of respiratory failure. Alveolar-arterial gradient (A-a) = oxygen tension in alveolar air (PAo2) minus oxygen tension in arterial blood: A - ao2 = PAo2 - Pao2 The oxygen tension in alveolar air (PAo2) = oxygen tension in inspired air (P102) minus the arterial C02 tension (Paco2)/Respiratory Quotient (R): PAo2 = Pio2 - Paco2/R Thus in a normal subject. PA02

- [0.21 x (760 - 47)1 - 40/0.8 = 100mmHg A-ao 2 = 100-98 = 2mmHg (normal gradient is small, rising with age, and is less than 15mmHg; 2kPa) For a patient with severe respiratory failure on the ICU, ventilated with 50% oxygen who has an arterial Pao2 of 80mmHg, Paco2 of 48mmHg, the results could be: PA02

- [0.5 x (760 - 47) - (48/0.8)] = 297mmHg A-ao 2 = 297-80 = 217mmHg Serial measurement of the A-a gradient provides excellent information on oxygenation and allows day-to-day comparisons despite changes in fio2 and Paco2. * Water vapour pressure.

sary to increase this fraction reflect the severity and progression of disease. Arterial blood gases provide a single respiratory assessment of the patient, and can be misleading when the patient's circumstances are changing rapidly. Repeated samples are often preferable and require the insertion of an arterial cannula. The clinical context of the arterial sample (e.g. Fio2, ventilator settings) should always be documented. Oximeters that continuously and non-invasively measure oxygen saturation (Sao2) are very useful. Oxygen must be delivered to the tissues, and therefore the state of oxygen transport and uptake from the circulation is important. Transport of oxygen depends on the amount of haemoglobin and its ability to take up oxygen (O2 dissociation curve, p. 606). The cardiac output and state of the peripheral microcirculation then determine the delivery of oxygen to the respiring cells. 1

ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS) This is one of the success stories for intensive care, as mortality has declined steadily from 70 to 90% in the 1970s to approximately 40% in the late 1990s. ARDS is defined as a refractory hypoxaemia (Pao2/Fio2 <26.7kPa) with diffuse shadowing on the chest X-ray resulting from a known

acute precipitating cause and not related to left heart failure. ARDS is classically viewed as beginning with a phase of capillary leak, proceeding to an exudative phase and then to a fibrotic phase. This view is simplistic, and there is good evidence that inflammation and fibroproliferation occur in parallel and both are present at the very earliest stages of the condition. At present there are no specific therapies to prevent progression to ARDS, although there is increasing evidence that the use of a prolonged course of methylprednisolone in those who are not improving after 1 week does improve outcome, probably through an effect on fibroproliferative mechanisms. Otherwise the management of ARDS is conservative, with most (but not all) patients requiring mechanical ventilation while awaiting a recovery of lung function. This period of support can be prolonged and often is complicated by pneumothoraces and episodes of ventilator-associated pneumonia (see below).

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INDICATIONS FOR MECHANICAL VENTILATION Intubation and ventilation are easier to undertake as a considered manoeuvre than as an emergency event. The entire clinical situation is relevant, and ventilation is seldom indicated solely on blood gas results. An increasing demand for oxygen over a few hours, failure to oxygenate the patient adequately with a face mask, or mental deterioration, indicate the likely need for mechanical support. Patients who are initially distressed often have a normal or slightly lowered Paco2, with rapid shallow respirations. Further distress, an increase in the respiratory rate or increasing sympathetic activity (tachycardia, hypertension) indicate greater difficulty in eliminating CO2, and exhaustion, with associated hypercapnia, is a common end-point prior to ventilation. The clearance of secretions by the patient is dependent on the ability to cough vigorously, and sputum retention may worsen or precipitate respiratory failure. Endotracheal intubation allows efficient removal of secretions by suction, protects the upper airway from aspiration, and should be considered in all patients with a Glasgow Coma Scale (GCS) of less than 8. Many postoperative patients are ventilated electively to provide a period of stabilization. Some patients are intubated during resuscitation. Mechanical ventilation is sometimes required to provide a stable setting during the management of the pulmonary oedema of left heart failure, where it reduces the workload of the myocardium and can improve oxygenation. For artificial ventilation to be initiated, the patient must be anaesthetized and intubated. Patients may already be critically ill; if so, the cardiovascular effects of the anaesthetic agents, loss of reflexes guarding the larynx, mechanical problems in passing the tube and the effects of positive intrathoracic pressure on venous return make intubation and ventilation a potentially dangerous procedure. 2

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CASE STUDY 14.1 PROGRESSIVE HYPOXAEMIA IN A 38-YEAR-OLD MAN WITH PNEUMONIA A 38-year-old banker presented to casualty with a 3 day history of fever, pleuritic left-sided chest pain and breathlessness. He had no significant previous medical history and was a non-smoker and non-drinker. On examination he was clearly unwell, flushed and his temperature was 38.9°C; the pulse was 120 and regular, and blood pressure was 105/45 mmHg. He was tachypnoeic with a respiratory rate of 32 breaths per minute, and there was marked bronchial breathing at the left lung base. The oxygen saturation was 94% on 60% inspired oxygen and arterial blood gases showed a pH of 7.28, Paco2 4.1 kPa, Pao2 9.7 kPa and a base deficit of -7. The white count was elevated but his biochemistry was normal. A clinical diagnosis of left lower lobe pneumonia was made and confirmed on chest X-ray. He was admitted to the high dependency unit for close monitoring where he was reviewed by the intensive care team. He was commenced on intravenous cefuroxime and erythromycin (changed the next day to intravenous benzylpenicillin when blood cultures grew S. pneumoniae}. He had a central venous line inserted and required 3 fluid challenges of 200 ml of colloid each to raise his mean blood pressure to 60 mmHg. He was managed with continuous humidified oxygen (60%) and his oxygen saturations, blood pressure and clinical state were closely monitored. Analgesia was prescribed to reduce the pleuritic chest pain and enable an effective cough. Overnight he remained breathless and his saturations began to fall below 90% despite maximal facemask oxygen. The chest X-ray now showed progressive shadowing with diffuse changes throughout both lung fields (Case Fig. 14.1.1). To achieve adequate oxygenation he was intubated and mechanically ventilated; with a tidal volume of 375 ml, positive end expiratory

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pressure (PEEP) of 15 cm H2O, and a fractional inspired oxygen concentration of 0.85 which give a Pao 2 of ll.lkPa.

Question 1. What is the diagnosis and wliat js the correct rttianagement?

The diagnosis is now that of the acute respiratory distress syndrome (ARDS), as the Pao2 to Fio2 ratio is <26.7kPa (11.1/0.85 = 13.1), there is diffuse chest X-ray shadowing, and a recent precipitating cause (pneumonia). A CT scan taken a few days later showed typical ARDS changes (Case Fig. 14.1.2). For complete accuracy the possibility of left ventricular failure as a cause of these changes needs to be eliminated (this can be achieved with a pulmonary artery catheter, demonstrating a pulmonary artery

wedge pressure of <18mmHg, or by echocardiography). Correct management is treatment of the underlying cause (S. pneumoniae) and supportive therapy. A recent large multi-centre trial has shown that limiting tidal volumes and airway pressures leads to a 25% reduction in mortality. The accepted upper limit for tidal volumes is 0.5 ml/kg. Oxygenation is maintained using high PEEP, with values of 10 to 20 cm H2O being appropriate for this patient (although there is little definitive evidence for how PEEP should be titrated). Early enteral nutrition is beneficial for these patients. Management of fluid balance is controversial; although most clinicians would aim to maintain patients appropriately filled (best done by monitoring stroke volume and response to fluid challenges), some would aim to restrict fluids and maintain pressures using inotropes, and this issue is currently being addressed in a large multi-centred trial in the USA.

CASE FIG. 14.1.1 Chest X-ray. There is dense consolidation in the left lower lobe and diffuse shadowing throughout both lung fields. The patient developed a right pneumothorax (relatively common in ventilated ARDS patients) requiring tube drainage.

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CASE STUDY 14.1 CONTINUED Question 2. What rescue therapies are available? A number of trials have been conducted examining the use of different ventilatory strategies (including extracorporeal membrane oxygenation - ECMO), surfactant replacement, inhibitors of inflammatory pathways (e.g. cyclooxygenase inhibitors) and free radical scavengers. As a treatment for severe sepsis (rather than ARDS), activated protein C has been shown to be beneficial; however, to date, as a specific therapy for ARDS, the only trial with convincing data showing improved outcomes (aside from the limitation of tidal volumes) is that for the late use of low doses of steroids. This trial suggests that in those patients who fail to improve, or in whom there is a deterioration by day 7 after initiating mechanical ventilation, a trial of methyl prednisolone (2 mg/kg daily for 14 days) should be considered. There is reasonable evidence that this improves lung function and survival although the risk of infection needs to be considered. In those that respond, steroids can be weaned off slowly over the next 16 days, and the non-responders (usually less than 30% of cases) can be weaned more rapidly. However, the evidence is based on a trial with relatively small numbers, and the definitive role of steroids in ARDS awaits the results from an ongoing trial run by the National Institutes of Health in the USA.

Question 3. What is the outcome for patients with ARDS and what is the long term prognosis for iiirvivors?

Mortality from ARDS has fallen steadily over the last few decades and is now approximately 40%. Patients with a high number of organ failures, older patients and those with liver failure do worse. The ICU and hospital stays for survivors are still prolonged, with many patients being hospitalized for three months or more. The pulmonary fibrosis so characteristic of ARDS can lead to persisting respiratory problems after patients leave ICU. Recovery in lung function can be slow, with some

patients taking up to twelve months to return to baseline, while a few may show some degree of chronic abnormality including low diffusion capacity and elevated pulmonary artery pressures. In the majority, however, lung mechanics recover fully suggesting that the pulmonary fibrosis in ARDS is reversible. The prolonged period of hospitalization and slow recovery, along with the nature of the initial injury and the invasive therapies required to support life on the ICU, can lead to significant psychological stress and many patients benefit from counselling and from close follow-up after discharge from hospital. The patient described in this case survived, but when receiving ventilation he developed a pneumothorax and in all required 7 weeks of ICU support. One year after his illness the lung function was virtually normal.

CASE FIG. 14.1.2 CT Scan. Widespread airspace consolidation of ARDS, most marked in the dependent parts of the lungs.

METHODS OF VENTILATION The ventilator provides the motive power to drive oxygenenriched air into the patient's lungs. This may need to be done at high pressure as, for example, when ventilating an asthmatic with severe bronchoconstriction. With modern

ventilators it is possible to determine the respiratory rate, tidal volume, driving pressure, and the timing and waveform of the inspiratory cycle. Many patients on the ICU are deeply sedated and sometimes paralysed. All the ventilatory requirements of such patients are provided by the mechanical ventilator: this is termed controlled mandatory ventilation (CMV). Other patients often require partial

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support from the ventilator, and may breathe spontaneously between machine breaths. In order to avoid a machine breath coinciding with spontaneous exhalation the inspiratory cycle of the ventilator is synchronized to the patient's own inspiratory effort. This is sensed at the start of each breath, and the inspiratory cycle of the machine is initiated. The machine rate and tidal volume are set to provide adequate alveolar ventilation; this is termed synchronized intermittent mandatory ventilation (SIMV). Newer ventilators can now assist each spontaneous breath, the level of assistance ranging from partial support to full ventilation. This is performed by providing a constant, positive pressure to the patient with each spontaneous breath (inspiratory pressure support, IPS). The amount of IPS can be adjusted up and down. However, this form of respiratory support is critically dependent on the patient's spontaneous effort, and will provide no support if the patient becomes apnoeic. A further feature of ventilators is the capacity to add a positive (greater than atmospheric) pressure throughout the expiratory phase of the respiratory cycle. The purpose of such positive end-expiratory pressure (PEEP) is to prevent collapse of peripheral airways and subsequent atelectasis, thereby improving gas exchange. The addition of PEEP - commonly 5-10cmH2O - usually improves arterial oxygen tension, but impedes venous return and can reduce the CI. Oxygen delivery to the tissues may therefore be decreased despite an improvement in Pao2. PEEP may also increase pressure damage to the lung. The optimum level of PEEP for a particular patient is that which maximizes tissue oxygen delivery.

NON-INVASIVE VENTILATION

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Mechanical ventilation does not require endotracheal intubation, and respiratory support is frequently provided with a tightly fitting face mask during resuscitation and by anaesthestists in the operating theatre. This technique has been adapted in order to support patients on the ICU, using a simple ventilator and accepting that some of the ventilated gas may leak away. Such support is non-invasive and has many advantages. The patients do not need to be intubated, are not sedated, and may spontaneously cough and expectorate their own secretions. Additionally, the face mask may be removed intermittently and the patient may be able to speak and communicate during therapy. This type of treatment is now termed non-invasive ventilation (NIV). NIV is a generic term used to describe any form of positive-pressure facemask therapy; it begins with CPAP (continuous positive airway pressure) and also includes volume- or pressure-controlled mechanical ventilation. NIV was initially used in patients with severe chronic hypercapnic respiratory failure as an alternative to mechanical ventilation with an artificial airway. Success in this area is widespread, and the treatment is no longer restricted to the ICU. Rather, ward-based care is

usual. Frequently patients require long-term treatment and domiciliary NIV is provided, with specifically designed ventilators. NIV is used in acutely ill patients in respiratory failure. NIV is particularly successful when used at an early stage when the patient can cooperate effectively. Several studies have demonstrated that NIV decreases morbidity and mortality in acute ventilatory failure due to chronic destructive pulmonary disease (COPD), possibly owing to the decrease in pneumonia associated with endotracheal intubation. Not all patients are suitable for this form of therapy. Patients with decreased level of consciousness, those who are unable to cough and expectorate, or who are unable to swallow or protect their upper airway are difficult to manage with NIV and may need to be intubated. NIV demands an effective team of nurses, doctors and physiotherapists. In the acutely ill the first few hours of treatment demand intensive input from the team. The case for NIV in hypoxaemic respiratory failure is more complex, and some studies have suggested that treatment may not prevent more invasive therapy involving endotracheal ventilation. Nevertheless, the use of NIV is widespread.

COMPLICATIONS OF VENTILATION There is significant morbidity and occasional mortality associated with mechanical ventilation. Pressure damage to the lung is termed barotrauma, and the incidence is increased when high airway pressures are required to ventilate the lungs. A recent large multicentre trial in the USA has demonstrated improved survival in patients with acute lung injury or ARDS who are ventilated at lower tidal volumes (5-6mL/kg) rather than standard tidal volumes (10-12 mL/kg), although the exact mechanisms whereby this benefit is achieved are not yet clear. Pneumothorax is not uncommon and may present as gas in the pleural space, mediastinum or soft tissues (surgical emphysema). A tension pneumothorax can occur. When drained, the pleural leak may persist (bronchopleural fistula) and, if severe, the volume of gas escaping from the leak may exceed the capacity of the ventilator, leading to hypoventilation. Selective ventilation of each lung (differential ventilation) can isolate the side with the leak. High levels of oxygen produce lung damage and cause or exacerbate the acute respiratory distress syndrome (ARDS, p. 697). Patients on ventilators are often deeply sedated and therefore totally dependent on the correct functioning of equipment. They are also dependent on a supply of humidified, oxygen-enriched air. Constant nursing care is crucial. Secretions in the respiratory tract must be aspirated by the ICU staff, and airway collapse and atelectasis are common complications. The artificial airway is a portal for the entry of pathogens. Patients can be ventilated via an endotracheal tube for several weeks, but because the tube is a constant source of

TABLE 14.7 Major indications for tracheostomy • • • •

Provision of prolonged positive pressure ventilation Control of secretions To prevent aspiration To bypass upper airway obstruction

irritation to the mouth, a tracheostomy is often performed when it is likely that an artificial airway will be required for a prolonged period (Table 14.7).

TABLE 14.8 Metabolic abnormalities that impair respiratory muscle contractility • • • • • • • • •

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Acidosis Hypophosphataemia Hypomagnesaemia Hypokalaemia Hyper- and hypothyroidism Steroid therapy Other drugs (e.g. drug-induced myasthenic syndromes) Hypoxia Hypercapnia

WITHDRAWAL OF MECHANICAL VENTILATION As patients on the ICU recover, the aim is to withdraw mechanical ventilation. For this to be feasible the patient's cardiovascular system must be stable, with good peripheral perfusion. Gas exchange must be good, with satisfactory oxygenation and an inspired oxygen concentration of less than 50%. The patient should not be septic. There should be no gross acid-base or electrolyte abnormality. In patients where the period of ventilation has been short (hours), the withdrawal of assisted ventilation usually poses few problems. Sedation is withdrawn, the patient wakes up and breathes spontaneously from a source of oxygen, and is then extubated. In patients who have been ventilated for a number of days it is often not possible to withdraw ventilation suddenly, and a period of gradual withdrawal, or weaning, is necessary. Successful weaning requires careful consideration of the following interrelated questions: • Is central drive optimal? • Is the respiratory muscle pump as effective as possible? • Has the load on the respiratory muscle pump been reduced to the minimum? • Given the capacity of the respiratory muscle pump (Fig. 14.9), can the ventilatory load be sustained or is fatigue likely? Gradual withdrawal of ventilation can be achieved in many different ways. When the different methods are compared, SIMV is consistantly worse than using pressure support or a simple T-piece breathing system. Considerable effort has gone into the development of 'smart' ventilators which can detect when the load applied to the respiratory muscles changes. This allows the ventilator to automatically compensate, increasing ventilatory support. Alternatively, if the load diminishes, support may be reduced. A gradual reduction in the number of machine breaths, using SIMV, allows the patient to breathe spontaneously with a background of support from the ventilator. Alternatively, the inspiratory pressure support (IPS) can be gradually reduced so that the patient progressively takes

FIG. 14.9 The respiratory muscle pump When assessing the likelihood of successful weaning from mechanical ventilation the key factors are ventilatory load, drive and capacity. If the demands made of the pump exceed capacity, weaning will fail.

over the work of breathing. Another approach is to allow the patient to breathe spontaneously and unaided for successively longer periods, alternating with machine ventilation. In some patients the work of breathing can be reduced and weaning facilitated by continuous positive airway pressure (CPAP), which can be continued post extubation via a face or nasal mask. Some patients can be weaned by using non-invasive ventilation. During weaning it is important to optimize the function of the respiratory muscle pump. Any metabolic disturbances known to reduce the contractility of the respiratory muscles should be corrected (Table 14.8). In patients with airways obstruction bronchodilatation is helpful in reducing hyperinflation and improving muscle efficiency, as well as reducing ventilatory load. Treatment of pulmonary oedema also reduces the work of breathing. The effort of breathing through the tubing, ventilator and endotracheal tube should be minimized and the airway made as comfortable as possible. The patient should be sitting upright, preferably in a chair, and the abdomen should be free to allow the diaphragm to descend. During weaning, nutritional support must be maintained.

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fying, especially as the patient has difficulty with communication, and much psychological support is needed. In the early stages of weaning the patient should receive full ventilation during the night, and the benefit of a full night's sleep. Sedative drugs are in general best avoided, but may be required if the patient is sleep deprived. 1

CENTRALNERVOUSSYSTEMPROBLEMS Following an injury, the brain is at risk from the development of secondary damage that is essentially ischaemic in nature. Many factors can contribute to secondary brain injury: these include expanding intracranial haematomas, systemic hypotension, hypoxaemia and raised intracranial pressure (ICP). ICU therapy is aimed at protecting the brain from further damage to allow the best chance of neurological recovery. Treatment includes maintenance of cerebral oxygenation and perfusion, cerebral protection, and management of raised ICP. Appropriate monitoring allows a rational approach to therapy.

PATHOPHYSIOLOGY OF BRAIN INJURY Cerebral ischaemia

FIG. 14.10 An algorithm for weaning from mechanical ventilation

Injury to the brain initiates a cascade of ionic and metabolic changes that cause brain swelling and a reduction in cerebral blood flow (CBF), leading to a vicious cycle of worsening cerebral ischaemia. As blood flow is reduced there is sequential loss of cellular function that leads to uncontrollable movement of ions (especially calcium and potassium) across the cell membrane, and ultimately to cell death. Ischaemic brain tissue releases inflammatory mediators and excitatory amino acids that worsen cerebral injury.

Cerebral blood flow and metabolism Several factors distinguish patients who will sustain spontaneous ventilation from those who are ventilator dependent. A simple test to assess the likelihood of weaning success is to assess rapid shallow breathing by measuring the f/Vt ratio (f = frequency, Vt = tidal volume measured in litres). If this ratio exceeds 105 (i.e. rate of 40, Vt = 0.31,f/Vt = 133), weaning is unlikely. A suggested application of this test is shown in Figure 14.10. The patient should not be allowed to become distressed off the ventilator. The sensation of breathlessness is terri-

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742

Case 14.1

The effects of severe head injury on CBF and metabolism are variable. The majority of patients suffer an initial reduction in CBF that puts them at risk from further ischaemic damage. This is usually followed by a return to normal or a period of higher than normal flow (hyperaemia). Normally CBF and cerebral metabolism are coupled, to allow blood flow to be directed to metabolically active areas. After head injury this relationship may be lost, and in particular may vary in different parts of the brain. Under normal circumstances CBF is also controlled by autoregulation of cerebral vessels. After severe head injury autoregulation may be abolished and CBF changes directly with cerebral perfusion pressure. Systemic hypotension therefore increases the risk of cerebral ischaemia and is associated with a poor neurological outcome after head injury.

Intr a crania I pressure The cranium is a rigid box containing brain, cerebrospinal fluid (CSF) and blood, and the pressure inside the head (the ICP) is determined by the contents. Figure 14.11 shows the relationship between intracranial volume and pressure. In normal individuals a small increase in the volume of one compartment of the intracranial contents is compensated for by a reduction in another, thereby maintaining a constant pressure (point A in Figure 14.11). For example, as the brain swells, CSF and blood are driven out of the intracranial cavity. However, if there is continued brain swelling a stage is reached where compensation can no longer take place, and further small increases in volume cause large increases in pressure (points C-D in Figure

14.11). The blue lines in Figure 14.11 show the changes in pressure that occur when small aliquots of fluid are added via a catheter placed in a lateral ventricle. At the beginning of the curve, addition of a small volume of fluid causes a small, transient rise in ICP. Further along the curve, the addition of a similar volume of fluid causes a substantial rise in ICP although the baseline pressure has only risen slightly. Rises in ICP are important for two reasons. The cerebral perfusion pressure (CPP) is related to the mean arterial blood pressure (MAP) and ICP in the following way:

14

CPP = MAP - ICP

Increase in ICP may therefore reduce the supply of blood to the brain. A reduction in CBF below a certain critical level results in cerebral ischaemia. Intractable rises in ICP may also cause direct pressure effects on the brain and a downward shift of brain substance. This is termed coning and leads to recognizable clinical features, including the Cushing response (hypertension and bradycardia), ipsilateral pupillary dilatation and abnormalities of respiratory pattern, including apnoea. It should be noted that these changes occur late, often when irreversible brain damage has occurred. Coning therefore adversely affects outcome and is often fatal.

Causes of raised ICP

FIG. 14.11 The intracranial pressure-volume relationship • Between points A and B an increase in the volume of one component of the intracranial contents does not cause a rise in intracranial pressure because of a compensatory reduction in volume of the other two. • Between points C and D the intracranial compliance is critically low and a small rise in volume causes a substantial rise in pressure. • The intracranial compliance can be determined by a small volume challenge (blue lines)-see text.

Rises in ICP may occur for a variety of reasons. Spaceoccupying lesions, such as a haematoma, can expand. The ICP can also rise because of brain swelling, and this is usually due to cerebral ischaemia. Dilation of cerebral vessels causes an increase in cerebral blood volume (CBV) and ICP. Cerebral hyperaemia may occur as a direct result of brain injury (see above), but also because of dilatation of cerebral vessels secondary to a rise in Paco2. Cerebral vessels are exquisitely sensitive to changes in arterial carbon dioxide tension, and to a lesser degree to changes in oxygen tension. Figure 14.12 shows that a small rise in

FIG. 14.12 Cerebral blood flow [A] Effect of arterial C02 tension (Paco2) on cerebral blood flow. CBF changes in a linear fashion with Paco2 between 3.3 and 10.0kPa. B Effect of arterial 02 tension (Pao2) on cerebral blood flow. CBF does not change until Pao2 falls below 5.0kPa.

743

TABLE 14.9 Indications for cranial CT scan following bead injury 1. Immediate referral - Patient in coma - GCS <8 - Deterioration in conscious level - GCS falls by >2 - Focal pupil or limb signs 2. Urgent referral - Contusion persisting for >8 hours - Depressed or compound skull fracture - Base of skull fracture - Signs of rising ICP

TABLE 14.10 Targets for treatment of head injured patients • • • • •

Pao 2 >13.5kPa Paco2 4.0-4.5 kPa Mean arterial blood pressure >100mmHg Cerebral perfusion pressure >70mmHg Intracranial pressure <20mmHg

haematomas or the presence of brain swelling. The indications for an urgent CT scan are listed in Table 14.9. Management

CO2 can lead to a substantial rise in CBF whereas a low arterial CO2 cause a reduction in CBF. It is therefore crucial that Paco2 is maintained within normal limits during management of brain-injury. Severe hypoxaemia also increases CBF (Fig. 14.12) and ICP. Brain swelling or space-occupying lesions may obstruct CSF outflow and lead to a secondary hydrocephalus that may also contribute to raised ICP. 1

INITIAL ASSESSMENT It can be difficult to assess the central nervous system in patients on the ICU because the usual signs may be masked by sedation. Conscious level is usually assessed by the Glasgow Coma Score (GCS), based on the best verbal, motor and eye-opening responses. The score is described in detail on page 1283. The GCS is a measure of conscious level and therefore it is also important to document pupillary responses and focal neurological deficits. The initial GCS after resuscitation is a useful prognostic indicator after traumatic head injury, and sequential measurements give an indication of response to treatment. An assessment of the cardiovascular system should be made in all patients following brain injury, and serial recordings made of blood pressure and heart rate. About 40% of head-injured patients have other injuries that might affect outcome, and a full trauma survey should be carried out and appropriate investigations ordered. Up to 10% of patients with severe head injury have an associated cervical spine injury and precautions should be taken to protect the cervical spine (e.g. cervical collar) until this can be excluded by high-quality radiographs or CT scan. A chest radiograph should also be obtained because pneumothorax is a continued cause of mortality after head injury. CT examination of the head is the investigation of choice after severe head injury, and may reveal intracranial 1

744

MCQ14.7

ICU therapy for brain-injured patients is aimed at providing ventilatory and circulatory support to ensure adequate cerebral oxygenation and perfusion. Treatment may also be required to reduce ICP. General targets for therapy are shown in Table 14.10. Ventilation Hypoxaemia occurs in up to 65% of severely head-injured patients, and endotracheal intubation and mechanical ventilation are mandatory to ensure maintenance of adequate oxygenation. Ventilation should also be adjusted to maintain normal PaCO2 levels. Hypercapnia may cause rises in ICP secondary to cerebral vasodilatation, and hypocapnia may lead to critical reductions in CBF and the development of cerebral ischaemia. Blood pressure Prolonged periods of even modest hypotension (systolic BP < 90mmHg) are associated with poor neurological outcome after head injury. Maintenance of a stable cardiovascular system is therefore essential to protect the brain from secondary damage. Fluid resuscitation can be carried out with crystalloids or colloids, but 5% dextrose should be avoided unless hypoglycaemia is suspected. CPP should be maintained >70mmHg, and if the ICP is elevated it will be necessary to increase systemic blood pressure. If adequate blood pressure cannot be achieved with fluid resuscitation alone, inotropes or vasopressors should be introduced. Maintenance of adequate CPP is one of the most important aspects of treatment of brain-injured patients on the ICU. Control of intracranial pressure Provision of adequate analgesia and sedation (see below) prevents rises in ICP during mechanical ventilation and invasive interventions on the ICU. If patients are well sedated but continue to cough and strain, muscle relaxants may be used. Good patient positioning, with a 20° head-up tilt, the neck in the neutral position and neck veins free from obstruction, allows maximum venous drainage from the brain and a reduction in ICP. Surgical evacuation is the primary goal in the presence of an expanding mass lesion causing effects on ICP.

However, in some cases the lesion may be inaccessible or the brain swelling diffuse, in which case other methods must be used. Insertion of a catheter into the lateral ventricle of the brain allows small amounts of CSF to be withdrawn to control raised ICP. Drugs such as mannitol have been used for some time and decrease brain bulk by an osmotic effect. In an acute situation a single dose of mannitol (0.5g/kg) can be lifesaving because it 'buys time' prior to definitive surgical treatment. It can also be used on the ICU to treat increases in ICP, but long-term treatment does not improve outcome. As well as having an osmotic effect, mannitol also lowers blood viscosity and might increase cerebral microcirculatory flow. Excessive use of mannitol results in fluid depletion and hypernatraemia. Barbiturates have been the mainstay of treatment for raised ICP for many years. They increase cerebrovascular resistance and reduce CBF and ICP secondary to dose-dependent suppression of brain electrical activity and oxygen consumption. However, controlled studies have not shown that barbiturates improve outcome after head injury. They cause hypotension that might be detrimental to the injured brain, and are also long-acting. It can therefore be difficult to assess neurological status because of residual sedation when the drug is discontinued. Propofol also causes a dose-dependent fall in ICP and, because of its rapid metabolism and favourable pharmacological profile, is associated with good control of sedation level and ICP. It allows rapid wake-up when it is discontinued, and has become the first-line sedative for brain-injured patients on the ICU. For many years hyperventilation has been used as a treatment for raised ICP. Lowering Paco2 reduces CBF and ICP secondary to constriction of cerebral vessels. However, excessive hyperventilation should be avoided because it can cause a dangerous reduction in CBF and precipitate cerebral ischaemia. It is now known that overzealous hyperventilation is associated with worsened neurological outcome after head injury. Modern practice uses a target Paco2 of 4.0-4.5 kPa. In selected patients lower levels of Paco2 might be beneficial, but hyperventilation to such levels should only be undertaken in association with appropriate monitoring to check the adequacy of cerebral oxygenation (see below).

CEREBRAL PROTECTION There have been many attempts to develop a 'magic bullet' to block the cellular events that occur during cerebral ischaemia and therefore prevent secondary brain damage. It is unlikely that such a solution will be reached in the near future, but there are many strategies available on the ICU that protect the brain from further damage. Maintenance of cerebral perfusion and oxygenation is the cornerstone of cerebral protection, and control of cerebral metabolic rate with sedative drugs prevents oxygen demand outstripping delivery. It is also important to

prevent hyperglycaemia. A high level of plasma glucose leads to elevated levels of lactate in areas of ischaemic brain, and this is associated with poor neurological outcome. Plasma glucose levels should be maintained within the normal range. High temperature is also associated with worsened neurological outcome, and pyrexia must be treated aggressively. It has been suggested that modest reductions in temperature to 33-34°C might improve neurological outcome. Large studies are under way to determine the exact role of hypothermia in the management of brain injury.

14

GENERAL THERAPY Other organ system failure is common in patients with brain injury. Acute lung injury occurs in about 25% of head-injured patients because of pulmonary complications such as aspiration, or because of direct complications of the brain injury itself, such as neurogenic pulmonary oedema. Electrolyte disturbances occur in almost 60% of patients after severe head injury. In particular, disorders of sodium balance occur secondary to diabetes insipidus (DI) or the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Urine and plasma electrolytes must be closely monitored and appropriate treatment initiated (see Ch. 17). Early provision of an adequate calorie intake is associated with improvement in outcome after traumatic head injury, and enteral feeding should be instituted soon after admission to the ICU. An orogastric tube should be used for feeding in the presence of a fracture of the skull base. Because many brain-injured patients require longer-term enteral nutrition, early consideration should be given to placement of a percutaneous gastrostomy. Coagulation abnormalities can also be associated with brain injury because the ischaemic brain releases tissue thromboplastin. Coagulation studies guide replacement of clotting factors. Brain-injured patients fall into a high-risk group for the development of venous thromboembolism. Heparin prophylaxis may increase the risk of intracranial bleeding following craniotomy, and so physical methods of prevention, such as antitrombotic stockings and calf compression, should be used. The physiotherapist plays a key role in the management after brain injury, and in the early stages will be active in the prevention and treatment of chest infection. Early physiotherapy to the limbs and trunk prevents later contractures, and the patient must be sat and stood up as soon as their general condition allows. Such manoeuvres ensure the return of autonomic control of blood pressure and heart rate reflexes, and maintain body and limb alignment.

MONITORING Routine monitoring should include ECG, Spo2, measurement of direct arterial blood pressure, CVP, temperature,

745

urine output and regular blood gas analysis. In the presence of cardiovascular instability an oesophageal Doppler probe or pulmonary artery catheter will allow optimization of circulatory support. Treatment of brain-injured patients with appropriate amounts of sedation removes the clinical signs that would otherwise indicate changes in their neurological status. Brain monitoring is therefore crucial to assess the effects of treatment. Monitoring of ICP allows measurement of CPP and guides therapy. The 'gold standard' for ICP monitoring is measurement of the pressure in the lateral ventricles via a catheter and pressure transducer system. However, under most circumstances ICP is monitored using a miniature sensor placed in the brain tissue via a small burr hole through the skull. Such monitoring devices are safe and reliable. A well as measuring ICP and CPP, pressure monitors are able to detect abnormal ICP waveforms that reflect decreased intracranial compliance. Persistent rises in ICP above 25 mmHg are associated with poor outcome. Measurement of cerebral oxygenation is now standard practice in the ICU management of brain-injured patients. When perfusion of the brain is not adequate, the brain tissue extracts more oxygen from the blood than usual. This results in a reduction in the amount of oxygen in the blood leaving the brain, reflected by a fall in the cerebral venous oxygen saturation. A small catheter can be placed in the internal jugular vein so that its tip lies in the jugular venous bulb. Intermittent blood samples can be withdrawn via the catheter to measure jugular venous oxygen saturation (Sjo2) and venous lactate levels. A reduction in Sjo2 associated with a rise in lactate suggests inadequate cerebral perfusion. Specialized catheters, incorporating fibreoptic technology, allow continuous measurements of Sjo2 to be made in a similar manner to the measurement of mixed venous saturation by pulmonary artery catheters. This allows reductions in cerebral saturation to be monitored in real time and therapy to be initiated early. A reduction in Sjo2 to <50% or multiple episodes of desaturation are associated with poor neurological outcome. Two new technologies have recently been used to measure cerebral oxygenation. Small multiparameter probes that measure brain tissue Po2, ,Pco2, pH and temperature have recently become available. They are inserted into the brain in a similar manner to an ICP monitor, and reductions in tissue Po2 are associated with reductions in focal CBF and poor outcome. Near-infrared spectroscopy (NIRS) is also able to measure cerebral oxygenation by measuring the absorption of near-infrared light by oxygenated and reduced haemoglobin in the brain. The advantage of NIRS is that it is non-invasive and allows continuous monitoring. Both NIRS and brain tissue probes are still

research tools, but offer exciting possibilities for the future of cerebral monitoring. It is difficult to measure CBF at the bedside and the available techniques are invasive or require the use of radioisotopes. Transcranial Doppler (TCD) allows bedside measurement of the flow velocity of blood in the major cerebral vessels. If the diameter of the vessel remains unchanged, flow velocity can be used as an indirect measure of CBF. The TCD waveform can also be analysed to give additional information, such as the presence of vasospasm. The detection of epileptiform activity can be difficult in sedated and paralysed patients. Seizures can occur after head injury, and are associated with a massive rise in cerebral metabolic rate that leads to further secondary damage if untreated. Characteristic changes in the electrical activity of the brain during seizure activity can be monitored using the electroencephalogram (EEG). Analysis of the 16-lead EEG requires specialist training, but processed EEG techniques allow easy recognition of seizure activity on the ICU.

OUTCOME AFTER HEAD INJURY Outcome can be improved by appropriate therapy in the acute phase. No intervention can attenuate the primary injury, but recovery and survival can be jeopardized by secondary complications. The mortality after head injury remains high: of those patients who reach hospital 50% will make a good recovery, whereas 50% will either die or remain severely disabled. It is not possible in the early stages after injury to predict which patients will do well, but prevention of the factors known to cause secondary brain injury is of crucial importance. The major predictors for outcome after head injury are the initial GCS, pupillary size and reaction, and age. This last is by far the most important factor, with young adults having the best chance of a good outcome. GCS < 8 after resuscitation is associated with a worse prognosis than higher scores, and about 40% of patients in coma after 6 hours will die. The prognostic importance of the GCS is shown in Figure 14.13. Recovery from brain injury has three main components, physical, mental and social. Most physical recovery takes place within the first 6 months, but improvements in mental state and social integration may be slower. In general terms, about 80% of recovery is achieved within the first 6 months.

BRAINSTEM DEATH 1

746

MCQ 14.8

Many of the physiological functions of the body can be maintained artificially, but brain function cannot be replaced. Patients who have sustained irreversible struc-

TABLE 14.11 Diagnosis of brainstem death in the UK

14

1. Preconditions • Diagnosis compatible with brain stem death • Presence of irreversible structural brain damage • Presence of apnoeic coma 2. Exclusions • Drug effects (sedatives, hypnotics, muscle relaxants) • Hypothermia • Metabolic abnormalities (sodium, glucose, pH) • Endocrine abnormalities • Intoxication (alcohol, drugs) FIG. 14.13 Post-resuscitation Glasgow coma score and prognosis following traumatic head injury

tural damage to the brain stem as a result of head injury, stroke or cerebral anoxia lie in a deep coma without the capacity to breathe. Prompt medical attention on the ICU may have taken over ventilation and, because of continued oxygenation, the heart continues to beat. Recovery, however, is impossible and this state has become widely known as brainstem death (BSD). In the UK the uncertainty of how to confirm death under such circumstances has been removed by the development of strict guidelines for the diagnosis of BSD. Confirmation of BSD is essential to prevent the continuation of useless treatment, and is a prerequisite for organ donation. Diagnosis of BSD is in three stages (Table 14.11). Certain preconditions must be met. Irreversible structural brain damage compatible with the diagnosis of brainstem death must be present and the patient must be in apnoeic coma (i.e. unresponsive and dependent on mechanical ventilation). Reversible causes of coma must then be excluded. In particular, sedative drug effects, hypothermia and metabolic or endocrine disorders should be considered. Alcohol intoxication or drug overdose should also be excluded. The final part of the diagnosis of BSD is designed to demonstrate the absence of brainstem reflexes and confirm the presence of persistent apnoea by clinical tests (Table 14.11). The diagnosis should be made by two of the most senior doctors available, at least one of whom should be a consultant. If the patient is to become an organ donor, no member of the transplant team may be involved in performing the tests. Two sets of tests for the confirmation of BSD should always be performed to remove the risk of observer error. There is no prescribed time interval between the two sets of tests: this should be determined for each patient individually and is a matter for clinical judgement. In general, the interval will depend upon the primary pathology and the clinical course of the patient. The clinical findings must be documented in the case notes. Although death is not confirmed until the second set of tests have been completed, the legal time of death is when the first set of tests confirms brainstem death. 1

3. Clinical tests • Confirmation of absent brain stem reflexes - No pupillary response to light - Absent corneal reflex - No motor response within the cranial nerve distribution - Absent gag reflex - Absent cough reflex - Absent vestibulo-ocular reflex • Test for confirmation of persistent apnoea - Preoxygenation with 100% oxygen for 10 minutes - Disconnect from ventilator - Insufflate oxygen at 6 L/minute via endotracheal tube to maintain adequate oxygenation during test - Allow Paco2 to rise to >6.65kPa - Confirm no spontaneous respiration - Reconnect ventilator

TABLE 14.12 Suitable organ donors • • • • • • •

Age 0-70 years Patient has suffered irreversible brainstem death Ventilator-dependent No malignancy (except primary brain tumour) No systemic sepsis Hepatitis and HIV negative ABO compatibility

ORGAN DONATION Patients who are BSD might be suitable to become organ donors (Table 14.12). In the UK this is coordinated by UK Transplant (UKT). Regional transplant coordinators are available to support and advise relatives, to offer advice on the management of the potential donor, and to organize the transplant of suitable organs. These can include heart, lungs, liver, kidneys and pancreas, as well as corneas, skin and bone.

747

TABLE 14.13 Physiological complications after brainstem death Hypotension Diabetes insipidus Disseminated intravascular coagulation Cardiac arrhythmias Pulmonary oedema Hyperglycaemia Acidosis Seizures

There is a high incidence of complications likely to jeopardize vital organ function after BSD (Table 14.13). The many physiological changes that occur following cessation of brainstem function cause the multiple organ donor to become very unstable and active support is required. Following the diagnosis of BSD there is a change in the emphasis of care. Therapy has previously been aimed at preserving residual brain function, but after BSD has been confirmed the emphasis of care switches to optimizing organ function for subsequent transplantation. If it is the family's wish that their relative should become an organ donor, it is the duty of the ICU staff to provide organs in optimum condition.

RENAL PROBLEMS

The development of renal failure is a common and serious complication in the critically ill, associated with high mortality. The most common cause of renal failure is relative hypotension (prerenal), although this often proceeds to acute tubular necrosis. Although the major insult to the kidney may have occurred prior to admission, rapid and effective resuscitation may prevent further deterioration of renal function. Incipient and established renal failure are discussed in Chapter 20. Sepsis, sometimes occult, is a common cause of renal failure on the ICU. Other causes must not be forgotten, however, and a renal ultrasound to exclude obstruction is important at an early stage. Commonly, the first indication of renal dysfunction is reduced urinary volume. Assessment and manipulation of the CVS are often important. Despite hypovolaemia, the blood pressure may be normal because of vasoconstriction, but the urine will be concentrated, with a urinary sodium often less than 20mmol/L.

1 748

MCQ14.9

2

MCQ 14.10

Once an adequate circulation has been established some clinicians try to enhance urinary output with lowdose dopamine (<5ug/kg/min), but this is not of proven benefit. A further reduction in urine output is likely to herald established renal failure; although output may be enhanced by high-dose furosemide (frusemide), this may only postpone eventual anuria. Glomerular filtration will be depressed by severe acidosis. Fluid intake should be adjusted to the falling urine output. The multiplicity of intravenous infusions makes volume overload a possible error. Drug dosages should be reviewed in the light of the patient's renal function, and nephrotoxic drugs avoided (e.g. aminoglycoside antibiotics, NSAIDs, furosemide (frusemide)). Indications for dialysis include the control of extracellular volume, electrolyte imbalance and acidosis, and uraemia. Intermittent haemodialysis or peritoneal dialysis can be difficult in the seriously ill. Newer techniques have revolutionized the management of renal failure. Haemofiltration filters can be perfused with blood and require only a small driving pressure to produce a urine-like filtrate. Although this continuous filtration can control extracellular volume, the clearance of urea and electrolytes requires high volumes of filtrate per day and, without skill, fluid imbalance can lead to circulatory collapse. By passing a solution across the membrane against the direction of blood flow, dialysis of urea and other molecules occurs by diffusion and convection gradients. This is now achieved by a continuous-flow machine, removing blood from the venous circulation and returning it into the second lumen of a multichannel central venous catheter. Devices are now available to automatically compute the amount of fluid removed, and fluid balance can be adjusted by simply setting the difference between filtration and concomitant fluid replacement. 1

NUTRITION In normal individuals there is a limited reserve of rapidly available energy substrates (glucose and glycogen), which are depleted within 24-36 hours of starvation. Prolonged fasting leads to the production of glucose from protein catabolism via gluconeogenesis, and metabolism is shifted towards the utilization of fats. In starvation the metabolic rate is decreased and nitrogen loss (from protein breakdown) reduced, with the result that previously well-nourished patients can fast for several weeks. In the severely ill, not only is protein catabolized to glucose at a faster rate, but calorie requirements are also raised, by as much as 125% in those with extensive burns (Fig. 14.14). Many patients are compromised by a degree of malnutrition prior to admission to the ICU. Nutritional failure is associated with increased morbidity and mortality. Synthetic capability is reduced, one of the

TABLE 14.14 Sedative drugs used in ICU Agent

Properties

Comments

Benzodiazepines

Hypnosis and anxiolysis

Narcotics

Analgesia and hypnosis

Propofol

Intravenous induction agent

Ketamine

Intravenous induction agent

Isotlurane

Volatile anaesthetic agent

Inexpensive but may accumulate especially in the critically ill. This is of less importance when illness is prolonged Often successfully combined with benzodiazepines. Low cost advantageous. Alfentanil (newer synthetic narcotic) is used in renal failure Smooth, rapidly reversible, expensive agent. Not used in children but excellent for short-term sedation where rapid changes of consciousness are wanted receptor stimulant effect useful in bronchospasm although cost and dreaming/ psychosis limits its use Very effective and quickly reversible. Bronchodilating properties used in asthmatic emergencies

FIG. 14.14 Calorie requirements in normal individuals compared with those starved or critically ill and hypercatabolic

consequences of which is decreased immunocompetence and increased susceptibility to infection. Nutritional status requires careful assessment in the critically ill, and the history and length of illness should be noted. Precise measurement of nutritional status and requirements is difficult. Easily available measurements of synthetic capacity (albumin, total proteins) are rather variable and discriminate poorly between nutritional states (nutrition is discussed fully in Chapter 5). If possible, feeding should be continuous and controlled using a fine-bore nasogastric tube. This route is simple, economical and less likely to lead to infection. The incidence of gastric erosions is reduced in the enterally fed. However, absorption is often decreased by gastric stasis, or by the volume that can be given limited by diarrhoea. Several strategies may overcome this problem. Often, reduced gastric motility occurs when absorption in the small bowel is adequate. Gastric motility is increased by metoclopramide and erythromycin. If this fails, nasojejunal tubes can be inserted with a gastroscope, bypassing the stomach. If these efforts fail, a minority of patients require parenteral nutrition (p. 134), which requires the placement of a dedicated intravenous line. Patients often tolerate high fluid loads poorly, and feeding therefore requires concentrated solutions which may only be administered via a central vein. The constituents of intravenous feeding are ideal culture media and there is always a risk of infection. The volume of fluid, even when made up of highly calorific fats and concentrated glucose solutions, can precipitate volume overload. Careful attention to detail is required to provide appropriate quantities of trace elements and vitamins. During cellular respiration, fats and carbohydrates, when metabolized, produce differing amounts of CO2, to be excreted mainly by the lungs. High-carbohydrate feeds increase CO2 production and can contribute to CO2 retention and breathlessness in patients with marginal ventilatory function. 2

14

GENERAL CARE OF THE CRITICALLY ILL

Care on the ICU must be total as well as intensive. The patient who recovers from serious illness may have decades of life ahead and any residual handicap will be important. Attendant injuries, especially to the peripheral limbs, can be overlooked in the initial effort to resuscitate the patient, but may result in significant disability once the drama of intensive care is over. The maintenance of limb mobility and the prevention of contractures are important in bedbound supine patients. Skin and pressure area care is crucial. Poor peripheral perfusion commonly contributes to skin breakdown. Healing is enhanced when pressure is relieved, and this can be facilitated by air beds. Reflexes are lost during paralysis and sedation. The eyes and mouth are vulnerable. If the patient is ventilated the artificial airway must be kept clear and clean.

SEDATION There is no ideal sedative drug for patients on the ICU. The administration of sedation does not imply unconsciousness, and levels of sedation can be difficult to judge if the patient is receiving neuromuscular blocking drugs. For this reason local anaesthesia should always be used during painful procedures. Discussions around the bedside should be conducted as if the patient were aware (Table 14.14).

749

TABLE 14.15 Outcome Outcome from a single treatment technique for a defined disease • IPPV for severe asthma: >80% of patients discharged from hospital • IPPV for poisoning: >80% of patients discharged from hospital • IPPV for pneumonia or non-traumatic coma: <35% of patients discharged from hospital Outcome for organ system failure (e.g. cardiac, respiratory or renal failure) • Failure of one organ system for more than 1 day: mortality approximately 35% • Failure of two organ systems for more than 1 day: mortality approximately 60% • Failure of three or more organ systems for more than 3 days: mortality approximately 90%

Deep sedation is also harmful to the patient, and contributes to the depression of haemodynamics in the critically ill. It is easy for sedative drugs to accumulate, especially when renal or hepatic failure is present. The best management involves the use of a clinical scoring system which can be recorded frequently. If deep sedation is detected, the sedation can be stopped and the level of consciousness reassessed. Despite this approach, some patients, especially the elderly with multiple organ failure, can take many days to recover. The effect of sedation can be monitored by sophisticated processing of the EEG, and in the future it may be practical to use this technique to monitor the effect of sedative drugs in the critically ill. Patients are often mentally obtunded, or may experience hallucinations and paranoia, causing severe agitation. A nighttime sleeping regimen (or, better still, a daytime wakeful regimen) is of great help in the care of the longerterm patient on the ICU, especially during weaning from mechanical ventilation.

OUTCOME The outcome of patients admitted to the ICU can be assessed in different ways (Table 14.15). Survival is, in general, related to the severity of the presenting illness and the response to therapy. Patients with multiple organ failure have a particularly poor prognosis. Great care should be taken, however, when judging the prognosis of an individual patient, and the application of scoring systems to assess prognosis for a particular case has limited value. All staff on intensive care units have seen occasional patients survive against massive odds. The morale of patients and staff is central to the success

1

750

MCQ 15.1, MCQ 15.2

of an intensive care unit. The sustaining of morale, along with high standards of patient care, is a great challenge for the critical care team.

FURTHER READING Abraham E 1993 Sepsis: cellular and physiological mechanisms. New Horizons 1:1-159. A general article introducing the cellular biology of sepsis. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes and clinical trial co-ordination. Bernard G R, Artigas A, Brigham K L et al. 1994 Am J Respir Crit Care Med 149(3 Pt l):818-824. Bone R C, Sibbald W J, Sprung C L 1992 The ACCP-SCCM consensus conference on sepsis and organ failure. Chest 101(6):1481-1483. Brochard L, Rauss A, Benito S, et al. 1994 Comparison of three methods of gradual withdrawal of ventilatory support during weaning from mechanical ventilation. Am J Respir Crit Care Med 150:896-903. A careful analysis of the impact of different modes of weaning in a group of patients over a period of 21 days. Esteban A, Frutos F, Tobin M J et al. 1995 A comparison of four methods of weaning patients from mechanical ventilation. Spanish Lung Failure Collaborative Group. New England Journal of Medicine 332(6):345-350. A short term assessment of different weaning techniques. Boyd O, Grounds R M, Bennett F D 1993 A randomised clinical trial of the effect of deliberate peri-operative increase of oxygen delivery on mortality in high risk surgical patients. Journal of the American Medical Association: 2699-2707. A prospective analysis of optimizing the cardiovascular system and its impact on peri-operative mortality. Hayes M, Timmins A C, Yau E H S, Palazzo M, Hinds C J, Watson J D 1994 Evaluation of systemic oxygen delivery in the treatment of critically ill patients. New England Journal of Medicine 330:1717-1722. A seminar paper describing the problems of applying optimization theory to patients on general Intensive Care Units. Lang C H, Abumrad N N 1995 Nutrition in the critically ill patient, vol 11, no. 3. W B Saunders, Philadelphia. A good review of the subject. Palmer R M J, Ferrige A G, Moncada S 1987 Nitric oxide release accounts for the biological activity of endolthelium-derived relaxing factor. Nature 327:524-526. The original paper describing nitric oxide and its vasodilating properties. A good review of the problems of systemic circulation. Rachon E C, Astiz M E 1993 Mechanisms and management of septic shock. Quote cares clinics vol 9:219-237. W B Saunders, Philadelphia. The Acute Respiratory Distress Syndrome Network 2000 Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 342: 1301-1308. Tobin M J 1988 State of the art: Respiration monitoring in the intensive care unit. American Review of Respiratory Disease 138:1625-1634. An excellent review of all aspects of respiratory monitoring. Yang K L, Tobin M J 1991 A prospective study of indexes predicting the outcome of trials of weaning from mechanical ventilation. New England Journal of Medicine 324:1445-1450. An assessment of weaning from mechanical ventilation.

15 Gastrointestinal Disease Richard G Long and Brian T Cooper

Introduction 751

Colorectal disease 797

Clinical features of gastrointestinal disease 751

Inflammatory bowel disease 804

Investigation of gastrointestinal disease 751 The mouth 760 The oesophagus 762 Gastrointestinal bleeding 772

Infective, microscopic, ischaemic and radiation colitides 815 Functional bowel disorders 817 Self-induced bowel disease 823

describe a variety of different symptoms related to eating. It is important that patients define precisely what they mean. Proctalgia fugax is a transient shooting pain in the rectum. Tenesmus, an uncomfortable desire to defecate, often when there is no stool in the rectum, may be associated with rectal inflammation and the irritable bowel syndrome. Abnormal signs in patients with gastrointestinal disease are summarized in Table 15.2. Diseases of the gut can result in malnutrition; failure of fluid intake or increased loss due to vomiting or diarrhoea results in dehydration. Peripheral oedema and ascites occur because of hypoproteinaemia due to protein loss, malabsorption or malnutrition. Vitamin D and calcium malabsorption result in hypocalcaemia and osteomalacia (Ch. 18). Finger clubbing can be associated with inflammatory bowel disease and coeliac disease, leukonychia (white nails) with hypoalbuminaemia, and koilonychia (spoonshaped nails) with chronic iron deficiency anaemia. Aphthous ulcers occur in patients with coeliac disease, and more indolent mouth ulcers in Crohn's disease. Angular cheilitis, stomatitis and glossitis occur in patients with iron and water-soluble vitamin deficiencies. Facial and oral telangiectasia are associated with telangiectasia lower in the gut, and these may bleed.

Diseases of the peritoneum 823 The pancreas 824

The stomach and duodenum 775 The small intestine 786

INTRODUCTION Despite important developments in our understanding of the causes of many important gastrointestinal diseases, coupled with major improvements in therapy, such diseases remain a major cause of morbidity and mortality throughout the world. In the UK gastrointestinal disorders are responsible for one in 10 of all deaths, one in six of all admissions to general hospitals, and two in 10 of all visits to a general practitioner. The gastrointestinal tract is the commonest site for cancer. Worldwide, gastrointestinal disease is a vast cause of ill health and it has been estimated that on any one day, 200000000 people suffer from diarrhoea.

CLINICAL FEATURES OF GASTROINTESTINAL DISEASE Typical symptoms of gastrointestinal disease are shown in Table 15.1. General symptoms are useful in assessing the state of health of many patients with gastrointestinal symptoms. Patients commonly complain of non-specific symptoms, but these are rarely associated with serious disease. Dyspepsia and indigestion are non-specific terms which

INVESTIGATION OF GASTROINTESTINAL DISEASE 1 HAEMATOLOGICAL AND BIOCHEMICAL ABNORMALITIES Iron and folate are absorbed from the upper small intestine, and malabsorption of either results in characteristic haematological changes (Table 15.3). In some patients with upper intestinal malabsorption (especially coeliac disease), a mixed folate and iron deficiency may be seen (dimorphic anaemia). Dietary iron deficiency can occur in patients with diets low in meat, and is particularly common in the elderly and in vegans. Blood loss can occur throughout the gut, with consequent iron deficiency and anaemia. Gastric surgery can cause iron deficiency by reduced acid secretion impairing absorption, by bypassing the upper small intestinal mucosa, and by intestinal hurry. Folate is present in large amounts in green vegetables and liver, but dietary deficiency may occur if the diet is inadequate. Vitamin B12 is bound to intrinsic factor in the stomach and is absorbed specifically in the terminal ileum (as are bile acids). Intrinsic factor deficiency can be congenital or secondary to pernicious anaemia or gastrectomy. Malabsorption of the B12-intrinsic factor complex is generally due to terminal ileal resection or disease (usually Crohn's disease). However, it can also occur (rarely) secondary to infestation with the fish tapeworm (Diphyllobothrium latum), to intestinal fistulae and blind loops, or with chronic pancreatitis (p. 829). The double-isotope Schilling test

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CASE STUDY 15.1 CHRONIC IRON DEFICIENCY ANAEMIA IN A 48-YEAR-OLD NURSING SISTER History A 48-year-old white Caucasian nursing sister presented with a 3month history of increasing malaise and breathlessness. Her GP had checked her full blood count and found that her haemoglobin was 7.6, with a blood film showing red cell microcytosis and hypochromia. Haematinic estimation showed a low serum iron and ferritin, a high total iron binding capacity and normal folate and B12 levels. By the time that she was seen in the clinic, she had been taking ferrous sulphate 200 mg b.d. for 3 weeks and her symptoms had improved. Question 1. What are the most important questions to ask with regard to the predisposing cause? She had light periods for 3 days in every 28. She ate meat regularly and appeared to have a good oral iron intake. She was on no medication apart from occasional paracetamol. In particular, she did not use aspirin or non-steroidal anti-inflammatory drugs. She had no upper or lower gastrointestinal symptoms. There was no relevant family history of upper or lower gastrointestinal diseases causing bleeding or malabsorption. She drank five units of alcohol a week and was a nonsmoker. There was no relevant family history. Examination She was clinically anaemic. The chest, heart and abdomen were

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1

Figs 15.1,15.2

4

Case 15.1

2 Fig. 15.3

unremarkable. Sigmoidoscopy showed no polyps or inflammation. Investigations Upper gastrointestinal endoscopy showed the oesophagus, stomach and first part of the duodenum to be normal. The circular folds in the second part of the duodenum were reduced in number and height, which is a marker of coeliac disease. 1 She was also IgA endomysial and gliadin antibody positive. Question 2. What histological changes would you expect in the second part of the duodenum in a patient with coeliac disease? Biopsies of the second part of the duodenum showed total villous atrophy with increased intraepithelial lymphocytes. 2

Question 3. Does she need further investigation? She should have imaging of her large bowel, as right-sided colonic tumours are relatively common in patients with iron deficiency anaemia. The large bowel could be visualized by colonoscopy, which has the advantage of a direct view, the ability to take histology and good views of mucosal lesions such as ulcerative colitis or angiodysplasia, or by a barium enema which has a high chance of obtaining good images of the right colon. She

3 Fig. 15.4

had a colonoscopy, which showed a large carcinoma of the ascending colon. 3 Treatment The patient was started on a glutenfree diet. She had a right hemicolectomy for her carcinoma, which was a Duke's stage B. She made a good recovery from the operation. She was treated with adjuvant chemotherapy in a randomized placebo-controlled clinical trial. Discussion Iron deficiency anaemia is a very important clinical finding which, unless there is severe menorrhagia, should always lead to investigation of the gastrointestinal tract. In about 10% of cases lesions are found in both the upper and the lower gastrointestinal tracts. In general, most patients consequently require imaging of both ends of the gut. It is unusual for patients presenting with iron deficiency anaemia to have lesions between the second part of the duodenum and the distal terminal ileum. Small bowel radiology and enteroscopy therefore have only a small role. This patient should have a longterm cure rate of about 50% from her Duke's B tumour. Coeliac disease is associated with an increased risk of certain rare gastrointestinal malignancies. It is generally accepted that this risk returns to that of the normal population after 5 years on a gluten-free diet. Four years after the initial presentation, the patient remains well.

(p. 1210) is used to determine whether B12 deficiency is due to lack of intrinsic factor or to malabsorption of the intrinsic factor-Bi2 complex. Vegans have a diet very low in B12 and thus may become deficient. Hyposplenism is a feature of some bowel disorders, particularly coeliac disease. The typical finding on a blood film is of Howell-Jolly bodies (red cells containing small

TABLE 15.1 Symptoms of gut disease Small intestinal symptoms Diarrhoea Steatorrhoea Symptoms of anaemia Abdominal colic Abdominal distension

General symptoms Anorexia Weight loss Nausea and vomiting Malaise and lethargy Non-specific symptoms Flatulence Abdominal bloating Poorly or variably localized pain Oesophageal symptoms Dysphagia Heartburn Regurgitation Retrosternal pain Painful swallowing (odynophagia)

4

Large intestinal symptoms Symptoms of anaemia Diarrhoea Constipation Abdominal colic Blood and mucus per rectum Tenesmus Proctalgia Incontinence

Gastroduodenal symptoms Upper abdominal pain/discomfort Early satiety Haematemesis and melaena

nuclear fragments). It also occurs in some patients with inflammatory bowel disease. Neutrophil leukocytosis and raised acute-phase reactants (e.g. ESR, serum orosomucoids or C-reactive protein) are useful non-specific markers of intra-abdominal inflammation, particularly inflammatory bowel disease, and sepsis. A low serum albumin is commonly seen in patients with bowel disease (Table 15.4) and reflects protein leakage into the gut, decreased dietary intake, reduced absorption and, rarely, decreased synthesis. Albumin has a plasma half-life of about 23 days. Proteins such as transferrin and prealbumin have a shorter half-life and plasma levels consequently fall earlier. Electrolytes may be deranged. In patients with gastric outflow obstruction (pyloric stenosis), a hypochloraemic hypokalaemic alkalosis may occur. Diarrhoea may result in dehydration and electrolyte loss, particularly potassium. Postgastrectomy patients and patients with severe small bowel disease causing malabsorption may have a low serum calcium and osteomalacia. These patients develop secondary hyperparathyroidism, hyperphosphaturia and hence hypophosphataemia. Patients, especially postmenopausal females, with small bowel disease and/or costicosteroid therapy can develop osteoporosis.

ENDOSCOPY The development in the 1970s and 1980s of flexible fibreoptic and video endoscopes revolutionized the gastro-

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TABLE 15.2 Signs of gut disease General Malnutrition Dehydration Anaemia Oedema Bone tenderness Chvostek's sign Trousseau's sign Finger clubbing Leukonychia Koilonychia Oral Aphthous ulcers Other oral ulcers Angular cheilitis Stomatitis Glossitis Telangiectasia

Gastroduodenal Epigastric tenderness Epigastric mass Succussion splash | 1 Hypocalcaemia

Small intestinal Diarrhoea steatorrhoea Mass Abdominal distension Intestinal obstruction Colonic Mass Obstruction Distension Anorectal Anal fissures, tags, haemorrhoids, sinuses, fistulae Rectal examination: mass, blood, mucopus Sigmoidoscopy: proctitis, ulcers, tumours, melanosis, haemorrhoids

enterologist's view of the gut. Endoscopy is generally superior to radiology as an investigative technique, as it provides a direct mucosal view, enables biopsies to be taken for histological and biochemical analysis, and permits therapeutic manoeuvres (Table 15.5). Endoscopes are used in the upper gut to examine the pharynx, oesophagus, stomach and duodenum. Oesophageal strictures can be dilated using balloons or bougies, and metal or plastic stents can be put through strictures (usually malignant). Bleeding lesions can be cauterized by electric current or lasers. The ampulla of Vater can be cannulated and contrast medium injected to reveal the anatomy of the pancreatic ducts and biliary tree (endoscopic retrograde cholangiopancreatography, ERCP). If there are stones in the biliary tree, a sphincterotomy can be performed to allow them to fall out or be extracted by baskets or balloons. Malignant strictures in the biliary tree can be bypassed by Teflon or metal stents passed endoscopically or percutaneously through the liver. The anorectum can be examined by a rigid proctoscope, which is particularly useful for demonstrating haemorrhoids, and the rectum and lower sigmoid colon by a 25 cm rigid sigmoidoscope. A flexible fibreoptic sigmoidoscope can be used for the distal colon and rectum, and may be advanced to the splenic flexure (Fig. 15.1). Colonoscopes can be passed to the caecum and thence, via the ileocaecal valve, into the terminal ileum. Suspicious lesions can thus be biopsied, polypoid lesions snared by excision diathermy, and abnormal colonic blood vessels (angiodysplasia)

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TABLE 15.3 Haematological abnormalities in gut disease Abnormality

Laboratory changes

Causes

Iron deficiency anaemia

Blood film: hypochromic microcytic red cells Low mean cell volume (MCV) Low serum iron and high total iron-binding capacity

Blood loss Malabsorption

Dietary

Postgastrectomy Upper small bowel disease Folate deficiency anaemia

B12 deficiency anaemia

Blood film: macrocytic red cells High MCV

Dietary Upper small bowel disease

Low red cell folate

Drugs (e.g. sulphasalazine) Pernicious anaemia

Blood film: macrocytic red cells High MCV

Terminal ileal disease Postgastrectomy Chronic pancreatic disease

Low serum B12

Bacterial overgrowth of the small intestine

Fish tapeworm (Diphyllobothrium latum) Hyposplenism

Coeliac disease Tropical sprue Crohn's disease and ulcerative colitis

Howell-Jolly bodies Giant platelets

Neutrophil leukocytosis and high ESR

cauterized. The small bowel mucosa from the end of the second part of the duodenum to the terminal ileum cannot normally be viewed endoscopically, except by the littleused enteroscope; at laparotomy, however, it is possible to make an enterotomy and inspect the whole small bowel endoscopically.

Chronic inflammation, e.g. inflammatory bowel disease, abscess etc.

TABLE 15.4 Gastrointestinal causes of a low serum albumin Increased loss (protein-losing enteropathy) Stomach Menetriere's disease (giant rugae) Multiple gastric ulcers Gastric tumours

BIOPSY Diffuse mucosal disorders and focal lesions can be diagnosed by histological examination of tissue biopsies. Biopsies of the stomach, duodenum and colon are taken via the appropriate endoscope. A proximal small bowel biopsy is essential in suspected small bowel disease (e.g. coeliac disease). In the past proximal small bowel biopsies were taken from the jejunum with a swallowed capsule, but now such biopsies are usually taken from the distal duodenum via a fibreoptic endoscope. All gastrointestinal biopsies should be correctly orientated on card. This is especially important with small bowel biopsies so that the villous pattern can be assessed with a hand lens or dissecting microscope before being processed for histological examination. Some disorders (e.g. Crohn's disease) show a

Small intestine Coeliac disease Crohn's disease Tropical sprue Lymphoma

Decreased intake Anorexia Protein-deficient diet Decreased synthesis Associated liver disease (as can occur in inflammatory bowel disease) Decreased absorption Coeliac disease Crohn's disease Tropical malabsorption .

Lymphangiectasia Large intestine Crohn's disease Ulcerative colitis Colonic tumours

predilection for the distal ileum, and this can be biopsied via a colonoscope passed through the ileocaecal valve.

BARIUM STUDIES 1

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MCQ15.3

If a patient has difficulty with swallowing (dysphagia) a barium swallow is often recommended before

15

TABLE 15.5 Endoscopic procedures Procedure

Range of examination

Therapeutic procedure

Oesophagogastroduodenoscopy (upper Gl endoscopy)

Mouth to third part of duodenum

Oesophageal dilatation and stent insertion Oesophageal varices sclerosis or banding Tumour destruction by laser or alcohol injection Injection or laser of bleeding sites Balloon dilatation of pyloric stenosis Percutaneous endoscopic gastrostomy (PEG)

Endoscopic retrograde cholangiopancreatography (ERCP)

Ampulla and second part of duodenum (visual) Biliary tree and pancreatic duct (radiological)

Sphincterotomy Stone extraction Stent insertion Stricture dilatation Nasobiliary drainage

Enteroscopy Colonoscopy

Duodenum to ileum Anus to caecum/terminal ileum

Flexible sigmoidoscopy

Anus to descending colon (sometimes to splenic flexure)

endoscopy to outline the anatomy and to reduce the risk of endoscopic perforation. However, many endoscopists would not agree and use endoscopy as their first investigation for dysphagia. A barium swallow on video is very helpful in elucidating motor problems of the oesophagus, such as bulbar palsy, spasm and achalasia. In the investigation of gastroduodenal symptoms upper gastrointestinal endoscopy is preferred to a barium meal, as it is more accurate and allows biopsy and cytology specimens to be obtained. The small intestine can be examined by a small bowel meal, in which barium is swallowed and its progress followed to the terminal ileum. For better views of the distal small bowel and focal lesions a small bowel enema, in which contrast medium is placed directly into the upper jejunum via a nasal tube, is performed (Fig. 15.2). Double-contrast enemas with air and barium are useful in demonstrating colonic lesions such as carcinomas, polyps and inflammatory bowel disease. Barium enema should be delayed for at least 1 week after rectal biopsy to avoid the risk of perforation. Colonoscopy should be performed if there is doubt about the barium appearances, if angiodysplasia is suspected and if lesions requiring polypectomy are present.

Polypectomy Stricture dilatation Tumour destruction by laser Injection or laser treatment of bleeding sites As for colonoscopy

liver, biliary tree, spleen, pancreas, pelvis and retroperitoneal structures. They are helpful in demonstrating tumours, abscesses and stones, but are of little help in outlining the bowel. Isotopic techniques can be used to investigate gut disease. Technetium-99m (99mTc) sulphur colloid can be used to monitor the liquid and solid phases of gastric emptying (in general, liquids empty faster) and to measure the time taken by nutrients to pass through the small bowel (small bowel transit). Red cells can be radiolabelled with chromium-51 (51Cr) to demonstrate active gastrointestinal blood loss, especially when this cannot be demonstrated by conventional endoscopic and radiological means. White cells can be radiolabelled to demonstrate abscesses and areas of active inflammatory bowel disease. Meckel's diverticula often contain gastric epithelium and can be localized by radiolabelled pertechnetate, which is secreted by the parietal cells. Arteriography outlines the coeliac axis and superior and inferior mesenteric arteries, and can define stenosis or occlusion of these arteries in patients with pain after eating (mesenteric angina) and sites of active bleeding (e.g. tumours and angiodysplasia).

GUT REGULATORY PEPTIDES 1 IMAGING TECHNIQUES Ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI) are all useful in imaging the

Three classes of regulatory peptides have been defined: • Hormones, such as secretin and gastrin, are released as a result of food in the gut and have effects at distant sites.

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FIG. 15.2 A normal small bowel enema This shows the jejunum and ileum in the upper and lower parts of the picture, respectively.

RECENT ADVANCES IN ENDOSCOPY, IMAGING AND ENDOSCOPIC THERAPY

FIG. 15.1 Endoscopic instruments A A rigid proctoscope and Sigmoidoscope with their respective trocars removed are seen centrally. They are surrounded by a diagram of a typical fibreoptic gastroscope. B Diagram of the distal end of a typical video or fibreoptic gastroscope, Light is provided by the guides and the image is transmitted via the objective lens to the operator. The air and water outlets allow insufflation of the gut with air and cleansing of the lens with water. Gastric contents and secretions can be removed via the suction channel and biopsy forceps, and cytology brushes can also be passed by this route. C Diagram of the movements which the tip of a typical fibreoptic endoscope can achieve.

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Videoendoscopy has now largely replaced the older optical instruments. Videoendoscopy is more comfortable for the endoscopist and allows assistants and trainees to see the same image as the endoscopist. A permanent record (polaroid photograph or videofilm) is much easier to obtain. Ultrasound scanning via special probes passed through the endoscope is a new and rapidly developing technique. It seems to have significant advantages over external ultrasound, CT and MRI in the diagnosis of pancreatobiliary disorders and in staging and assessing the operability of GI tumours, especially of the oesophagus and rectosigmoid colon. The development of spiral (helical) CT scanning raises the prospect of such superior and detailed images of the biliary tree and pancreas that diagnostic ERCP will be unnecessary. Spiral CT scanning of the colon (colography, virtual colonoscopy) gives images approaching those of endoscopic colonoscopy. The endoscopic stenting of oesophageal and biliary malignant strictures as part of palliative therapy has been greatly simplified and made much less dangerous by the use of expanding metal stents. Paracrine regulatory peptides, discovered in the gut mucosa, are released locally and have profound effects on neighbouring cells. Neurotransmitters. Immunocytochemistry has demonstrated some peptides in the nerves of the gut,

e.g. somatostatin, vasoactive intestinal polypeptide (VIP) and substance P, which are thought to act as non-adrenergic non-cholinergic neurotransmitters (neuropeptides). The site of origin, mechanism of action and main physiological effects of the best-documented regulatory peptides are summarized in Table 15.6. Clinically, the most important aspects of these hormones are their use in diagnostic tests (e.g. the pentagastrin test for gastric acid secretion and the secretin-cholecystokinin test for pancreatic function) and their role in tumour syndromes (p. 833). Measurement of the peptides in plasma or tissue can be performed by radioimmunoassay. The following abnormal results may have a role in diagnosis: • In functioning tumours, plasma levels of peptides are high (e.g. gastrin in gastrinoma and vasoactive intestinal polypeptide in VIPoma). • In untreated coeliac disease, which is a proximal enteropathy, meal-stimulated plasma levels of the upper small intestinal hormones (secretin, cholecystokinin and gastric inhibitory polypeptide) are low. The terminal ileal hormones (neurotensin and enteroglucagon) are increased. • In chronic pancreatitis with steatorrhoea, levels of mealstimulated plasma pancreatic polypeptide are reduced. • In neuropathic diseases of the gut, such as Hirschsprung's disease and Chagas' disease, tissue neuropeptide levels are reduced.

TESTS OF FUNCTION

pylorus, the ileocaecal valve and the rectum. Control of gut motility is thought to be mainly neural but hormones, in particular motilin, may also play a role. The stomach plays a major role in grinding food to small particles and in controlling the exit of contents into the duodenum, which may take up to 5 hours after a large meal. Oesophageal motility can be investigated by a barium swallow on video, by static or 24-hour ambulatory manometric pressure studies, and by radionuclide transit studies. A pH probe in the lower oesophagus can assess gastrooesophageal reflux. Gastric emptying can be investigated by labelling the solid or the liquid phase with an isotope. Small intestinal motility can be assessed by the time taken for isotopes to reach the caecum, by demonstrating a peak of breath hydrogen excretion liberated from bacterial breakdown of a carbohydrate load when a test meal reaches the distal ileum and caecum, or by radiotelemetry, where a radiotransmitter capsule is swallowed and signals are received, allowing direct measurement of gut motility patterns. Whole-gut motility can be assessed by measuring mouth-to-anus transit time using swallowed radiolucent beads or non-absorbed radionucleotides. Disruption of anal function causing incontinence can be assessed by ultrasound. Obstructive defecation, where patients either contract rather than relax their anal muscles at defecation, or have other problems with rectal evacuation, can be assessed by putting barium paste in the rectum and then monitoring the speed of evacuation and the appropriateness of muscle action (proctography). A variety of clinical syndromes give rise to abnormal motility (Table 15.7). This usually causes a delay in transit, but gastric and other surgery can result in excessively rapid transit.

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Motility Normal gut motility promotes the passage of food and food residue along the lumen at a rate that allows the appropriate physiological processes to take place. Well-regulated 'brakes' occur at the gastro-oesophageal junction, the

Gastrointestinal secretion The salivary glands, stomach, pancreas, biliary tree and intestine all produce a large volume of secretions; these change the pH and produce enzymes that allow

TABLE 15.6 Origin and action of some gastrointestinal regulatory peptides Regulatory peptide

Site of origin

Mechanism of action

Main physiological effect

Gastrin Secretin Cholecystokinin

Gastric antrum Duodenum Duodenum

Hormone Hormone Hormone

Motilin Gastric inhibitory polypeptide (GIP) Enteroglucagon Neurotensin Pancreatic polypeptide Somatostatin

Upper small bowel Upper small bowel Terminal ileum and colon Terminal ileum Pancreas Pancreas and all the gut

Vasoactive intestinal polypeptide (VIP)

Pancreas and all the gut

Hormone Hormone Hormone Hormone Hormone Hormone Paracrine Neu retransmitter Neurotransmitter

Stimulates gastric acid secretion Stimulates pancreatic bicarbonate secretion Stimulates pancreatic enzyme secretion and gallbladder contraction Increases gastric emptying and gut motility Stimulates insulin secretion Delays gastric emptying; trophic effects on gut mucosa Delays gastric emptying Decreases pancreatic and biliary secretion Reduces hormonal and intestinal secretions Increases intestinal secretion

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TABLE 15.7 Disorders of gut motility Oesophagus

Stomach

Small bowel

Colon

Anatomical Tumours Inflammatory stricture (e.g. acid and acid/alkali burns) I

Tumours Pyloric stenosis Postgastrectomy

Tumours Inflammatory stricture (e.g. Crohn's disease and tuberculosis) Postsurgical resection

Tumours Inflammatory strictures (e.g. Crohn's disease) and ischaemic colon Postsurgical resection

Postvagotomy Diabetes mellitus

Diabetes mellitus Systemic sclerosis 4

Hirschsprung's and Chagas' diseases Diabetes mellitus

Non-ulcer dyspepsia Vomiting Aerophagy

Irritable bowel syndrome

Irritable bowel syndrome Slow-transit constipation

Neuropathic Achalasia Systemic sclerosis Functional Globus hystericus

increased motility

decreased motility

the digestion of food and thus absorption of nutrients (Fig. 15.3). The secretions are controlled by vagal nerves, including non-cholinergic non-adrenergic fibres, by local paracrine substances and by classic hormones. Modes of investigation and abnormalities of secretion are shown in Table 15.8. In general, meal tests are more physiological than hormonal tests, e.g. the pentagastrin and secretin-cholecystokinin tests, where pharmacological doses of hormones are given intravenously. The triplelumen tube can be passed perorally into the intestine and various solutions containing a non-absorbable marker may then be perfused. By sampling at the end of the tube, the amount of secretion or absorption can be assessed.

Gastric acid studies Gastric acid secretion can be assessed by collecting gastric juice via a nasogastric tube in the fasting state, measuring basal acid output and, after stimulation with a gastrin analogue, pentagastrin, assessing maximal acid output. Very high levels of basal acid outputs are seen in patients with gastrin-secreting tumours (gastrinomas), and high maximal acid outputs often occur in patients with duodenal ulcers. Twenty-four-hour acid secretion can also be monitored, to assess the effects of drugs that reduce acid secretion. Insulin hypoglycaemia stimulates gastric acid secretion via the vagus and can therefore be used postoperatively to assess the efficacy of surgical vagotomy. pH probes can also be placed in the oesophagus to monitor acid reflux, and in the stomach to monitor the effects of treatment.

Intestinal digestion and absorption 758

The stomach secretes acid and pepsin and, by physical churning and mixing, breaks down food into proportions that allow pancreatic and small intestinal brush border

FIG. 15.3 Typical daily fluid intake, secretions and absorption in a healthy person

enzymes to digest it ready for absorption. Fat and fatsoluble vitamins require bile acids, lipase and micelle formation to permit absorption. Proteins require gastric pepsin, pancreatic trypsin and brush border peptidases to break down proteins to absorbable single amino acids or 2-A amino acid peptides. Carbohydrates require pancreatic amylase, and then brush border disaccharidases, to form monosaccharides which can be absorbed (Fig. 15.4). Calcium, iron and folic acid are absorbed in the duodenum and upper jejunum, whereas vitamin Bi2 and bile acids are

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TABLE 15.8 Investigation and examples of important hyper* and hyposecretion syndromes Type of secretion

Modes of investigation

Examples of increased secretion

Examples of reduced secretion

Salivary glands

Volume, pH and amylase levels, with or without local oral stimulant

Sialorrhoea

Sjogren's disease

Stomach

Pentagastrin and meal-stimulated acid output

Duodenal ulcer Gastrinoma

Carcinoma of stomach Atrophic gastritis

Pancreas

Lundh test meal and secretion-cholecystokinin stimulation

Small intestine

Triple lumen tube and assessment of secretion/ absorption over given length of intestine

VIP-secreting tumours Cholera Phenolphthalein ingestion

Large intestine

Triple-lumen tube

VIP-secreting tumours Dihydroxy bile acids Long-chain fatty acids

Chronic pancreatitis with exocrine insufficiency

Lactase

FIG. 15.4 Intestinal digestion and absorption A Enzyme activity allowing the conversion of major unabsorbable disaccharides to monosaccharides, which the enterocyte then can absorb. B Glucose is transported by an active carrier with sodium at the brush border membrane. The gradient of sodium across the enterocyte is maintained by the Na+-K+-ATPase at the basolateral membrane, which allows sodium to pass out of the cell in exchange for potassium. Glucose leaves the cell at the basolateral membrane by a Na+-independent carrier.

absorbed in the terminal ileum; all other nutrients are absorbed throughout the small intestine. Small intestinal absorption requires active or passive transport across the brush border membrane, transport through the cell (often in Golgi or mitochondria), and then extrusion through the cell's basolateral membrane. The most important test of small bowel function is the measurement of fat absorption, because most diffuse disorders of the small intestine can cause fat malabsorption. This can be performed by measuring faecal fat excretion or the 14C-triolein breath test, whereby fat digestion is measured by 14CO2 excretion. Specific tests of carbohydrate digestion and absorption are available; brush border disaccharidase activity (e.g. lactase) can be measured in small bowel biopsies, and digestion and absorption of specific disaccharides can be assessed by measuring blood sugar levels after oral ingestion of the test sugar or by specific breath hydrogen tests. Protein absorption is assessed rarely, although faecal nitrogen excretion and faecal protein loss can be measured. Terminal ileal function is assessed by B12 absorption (e.g. Schilling) tests or bile salt absorption tests (e.g. 75Selabelled homocholic acid conjugated with taurine (75SeHCAT)). The integrity of the small bowel mucosa can be assessed by measuring the permeability of the mucosa to small inert hydrophilic non-metabolized molecules of varying molecular sizes (e.g. L-rhamnose, mannitol, lactulose, cellobiose, EDTA). Exocrine pancreatic function can be assessed by faecal fat measurement and specific pancreatic function tests (p. 824). The colon is primarily involved in the absorption of water and electrolytes. Normally, up to 1500mL of fluid passes through the ileocaecal valve daily, and this is concentrated to a 100 g formed stool. Specific colonic function tests are of research interest only.

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THE MOUTH NORMAL AND ABNORMAL FUNCTION The importance of the mouth, tongue, teeth and salivary gland secretions in starting the digestive process is often overlooked. Mastication and lubrication of the food bolus is desirable to facilitate its painless progression. Once swallowing has been voluntarily initiated, the rest of the act is automatic. Coordination of the soft palate rising to occlude the nasopharynx, the epiglottis tilting backwards to occlude the larynx, and the temporary cessation of respiration, is under complex neurological control, principally by the brainstem. Afferent pathways from taste and olfactory receptors initiate the cephalic phase of vagally mediated gastric secretion. Saliva contains two digestive enzymes, an amylase and a lipase. Lingual lipase may be important in patients with chronic pancreatic insufficiency. Xerostomia (dry mouth) can be severe enough to cause problems in initiating swallowing. Lack of saliva may predispose to ascending bacterial infections of the salivary glands (sialadenitis), especially the parotids (parotitis). Saliva also contributes to the prevention of dental caries, the pathogenesis of which involves the facultative anaerobe Streptococcus mutans, together with carbohydrate (mainly sucrose) and the formation of dental plaque. Both the edentulous and patients with ill-fitting or painful dentures may limit their food intake, often unconsciously, and thus lose weight. Other painful lesions of the mouth or tongue may have a similar effect but, being more obvious, come readily to medical attention.

DISEASES OF THE MOUTH Disease of the mouth may be important because: • The disease, although confined to the mouth, may give rise to unpleasant symptoms and disordered function (Table 15.9). • It may represent mucous membrane involvement of a generalized dermatological condition (Table 15.10). • Involvement of the mouth may be part of a systemic disease (Table 15.11). • The condition may be iatrogenic (Table 15.12).

ORAL ULCERATION 1 Recurrent aphthous ulcers There are many possible causes of oral ulceration (Tables 15.9-15.12) but the commonest is idiopathic aphthous 1

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MCQ 15.4

TABLE 15.9 Diseases confined to the mouth Ulceration

Plaques

Herpes simplex (HSV1) Recurrent herpes labial is Primary gingivostomatitis

Candida Leukoplakia Carcinoma

Acute ulcerative gingivitis (Vincent's angina, caused by Fusobacterium fusiformis and Borrelia vincenti) Cancrum oris Coxsackie A Herpangina Hand, foot and mouth disease Recurrent aphthous ulcers Minor Major Denture gingivitis

TABLE 15.10 Dermatological conditions involving the mouth Ulceration (burst bullae)

Plaques

Pemphigus vulgaris Pemphigoid Erythema multiforme Lichen planus

Lichen planus Psoriasis

ulceration. This occurs in up to 20% of patients seen in hospital and 10% in general practice. It often begins in late childhood or the early teens and frequently recurs. In about 80% of cases the condition (though still unpleasant) is regarded as minor, with up to five ulcers, less than 1 cm in diameter, affecting the lips, cheeks and tongue and healing within a week. Major ulcers are larger, often more numerous, and may involve the pharynx and palate. Cervical lymph node enlargement may occur and healing may be delayed for several weeks, leaving scarring. The aetiology of aphthous ulcers is unknown. The preponderance of the disease in females, its onset at the menarche, relationship to menstruation and improvement in pregnancy have led to the postulation of hormonal factors. A proportion of patients with coeliac disease present in this way and appropriate tests, including small bowel biopsy, are indicated. Treatment is with tetracycline mouthwash to prevent secondary infection, local corticosteroids and, in severe cases, systemic corticosteroids.

Herpes simplex The commonest manifestation of herpes simplex (HSV 1)

TABLE 15.11 Mouth involvement in systemic disorders Mouth involvement

Systemic disorder

Mucocutaneous pigmentation of lips

Peutz-Jeghers syndrome

Telangiectasia (lips)

Scleroderma (CRST syndrome) Hereditary haemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)

Buccal pigmentation

Addison's disease ACTH-producing tumour

Macroglossia

Hypothyroidism Acromegaly Amyloid

Glossitis

Iron deficiency (also angular cheilitis) Folate and vitamin B12 deficiency

Gingival hypertrophy

Acute leukaemia Amyloid

Gingivitis (with or without bleeding)

Acute leukaemia Scurvy Thrombocytopenia Agranulocytosis

Oral ulceration

Behget's disease Reiter's syndrome Crohn's disease Coeliac disease Wegener's granulomatosis Systemic lupus erythematosus Tuberculosis Syphilis Glandular fever Agranulocytosis

TABLE 15.12 latrogenic disorders of the mouth latrogenic disorder

Cause

Xerostomia

Atropine-like drugs Tricyclic antidepressants

Gingival hyperplasia

Phenytoin, primidone, phenobarbitone, ciclosporin

Gingival pigmentation

Bismuth, mercury, lead, arsenic, silver

Ulceration

Sulphonamides, barbiturates, penicillin (cause erythema multiforme) Gold Penicillamine Cytotoxics Drugs causing agranulocytosis, e.g. carbimazole, sulphasalazine

is of recurrent herpes labialis (cold sore). The virus lies dormant in the trigeminal ganglion. Antiviral therapy with local idoxuridine or acycloguanosine (aciclovir) is probably only necessary in the immunocompromised patient. A rarer, more severe and usually non-recurrent infection is primary herpetic gingivostomatitis. It occurs primarily in childhood and the sore mouth and gums, with vesicles preceding ulceration, is accompanied by fever and regional lymphadenitis. Treatment is analgesia and antibiotics to prevent secondary bacterial infection.

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Acute ulcerative gingivitis Acute ulcerative gingivitis (Vincent's angina) is thought to be due to bacterial infection; Fusobacterium fusiformis and Borrelia vincenti are the currently incriminated organisms. This disease affects young adults and the immunosuppressed, and is again accompanied by fever and lymphadenitis. The painful gums may bleed. Vincent's angina may be distinguished from herpes by the foul fetor and the absence of vesicles. Penicillin or metronidazole are usually effective treatments.

Crohn's disease Oral lesions are relatively common, particularly if there is colonic involvement (p. 808). The lesions include aphthous ulceration and cobblestoned or fissured epithelium. They can be the sole presenting feature of the disease and may be painful. Biopsies of the lesions may show typical noncaseating granulomata.

Other causes of ulceration Oral ulceration may predominate in Behcet's disease, Reiter's syndrome and erythema multiforme. In all three conditions ocular and genital lesions may be present. Although many cases of erythema multiforme have no apparent cause, some are induced by herpes simplex and drugs such as sulphonamides, barbiturates and penicillin. Bullous disorders of mucous membranes result in their rupture to form ulcers in the mouth. As at other sites, differentiating the intraepithelial bullae of pemphigus from the subepithelial bullae of pemphigoid may be difficult (p. 410). Lichen planus may also present with erosion of vesicles causing ulceration, and in a significant number of patients the mouth may be the only site of the disease (p. 413).

PLAQUE LESIONS Candida Candidiasis usually arises as a result of a defect in immunity, as the causative fungus is a common commensal. Candidiasis may complicate HIV infection and is common in poorly controlled diabetics and asthmatic patients on corticosteroid inhalers (see Ch. 9, p. 332 and Ch. 10, p. 391).

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Leukoplakia Leukoplakia is a serious condition because of its propensity for malignant transformation in about 5% of cases. The white patches can occur anywhere within the oral cavity. Biopsy, which must be repeated regularly to detect atypia or early cancer, confirms the diagnosis by showing epithelial keratosis and hyperplasia. The aetiology is multifactorial, but idiopathic cases do occur. There is no specific treatment other than excision and avoiding the presumed causative factors. These include smoking, local friction and chronic infection, e.g. chronic candidiasis or tertiary syphilis; the latter has a worse prognosis regarding malignant change. Leukoplakia is an important manifestation of HIV infection (p. 444).

Carcinoma Squamous carcinoma of the oral cavity may affect the lips, tongue or any other part of the mouth, and may present as a nodular or ulcerating lesion. As with leukoplakia, its incidence appears to be declining, emphasizing the important association between the two conditions. Pipe and cigar smoking is strongly associated with oral cavity carcinoma, as is the chewing of tobacco or betel nut.

OTHER LESIONS Other disorders of the mouth are listed in Tables 15.9-15.12. Minor abnormalities of the tongue may, because they are easily seen by the patient, give rise to considerable anxiety. Georgraphic tongue (benign migratory glossitis) is caused by shifting areas of desquamation of short duration in any one location. It is invariably symptomless and the patient should be reassured of this. Fissure tongue may be associated with symptomatic glossitis but, if symptomless, the patient can be reassured. Black hairy tongue is asymptomatic but may cause anxiety. Tripotassium dicitrate bismuthate (Denol) in liquid form is an obvious cause and the disorder may also follow antibiotics, but the aetiology is usually unknown. Reassurance is required. Brushing the tongue surface may help.

THE OESOPHAGUS Normal swallowing involves coordinated action of the oropharynx, relaxation of the cricopharyngeus, peristalsis down the oesophageal body (upper one-third striated muscle, lower two-thirds non-striated muscle) and relaxation of the lower oesophageal sphincter.

1

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Case 15.2

CLINICAL FEATURES OF OESOPHAGEAL PATHOLOGY Dysphagia 1

Difficulty with swallowing (dysphagia, or 'food sticking') is a most important symptom. Some of the causes are shown in Table 15.13. When there are obstructive lesions, such as carcinoma, dysphagia is initially for large boluses of food but then progresses to less solid food and finally to liquids ('total dysphagia'). Most of the causes can be elucidated by a good history, examination, barium swallow and endoscopy. Patients with central and peripheral nervous diseases and primary muscle disorders usually have other neuromuscular symptoms and signs. Hysterical dysphagia is a diagnosis of exclusion and usually occurs in psychiatrically disturbed patients.

Other symptoms Painful swallowing and retrosternal pain are important symptoms. On occasions it may be difficult to differentiate oesophageal and cardiac pain, and there is evidence that gastro-oesophageal reflux may lower the threshold for angina. Regurgitation of gastric juice into the lower oesophagus and the back of the mouth may cause heartburn and is due to an incompetent lower oesophageal sphincter; this is commonly precipitated by raising the intra-abdominal pressure (lifting, pregnancy). If food accumulates in the oesophagus nausea, vomiting and weight loss may occur. The oesophagus is also a site of bleeding from varices, ulcers and inflammatory lesions (oesophagitis).

Signs Abnormal physical signs are unusual in patients with oesophageal disease, but epigastric tenderness may indicate oesophagitis, peptic ulceration or a carcinoma. Neurological examination of palatal movement and the gag reflex are important when dysphagia could be due to a

TABLE 15.13 Causes of dysphagia • Local oropharyngeal problems, e.g. infections, tumours • Central nervous system disorders affecting oropharyngeal function, e.g. brainstem lesions associated with multiple sclerosis, cerebrovascular disease, Parkinson's disease, Huntington's chorea and motor neuron disease • Malignant and benign oesophageal strictures • Other local oesophageal problems, e.g. reflux oesophagitis, infections, web, diverticulum • Disorders affecting oesophageal unstriated muscle, e.g. achalasia, chronic alcoholism, diabetes mellitus • Generalized striated muscle diseases, e.g. myasthenia gravis, dystrophia myotonica • Extrinsic compression (e.g. mediastinal tumour) • Psychiatric, i.e. globus hystericus

neurological cause. An epigastric mass or palpable supraclavicular lymph nodes suggests a neoplasm. Decreased oesophageal clearance of solids and fluids (especially in patients with achalasia and carcinoma) may cause pulmonary aspiration.

INVESTIGATION OF OESOPHAGEAL PATHOLOGY A barium swallow outlines the oropharyngeal and oesophageal anatomy, and a video recording can be taken to look for disordered motility. A chest X-ray helps to assess oesophageal dilatation. If a patient has dysphagia a barium swallow can be carried out before endoscopy; this is because symptoms alone cannot always localize the site of the lesion, and if the endoscopist is unprepared for the abnormal anatomy, perforation of an oesophageal carcinoma or diverticulum may occur. However, experienced endoscopists would perform endoscopy as the first investigation. Manometry is useful to assess the oesophagus and lower oesophageal sphincter in achalasia and other motility disorders. It can be performed on one occasion or dynamically over a 24-hour period. Reflux can be monitored by a pH-sensitive probe in the distal oesophagus (24-hour ambulatory oesophageal monitoring).

patients with reflux there are repeated episodes of significant quantities of acid, bile and food regurgitating into the lower oesophagus. This can lead to inflammatory change (reflux oesophagitis), which is associated with decreased oesophageal clearance of liquids and solids. Gastro-oesophageal reflux causes a spectrum of oesophageal abnormalities (Table 15.14a)

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Aetiology The main cause of gastro-oesophageal reflux is the failure

TABLE 15.14a The spectrum of gastro-oesophageal reflux disease Reflux symptoms without oesophageal damage Reflux oesophagitis Oesophageal ulcer Benign oesophageal stricture Barrett's oesophagus Oesophageal adenocarcinoma

TABLE 15.14b Factors predisposing to gastro-oesophageal reflux GASTRO-OESOPHAGEAL REFLUX Normally, gastro-oesophageal reflux is prevented by the lower oesophageal sphincter, aided by the diaphragm. In

SUMMARY 1 The main symptoms, signs and investigations of oesophageal disease Symptoms Difficulty with swallowing (dysphagia) Painful swallowing (odynophagia) Refrosternal pain Heartburn Regurgitation Vomiting Weight loss Gastrointestinal bleeding Signs Epigastric tenderness or mass Abnormal palatal movement Supraclavicular lymphadenopathy Chest signs due to aspiration Investigations Full blood count Barium swallow Chest X-ray Endoscopy Manometry pH monitoring

Cause

Example

Disordered anatomy

Hiatus hernia Obesity Post-surgical treatment of achalasia Presence of tube for treating carcinoma

Myogenic

Systemic sclerosis Reflux oesophagitis

Hormonal

Pregnancy Menstruation

External influences

Smoking Eating fat/chocolate Coffee/tea Large meals Alcohol Drugs

TABLE 15.14c Non-oesophageal manifestations of gastro-oesophageal reflux Pulmonary aspiration -> wheeze and cough (especially nocturnal); recurrent chest infections Reflux laryngitis/pharyngitis -> sore throat, hoarseness Regurgitation into the mouth -> sore tongue, glossitis, dental enamel damage

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CASE STUDY 15.2 A 60-YEAR-OLD MAN WITH A 3-MONTH HISTORY OF PROGRESSIVE DIFFICULTY IN SWALLOWING History A 60-year-old white Caucasian male clerical officer presented with a 3month history of progressive dysphagia. Initially the dysphagia was intermittent but it had become steadily worse, so that all solids 'stuck'. He had no difficulty in swallowing liquids. He felt food sticking in the low retrosternal area and was aware of discomfort in this area after swallowing. Over the previous 2 weeks he had regurgitated solid food after swallowing. He had become anorexic and had lost 1 stone in weight. On direct questioning he gave a history of intermittent heartburn and regurgitation for more than 10 years. These symptoms were controlled with the alginate/antacid mixture Gaviscon. He was a lifelong smoker, currently smoking 25 cigarettes a day. He had mild shortness of breath on exertion and coughed mucoid sputum first thing in the morning on most days, and had done so for several years. He was often wheezy. There was no other previous medical history and he had had no operations. He was taking a (32 agonist and beclomethasone by inhaler daily, and Gaviscon as required. He drank three pints of beer a day. There was no relevant family history. Examination He looked thin but not ill. He had a barrel chest with loss of cardiac dullness to percussion, and prolonged expiration over both lung fields on auscultation. He had no lymphadenopathy and his abdomen was normal. Investigations Haemoglobin 10.5 g/dL, MCV 70 fl, MCH 24 pg; white cell count and platelets, normal; plasma viscosity 2.00; biochemical profile normal except for serum alkaline phosphatase 150iu/L and y-glutamyl transferase 90iu/L;

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chest X ray, emphysematous changes. Question 1. What is the most likely cause of the dysphagia, and why? Is the history of heartburn arid regurgitation significant? The patient had an upper GI endoscopy which showed that the last 10cm of the oesophageal body were replaced with Barrett's oesophagus. There was an ulcerated stricture extending 2 cm above the oesophagogastric junction. The scope passed with some difficulty through the stricture. There was a hiatal hernia and the stomach and duodenum were normal. Question 2, What histological changes would you expect in the distal oesophagus and stricture? Biopsies of the distal oesophagus showed specialized columnar epithelium (intestinal metaplasia) with areas of low-grade dysplasia, and biopsies of the stricture showed highgrade dysplasia and invasive adenocarcinoma. Brush cytology of the stricture revealed adenocarcinoma cells. Questions 3. What is the treatment of choice? What further investigations are needed? Abdominal and chest CT scans showed a concentric bulky tumour above the oesophagogastric junction. There was no involvement of the aorta and no lymphadenopathy, but a single metastasis was seen in the left lobe of the liver.

Treatment The results of the CT scan showed that a curative resection was not an option; therefore, he was considered for palliation. Radiotherapy was not considered as adenocarcinomas are poorly radiosensitive. The patient did not want to be considered for chemotherapy because he felt that as the results were so poor, he wanted to enjoy his remaining life without the side-effects of chemotherapy drugs. Question 4. What are the options for palliation? Endoscopic palliation was instituted. His malignant stricture was dilated and any exophytic tumour was injected with absolute alcohol to cause necrosis. He was started on omeprazole 40 mg daily to control symptoms of reflux, a potential problem after stricture dilatation. His swallowing was satisfactory for 5 weeks, but troublesome dysphagia returned. At a second endoscopy the stricture was again dilated and the tumour injected. However, he had only 10 days of improvement in his swallowing. Therefore, an expanding covered metal stent was placed through the stricture endoscopically. Two weeks later, he had sudden onset of complete dysphagia.

Question 5. What is the most likely reason for the sudden onset of dysphagia in this situation? Urgent endoscopy showed food bolus obstruction of the stent, which was easily relieved. He was discharged the same day after seeing the dietitian for further advice. He died 4 months later without having had any more troublesome dysphagia.

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CASE STUDY 15.2 CONTINUED Latterly he had required opiate analgesia to control retrosternal chest pain and right upper quadrant abdominal pain. Discussion Dysphagia is a very important symptom which always requires investigation. In this case the dysphagia was progressive, which was suspicious of malignancy. However, other causes must be considered (see Table 15.13). There is debate as to whether the first investigation should be barium swallow or upper GI endoscopy. The patient can usually (but not always) localize the level of the obstruction accurately. Occasionally a high stricture may be associated with low dysphagia. Instrumentation of any stricture, especially a malignant one, is associated with an increased risk of perforation. Thus there is a risk that the endoscopist might perforate an unsuspected high oesophageal malignant stricture. For these reasons some specialists still insist that a barium swallow precede endoscopy. However, most endoscopists would not agree and regard a careful endoscopy by an experienced endoscopist as the appropriate first investigation of the patient with dysphagia.

This patient had Barrett's oesophagus (BO) complicated by an oesophageal adenocarcinoma. BO is a complication of long-standing gastro-oesophageal reflux (GOR): 10% of patients with endoscopic GOR have associated BO. Our patient had symptoms of GOR, namely heartburn and regurgitation, predating the development of dysphagia. Moreover, 2 agonist therapy taken for COPD will have reduced lower oesophageal sphincter tone and predisposed to GOR. BO can progress to oesophageal adenocarcinoma and 10% of BO patients have associated oesophageal adenocarcinoma at diagnosis. BO patients without carcinoma at diagnosis are offered endoscopic surveillance every 1-2 years, with multiple biopsies looking for premalignant dysplastic changes. BO is commoner in males; smoking and alcohol may be risk factors. Oesophageal adenocarcinoma has a much poorer prognosis than squamous carcinoma of the oesophagus, even if it appears operable initially. Less than 20% are deemed operable at diagnosis. The treatment options are more limited in that adenocarcinomas are less radiosensitive and respond less well to chemotherapy than do

of lower oesophageal sphincter tone and of secondary peristalsis in the oesophageal body. The initial pathological events are transient losses of lower oesophageal sphincter tone. Various other factors may predispose to reflux (Table 15.14b). Pregnancy is commonly associated with reflux, owing partly to sex hormones lowering the gastrooesophageal sphincter pressure, and partly to pressure from the intra-abdominal mass. Smoking, eating fat and chocolate, drinking coffee, tea and alcohol, and certain drugs (e.g. calcium antagonists and 2 agonists) act by reducing lower oesophageal sphincter pressure. The presence of a hiatus hernia is not necessary for reflux but is often an associated finding.

Clinical features The typical symptoms of gastro-oesophageal reflux are

squamous carcinomas. If surgery is to be considered, accurate preoperative staging with endoscopic ultrasound is increasingly thought to be essential. CT can miss local tumour infiltration of adjacent structures and local lymph node metastases. The present case was deemed inoperable because of the presence of a hepatic metastasis. If he had been a candidate for surgery the risks of the surgery would have been increased by his COPD. He would have needed preoperative lung function tests and assessment by a respiratory physician and anaesthetist. Most oesophageal adenocarcinomas are treated by palliation only. Simple dilatation with tumour destruction by laser or alcohol injection can give symptomatic relief for weeks or even months, but most patients will require stenting sooner or later. Covered metal stents require less oesophageal dilatation than do plastic stents, with a lower risk of perforation, and have a lower risk of tumour ingrowth than uncovered ones. With all stents, food bolus obstruction is a problem and all patients must receive appropriate dietary advice to minimize its occurrence.

heartburn and regurgitation; chest pain may also occur. They are often aggravated by lying down, bending or raising intra-abdominal pressure (e.g. by lifting). If reflux is complicated by oesophagitis or stricture formation, vomiting, haemorrhage, anaemia, dysphagia and pulmonary aspiration may occur. Gastro-oesophageal reflux may present with nonoesophageal symptoms (Table 15.14c).

Investigation Gastro-oesophageal reflux with typical symptoms requires little investigation. However, if the symptoms are less typical, severe, or include gastrointestinal bleeding or dysphagia, further investigation is indicated. Endoscopy is preferred, as this allows more accurate visualization of

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associated lesions (oesophagitis, ulcers, stricture formation etc.) and permits biopsies of inflamed, ulcerated or questionably malignant areas. However, endoscopy does not permit satisfactory demonstration of reflux itself; this can sometimes be achieved by a barium swallow or the ingestion of a radioisotope. Objective assessment of reflux can be obtained by placing a pH probe in the lower oesophagus and measuring falls in pH due to acid regurgitation over a 24-hour period. Manometry demonstrates the loss of lower oesophageal sphincter tone but is not necessary as a routine test.

REFLUX OESOPHAGITIS 1 Reflux oesophagitis is an inflammatory response secondary to gastro-oesophageal reflux. It can be graded into four stages: 1. Mild. Single or non-confluent areas of superficial mucosal erosions and erythema. 2. Moderate. Confluent erosions not including the whole circumference of the oesophagus. 3. Severe. Confluent erosions including the whole oesophageal circumference. 4. Complicated. Oesophagitis with additional complications, e.g. peptic ulcers, strictures.

Management Medical Obesity is frequently a major causal factor. Raising the head of the bed on blocks by 20cm or more discourages nocturnal acid regurgitation and is more satisfactory than increasing the number of pillows. The avoidance of big meals before going to bed and precipitating foods and drinks also often helps. In mild cases a mixture of alginic acid and a simple antacid is effective. In patients with persisting symptoms (e.g. Gaviscon), a 6-week course of fulldose H2-receptor antagonists (taken twice daily or all at night) or a prokinetic drug (e.g. metoclopramide or domperidone) is often effective. Prokinetic drugs increase lower oesophageal sphincter tone and gastric emptying, and H2-receptor antagonists reduce gastric acid secretion. However, there is increasing use of proton pump inhibitors as first-line therapy in all patients with persisting reflux symptoms. Proton pump inhibitors profoundly reduce hydrogen ion secretion from gastric parietal cells. In severe erosive oesophagitis or cases resistant to other therapy, proton pump inhibitors for at least 8 weeks are the treatment of choice. Relapse after stopping treatment is a problem in 30-80% of patients, who may require maintenance antacid treatment. 1 Fig. 15.5

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4 Fig. 15.8

2

Fig. 15.6

3 Fig. 15.7

SUMMARY 2 Treatment of gastro-oesophageal reflux and oesophagitis • Simple measures - Lose weight - Raise head of bed on blocks - Avoid bending • Avoid possible aetiological factors which reduce lower oesophageal sphincter pressure - Smoking - Eating fat/chocolate - Coffee/tea - Alcohol • Drugs to reduce gastric acid secretion - H 2 -receptor antagonists (cimetidine, ranitidine, famotidine, nizatidine) - Proton pump inhibitors (omeprazole, lansoprazole, pantoprazole, rabeprazoie) • Drugs to increase gastric emptying and increase lower oesophageal sphincter tone - Metoclopramide - Domperidone • Drugs to protect mucosal lining - Alginic acid containing antacid - Carbenoxolone • Drugs to neutralize gastric acid - Simple antacids • Surgery

Surgical Surgery may be indicated for the very few patients with severe symptoms of reflux unresponsive to all medical treatment. It should be considered in young patients who require maintenance acid suppression treatment to prevent relapse. Selected patients should preferably be non-obese, free of serious medical problems and under 70 years of age. Surgery involves an antireflux procedure (e.g. fundoplication) and can now be done laparoscopically. The short- and long-term results of antireflux surgery are sometimes disappointing.

HIATUS HERNIA Hiatus hernias can be congenital, in which case they usually present and are treated during childhood. Acquired hiatus hernias are often of the sliding type and result in varying lengths of the stomach being in the chest (Fig. 15.5). The rolling or paraoesophageal type is less common, and occurs when a portion of the fundus of the stomach lies anterior to the oesophagus.

Clinical features Sliding hiatus hernias may be asymptomatic or associated with symptoms of gastro-oesophageal reflux. Difficulty with swallowing suggests the presence of a complicating stricture.

symptoms of reflux as appropriate and are offered surveillance endoscopy, with multiple biopsies every 1-2 years looking for dysplastic or frank malignant changes. Patients with high-grade dysplasia or carcinoma are offered oesophagectomy. An alternative treatment for patients unfit for surgery is laser or photodynamic therapy. PPI therapy or antireflux surgery do not cause complete regression of Barrett's oesophagus, but it is possible that they prevent progression or the development of dysplasia.

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OESOPHAGEAL ULCERATION FIG. 15.5 Diagram of A normal anatomy, B sliding hiatus hernia and C rolling hiatus hernia

The symptoms of rolling hiatus hernia do not include reflux and are commonly very non-specific, such as vague upper abdominal discomfort, nausea, and fullness after eating. Complications include bleeding from gastritis or a gastric ulcer (sometimes presenting as an iron deficiency anaemia), gastric volvulus and hernial strangulation.

Peptic ulcer in the oesophagus is caused by acid reflux and may be located in squamous mucosa above the cardia or within a segment of Barrett's oesophagus in the distal oesophagus. Oesophageal ulcer may present with retrosternal pain, odynophagia, dysphagia, and overt or occult bleeding in patients who often have a history of heartburn. It is diagnosed endoscopically and must be biopsied to exclude malignancy. It is treated with a PPI for 8 weeks and healing is confirmed by repeat endoscopy. Most patients will require maintenance acid suppression after healing. Healing may be associated with stricture formation.

Investigation If a sliding hiatus hernia is large it may be seen on a chest X-ray as a retrocardiac shadow with a fluid level. Endoscopy is the diagnostic procedure of choice, allowing direct assessment of hernial size, oesophagitis and stricture formation, the taking of diagnostic biopsies and the passage of dilating bougies to treat a stricture. Alternatively, a barium swallow can be used to assess hernia size and the development of complications.

Management A sliding hiatus hernia does not require treatment but its complications, such as reflux, oesophagitis and stricture formation, do. Surgery is sometimes indicated to reduce a large rolling hernia in view of the risk of strangulation. However, as rolling hernias are often found in the very elderly, surgery may be postponed until a major complication occurs.

PEPTIC OESOPHAGEAL STRICTURE 4 Peptic oesophageal strictures are fibrous strictures which occur at the lower end of the oesophagus as a result of persistent gastro-oesophageal reflux. The main symptom is intermittent and then progressive dysphagia, first for solids and then for liquids. Patients become frightened to eat, regurgitate meals, develop increasing pain and sometimes aspiration, and as a result become anorexic and lose weight. Treatment is by the passage of dilators with the aid of an endoscope. Treatment can be repeated if symptoms recur, but many patients only require it once or every few years. Oesophageal perforation is rare. Maintenance proton pump inhibitor therapy reduces the risk of restricturing. Surgery may be indicated in younger individuals requiring frequent dilatation.

DISSECTING INTRAMURAL HAEMATOMA BARRETT'S OESOPHAGUS 2 Barrett's oesophagus is a complication of long-standing gastro-oesophageal reflux. In response to the reflux, the squamous epithelium in the distal oesophagus is replaced by a columnar epithelium which usually includes areas of intestinal metaplastic epithelium. The latter is unstable and can become dysplastic, with eventual progression to adenocarcinoma. 3 Barrett's oesophagus is discovered during the investigation of patients with reflux symptoms or complications such as ulcer or stricture. Patients are treated for

This condition typically presents with chest pain, odynophagia, dysphagia particularly for solids, and minor haematemesis. The onset of pain is usually sudden and may follow retching or a Valsalva manoeuvre. The diagnosis is made by endoscopy, when a long dark submucosal haematoma projecting into one side of the oesophageal lumen is seen. Management is conservative, with the patient being kept nil by mouth until the pain and dysphagia have settled. Conservative treatment results in complete resolution of symptoms after 1-2 weeks.

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CORROSIVE AND FOREIGN BODY INGESTION

In certain parts of the world (e.g. India and South America), strong acid or alkali solutions are commonly taken with suicidal intent. These cause severe inflammation, most commonly affecting the oesophagus, although the stomach and duodenum can also be damaged. In some patients oesophageal perforation requires urgent surgery. In patients without perforation, conservative treatment with neutralizing lavage can be successful without long-term complications, but in others a stricture develops. Gastric or duodenal strictures usually require surgical intervention. Foreign bodies (e.g. fish bones, coins) may stick in the oesophagus and cause dysphagia. Small articles can be extracted endoscopically. A bolus of food often obstructs the oesophagus of patients with benign or malignant strictures, and this can usually be treated by using the endoscope to push the bolus distal to the obstruction. When larger solid articles are swallowed and are thought likely to obstruct the bowel or cause perforation, a laparotomy should be considered.

The incidence of squamous oesophageal cancer varies greatly in different regions of the world, with a high incidence in central Asia, the Far East and Transkei (Fig. 15.6). The age-specific incidence is shown in Figure 15.7. There are also racial differences: squamous carcinoma is commoner in North American blacks than in whites.

Aetiology Possible aetiological factors in squamous cell carcinomas of the oesophagus are cigarette smoking, high alcohol intake, coeliac disease, radiation, achalasia, ingestion of strong acids and alkalis, environmental carcinogens, hot drinks, nutritional deficiencies and human papilloma virus. Squamous carcinoma is rarely preceded by histological dysplasia, which can be detected by endoscopic biopsies. Barrett's oesophagus predisposes to the development of adenocarcinomas and premalignant dysplasia may be seen. The Plummer-Vinson syndrome, which occurs in

OESOPHAGEAL TUMOURS 1 A basic classification of oesophageal tumours is shown in Table 15.15. Benign tumours are rare. Malignant tumours occur in the upper third of the oesophagus (about 15%) but are more common in the middle (about 40%) and lower thirds (45%). Half of oesophageal tumours are squamous cell in origin and half are adenocarcinomas. The incidence of adenocarcinoma is increasing, probably secondary to the increasing incidence of reflux and Barrett's oesophagus. There were 6240 deaths from carcinoma of the oesophagus in the UK in 1992. The tumours spread early by local invasion and lymphatic and bloodborne metastases.

FIG. 15.6 Areas of high incidence of oesophageal squamous carcinoma worldwide

TABLE 15.15 Basic classification of oesophageal tumours

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Class

Example

Malignant

Squamous cell carcinoma Adenocarcinoma Adenosquamous carcinoma Melanoma Sarcoma (usually leiomyosarcoma)

Benign

Leiomyoma Adenoma Cysts

1 MCQ 15.5

2 Fig. 15.9

4 Fig. 15.11

5 MCQ 15.6

3 Fig. 15.10 FIG. 15.7 Age-specific incidence of squamous carcinoma of the oesophagus in the UK

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SUMMARY 3 Symptoms and signs of oesophageal carcinoma Symptoms Dysphagia (initially solids, then liquids, then complete) Pain Weight loss Cough Acute gastrointestinal bleeding

Signs Weight loss Anaemia Enlarged cervical and supraclavicular lymph nodes Hepatomegaly

long-standing iron deficiency anaemia is, rarely, associated with postcricoid squamous carcinoma. A rare inherited syndrome of palmar hyperkeratosis (tylosis palmaris) is associated with squamous oesophageal cancer.

Clinical features Dysphagia is the main symptom of oesophageal carcinomas, and is rapidly progressive. Pain is usually retrosternal and is due to invasion into the mediastinum. A productive cough may reflect aspiration or a broncho-oesophageal fistula. Patients with adenocarcinoma may give a history suggestive of gastro-oesophageal reflux. Paraneoplastic syndromes, e.g. hypercalcaemia, may be seen in patients with squamous carcinomas. On examination, weight loss is often obvious. Anaemia usually reflects bleeding. Lymph node enlargement and hepatomegaly due to distant spread are late signs.

Investigation Patients who present with dysphagia often localize the point where food sticks, but this does not always correlate with the anatomical site of obstruction. The first investigation is a barium swallow (Fig. 15.8) 2 or an endoscopy 3 with biopsy to ascertain cell type. A chest X-ray is performed to assess mediastinal spread, and liver function tests and ultrasound are performed to detect metastases. Distant metastases, usually hepatic, are a contraindication to surgery. If curative surgery is contemplated imaging of the chest and abdomen with CT or MRI is necessary to stage the tumour. 4 Endoscopic ultrasound gives useful information about local spread.

Management The management of squamous oesophageal carcinoma (Table 15.16) is controversial because the tumours are radiosensitive and the best results after radical radiotherapy may be as good as after surgery. Surgery or radical radiotherapy may be effective in patients who are fit, with no involved nodes or metastases, but these patients make up only 30-40% of those presenting with the disease. In the upper third radiotherapy may be the preferred treatment, as radical surgical treatments are technically difficult. Surgery involves total oesophagectomy and colonic

FIG. 15.8 Barium swallow examinations A A smooth benign oesophageal stricture (white arrow) above a hiatus hernia B A typical carcinoma with a long irregular stricture narrowing the oesophageal lumen.

interposition. In the middle and lower thirds surgery is preferred to radiotherapy if the patient is fit enough. The stomach is mobilized and anastomosed to the oesophagus in the chest. Radiation may be complicated by oesophagitis and stricture, and surgery by stricture, mediastinitis and anastomotic leaks. Overall survival with either treatment is probably no better than 5%, but some surgical series report 30% survival at 5 years. Malignant stricture formation can be palliated by repeated endoscopic dilatations; when these are needed more than once every 6 weeks it is useful to insert an expanding metal stent to keep the lumen open and to allow liquidized food to pass. The stent can be placed using a fibreoptic endoscope under local or general anaesthesia, and is also useful for sealing off fistulae with bronchi or the trachea. Stents can become blocked by food and fizzy drinks, and endoscopic procedures can be used to clear the blockage. Repeated endoscopic laser treatments or absolute alcohol injections cause tumour destruction and are alternatives to stents, and can be used to deal with tumour overgrowth of a stent. Adenocarcinomas are not radiosensitive and few are amenable to curative surgery, with less than 5% 5-year survival.

ACHALASIA 5 Achalasia is a functional obstruction at the level of the lower oesophageal sphincter caused by a failure of relaxation. It results in progressive dilatation of the oesophagus proximal to the 'obstruction'. Achalasia is caused by the

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TABLE 15.16 Treatment of squamous carcinoma of the oesophagus Aim

Treatment modality

Criteria

Result

'Curative'

Radical surgery (with or without pre- or postoperative radiotherapy) Radical radiotherapy

Tumour localized to oesophagus

Less than 40% 5-year survival for squamous cell carcinoma Less good than surgery, usually reserved for elderly and infirm

Palliative

Radiotherapy Endoscopic dilatation Endoscopic intubation Endoscopic laser therapy Pain relief and general nutritional support Percutaneous endoscopic gastrostomy

Tumour localized to oesophagus Widespread local tumour; distant metastases; other medical conditions preclude surgery or radical radiotherapy

Good palliation, but few survive more than 6 months

degeneration of ganglion cells in the muscle of the mid and lower oesophagus. In the west the aetiology is obscure, although the disease is sometimes familial. In South America a similar problem occurs as a late result of destruction of the ganglion cells by the protozoon Trypanosoma cruzi (Chagas' disease; see p. 354). Pseudoachalasia may be seen in malignant disease. The symptoms and manometric characteristics are similar to those of conventional achalasia.

Clinical features and investigation Presentation is usually with intermittent but slowly progressive dysphagia for both solids and liquids. There may be associated pain, and regurgitation of food swallowed some hours before may occur; heartburn is unusual. Anorexia and weight loss may also occur and some patients develop symptoms of pulmonary aspiration. Carcinoma of the oesophagus is a rare complication of achalasia. The diagnosis is often made radiologically. A barium swallow reveals a failure of the lower oesophageal sphincter to relax, and sometimes proximal dilatation with food and fluid in the lumen (Fig. 15.9). However, the barium swallow can be normal, and therefore patients with dysphagia who have a normal swallow and endoscopy should have oesophageal manometry. Manometry confirms the diagnosis by demonstrating high lower oesophageal resting tone with poor relaxation to swallowing, associated with weak or absent peristalsis in the oesophageal body. Upper gastrointestinal endoscopy excludes mechanical obstruction at the cardia, especially malignancy, and often reveals food in the oesophagus despite a prolonged fast.

Management

FIG. 15.9 Barium swallow examination showing oesophageal achalasia There is hold-up of barium at the level of the gastro-oesophageal junction (arrow) and oesophageal dilatation and lack of contractions above. Advanced cases also have a fluid level which may be seen on a chest X-ray. 1

Achalasia may be treated with:

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Fig. 15.12

• pneumatic balloon dilatation under endoscopic control; • oesophageal myotomy (Heller's operation); • intrasphincteric botulinum toxin. All these treatments can be effective but can lead to troublesome reflux. Botulinum toxin injection has the

poorest medium-term results. Balloon dilatation has good medium- to long-term results, but if more than three dilatations are required surgery should be considered.

OTHER OESOPHAGEAL DYSMOTILITY SYNDROMES Diffuse oesophageal spasm is usually seen in the elderly and presents with retrosternal chest pain and/or dysphagia. A barium swallow shows a normal oesophagus, but the oesophagus may undergo diffuse spasm during the investigation to produce a corkscrew configuration. Manometry shows intermediate bursts of high-amplitude contractions, often unrelated to swallowing. Angina is a major differential diagnosis, but oesophageal spasm is not precipitated by exertion and stress. Treatment is also similar to that for angina, as glyceryl trinitrate sublingually (as necessary) and regular isosorbide dinitrate or nifedipine often help. In resistant cases balloon dilatation or myotomy can be considered, but the results are not as good as for achalasia. Other motility disorders. Nutcracker oesophagus and hypertensive lower oesophageal sphincter are defined manometrically, present with chest pain and dysphagia, and respond variably to nitrates, calcium channel blockers and antidepressants. Irritable oesophagus (p. 820) is seen in association with irritable bowel syndrome and manometry is usually normal.

SYSTEMIC SCLEROSIS Systemic sclerosis causes loss of oesophageal contractions (which may also occur in patients with Raynaud's phenomenon, systemic lupus erythematosus and polymyositis). Dysphagia and heartburn may occur. A barium swallow shows lack of peristalsis and hence failure of the barium to move if the patient lies flat. The gastrooesophageal sphincter may become incompetent, with consequent risk of reflux, oesophagitis and peptic stricture.

ANATOMICAL ABNORMALITIES Oesophageal diverticula are outpouchings of the oesophageal wall that can occur at three main locations: immediately above the upper oesophageal sphincter (Zenker's diverticulum, or pharyngeal pouch), midoesophagus (traction diverticulum) and immediately above the lower oesophageal sphincter (epiphrenic diverticulum). Dysphagia and regurgitation are typical symptoms of pharyngeal pouch. If symptoms become severe, corrective surgery may be necessary. Traction and epiphrenic diverticula rarely cause symptoms. Oesophageal webs are thin structures impinging a few millimetres into the lumen and consisting of mucosa and

submucosa. They occur throughout the oesophagus and can be multiple. An association with chronic iron deficiency is now rare; treatment of the latter may prevent an associated postcricoid carcinoma. Dilatation helps if dysphagia occurs. Oesophageal rings occur at the lower end of the oesophagus and contain muscle as well as mucosa and submucosa. They can be asymptomatic or present with intermittent dysphagia, which may become more common as the years pass. If symptoms are serious, endoscopic dilatation usually relieves them.

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OESOPHAGEAL INFECTIONS The most important oesophageal infections are candidiasis and herpes simplex. Both occur in patients who are immunosuppressed, e.g. patients who are receiving corticosteroids or cytotoxic drugs, or who have HIV infection or diabetes. Antibiotic treatment predisposes to candidal infections. Patients with oesophageal infections usually present with dysphagia and odynophagia. Diagnosis of candidiasis is by endoscopic demonstration of the creamy exudates on the oesophageal wall (the mouth and pharynx are often also involved) and by demonstration of the typical yeast hyphae on biopsy. Herpes simplex appears similar at endoscopy, but can be confirmed by histological demonstration of inclusion bodies in epithelial cells and by viral culture. The treatment of oesophageal candidal infection is with nystatin or amphotericin suspension, but severe or recurring attacks are treated with a systemic antifungal drug, e.g. fluconazole. Herpes simplex is treated symptomatically with local anaesthetic drinks, although acyclovir is necessary in severaly immunosuppressed patients. Herpes usually settles over 1-2 weeks.

FURTHER READING ON THE OESOPHAGUS Barham C P, Jones R L, Biddlestone L R, Hardwick R H, Shepherd N A, Barr H 1997 Photothermal ablation of Barrett's oesophagus. Endoscopic and histological evidence of squamous reepithelialisation. Gut 41:281-284. Pera M, Cameron A J, Trastek V F, Carpenter H A, Zinsmeister A R 1993 Increasing evidence of adenocarcinoma of the esophagus and esophago-gastric junction. Gastroenterology 104:510-513. El-Serag H B, Sonnenberg A 1997 Comorbid occurrence of laryngeal or pulmonary disease with esophagitis in US military veterans. Gastroenterology 113:755-760. Klinkenberg Knol E C, Festen H P M, Jansen J B M J, Lamers C B H W, Nelis F, Snel P 1994 Long term treatment for erosive esophagitis with omeprazole; efficacy and safety. Ann Intern Med 121:161-167. McDougall N I, Johnson B T, Kee F, Collins J S A, McFarland R J, Love A H G 1996 Natural history of reflux oesophagitis: a ten year follow up of its effect on patient symptomatology and quality of life. Gut 38:481-486. Katz P O, Gilbert J, Castell D O 1998 Pneumatic dilatation is effective in long term treatment for achalasia. Dig Dis Sci 43:1973-1977.

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Knyrim K, Wagner H-J, Bethge N, Keymling M, Vakil N 1993 A controlled trial of an expansile metal stent for palliation of oesophageal obstruction due to inoperable cancer. N Engl J Med 329:1302-1307. Trimble K C, Pryde A, Heading R C 1995 Lowered oesophageal sensory thresholds in patients with symptomatic but not excessive gastro-oesophageal reflux: evidence for a spectrum of visceral sensitivity in gastro-oesophageal reflux disease. Gut 37:7-12.

GASTROINTESTINAL BLEEDING ACUTE GASTROINTESTINAL BLEEDING

1

Upper gastrointestinal bleeding presenting with haematemesis (vomiting blood or altered 'coffee ground' material) and/or melaena (the passage of black tarry faeces) is a common medical emergency. In the UK it has an annual prevalence of about 50 cases per 100000 population. The different sites of gastrointestinal bleeding and approximate mortality rates in the UK are shown in Figure 15.10.

Aetiology The causes of gastrointestinal bleeding are shown in Table 15.17. Peptic ulcers, gastritis, oesophagitis Mallory-Weiss tears, varices and tumours account for the majority of cases. Bleeding may be provoked by the ingestion of alcohol, aspirin and non-steroidal anti-inflammatory drugs (NSAIDs). Corticosteroids may cause existing peptic ulcers to bleed. A Mallory-Weiss tear is a small lesion at the gastro-oesophageal junction, which usually follows vomiting and causes an episode of self-limiting bleeding. Systemic and vascular causes are rare. Occasionally patients invent the symptoms, ingest blood from outside (e.g. from animals) or deliberately break their mucosa to cause bleeding. Haematemesis is usually from a bleeding site proximal to the distal duodenum. If there is rapid intestinal transit and very severe haemorrhage, fresh blood from upper gastrointestinal lesions may be passed per rectum. Melaena is altered, partially digested blood passed per rectum. Meckel's diverticula are uncommon developmental abnormalities in the distal ileum; these frequently contain gastric acid-secreting cells, and usually present with recurrent melaena before adolescence. Angiodysplasia is increasingly recognized as a cause of melaena in the elderly. In this condition there are leashes of dilated mucosal vessels which usually occur in the ileum and right side of the colon, although any part of the gastrointestinal tract may be involved.

1 MCQ15.7 772

FIG. 15.10 Gastrointestinal bleeding: sites of origin and mortality rates in the UK A Typical values for the site of origin of gastrointestinal bleeding. B Approximate mortality rates for different causes of gastrointestinal bleeding. C Mortality rates related to age showing a rise from 60 years of age onwards.

Clinical features The history is important in diagnosis, particularly with regard to previous symptoms (e.g. dyspepsia, pain, vomiting, weight loss), past medical history (e.g. previous episodes, ulcers, liver disease) and ingestion of alcohol, aspirin, NSAIDs, warfarin and corticosteroids. Overt gastrointestinal bleeding may present with haematemesis, melaena or rectal bleeding. With severe bleeding there will be signs of shock, with a tachycardia and hypotension (particularly a postural drop in blood pressure). Anaemia suggests either acute bleeding over several days with time for haemodilution, or an underlying chronic disease which has been causing blood loss over weeks or months. Spooning of the nails (koilonychia) implies long-standing iron deficiency. Signs of chronic liver disease suggest varices as a possible aetiology. Vascular

CASE STUDY 15.3 HAEMATEMESIS AND MELAENA IN A 66-YEAR-OLD MAN History A 66-year-old white Caucasian retired postman was admitted with a 5-day history of passing black tarry stools. On the day of admission he had vomited a teacupful of dark blood. For more than 20 years he had had occasional episodes of mild epigastric pain and indigestion. The symptoms tended to occur 1 hour or so after eating and in bed at night, and were relieved with antacids. Two days before the onset of black stools he had taken ibuprofen for a sore left knee. Since then he had had severe epigastric pain. There was no other relevant history. Examination He was pale, sweaty and agitated, with a pulse of 110pm and a blood pressure of 90/50. He had epigastric tenderness to light palpation. Rectal examination revealed black stool.

Questions 1. What is the likely diagnosis? 2. What is your immediate management? 3. What tests would you arrange? Investigations Haemoglobin 9.8g/dL; red cell indices, white blood cell count and platelet count, normal. Routine biochemistry, normal except for blood urea 15.5mmol/L. Prothrombin time, normal. Upper GI endoscopy, no blood in upper gastrointestinal tract; chronic duodenal ulcer (DU) on anterior wall of duodenal cap with fresh clot; rapid urease test for H. pylori, positive at 2 hours.

Questions 4. How severe was this bleed? 5, What factors are present in this case which increase the risk of a poor outcome?

Management After initial assessment he was given oxygen and a large-bore i.v. cannula was inserted immediately, through which crystalloids were infused. A CVP line and urinary catheter were then inserted. His blood pressure improved and his urine output was good. He was transferred to a highdependency area for monitoring. As soon as it was available, he was transfused four units of blood.

Question 6. At what stage is acid suppression therapy given in acute upper GI haemorrhage?

Six hours after admission he was endoscoped, which showed a chronic DU with a stigma of recent haemorrhage. The clot was gently washed off the ulcer and the bleeding point injected with 1:1000 adrenaline (epinephrine). Afterwards he was started on omeprazole 20 mg b.d. There was no rebleeding and he was able to go home after 48 hours. He was discharged on omeprazole 20 mg b.d. for 1 month and amoxycillin 1 g b.d. and clarithromycin 500mg b.d. for 1 week; he was told to avoid aspirin and NSAIDs. On review 6 weeks later he was well. A urea breath test confirmed the eradication of H. pylori. Discussion This man gave a typical history of duodenal ulcer. He bought ibuprofen over the counter for a sore knee, with the result that the NSAID induced the ulcer to bleed. The bleed was a severe one, as the presence of tachycardia, hypotension and raised blood urea at presentation indicated. Risk factors for a possible poor outcome were haematemesis, anaemia, shock and raised blood urea at presentation, age, bleed as a result of chronic peptic ulcer and NSAID

15

ingestion. In view of the shock, oxygen was given and a CVP line and a urinary catheter were inserted. All patients who have had an acute upper GI bleed are potentially unstable, and must be monitored closely for continued bleeding and rebleeding in a high-dependency area. Upper GI endoscopy is mandatory in all cases of acute upper GI haemorrhage and should be performed after the patient has stabilized, if that occurs, and no later than 18 hours after the bleed. In practice, this means the morning after admission in most cases. Endoscopy allows identification of the source of the bleed and permits topical therapy where appropriate. In this case the ulcer showed one of the stigmata of recent haemorrhage, fresh clot, which indicates a high risk of rebleeding. This risk is reduced by injecting the bleeding point in the ulcer with adrenaline (epinephrine). Other therapies available are injection with sclerosant, heater probe coagulation and laser coagulation. There is no evidence that immediate treatment with acid suppression improves outcome, and so this can be delayed until the cause of the bleed is known. In peptic ulcer H. pylori infection is highly likely, therefore gastric antral biopsies can be taken. However, biopsies should probably not be taken if the patient is actively bleeding, and the presence of blood in the stomach can cause antral biopsies to be falsely negative for H. pylori. Although NSAID ingestion caused the duodenal ulcer to bleed, the patient clearly had a long-standing DU as indicated by the history. Therefore, the presence of H. pylori would be suspected and was confirmed at endoscopy. However, H. pylori is present in 75% of patients with NSAID-induced peptic ulcers. Because of the role of H. pylori in causing PU relapse, eradication therapy is essential and particularly so in a patient who has

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CASE STUDY 15.3 CONTINUED bled from a PU. Moreover, eradication must be confirmed by the most accurate method, a urea breath test. Failure to eradicate first time round occurs in up to 20% of well motivated patients whatever the regimen, and therefore a further

course of eradication therapy and a repeat urea breath test are required. There is no need to repeat the endoscopy in a DU patient who is asymptomatic after treatment and has had H. pylori eradication confirmed. NSAIDs should be stopped if

malformations on the face and mucous membranes of the lips or mouth suggest hereditary telangiectasia.

Investigation The most precise investigation for finding the cause of upper gastrointestinal bleeding is endoscopy. The patient should be resuscitated and endoscoped as soon as is practicable. At this stage most Mallory-Weiss tears, acute ulcers and areas of acute inflammation are obvious and the bleeding point may be identified. The presence of stigmata of recent bleeding implies a bad prognosis for ulcer rebleeding; in order of importance these include: • • • • •

a spurting artery active oozing fresh blood clot organized blood clot black spots.

The small intestine, beyond the distal duodenum and proximal to the distal terminal ileum, can be reached by enteroscopy or endoscopy during a laparotomy. Small intestinal bleeding may, however, be identified preoperatively by arteriography. Colonic bleeding may be identified by sigmoidoscopy or colonoscopy, or by arteriography if the bleeding is sufficiently profuse.

Management

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A joint medical and surgical approach to acute gastrointestinal bleeding is important. Before investigation, if there are signs of shock, a central venous pressure line and urinary catheter are essential. Blood should be given if the haemoglobin is less than lOg/dL or if there is a tachycardia or hypotension. Antisecretory drugs should be avoided in upper gastrointestinal haemorrhage until a diagnosis has been made, as there is little evidence that early use reduces operation rates or mortality. Tranexamic acid (which inhibits fibrinolysis) and octreotide (which reduces acid secretion and splanchnic blood flow) may have a role in controlling bleeding. Vasopressin is usually reserved for variceal bleeding (Ch. 16, p. 873). A management summary of acute upper gastrointestinal bleeding is shown in Table 15.18. Perendoscopic thermal coagulation, laser therapy or injection with adrenaline and

possible, and this was not a problem in the present case. However, in cases where continued NSAID therapy is necessary to control symptoms, e.g. in severe arthritis, PPIs are as effective in healing PUs as when the patient is not taking an NSAID.

sclerosants may be used on any bleeding vessels seen. Surgery is usually limited to peptic ulcer bleeding and is indicated if the bleeding is life-threatening, restarts after apparently stopping, or is persistent despite receiving 3 or more litres of blood, especially if the patient is over 60 years of age. Early surgery is indicated if there is a visible vessel at the base of an ulcer, or if an operable carcinoma is present. Surgery is best avoided in self-limiting conditions, such as Mallory-Weiss tear, and in clotting disorders or varices (Ch. 16, p. 873). The overall mortality of acute upper gastrointestinal bleeding is 5-10% with each episode. However, this relatively high mortality is mostly due to deaths in patients aged over 65 (Fig. 15.10) who have associated disorders (such as cardiovascular, pulmonary or renal diseases) rather than to exsanguination. Lower gastrointestinal haemorrhage rarely requires emergency surgery, but surgery may be necessary for the cause of the bleed (e.g. cancer or diverticular disease).

CHRONIC GASTROINTESTINAL BLEEDING Aetiology and clinical features A microcytic hypochromic anaemia is a common presentation of chronic gut blood loss. The commonest causes are shown in Table 15.19. Patients usually present with symptoms of anaemia - malaise, dyspnoea and angina. Clinical examination usually shows signs of anaemia, but the classic signs of iron deficiency (glossitis, cheilitis and koilonychia) are rare.

Investigation The purpose of investigations is to identify the site of the bleeding. Positive faecal occult blood testing indicates gastrointestinal blood loss, but bleeding may be intermittent and so false negatives can occur. False positives may occur with meat ingestion and bleeding gums. Other causes of blood loss (e.g. from the genital and urinary tracts) must be considered. In the presence of upper gastrointestinal symptoms, or if there are no specific symptoms and signs, upper gastrointestinal endoscopy is usually performed first. This may

TABLE 15.17 Causes of gastrointestinal bleeding (parentheses indicate a rare cause)

TABLE 15.18 Management guidelines for acute upper gastrointestinal haemorrhage

Causes of haematemesis Oesophagus Carcinoma Oesophagitis Peptic ulcer Varices

• Initial assessment Full history and examination after any appropriate initial resuscitation (oxygen; i.v. fluids to expand plasma volume) especially noting history of previous dyspepsia and Gl bleeds, NSAID, aspirin and corticosteroid therapy, alcohol abuse, signs of shock and liver disease. A rectal examination is essential. • High-risk patients Patients at higher risk of rebleeding or of bleed-related mortality include those aged more than 70, and those with other serious diseases, hypovolaemic shock, evidence of chronic liver disease (suggesting varices) or evidence of continued bleeding or rebleeding. • Intravenous therapy Insert a large bore i.v. cannula or, in cases of shock, a CVP cannula. Give plasma expanders until blood is ready in shocked patients. Give blood transfusion to shocked patients and to patients with a haemoglobin <10g/100mL In shocked patients insert a urinary catheter. • Blood tests Take blood for haemoglobin, prothrombin time, serum urea, electrolytes and liver function tests and for cross-match (at least 4 units of blood). • Admit to clinical area to monitor closely for continued bleeding or rebleeding. Notify on-call surgical team. • Upper Gl endoscopy is required within 18 hours of admission or earlier if the patient continues to bleed after admission. Local injection therapy is used for active bleeding sites. • Treatment depends on endoscopic findings; antacid drugs given on admission do not reduce mortality from bleeding. • Surgery is indicated in non-variceal patients if: - hypovolaemia cannot be controlled - there is evidence of rebleeding - transfusion requirements are more than 4 units in those aged over 60 and more than 8 units in those aged less than 60.

Stomach Peptic ulcer Acute erosions (often NSAID associated) Carcinoma Acute gastritis (often alcohol associated) Mallory-Weiss tear (Varices) (Other tumours) (Angiodysplasia) (Portal hypertensive gastropathy) Duodenum Peptic ulcer Duodenitis (Tumours)

Systemic causes Chronic renal failure (Thrombocytopenia) (Clotting factor deficiency) (Anticoagulant therapy) Vascular causes (Mesenteric ischaemia) (Hereditary telangiectasia) (Systemic vasculitis) Swallowed blood from oropharynx, nose and respiratory tract (Munchausen's syndrome) - symptom invented - ingested blood - self-induced

Causes of melaena Causes of haematemesis (see above) Jejunum and ileum (Meckel's diverticulum) (Angiodysplasia) (Tumours) (Crohn's disease) (Infarction of bowel) Colon Right-sided tumours Angiodysplasia (Inflammatory bowel disease) Causes of blood intermixed with stool Colon Left-sided colonic tumours (benign or malignant) Inflammatory bowel disease Diverticular disease Infective colitis Angiodysplasia Ischaemic colitis Causes of fresh blood per rectum Anus and rectum Haemorrhoids Proctitis of any cause Carcinoma of anus or rectum Crohn's disease of anus

15

Management Wherever possible, the primary cause of the bleeding is treated. The iron stores are replenished by giving oral iron in the form of ferrous sulphate, fumarate or gluconate. Oral iron can cause nausea, dyspepsia and altered bowel habit. If these side-effects develop, a lower dose or a different preparation should be tried. If the patient is unable to tolerate oral iron, a total dose infusion of intravenous iron dextran, or intramuscular doses of smaller amounts of iron sorbitol, can be used (p. 1207). Severe symptomatic anaemia may require blood transfusion; this is especially likely to occur if the primary cause cannot be found or treated successfully. If no cause is found, the patient is followed carefully and reinvestigated if the problem recurs.

THE STOMACH AND DUODENUM be combined with small bowel biopsy if there is a possibility of underlying iron malabsorption. If no abnormality is found in the upper gut, sigmoidoscopy with barium enema or colonoscopy are the next investigations. If still no cause is evident, colonoscopy (if not yet performed) and investigation of the small bowel - e.g. small bowel enema, Meckel scan (p. 755), arteriography or enteroscopy - must be considered.

Anatomy and physiology The lower end of the oesophagus and the fundus of the stomach are separated by the gastro-oesophageal sphincter at the cardia. which prevents reflux and allows the downward passage of food. The stomach is divided into three parts: fundus, body and antrum. The pyloric sphincter controls passage of gastric contents into the first part of

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TABLE 15.19 Causes of chronic occult gastrointestinal bleeding in the UK (In approximate order of frequency) • Colonic neoplasm • • • • • • • •

Duodenal ulcer Reflux oesophagitis/oesophageal ulcer Gastric ulcer NSAID or aspirin-induced erosions and gastritis Gastric carcinoma Colonic diverticular disease Meckel's diverticulum Angiodysplasia

Note: Hookworm is the commonest cause worldwide.

protects the small intestine from bacteria. The pH is kept at around 2. In humans, HC1 secretion is mainly stimulated by the hormone gastrin, which is released in response to dietary protein, gastric distension and vagal stimulation. At the level of the parietal cell the final common pathway of HC1 synthesis is K+-H+-ATPase, which pumps H+ ions into the lumen of the stomach. The interrelationships of these stimuli are shown in Figure 15.12. • Acting as a reservoir. The stomach constantly churns food into small particles. Gastric emptying proceeds slowly so that the small bowel can digest and absorb maximally. Gastric emptying is a complex process, dependent on duodenal receptors; it is, for example, slower for fats than for protein. Control is partly vagal and partly hormonal (motilin accelerates the process, whereas enteroglucagon and neurotensin slow it down). • Secretion of intrinsic factor (see p. 751). • Secretion of pepsinogen to initiate proteolysis. The duodenum is largely retroperitoneal and is divided into first, second, third and fourth parts. The pH is lowest in the first part and nearly all duodenal ulcers are sited here. The medial border of the second part of the duodenum receives alkaline biliary and pancreatic secretions. The duodenum contains Brunner's glands, which secrete bicarbonate and help bring pH towards neutral. Villi are present throughout the duodenum and increase in size down its length. Both enzyme digestion and absorption of small molecules not needing digestion (e.g. calcium, iron, folic acid) occur in the duodenum.

FIG. 15.11 Diagram showing secretion of H+ by a gastric parietal cell There are receptors on the basolateral membrane for histamine (H2), gastrin and acetylcholine, all of which can mediate the activation of second messengers. A complex series of metabolic events then occurs, with the result that H+-K+-ATPase at the apical surface pumps H+ into the gastric lumen in exchange for K+. Antagonists exist for each of the three basolateral receptors (e.g. cimetidine A , proglumide C and pirenzipine D and for H+-K+-ATPase (omeprazole). The prostaglandin E2 receptor B inhibits the stimulatory effect of histamine on cAMP; misoprostol is a PGE2 analogue.

the duodenum. Parietal cells in the fundus and body of the stomach synthesize hydrochloric acid and secrete intrinsic factor; gastrin is synthesized in the antral G cells and chief cells in the crypts secrete pepsinogens. The stomach has four main functions: • The secretion of HCl, which converts pepsinogen to pepsin to initiate protein digestion into polypeptides and

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MCQ15.8

Clinical features of gastroduodenal pathology The site of gastroduodenal pain is usually epigastric, but may radiate through to the back and to the right and left hypochondria. Duodenal ulcer pain is typically relieved by food and simple antacids. Functional (or non-ulcer) dyspepsia usually occurs at the time of maximal emotional stress and the site of pain is often poorly localized. Nausea, vomiting, anorexia and weight loss raise the possibility of luminal obstruction or a carcinoma. Bleeding can cause haematemesis and melaena. Epigastric tenderness may be present on superficial or deep palpation. An epigastric mass may be palpable, and can be difficult to distinguish from the liver. With gastric carcinoma, metastatic supraclavicular nodes and the liver may be palpable. A succussion splash, present 3 or more hours after the last drink or meal, suggests delayed gastric emptying, commonly due to pyloric obstruction. It is elicited by shaking the patient's upper abdomen while listening over the epigastrium.

Investigation of gastroduodenal pathology Upper gastrointestinal endoscopy is the preferred method

SUMMARY 4 The main symptoms, signs and investigations in the diagnosis of gastroduodenal disease

TABLE 15.20 Aetiological factors in peptic ulceration Causal factor

Gastric ulcer

Duodenal ulcer

Symptoms Pain or discomfort Site Relationship with food, drugs, stress Nausea and vomiting Haematemesis and melaena Anorexia Weight loss Heartburn Early satiety

Helicobacter pylori NSAIDs and aspirin Acid

Important important Normal or low acid output Important Important Evidence for head injuries and burns only Uncommon

Very important Important High or normal acid output Unimportant Important

Signs Tenderness Presence of an epigastric mass Succussion splash Supraclavicular lymphadenopathy Hepatomegaly

Bile retlux Smoking Stress Family history

15

Common

Investigations Endoscopy Barium meal Gastric acid secretory studies Plasma gastrin Full blood count Liver function tests

of investigation. A barium meal is reserved for patients who refuse endoscopy or who cannot swallow the endoscope. The clinical indications for measuring gastric acid secretion are to exclude a gastrinoma (when the basal acid secretion is very high) and to confirm that parietal cell innervation has been lost after a surgical vagotomy (if successful, insulin-induced hypoglycaemia no longer causes acid secretion).

PEPTIC ULCERS 1 Peptic ulcers can occur in the oesophagus (usually in association with gastro-oesophageal reflux), the stomach, the pyloric canal and the duodenum. An erosion is present when the mucosal surface is broken; ulcers are present when the muscularis mucosae is penetrated. In practice, it may be difficult to tell the difference at endoscopy. Lesions may vary in size from 1 mm to several centimetres in diameter.

Aetiology The aetiological factors in peptic ulceration are shown in Table 15.20. The aphorism 'no acid: no ulcer' is true for benign peptic ulcers. Gastric ulcers, however, are usually associated with normal or low acid outputs, although this may partly reflect duodenogastric reflux of alkaline juice. The bacterium Helicobacter pylori is present in the gastric antrum of more than 90% of duodenal ulcer patients and 75% of gastric ulcer patients, and its continued presence is related to a high rate of recurrence (90% of duodenal ulcer patients treated with H2-receptor antagonists or proton

FIG. 15.12 Incidence of peptic ulcer related to age, in the UK

pump inhibitors relapse in the first year after stopping treatment). H. pylori may also have an aetiological role in gastric ulcers. Duodenogastric reflux of alkaline juice, bile and pancreatic enzymes is thought to be important for gastric ulcers. NSAIDs and aspirin are associated with an increased incidence of peptic ulcers and of the complications of bleeding and perforation. These drugs are a particular problem in patients aged over 65. Smoking plays a role in pathogenesis and delays the healing of duodenal ulcers. The objective evidence that ordinary stress causes ulcers is poor, but severe head injuries (Cushing's ulcer) and burns (Curling's ulcer) are associated with the development of acute ulcers. Duodenal ulcers are often familial and are associated with blood group O. The factors involved in mucosal cell resistance or liability to ulceration are not understood. Other possibly important factors are gastric mucus, and gastric and duodenal bicarbonate secretion, which may have protective roles. An additional, and rare, cause of peptic ulceration is gastrinoma (p. 781). Duodenal ulcers are approximately four times as common as gastric ulcers. Whereas there appears to be a tendency for spontaneous remission with duodenal ulcers, the prevalence of gastric ulcer progressively increases with age (Fig. 15.12).

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Clinical features The symptoms and signs of ulcer disease are non-specific for each type of ulcer and commonly overlap those found in patients with cholelithiasis, oesophagitis, pancreatitis, gastric cancer and no demonstrable organic disease (nonulcer dyspepsia). Duodenal ulcer patients tend to have epigastric pain, which is worse with fasting, eased by antacids and food, and wakes them at 2-4 am. Gastric ulcer patients' epigastric pain is sometimes worse with food and relieved by vomiting. Nausea and vomiting are relatively unusual and imply outlet obstruction. Anorexia and weight loss can occur with both gastric and duodenal ulcers. Ulcers may be asymptomatic. In an uncomplicated peptic ulcer patient, epigastric tenderness is usually the only abnormal sign, and even this is often absent. If there is gastric outflow obstruction, a succussion splash may be present.

Investigation (see Fig. 15.13) Endoscopy is the procedure of choice in the diagnosis of peptic ulcers (Table 15.21 and Fig. 15.14). 1 It also enables accurate histological diagnosis of malignancy, and local treatment with injection, electrocautery or lasers as necessary. Endoscopic complications are rare, but bleeding, perforation, pulmonary aspiration, transmission of infection and excessive sedation can occur. Table 15.22 shows the methods for the diagnosis of H. pylori, which contains the enzyme urease.

Complications There are three main complications of peptic ulcers: • Gastrointestinal bleeding (p. 772) is the first symptom of a peptic ulcer in a small proportion of patients, but usually there is a variable period of preceding dyspepsia. • Perforation of an ulcer usually presents with acute severe upper abdominal pain, and circulatory collapse may rapidly develop. Specific symptoms may be minimal or absent in the elderly and in patients on corticosteroid therapy. After resuscitation, surgery should be performed to clean the peritoneum and oversew the ulcer; a procedure may also be performed to prevent further ulcers, e.g. a vagotomy with or without a drainage procedure. Rarely, surgery may be contraindicated by high anaesthetic risks. Under these circumstances the perforation will sometimes heal with conservative management. • Gastric outflow obstruction (pyloric stenosis) usually

1

778

Figs 15.13-15.16

RECENT ADVANCES IN HELICOBACTER PYLORI The major advance in gastroenterology in recent years is the understanding of the role of H. pylori in gastroduodenal disease. More than 90% of chronic duodenal ulcers and 75% of chronic gastric ulcers are associated with H. pylori antral gastritis; healing of the ulcer and eradication of the bacterium leads to very prolonged remission, if not permanent cure. Three-quarters of NSAID-associated peptic ulcers have H. pylori gastritis, but the role of the bacterium in NSAID ulcers is unclear. There is no evidence that H. pylori promotes gastro-oesophageal reflux disease. Chronic H. pylori gastritis may lead to intestinal metaplastic change in some individuals. This epithelium has malignant potential and has led to the hypothesis that H. pylori is a causative factor for gastric carcinoma. Most patients with gastric carcinoma have evidence of previous exposure to H. pylori, but definite evidence of a link is so far lacking. More than 90% of patients with gastric MALT lymphoma (B-cell lymphoma) have H. pylori in their stomachs. It has been suggested that MALT (mucosa-associated lymphoid tissue) develops in the stomach in response to H. pylori infection. There are reports that low-grade MALT lymphomas regress after H. pylori eradication without any other therapy. The complete genome sequence of a strain of H. pylori was reported in 1997. It has a circular genome of 1667867 base pairs and 1590 predicted coding sequences. It has well-developed systems for motility, for scavenging iron and for DNA restriction and modification. Many adhesins, lipoproteins and other membrane proteins showed the potential complexity of host-pathogen interaction. It was thought that the bacterium used recombination and slipped strand mispairing within repeats as mechanisms for antigenic variation and adaptive evolution. Its survival in acid depended in part on its ability to establish a positive inside membrane potential in low pH. Major implications of this discovery for clinical medicine include the ability to predict many different functions, the potential to develop strategies for new antimicrobial agents, and an insight into a range of potential vaccine candidates. The vaccine and new agents will then be tested in animals and, if appropriate, assessed in clinical trials.

follows long-standing duodenal ulcer or pyloric channel ulcer, which leads to oedema and scarring. Patients complain of vomiting food eaten many hours before. The failure of gastric emptying results in postprandial fullness, anorexia and weight loss. A succussion splash may be heard many hours after the last meal. If there is an

15

FIG. 15.13 Management plan for ulcer-like dyspepsia

TABLE 15.21 Relative merits of endoscopy and barium studies in the diagnosis of peptic ulcer Merit

Endoscopy

Barium study

Accuracy

Almost 100%

Ability to obtain biopsies and brush cytology Detection of H. pylori (by urease test) Enables other treatments (e.g. diathermy, lasers) Detection of bleeding Assessment of healing Complications

Yes

Lower, especially for superficial lesions No

Yes

No

Yes

No

Good Good Very few

Poor Poor for duodenal ulcers Very few

FIG. 15.14 Barium studies and endoscopy in diagnosis of peptic ulcer H Barium meal demonstrating a large gastric ulcer filled with barium. B Typical duodenal ulcer with pyloric stenosis. C Endoscopic appearance of a chronic prepyloric ulcer.

779

active ulcer with oedema, pyloric stenosis may respond to medical treatment alone. Otherwise, endoscopic balloon dilatation followed by proton pump inhibitor therapy and H. pylori eradication, or surgery can be considered.

Management Medical Before a definite diagnosis is made, patients can be treated with simple antacids. In standard doses these are effective symptomatically, but rarely heal ulcers. When a diagnosis is made, patients should be encouraged to give up smoking as this will improve their chance of healing and reduce relapse rate. Minimization of alcohol intake should also be encouraged. NSAIDs and aspirin should be avoided. Many effective medical treatments are now available (Table 15.23), but proton pump inhibitors are the most efficaceous drugs in terms of healing rates, speed of healing, symptom relief and speed of symptom relief. They also have anti-Helicobacter efficacy. In H. pylori-positive duodenal ulcer and gastric ulcer patients the organism should be eradicated. It is not known which is the best regimen, but regimens eradicating H. pylori in 80-90% of patients are shown in Table 15.24. If the bacterium is eradicated, ulcer recurrence is rare. More effective treatments with higher eradication rates are being sought. In H. pyloriassociated peptic ulcers the success of eradication should be confirmed by a urea breath test. For H. pylori-negative ulcers, H2-receptor or proton pump inhibitors are used and may sometimes be required for maintenance treatment. Gastric ulcers should be followed up by endoscopy at 6 weeks to check healing, and by rebiopsy to exclude a tumour if unhealed; repeat endoscopy is not necessary in duodenal ulcers. Surgical Surgery is now rarely needed for uncomplicated peptic ulcers. The indications for surgery for peptic ulcers are shown in Table 15.25. Severe haemorrhage and perforation are indications for surgery unless the patient is thought unfit for a general anaesthetic. Gastric outflow obstruction also often requires surgery, although occasionally medical treatment of an active ulcer may improve symptoms. The best current operations may be highly selective vagotomy for duodenal ulcers and Billroth I partial gastrectomy for gastric ulcers.

Complications of gastric surgery

780

Surgery for gastric and duodenal ulcers is usually successful, but in 10% of patients who have a highly selective vagotomy for a duodenal ulcer the ulcer may recur. Postoperative weight loss is a common symptom but usually

stabilizes. If a partial gastrectomy is performed, bile reflux may result and cause gastritis in the remnant. Following gastric surgery, gastric emptying into the small intestine may become very rapid. Hyperosmolar contents cause fluid to be secreted into the jejunum, the plasma compartment contracts and the haematocrit rises. This results in 'early dumping', and about 30 minutes after a meal the patient complains of sweating, palpitations, faintness and abdominal distension. These symptoms may be mediated in part by the vasomotor peptides neurotensin and vasoactive intestinal polypeptide (VIP, p. 757). The rapid emptying also results in increased early insulin secretion, so that reactive hypoglycaemia may occur 3^4 hours after a meal ('late dumping'). As a result of the

RECENT ADVANCES IN NSAIDs AND THE STOMACH AND DUODENUM

NSAIDs may cause gastric and duodenal erosions, haemorrhage and peptic ulcers. Healing is best achieved by proton pump inhibitors. The rate and success of healing of NSAID ulcers is not impaired by continuing NSAID treatment. This is not true for H2receptor antagonist treatment. Prophylactic treatment is indicated for patients who require NSAIDs but have a history of peptic ulcer, severe dyspepsia on upper GI haemorrhage. Trial data now suggest that PPIs are the most effective treatment for primary and secondary prophylaxis. The widely used misoprostil is less effective in preventing duodenal injury and frequently causes diarrhoea. There are two isoforms of the enzyme cyclooxygenase (COX). COX 1 is beneficial because it promotes the production of cytoprotective prostaglandin E2, thromboxane and prostacyclin from arachidonic acid in response to cell injury. COX 2 is harmful because it promotes the production from arachidonic acid in response to cell injury of mediators of inflammation, e.g. certain prostaglandins which are harmful to the gastroduodenum. NSAIDs block both COX 1 and COX 2. It is now realized that selective inhibition of COX 2 leads to reduced NSAID-induced gastroduodenal damage. Some NSAIDs (e.g. etodolac and meloxicam) are relatively COX 2 specific, but COX 2 inhibitors with no COX 1 effects are now available (e.g. refecoxib). Initial studies are encouraging in terms of their lack of GI sideeffects. Three-quarters of patients with NSAID-associated peptic ulcers have H. pylori in their stomachs. The relative roles of the NSAID and the bacterium remain unclear, but H. pylori should probably always be eradicated in NSAID ulcers. Nevetheless, it should be assumed that continued NSAID treatment in spite of H. pylori eradication may lead to further ulceration.

15

TABLE 15.22 Tests for diagnosis of Helicobacter pylori Test

Advantages

Disadvantages

Accuracy

Indirect tests (endoscopy not required) Helicobacter antibodies (IgG)

Single blood sample

++

14/13C urea breath test

Best test for checking eradication

Laboratory assay only as commercial bedside kits are inaccurate Remain positive at least 6 months after eradication Expensive technology

Direct (invasive) tests on gastric antral mucosa Rapid urease (CLO) test

Result in 2 hours

Can miss patchy infection High false negative rate 15% False positives due to other bacteria Can miss patchy infection Relies on pathologisfs skill and interest Can miss patchy infection Slow result

Histology Culture of bacteria in urea containing broth

+++

Antibiotic sensitivities can be determined

TABLE 15.23 Important drugs used In the treatment of peptic ulcer Healing rates Drug Antisecretory drugs H2-receptor antagonists (e.g. ranitidine 150mgb.d.: cimetidine400mgb.d.) Proton pump inhibitors e.g. omeprazole 20mgb.d., lansoprazoie30mgb.d.) Antimuscarinics* (e.g. pirenzepine 150mgb.d.) Prostaglandin analogues* (also cytoprotective) (e.g. misoprostil400ngb.d.)

DU

GU

75% (4 weeks) 60% 90% (8 weeks) 80% 95% (4 weeks) 80% 90%

Main side-effects (4 weeks) (8 weeks) (8 weeks) (8 weeks)

similar to H2-receptor antagonists

Rash, enzyme induction (cimetidine), antiandrogen effects (cimetidine) Diarrhoea, rash, headache Dry mouth Diarrhoea, abdominal pain, risk of abortion

Acid-independent therapies (?mucosal protective) Sucralfate+(lgq.d.s.) Colloidal bismuth* (e.g. Denol 240mgb.d.) Carbenoxolone* (20mgq.d.s.)

similar to H2-receptor antagonists

Constipation Black tongue and stools, bad taste in mouth Sodium retention causing hypertension and oedema

* Largely obsolete. tUsed to protect stomach in ITU. *Can be used as second-line H. pylori therapy.

rapid gastric emptying, there may be small bowel malabsorption, causing diarrhoea associated with raised faecal fat excretion (steatorrhoea). All these problems can be improved by small, regular and relatively iso-osmolar meals. After both partial and total gastrectomy some patients become deficient in iron, vitamin B12, calcium and vitamin D. A full blood count and plasma calcium, phosphate and alkaline phosphatase should be checked regularly, and lifelong vitamin supplements initiated as necessary. Adeno-carcinoma of the stomach is a risk after partial gastrectomy, particularly after 20 years.

GASTRINOMA Rarely, tumours secreting gastrin stimulate excessive gastric acid secretion, resulting in severe duodenal and upper small bowel ulceration. The primary tumours are usually in the pancreas or duodenum. Fifty per cent of tumours may be malignant, and have metastasized by the time of diagnosis. The gastrinoma syndrome (originally described by Zollinger and Ellison in 1955) is characterized by severe peptic ulceration, but 40% of patients may have diarrhoea, occasionally associated with malabsorp-

781

TABLE 15.24 Eradication treatment for Helicobacter pylori (after British National Formulary (Mf) 2001) Clarithromycin regimens (all for 7 days) Omeprazole 20mgb.d., Clarithromycin 500 mg b.d., amoxycillin 1 gb.d. (UK price £38.24) Lansoprazole 30mgb.d., Clarithromycin 500 mg b.d., amoxycillin 1 gb.d. (£35.84) Omeprazole 20mgb.d., Clarithromycin 500 mg b.d., metronidazole 400mgb.d. (£37.35) Lansoprazole 30mgb.d., Clarithromycin 500mgb.d., metronidazole 400mgb.d. (£34.95) Non-clarilhromycin regimens (all for 7 days) Omeprazole 20 mg b.d., amoxycillin 500 mg t.d.s., metronidazole 400 mg t.d.s. (£16.26) Lansoprazole SOmgb.d., amoxycillin 1 gb.d., metronidazole 400mg b.d. (£13.93) Ranitidine bismuth citrate 400 mg b.d., amoxycillin 1 gb.d., metronidazole 400 mg b.d. (£15.05) Failure of first treatment: Further course with different drugs; consider quadruple therapy for 2 weeks in resistant cases, e.g. omeprazole 40mgb.d. tetracycline 500mgq.d.s., metronidazole 400 mg t.d.s., colloidal bismuth (Denol) 1 tab q.d.s. Notes: • Highest eradication (90%) is achieved with PPI and Clarithromycin regimens. • All PPIs are probably equally good. • Metronidazole resistance is a problem in some areas. Tinidazole is an alternative. • Dual therapy is less effective than triple therapy. Triple therapy for 2 weeks may be better than for 1 week but side-effects and compliance become problems. • Tetracycline or erythromycin are alternatives for penicillin-hypersensitive patients.

782

tion of the tumour(s) is by CT scanning, arteriography and, if there is still doubt, portal venous sampling for gastrin. The tumours are usually slowly progressive, and should only be resected if they are thought to be single and nonmetastatic. The acid hypersecretion is best controlled by proton pump inhibitors (see Table 15.23).

GASTRITIS

In gastritis there are areas of inflamed red oedematous mucosa in the stomach and the diagnosis can be confirmed by biopsy. Acute Acute gastritis is commonly associated with infections, NSAIDs, alcohol or iron intake, and renal failure. It may cause dyspepsia and can present with gastric bleeding. It can be diagnosed by endoscopy, but not by a barium meal. Treatment involves removing the cause and giving simple antacids. Patients with renal disease have a poor prognosis if they bleed: prophylactic H2-receptor antagonists or proton pump inhibitors are therefore used in those with dyspeptic symptoms and/or inflammatory changes on endoscopy. Chronic Chronic gastritis may not give rise to symptoms, although occasionally it may be associated with dyspepsia. There are two types: chronic superficial and chronic atrophic. The former is usually associated with H. pylori colonization of the stomach and the latter may lead to vitamin B12 malabsorption. There is an increased incidence of gastric adenocarcinoma if atrophy or metaplasia is present.

TABLE 15.25 Indications for surgery for peptic ulcers

MENETRIERE'S DISEASE

• • • • • •

Menetriere's disease is a rare condition in which the normal gastric rugae are increased in height to 1-2 cm. The aetiology is unknown. The main problem is gastric protein loss leading to peripheral oedema (see Table 15.4). Reduced acid secretion and iron and vitamin B12 deficiency occur; occasionally a gastric ulcer develops. In some patients the condition may improve with a highprotein diet, antacid drugs or fibrinolysis inhibitors. There is a tendency to spontaneous remission. In some patients, only total gastrectomy relieves the problem. There is an increased risk of developing gastric adenocarcinoma.

Severe haemorrhage Perforation Gastric outflow obstruction Failure of healing on medical treatment (now rare) Repeated relapses despite treatment (rare if H. pylori is eradicated) Non-compliance with medical treatment

tion. The duodenal ulcers are often multiple and may be associated with perforation, bleeding and pyloric stenosis. The acid may also reflux into the oesophagus and cause oesophagitis and oesophageal strictures. About a third of the patients have a functioning parathyroid tumour causing hypercalcaemia, and adenomas also occur in the pituitary, adrenal and thyroid (multiple endocrine neoplasia type 1, see p. 833). Diagnosis is by demonstrating gastric hyperacidity and a high fasting plasma gastrin. Localiza-

DUODENITIS In duodenitis the mucosa appears inflamed, reddened and sometimes haemorrhagic. It may be seen in isolation or around ulcer craters and may follow or precede the devel-

opment of duodenal ulcers. When no break in the mucosa (i.e. ulcer) is present, histology shows acute and chronic inflammation. The relationship of duodenitis to symptoms is variable: sometimes patients are asymptomatic and sometimes they have typical ulcer symptoms. Treatment is by eradication of H. pylori, if present, and by avoiding other potential aetiological factors such as smoking, alcohol and NSAIDs. If symptoms are severe, H2receptor antagonists or proton pump inhibitors may help.

NON-ULCER DYSPEPSIA The differential diagnosis of epigastric pain is wide and is shown in Table 15.26. Non-ulcer dyspepsia is a functional disorder and is sometimes related to the irritable bowel syndrome. It is characterized by the symptoms of dyspepsia associated with negative investigations, especially endoscopy. Possible causes of non-ulcer dyspepsia can be divided into non-motility and motility associated (Table 15.27). Some patients have a history of peptic ulcer or duodenitis. Others may be found to have Helicobacter gastritis with a positive urease test. Many stressed patients develop dyspeptic symptoms (as others develop headache or diarrhoea), and hints to a psychosomatic aetiology are usually obvious from the history and examination. Non-erosive gastro-oesophageal reflux can be confirmed by the correlation between symptoms and episodes of acid or bile reflux during 24-hour oesophageal pH monitoring. Idiopathic gastroparesis is a rare cause of upper abdominal bloating and early satiety. Small intestinal and biliary tract motility disorders are causes of abdominal pain. Non-ulcer dyspepsia should be used as a positive diagnosis and an attempt should be made to define its cause. All patients should be reassured that there is no serious alternative pathology. Gastric acid suppression drugs have been shown to be effective in patients with ulcer-type reflux problems. H. pylori eradication helps a large proportion of patients with ulcer-type symptoms associated with the organism. Prokinetic agents such as metoclopramide and domperidone are particularly helpful in patients with motility symptoms, such as bloating and early satiety. Many patients with psychosomatic problems settle with reassurance and modification of lifestyle, but others require psychotropic medication such as tricyclic antidepressants and selective serotonin reuptake inhibitors.

MALIGNANT TUMOURS OF THE STOMACH: ADENOCARCINOMA There are marked geographic variations in the incidence of adenocarcinoma (Fig. 15.15). In the UK the incidence is 20 per 100000 for men and 10 per 100000 for women. The incidence of body and antral carcinomas is declining, but that for adenocarcinomas of the cardia is increasing in

TABLE 15.26 Differential diagnosis of recurring epigastric pain

15

Gastro-oesophageal reflux Peptic ulcer disease Gallstones Gastric cancer Pancreatitis (acute and chronic) Other cancer (e.g. pancreas, metastases) Drugs (e.g. aspirin, NSAIDs) Systemic disorders (e.g. hypercalcaemia) Gastroparesis Carbohydrate malabsorption (e.g. lactose) Parasites (e.g. Giardia) Non-ulcer dyspepsia

TABLE 11,27 Potential causes of non-ulcer dyspepsia Non-motility Peptic ulcer diathesis Gastritis Helicobacter pylori Bile reflux Duodenitis Augmented perception of visceral pain Psychosomatic Motility Non-erosive gastro-oesophageal reflux Idiopathic gastroparesis Small intestinal dysmotility Biliary tract dyskinesia Psychosomatic

western countries, in parallel with oesophageal adenocarcinoma. In England and Wales there were 5300 deaths each year in 1995-1997.

Aetiology and pathology Gastric carcinoma is five times more common in patients with pernicious anaemia. H. pylori is also found more frequently in patients with body and antral tumours. A common alternative is a polypoidal tumour with areas of necrosis. Other risk factors include intestinal metaplasia in the stomach, achlorhydria, previous partial gastrectomy, gastric adenomatous polyps and blood group A. It has been postulated that gastric atrophy leads to a fall in acid production, which allows colonization of the stomach with bacteria. The result of bacterial growth may be to convert dietary nitrates to nitrites, which then react with amino

783

acids in food to form 7V-nitroso compounds. These have been shown to be carcinogens in animals. The typical tumour is a diffuse infiltrating carcinoma of variable size with a rolled edge and a central ulcer. It spreads through the gastric wall, invades lymph nodes and metastasizes to the liver via the bloodstream. It may also seed into the peritoneal cavity, giving rise to abdominal and pelvic tumours and ascites. Less commonly, the tumour infiltrates diffusely through the stomach wall (linitis plastica, or 'leather bottle stomach'). Microscopically the carcinomas may resemble intestinal cells or may be diffusely infiltrating tumours. The 'intestinal' type of tumour has a better prognosis and is more frequent in areas of high incidence, such as Japan. In Japan, screening for gastric carcinoma has led to the detection of early-stage tumours limited to the mucosa or submucosa; such tumours have a good prognosis. Adenocarcinoma of the gastric cardia may be related to gastro-oesophageal reflux and the development of short segments of Barrett's oesophagus, or to H. pylori'-induced carditis.

Clinical features Gastric carcinoma is commonest in 55-65 year olds and is rare at less than 30 years of age. Typically, the patient presents with anorexia, nausea, early satiety and vague abdominal discomfort. More severe epigastric pain may develop later. Bleeding is common, leading to iron deficiency and, occasionally, frank haematemesis or melaena. There may be dysphagia if the tumour involves the gastrooesophageal junction, and vomiting if there is outflow obstruction. Non-metastatic paraneoplastic manifestations (p. 152) are unusual and include acanthosis nigricans (of which it is the commonest cause; p. 420), venous thrombosis and dermatomyositis. Physical examination may reveal evidence of weight loss, anaemia and an epigastric mass. Enlarged lymph nodes may be palpable in the supraclavicular region.

Investigation

FIG. 15.15 Gastric adenocarcinoma: incidence and mortality A Worldwide incidence per 100000. B Gastric adenocarcinoma mortality related to social class. Figures are for men aged 15-64 in England and Wales. Values for each social class are in proportion to 100, which represents all social classes combined. C Age-adjusted incidence of gastric carcinoma in England.

1

784

Fig. 15.17

The diagnosis should be suspected when dyspepsia appears for the first time in later life, and is usually made at endoscopy when an ulcer is found. It is safest to assume that every gastric ulcer is malignant until proved otherwise. Diffusely infiltrating tumours of the linitis plastica type may be missed at endoscopy and can be more easily diagnosed on a barium meal, when the stomach appears contracted and non-distensible. On barium meal the ulcerative neoplasms appear as an ulcer with irregular borders and disruption of the normal mucosal folds (Fig. 15.16). If there are no clinically evident metastases and surgery is a possible treatment, it is essential to stage the tumour further. This will include chest X-ray, liver function tests and abdominal imaging with liver ultrasound, CT or MRI and possibly endoscopic ultrasound. Tumour markers are not helpful in diagnosis 1 or management.

abdominal discomfort, nausea or gastrointestinal bleeding, and an ulcer is found on endoscopy. The histological appearances may be misinterpreted as inflammatory infiltrate and the diagnosis established only later when the disease is more florid. Gastric lymphoma is a tumour of B lymphocytes (centrocytes and centroblasts, see Ch. 23). Surgical resection may be curative in the early stages, but the prognosis with surgery alone is worse if local nodes are involved. These patients should receive combination chemotherapy following surgery. B-cell lymphomas in mucosa-associated lymphoid tissue (MALToma) may be caused by H. pylori infection and successfully treated by Helicobacter eradication alone.

15

BENIGN TUMOURS OF THE STOMACH Gastric leiomyomas Gastric leiomyomas are benign submucosal tumours which rarely become sarcomatous. They arise from the muscularis mucosae. The aetiology is unknown. In many patients they are asymptomatic, but in others may present with nonspecific features such as epigastric pain. The centre of the tumour often ulcerates and patients can present with haematemesis and melaena. In this situation, surgical resection is indicated. FIG. 15.16 Barium meal examination showing typical gastric carcinoma

Management Surgical resection is the only curative treatment for adenocarcinoma, and a total or partial gastrectomy is performed. The prognosis is directly related to stage, being good (5-year survival 55%) when the tumour is confined to the mucosa or submucosa. Only 2.5% of tumours are in this category. If the tumour has spread through the stomach wall (but no further) the survival falls to 25%; if the lymph nodes are involved few patients will survive 5 years. Overall, only 60% of patients undergoing surgery have respectable tumours, and of these only 20% will live 5 years. Chemotherapy may sometimes be helpful in palliating symptoms of metastatic disease. Radiotherapy may be helpful in the palliation of symptoms resulting from local recurrence.

MALIGNANT TUMOURS OF THE STOMACH: GASTRIC LYMPHOMA Although uncommon (less than 3% of neoplasms), gastric lymphoma is of interest because it remains localized for a considerable period and the prognosis is much better than that of gastric carcinoma. It typically presents with upper

Gastric polyps Gastric polyps are a common incidental finding at endoscopy and should always be biopsied. Hyperplastic polyps are not associated with specific symptoms, have no malignant potential, and can therefore be ignored. Adenomatous polyps may be premalignant and should be removed endoscopically or surgically. They are usually asymptomatic but can be associated with dyspepsia, gastrointestinal bleeding or gastric outflow obstruction.

FURTHER READING ON THE STOMACH AND DUODENUM Fisher R S, Parkman H P 1998 Management of nonulcer dyspepsia. N Engl J Med 339:1376-1381. Langman M J S, Weil J, Wainwright P et al 1994 Risk of bleeding peptic ulcer associated with individual non-steroidal antiinflammatory drugs. Lancet 343:1075-1078. Lau J Y W et al 1999 Endoscopic re treatment compared with surgery in patients with recurrent bleeding after initial endoscopic control of bleeding ulcers. N Engl J Med 340:751-756. Palmer K R, Choudari C P 1995 Endoscopic intervention in bleeding peptic ulcer. Gut 37:161-164. Rockall T A, Logan R F A, Devlin H B, Northfield T C 1995 Incidence of and mortality from upper gastrointestinal haemorrhage in the United Kingdom. Br Med J 311:222-226. Sayer J M, Long R G 1993 A perspective on iron deficiency anaemia. Gut 34:1297-1299. Thijs J C, Kuipers E J, van Zwet A A, Pena A S, de Graaff J 1995 Treatment of Helicobacter pylori infections. Q J Med 88:369-389. Tomb J-F et al 1997 The complete genome sequence of the gastric pathogen Helicobacter pylori. Nature 388:539-547.

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Wolfe M M, Lichtenstein D R, Singh G 1999 Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs. N Engl J Med 340:1888-1899.

THE SMALL INTESTINE The small intestine is the prime site of nutrient digestion and absorption. It is also a site of water and electrolyte secretion and consequent marked fluid fluxes.

Clinical features of small bowel disease The main symptoms and signs of small bowel diseases are shown in Table 15.28. The faeces must be examined for colour, consistency and amount, and a sigmoidoscopy performed to exclude rectal disease.

Investigation of small bowel disease Investigation of systemic effects The haemoglobin, blood film and serum vitamin B!2, folate and iron assess haematinic deficiency and hyposplenism. Raised white cell count, C-reactive protein or ESR are non-specific indicators of underlying inflammation. The albumin is measured to look for protein-losing enteropathy and nitrogen deficiency. The plasma urea and electrolytes are measured to assess renal function and hypokalaemia. A low plasma calcium usually indicates calcium deficiency, which is due in part to malabsorption of vitamin D, which is fat-soluble. This may be associated with low plasma 25-hydroxy and 1,25-dihydroxy vitamin D levels. As a consequence, there may be increased parathyroid hormone secretion (secondary hyperparathyroidism) resulting in hypophosphataemia and a rise in the plasma bone alkaline phosphatase. Abnormal liver function tests are associated with the hepatic complications of Crohn's disease. With steatorrhoea, malabsorption of the other fatsoluble vitamins (A, E and K) may lead to a low plasma vitamin A, and the prothrombin time may be prolonged owing to vitamin K deficiency. Water-soluble vitamin deficiencies are rare; thiamine can be assessed by the red cell transketolase level. Faecal weight and fat can be measured in a 3-day collection. Small intestinal function tests are discussed on page 758. Structure and function Investigations are listed in Summary Box 5. Endoscopy Upper gastrointestinal endoscopy allows visualization of the duodenum and colonoscopy permits inspection of the terminal ileum. The rest of the small bowel can be seen at

1

786

MCQ 15.9

2

Case 15.3

TABLE 15.28 Clinical features of small bowel disease Symptoms Diarrhoea - watery (due to osmotic effects of malabsorbed solutes) or to electrolyte secretion or steatorrhoeic (due to fat malabsorption) Central abdominal pain Abdominal bloating Anorexia; weight loss Sore tongue; sore mouth; mouth ulcers Bone pain Easy bruising Malaise; tiredness Ankle swelling Signs Weight loss; muscle wasting (due to anorexia or malabsorption) Abdominal tenderness; abdominal distension Anaemia (due to iron, folate or B12 deficiency) Aphthous ulceration (seen in coeliac disease, Crohn's disease and tropical sprue) Glossitis, angular stomatitis (seen in iron or B vitamin deficiencies) Finger clubbing (seen in coeliac disease and inflammatory bowel disease) Ankle oedema (due to hypoalbuminaemia as a result of anorexia, malabsorption of protein or Gl protein loss) Dehydration (due to severe watery diarrhoea) Ecchymoses (due to vitamin K malabsorption) Tetany (due to hypocalcaemia) and tender bones (as a result of vitamin D malabsorption)

SUMMARY 5 Investigation of small bowel disease Investigation of systemic effects Haemoglobin and blood film White cell count and acute phase reactants Serum vitamin B12, folate and iron status Plasma proteins Urea and electrolytes Calcium, phosphate and alkaline phosphatase Liver function tests Fat-soluble vitamin deficiency (vitamin A, D, E, K) Test of small bowel structure and function Small bowel endoscopy, histology and brush border enzyme analysis Faecal weight and fat content Absorption tests Triple-lumen tube tests for absorption and secretion Breath tests Radiology

Small bowel enema Small bowel meal Arteriography

Radioisotopes

Radiolabelled albumin for protein loss Radiolabelled white cells for sites of inflammation Radiolabelled red cells for sites of bleeding

enteroscopy, which is, however, time-consuming and rarely indicated. Radiology The small bowel can be visualized by a small bowel meal (patient drinks barium) or a tube small bowel enema (dilute barium is infused directly into the upper jejunum via a peroral tube). The former is adequate for diagnosing most diffuse mucosal disorders, but the latter is superior for demonstrating focal lesions and examining the terminal ileum. Arteriography is used to assess ischaemia and demonstrate bleeding sites. The small bowel cannot be satisfactorily imaged by ultrasound, CT or MRI. Radioisotopes Radiolabelled albumin is used to assess protein-losing enteropathy, and radiolabelled (e.g. indium) white cells are used to indicate the site of active inflammation in patients with Crohn's disease. Chromium-51 (51Cr)-labelled red cells can be used to indicate the site of small intestinal bleeding, if this is more than 1 mL blood per minute. Bile acid and vitamin B12 absorption can also be measured by the use of radioisotope (p. 759).

MALABSORPTION A simple classification of small intestinal diarrhoea is shown in Table 15.29. Osmotic diarrhoea occurs when the

luminal contents are osmotically active and draw excessive amounts of water into the small bowel. Secretory diarrhoea occurs when small intestinal water and electrolyte secretion is increased, leading to fluid loss into the gut lumen, which overcomes absorptive capacity. A number of drugs can cause malabsorption. The most severe steatorrhoea (more than 100 g fat/24 h) is seen in patients with very short small intestines or in pancreatic exocrine failure. The amount of fat malabsorption in most patients with small intestinal malabsorption is less than 40g/24h. Steatorrhoea is minimal or absent in patients with osmotic or secretory diarrhoea. Large volumes of stool (more than 1 kg/24 h) are usually seen in patients with secretory diarrhoea, and occasionally in patients with osmotic diarrhoea and in those with substantially reduced lengths of functional small intestine.

COELIAC DISEASE

15

12

Coeliac disease is also known as gluten-sensitive enteropathy or coeliac sprue. It is a genetically determined disease which requires exposure to an environmental factor (dietary gluten) for its clinical expression. The disorder results in abnormal small bowel mucosa, with loss of villi, crypt hyperplasia and infiltration with chronic inflammatory cells. The clinical syndrome and small bowel

TABLE 15,29 Classification of small intestinal diarrhoea Abnormality

Causes

Steatorrhoea

Watery stool

Other results

Upper small bowel disease

Coeliac disease Giardia etc.

+

+

Iron Folate Calcium

Osmotic diarrhoea

Disaccharidase deficiencies Magnesium salts

-

++

Secretory diarrhoea

Cholera VIP Phenolphthalein

Rapid transit

Postgastrectomy Thyrotoxicosis

+

+

Short gut

Surgery Fistula

++

++

llal dysfunction and resection

Crohn's disease Terminal ileal resection Tuberculosis

+

+

Drug-induced

Neomycin Cholestyramine Alcohol

+

±

+++

Dehydration Hypokalaemia

Vitamin B12 Bile acids

787

histology improve with the removal of dietary gluten, and return if gluten is eaten again.

Aetiology The aetiology of coeliac disease became clear at the end of World War II, when it was realized that Dutch coeliac children improved when wheat was unavailable (they subsisted on tulips and sugar-beet) but deteriorated when wheat was reintroduced into their diets. Wheat, rye, and barley glutens are toxic. During milling, bran is separated from flour. Gluten is contained in the water-insoluble portion of flour; the toxic moiety is present in an alcoholsoluble portion of gluten known as gliadin. Digestion of gliadin with pepsin and trypsin results in smaller toxic subunits. The mechanism of gluten toxicity is uncertain but past theories, such as missing intestinal peptidase, an enterocyte membrane defect and cross-reactivity with a protein produced by cells infected with adenovirus 12, are untenable. Evidence suggests that coeliac disease is a T-cell mediated enteropathy in which gluten (gliadin) activates CD 4+ Tcell lymphocytes in the lamina propria of the small intestinal mucosa. These lymphocytes damage the small intestinal mucosa by immunogenetic mechanisms related to the expression of HLA DQ2 or DQ8 molecules on immune cells. Moreover, there is evidence to suggest abnormal expression of these molecules on coeliac enterocytes, converting them into antigen-presenting cells. Ninety per cent of coeliacs have the haplotype of a variant of HLA DQ2, which is encoded by allelles HLA DQ A 1*0501 and HLA DQ B 1*0201. The remaining 10% have the haplotype HLA DQ8, which is encoded by allelles HLA DQ Al*0301 and HLA DQ Bl *0302. These allelles are located in the MHC locus on the short arm of chromosome 6. There is non-concordance for coeliac disease in some non-identical twins with identical HLA DQ haplotypes, suggesting that a non-HLA gene for susceptibility to coeliac disease must exist. The highest recorded incidence of coeliac disease is in the west of Ireland, where it is 1 in 300. In the UK the incidence is about 1 in 2000. The disease is very unusual in nonCaucasians. There is evidence that the incidence in children is falling in the UK, and this may reflect the fact that most infant feeds are now gluten free. There is a modest female preponderance. About 10% of asymptomatic first-degree relatives have the disorder.

Clinical features

788

Coeliac disease can present at any age, but there are peaks between 1 and 5 years of age and in the third and fourth decades. Typically, the disease is now diagnosed in patients found to be iron or folate deficient during investigations for non-specific symptoms. The extreme case of a cachectic, oedematous, clubbed, pigmented, dying patient with multiple vitamin deficiencies is now very rare.

The main symptoms and signs are shown in Table 15.30. In children the symptoms are often non-specific, with failure to thrive in infancy or growth retardation. Presentation in adolescence is unusual. Diarrhoea is more common in adults than in children, but is not universal and coeliacs may rarely present with constipation. Abdominal pain is usually mild. About 30% of patients have aphthous ulcers, which are usually severe and recurrent but respond to a gluten-free diet. Dermatitis herpetiformis is an itchy vesicular rash which is usually predominant on extensor surfaces such as the elbows and knees (p. 790). Coeliac disease is associated with other immune-mediated disorders such as insulin-dependent diabetes mellitus and thyroid disease. Examination is often non-contributory, with mild anaemia, weight loss, abdominal distension and diarrhoea

RECENT ADVANCES IN COELIAC DISEASE IgA class endomysial antibodies are present in the serum of 95% of adults and 100% of children with untreated coeliac disease. They are highly specific for coeliac disease and are useful for screening patients. On a strict gluten-free diet they disappear, and can be used to monitor response to the diet. The presence of these antibodies in individuals with minor small bowel mucosal abnormalities or with normal small bowel mucosa has led to the view that coeliac patients do not necessarily have severe small bowel mucosal damage. Endomysial antibodies react against tissue transglutaminase (TGase). Gliadin ingestion in coeliac patients causes gut inflammation, which leads to increased activity of TGase in small bowel mucosa. TGase effects deamidization of gliadins, which results in an epitope that binds to DQ2 and is recognized by gut-derived T cells. Therefore, TGase makes gliadin more efficiently recognized by DQ2-restricted gliadin-specific T cells, thereby modulating the activity of these cells. It is of interest that gut infections cause increased TGase activity, so could infection be a predisposing factor to the onset of coeliac disease in a genetically predisposed individual? The question arises, are endomysial antibodies involved in the aetiology of coeliac disease, or are they epiphenomena? They might appear in response to increased activity of TGase, itself a response to gliadininduced gut inflammation, and therefore be an epiphenomenon. However, the interaction between mesenchymal cells and gut epithelium is mediated by TGase and is important for maintaining normal small intestinal mucosal architecture. It is possible that antibodies to TGase interfere with this process and could therefore be a factor in the mucosal damage seen in untreated coeliac disease.

TABLE 15.30 Clinical manifestations of coeliac disease Symptoms/signs History Non-specific, e.g. malaise, anorexia Diarrhoea and steatorrhoea Weight loss Abdominal pain and bloating Aphthous ulcers Nausea and vomiting Itchy spots on extensor surfaces (dermatitis herpetiformis) Positive family history Irish background Oedema Pigmentation Tetany Bone pains; muscle weakness Bleeding tendency Night blindness In children Failure to thrive Irritability Growth failure Delayed puberty Examination Anaemia Weight loss Pigmentation Glossitis Angular cheilitis Aphthous ulcers Koilonychia Clubbing Oedema Bruising Abdominal distension Positive Chvostek's and Trousseau's signs Bone tenderness; proximal myopathy Reduced light adaptation Dermatitis herpetiformis

Mechanism Iron, folate or calcium deficiency Water, electrolyte and fat malabsorption Fat and carbohydrate malabsorption Distended bowel loops

Hypoproteinaemia

Vitamin D and calcium deficiency Vitamin K deficiency Vitamin A deficiency

Malabsorption

Iron and folate (and, rarely, vitamin B12) deficiency Malabsorption Unknown Iron and folate deficiency Gluten sensitivity and/or vitamin deficiency Iron deficiency Unknown Hypoproteinaemia Vitamin K deficiency Distended bowel loops Hypocalcaemia Osteomalacia Vitamin A deficiency

or steatorrhoea on rectal examination being the most common physical signs. Hypocalcaemia may develop relatively quickly, but bone tenderness and proximal myopathy imply long-standing hypocalcaemia with osteomalacia.

Investigations Small bowel histology The diagnosis is made by demonstrating the characteristic small bowel biopsy changes which improve on gluten withdrawal. The villi may be totally or, less commonly, partially lost (subtotal or partial villous atrophy, see Fig. 15.17). The duodenum and jejunum are predominantly affected, but in severe cases villous abnormalities may also be seen in the ileum. Subtotal villous atrophy usually indicates coeliac disease. However, in the absence of a response to a glutenfree diet and with lesser degrees of villous atrophy, conditions such as giardiasis, tropical sprue, small bowel ischaemia and gastrinoma must also be considered. Transient gluten intolerance with subtotal villous atrophy can be seen in children.

15

Haematology The most common haematological abnormality is anaemia due to iron and/or folate deficiency as a consequence of malabsorption. Folate deficiency is most reliably characterized by a low red blood cell folate, which reflects longstanding folate deficiency. Serum B12 levels are quite often low, often secondary to a defect in mucosal absorption as a result of folate deficiency. Hyposplenism is present in many patients, and Howell-Jolly bodies may be seen on the blood film. The ESR is raised in a minority of patients. Sideroblastic anaemia may occur as a result of vitamin B6 deficiency. If there is severe malabsorption of vitamin K the prothrombin time may be prolonged. Biochemistry Hypoalbuminaemia can occur and is due to protein loss from the small intestine and peptide malabsorption. Faecal fat levels are usually raised. Hypocalcaemia due to malabsorption of calcium is common, with consequent secondary hyperparathyroidism. In chronic hypocalcaemia the serum bone alkaline phosphatase rises. Some patients are vitamin D deficient, and this is best demonstrated by a low serum 25-hydroxy vitamin D. Serum vitamin A and magnesium levels may also be low. Zinc deficiency is rare. Absorption tests Absorption tests are not specific for coeliac disease. Radioisotopic fat tests can be used to screen for fat absorption and are less unpleasant for laboratory personnel, but less accurate than faecal fat estimation. Small bowel permeability tests are abnormal (p. 758). Radiology Small bowel radiology may be normal or may show nonspecific jejunal dilatation and flocculation of barium; its main value is to exclude anatomical abnormalities and inflammatory disorders (e.g. Crohn's disease). Bone radiology may show signs of osteomalacia (bone thinning and pseudofractures) and secondary hyperparathyroidism (subperiosteal erosions; see Ch. 18).

789

FIG. 15.17 Comparison of normal small bowel histology with that of a patient with coeliac disease A Photomicrograph of normal small intestinal finger-like villi with columnar surface cells. B Photomicrograph of small bowel biopsy in a patient with coeliac disease. There is total villous atrophy with complete loss of the villi, cuboidal surface cells, crypt hyperplasia and an increased number of lymphocytes.

Screening tests Whereas the diagnosis of coeliac disease requires the demonstration of villous atrophy at small bowel biopsy, some non-invasive tests can be helpful in screening patients for small bowel biopsy and in monitoring the response of coeliac patients to gluten withdrawal. IgA endomysial antibodies are present in the serum of most coeliacs (nearly 100% children, about 95% of adults) and false positives are very rare. Tests of small intestinal permeability are highly sensitive for severe villous atrophy but are not specific for coeliac disease. Antibody and permeability tests normalize as the coeliac intestine recovers on a gluten-free diet.

tional supplements. However, osteoporosis is a risk in all coeliac patients, even when there is a good response to the diet. Therefore, patients need DEXA scanning and appropriate treatment. Rarely, corticosteroids are indicated in patients who remain symptomatic and have a poor response to a strict gluten-free diet. Small bowel biopsies are repeated after 6-12 months of a gluten-free diet in all patients. Rebiopsy after a gluten challenge is required to confirm the diagnosis in children, but may not be essential in adults. For adults who are stable on a gluten-free diet an annual review is useful to check their weight and exclude deficiency states. In children, more frequent follow-up is necessary to monitor growth and development.

Management Management is with a strict gluten-free diet, avoiding flour from wheat, rye, barley and, occasionally, oats. This means the avoidance of most bread, cakes and biscuits, as well as foods where flour has been used as a thickening agent (e.g. gravy). Rice and maize can be used as substitutes. In the UK, gluten-free foods can be obtained on prescription. Such a diet allows the small bowel mucosa to return almost to normal in all children and most adults. A strict diet is essential in most cases, but in the newly diagnosed elderly patient with minor symptoms strict adherence to diet is less essential. In the UK, membership of the Coeliac Society should be encouraged. Supplements of folic acid, iron, vitamin B12, calcium, vitamin D etc. should be given to correct deficiency states. Most patients make a good response to the diet and nutri-

1

790

Figs 15.18,15.19

Development of malignancy 1 There is a greatly increased risk of developing nonHodgkin's lymphoma, which is of T-lymphocyte origin in most cases. It is usually multifocal throughout the small bowel and responds poorly to chemotherapy, with a very poor prognosis. There is also a higher incidence of adenocarcinoma of the small bowel and squamous cell carcinomas of the oesophagus and pharynx. Recent evidence suggests that a gluten-free diet may reduce the risk of lymphoma.

DERMATITIS HERPETIFORMIS Dermatitis herpetiformis is a blistering and pruritic skin eruption which particularly affects the extensor surface of the knees and elbows (p. 412). Most patients have associated small intestinal villous atrophy identical to that of coeliac disease, and may also develop other complications of coeliac disease. Histology of the skin lesions shows

blister cavities, and immunofluorescence shows IgA deposits at and just below the dermoepidermal junction (p. 411, Fig. 10.34). The rash and intestinal lesion improve with gluten withdrawal. The rash is also helped by treatment with oral dapsone.

15

BACTERIAL OVERGROWTH Aetiology Under normal circumstances the stomach and upper intestine have a low concentration of bacteria, owing to gastric acid secretion and normal small bowel motility. Greater numbers of bacteria, intermediate in amount between the jejunum and the colon, are found in the ileum. Bacterial overgrowth of the upper small bowel is associated with jejunal diverticular disease (Fig. 15.18), reduced or absent gastric acid secretion, partial gastrectomy, small bowel stasis due to strictures, systemic sclerosis, diabetic neuropathy, adhesions and fistulae from the small to the large bowel. It can also occur spontaneously in the elderly. Bacterial deconjugation and dehydroxylation of bile acids is thought to be the main mechanism of the steatorrhoea, but there is also some damage to the small intestinal mucosa.

Oral 14C glycocholate (Cholic acid + 14C glycinemam

Clinical features and investigation Patients present with weight loss, anorexia, nausea, diarrhoea (but sometimes constipation) and increased flatulence. Steatorrhoea and B12 malabsorption (resulting in red cell macrocytosis) are the commonest laboratory abnormalities. Deficiencies of iron, protein and calcium may occur. The red cell folate levels can be high because of bacterial synthesis of folic acid. The diagnosis can be confirmed by demonstrating increased numbers of bacteria in upper small bowel aspirates. This is technically difficult, however, and instead the 14 C-glycocholate breath test is often used to demonstrate early deconjugation of bile acids by bacteria (Fig. 15.18B). The diagnosis is supported by finding a high fasting breath hydrogen, which rises further after an oral glucose load. It is also important to demonstrate the cause of the overgrowth. This may be obvious from the history (such as a partial gastrectomy) or may require a small bowel enema (e.g. to show diverticular disease, systemic sclerosis or fistula formation).

Management If feasible, the underlying cause is treated, e.g. surgical correction of adhesions, fistulae and blind loops. Noncorrectable upper small bowel abnormalities, such as multiple diverticula and systemic sclerosis, have to be treated medically with broad-spectrum or anaerobe-directed antibiotics. Tetracycline, ampicillin, ciprofloxacin or metronidazole may be effective. There is a tendency for the problem to recur and cyclical antibiotic therapy can be

Disease or resection of terminal ileunm

Bacterial overgrowth in small bowel

Bile salts in colon

"C glycocholate deconjugated by bacteria in small or large bowel

"C glycine

B

"CO2in breath

FIG. 15.18 Diagnostic findings in bacterial overgrowth A Small bowel enema showing multiple small bowel diverticula. B In the normal 14C glycocholate breath test little 14C02 appears in the breath until 4-5 hours after ingestion. In the presence of small bowel bacterial overgrowth, there is early cleavage of glycine and thus an early peak of 14C02 at 1-2 hours.

indicated. If one antibiotic is ineffective another should be tried, but there is little evidence that bacterial aspirate sensitivities help in the choice of antibiotics. Deficiencies, particularly of vitamin B12, should be corrected. In severe cases there must be careful attention to nutrition, with the avoidance of dietary fats and their substitution with midchain triglycerides.

791

GIARDIASIS Giardia lamblia is a protozoon which colonizes the bowel, especially the upper small intestine, causing diarrhoea and malabsorption; it is discussed in Chapter 9 (p. 335).

TROPICAL SPRUE (POSTINFECTIVE TROPICAL MALABSORPTION) Tropical sprue is a chronic malabsorption disorder which occurs in patients who live, or have lived, in the tropics (in particular India and southeast Asia). The aetiology is uncertain, but viruses or toxin-forming coliform bacteria have been implicated in some patients. Tropical sprue results in small intestinal partial villous atrophy.

chest pain and lymphadenopathy. Intestinal symptoms such as diarrhoea, steatorrhoea, weight loss and abdominal pain occur 1-10 years later. Small bowel biopsy is diagnostic even before intestinal symptoms develop. Associated features are finger clubbing, cutaneous pigmentation, cardiac complications (such as pericarditis, myocarditis and left-sided valvular lesions) and central nervous system complications, such as depression, dementia and fits. Broad-spectrum antibiotics are rapidly effective in abolishing all the problems and are life-saving. It is generally suggested that intramuscular penicillin and streptomycin are used for 2 weeks and then replaced by tetracycline, continued for 1 year. About 30% of patients subsequently relapse, and so long-term follow-up is recommended.

LYMPHANGIECTASIA

Clinical features, investigation and management Symptoms include diarrhoea, steatorrhoea, weight loss, abdominal distension, oral ulceration with the clinical features of nutritional deficiency, and hypoproteinaemia. The diagnosis is made by demonstrating villous atrophy and malabsorption of more than one nutrient in a patient from an endemic area. If subtotal villous atrophy is present, coeliac disease must be considered. Many patients are cured by a 1-month course of oxytetracycline with folic acid and vitamin B12 supplements; any other deficiencies should be treated as necessary. The diarrhoea may be treated symptomatically with codeine phosphate or loperamide. There is a tendency to spontaneous remissions and relapses.

WHIPPLE'S DISEASE Whipple's disease is a rare multisystem disease caused by Trophyrema whippelli. The small intestine is characterized by large, foamy periodic acid-Schiff (PAS)-positive macrophages containing glycoprotein within the lamina propria. The overlying villi are distorted and upper small bowel radiology shows thickened and oedematous mucosa. The patients are often iron or folate deficient.

Primary lymphangiectasia is a rare idiopathic condition of children and young adults, associated with dilated lacteals in the villi due to hypoplasia of the lymphatics. Secondary lymphangiectasia may result from intra-abdominal malignancy or constrictive pericarditis.

Clinical features, investigation and management The most common symptom is peripheral oedema secondary to hypoproteinaemia due to protein-losing enteropathy. Diarrhoea, steatorrhoea, abdominal pain, hypocalcaemia and growth retardation occur. Protein loss leads to immunodeficiency. Diagnosis is by small bowel biopsy, which shows dilated lymphatics throughout the villi. A small bowel enema is characteristic and shows large intestinal folds, mucosal nodularity and contrast flocculation. The idiopathic variant should be treated with a low-fat diet and possibly substitution of dietary fat by mid-chain triglycerides. Occasionally only a small segment of bowel is involved, and this can be excised. Pericardectomy may result in complete resolution of the syndrome if constrictive pericarditis is the problem.

ABETALIPOPROTEINAEMIA

Clinical features, investigation and management The disease usually affects middle-aged men. Early symptoms are arthritis, fever, malaise, recurrent cough, pleuritic

1

792

Fig. 15.20

Abetalipoproteinaemia is a rare disorder, inherited as an autosomal recessive and usually presenting in childhood. Plasma betalipoproteins are absent and plasma cholesterol, triglycerides and phospholipid are low. The defect appears to be a failure of synthesis of apoprotein B, with defective transport of triglyceride from the liver and gut. The red cells are spiked acanthocytes. The patients initially have mild diarrhoea and steatorrhoea, but by 20 years of age most have developed progressive neurological deficits with peripheral neuropathy and cerebellar ataxia. A small

bowel biopsy shows cytoplasmic fatty vacuolation of the enterocytes at the apex of the villi. No treatment is known to affect the underlying problem, but a low-fat or mid-chain triglyceride diet is usually given and fat-soluble vitamin deficiencies are corrected.

SYSTEMIC SCLEROSIS 1 Systemic sclerosis (p. 1177) may affect the small bowel, causing a pseudo-obstruction syndrome with poor motility, duodenal dilatation and a distended jejunum with prominent folds. Histology shows submucosal collagen and muscle atrophy. Bacterial overgrowth often occurs. Weight loss, nausea, abdominal distension, diarrhoea and steatorrhoea occur, and colonic involvement may result in constipation. Treatment is of the nutritional deficiencies and bacterial overgrowth with antibiotics. No treatment influences the underlying disease process.

RADIATION ENTERITIS

in late childhood. Lactose is not split into its constituent monosaccharides, galactose and glucose, is not absorbed, and becomes osmotically active. Clinical features Eating dairy products (which are rich in lactose) results in loose stools, abdominal distension, borborygmi, colic and increased rectal flatus. The distension and flatus are due to colonic bacterial digestion of lactose. Symptoms may only become apparent if a colonic disorder such as ulcerative colitis develops, when there is decreased colonic fluid absorption. Most non-Caucasians have primary lactase deficiency and may suffer diarrhoea, bloating and flatulence if they eat lactose. The incidence of primary alactasia in the Caucasian population in Europe and North America is up to 20% (about 6% in the UK). Secondary lactase deficiency may also occur as a result of small bowel disease (such as coeliac disease and Crohn's disease) and during and after bowel infections. Investigation In many patients, especially where the symptoms occur following an acute infection, a response to a low-lactose diet allows a clinical diagnosis to be made. If definitive diagnosis is necessary, lactase activity is measured in a small bowel biopsy specimen. Bacterial breakdown of unabsorbed lactose in the colon results in abnormally high hydrogen excretion in the breath, so that measurement of exhaled hydrogen is an index of lactase deficiency.

Radiation enteritis usually occurs in the small intestine of patients who have undergone abdominal and pelvic irradiation. In the early phases of radiation treatment there is cell necrosis and shortening of the villi; with increasing dose, polymorphs become prominent. Oedema, collagen formation and telangiectatic blood vessels develop as longterm sequelae. During treatment, patients develop anorexia, nausea and diarrhoea; this usually settles when radiotherapy stops. Chronic complications are unusual and may follow years later. They include diarrhoea, steatorrhoea, intestinal obstruction from stricture formation, intestinal ulceration with haemorrhage or perforation, bleeding from telangiectatic vessels, fistula formation or infarction. Medical treatment of the chronic diarrhoea is unsatisfactory, but attention to diet, cholestyramine, corticosteroids and broad-spectrum antibiotics may help. Some patients require surgery for strictures but this can be hazardous.

Sucrase-isomaltase deficiency Sucrase-isomaltase deficiency is a rare enzyme deficiency which results in diarrhoea when sucrose is introduced into the diet in infancy. It responds to the elimination of sucrose, and tolerance may improve later in life. Very rarely the small intestinal glucose and galactose transport system itself is ineffective; this results in an infant with watery motions and glucose in the faeces. Treatment is by avoidance of glucose- and galactose-containing foods.

OSMOTIC DIARRHOEA

Purgative abuse

The two major causes of osmotic diarrhoea are brush border enzyme deficiencies and purgative abuse.

Brush border enzyme deficiencies Primary lactase deficiency Primary lactase deficiency is the commonest cause of osmotic diarrhoea and is an inherited deficiency of the brush border membrane enzyme, lactase. It develops

15

Management Lactose in the diet is reduced until symptoms resolve. If symptoms persist an underlying cause should be sought. The majority of patients with secondary hypolactasia can resume lactose some weeks after treatment.

The laxatives magnesium sulphate, magnesium hydroxide, magnesium carbonate and lactulose act by osmosis. Magnesium salts may be used for bowel preparation for surgery and colonoscopy, and lactulose (a synthetic disaccharide) is used for mild constipation and portosystemic encephalopathy. Patients may secretly take such drugs in excess (see also p. 823) to produce watery diarrhoea of unknown cause, but a diagnosis can be made by finding high faecal magnesium levels for the magnesium salts, and a low faecal pH for lactulose.

793

SUMMARY 6 Causes of secretory diarrhoea • Infection, e.g. cholera • Purgative abuse • Hormonal VIPoma Carcinoid syndrome Medullary carcinoma of the thyroid Gastrinoma • Bile salt malabsorption • Steatorrhoea

SECRETORY DIARRHOEA

Diarrhoea may be caused by the rapid transit of food and secretions through the small intestine. Causes include rapid gastric emptying, short bowel syndrome, enteroenteric or enterocolonic fistulae, thyrotoxicosis and the irritable bowel syndrome.

SHORT GUT

1

Under normal circumstances there is a daily flux of about 8L of water and electrolytes across the small intestinal mucosa, but only about 1L of this passes through the ileocaecal valve. Secretory diarrhoea is due to absorption being exceeded by active secretion, leading to profuse watery diarrhoea, often more than 1 kg/24 hours. The classic secretory diarrhoea is that caused by the enterotoxin of Vibrio cholerae (cholera), which stimulates adenylate cyclase. Oral rehydration solutions at up to 800mL/h are the mainstay of cholera treatment. Intestinal glucose and sodium absorption are interdependent and the solutions drive sodiumdependent glucose and water absorption. In the western world, secretory diarrhoea is usually due to a vasoactive intestinal polypeptide (VlP)-secreting tumour (p. 833) or stimulant abuse, especially phenolphthalein or castor oil (ricinoleic acid) (p. 823). Secretory diarrhoea may also occur with the carcinoid syndrome associated with small intestinal primary tumours, medullary carcinoma of the thyroid, and gastrinomas. Unabsorbed bile acids in patients with ileal resection and long-chain fatty acids in patients with Steatorrhoea can cause colonic secretion and diarrhoea.

Investigation The presence of secretory diarrhoea is suggested by the persistence of diarrhoea during fasting and a stool osmolarity similar to that of plasma. In cases of diagnostic difficulty confirmation of excess secretion is best obtained by placing a triple-lumen tube in the small intestine and measuring the absorptive and secretory response to various physiological solutions over a defined segment. Normally there is water and electrolyte absorption, but under these circumstances the solutions are further diluted by active intestinal secretion of water and electrolytes.

1

794

MCQ 15.10

DIARRHOEA DUE TO RAPID TRANSIT

Diarrhoea and malabsorption may follow small intestinal resection. This is most commonly due to Crohn's disease, ischaemia due to superior mesenteric artery occlusion, or radiation damage. The greatest problems with water and electrolyte handling occur with loss of the duodenum or upper small intestine. Heal resection leads to vitamin B12 and bile salt malabsorption (see below). Some patients can be managed by a low-fat diet with regular small meals, and isotonic glucose and electrolyte solutions to maintain hydration. If the patient continues to produce several litres of stool daily and to lose weight, long-term total parenteral nutrition must be considered.

ILEAL DYSFUNCTION AND RESECTION Heal dysfunction is most commonly seen as a result of Crohn's disease, but may also follow TB, tumours and radiation damage. These diseases often lead to ileal resection. Ileal resection following mesenteric vascular disease may be extensive.

Clinical features Ileal disease and/or resection result in vitamin B12 malabsorption and deficiency and malabsorption of bile acids, with disruption of their normal enterohepatic circulation. Bile acid malabsorption leads to: • Diarrhoea. This is the result of colonic secretion induced by the secretory effect of unabsorbed bile acids (e.g. chenodeoxycholic acid) on the colonic epithelium. • Depletion of the total body bile acid pool (if the disease or resection is extensive). This results in an increased cholesterol: bile acid ratio in the bile and the risk of gallstones. It also leads to reduced concentrations of bile acids in the jejunal lumen, with the consequence of steatorrhoea. In Steatorrhoea the unabsorbed long-chain fatty acids not only induce colonic secretion and diarrhoea, but also promote increased colonic absorption of dietary oxalate, leading to hyperoxaluria and oxalate renal stones.

Management Treatment is first of the causative disease process. Vitamin B12 deficiency is treated with an intramuscular loading dose

of 1 mg daily for 5 days; thereafter, 1 mg at 3-month intervals is adequate. Bile acid malabsorption can be assessed by giving a patient 75Se-labelled homocholic acid conjugated with taurine (75SeHCAT) and measuring whole-body retention at 7 days. Low values indicate bile acid malabsorption. Cholestyramine is an anion-exchange resin which can alleviate bile acid-induced diarrhoea by binding bile acids and reducing intracolonic free bile acid concentrations. Unfortunately, this often fails to cure the diarrhoea and results in steatorrhoea and further depletion of the bile acid pool, and hence a greater tendency to cholelithiasis. Gallstones should be treated surgically. Hyperoxaluria should be treated with a low-oxalate diet, which includes avoiding fruits such as strawberries; surgical treatment may be necessary for renal stones.

DRUG-INDUCED MALABSORPTION Numerous drugs have been implicated (Table 15.31); the effects are all dose related and reversible.

SMALL BOWEL ISCHAEMIA Aetiology

Aetiological factors in small intestinal ischaemia are shown in Table 15.32; experimentally, venous occlusion can cause infarction but it is not known whether this is the case in humans.

Clinical features and management Small bowel ischaemia may present acutely, with gut infarction following occlusion of the coeliac and superior mesenteric arteries, or chronically, with postprandial pain and weight loss.

15

Acute ischaemia Acute ischaemia presents with pain, diarrhoea, vomiting and an acute abdomen. The patient should be resuscitated with fluids and treated with antibiotics and urgent laparotomy performed. At operation, an attempt is made to restore patency to embolized or thrombosed major arteries, and all non-viable bowel is resected. The mortality is high and, if a large proportion of the upper jejunum and/or duodenum is removed, the patient has severe malabsorption, often with profuse diarrhoea. Such patients may require long-term total parenteral nutrition. Chronic ischaemia Chronic ischaemia is usually due to atheroma and, if undiagnosed, may progress to acute ischaemia. The patient is usually a middle-aged or elderly smoker with evidence of atheroma elsewhere, who complains of severe colicky abdominal pain after eating ('intestinal angina'). This may be relieved by analgesics or vasodilating drugs. Weight loss follows, due mainly to a fear of eating, but malabsorption may also occur. Examination is relatively unhelpful but intra-abdominal bruits may be audible. Investigation is by arteriography, which shows a localized narrowing at the origin of at least two of the major arteries off the aorta. Reconstruction of stenoses can help some patients.

SMALL BOWEL TUMOURS TABLE 15.31 Examples of drugs causing diarrhoea and malabsorption Drug

Mechanism of action

Cholestyramine

Binds bile acids

Steatorrhoea Gallstones Malabsorption of fat-soluble vitamins

Colchicine and cytotoxic drugs Neomycin

Arrest enterocyte mitosis Causes partial villous atrophy and enzyme inhibition

Diarrhoea

Methyldopa

Causes partial villous atrophy Binds with tetracycline

Ferrous sulphate Ethanol

Damage to enterocyte subcellular organelles

Result

Steatorrhoea Iron, vitamin B12 and glucose malabsorption Steatorrhoea Malabsorption of both drugs Folate deficiency and Steatorrhoea

Despite its long length, the small intestine is the site of less than 1% of all malignant tumours and less than 5% of gastrointestinal neoplasms. Malignant tumours occur more frequently in the duodenum and jejunum, and benign lesions, such as leiomyomas and adenomas, in the jejunum. Small bowel malignancy is more common in patients with coeliac disease, Crohn's disease and Gardner's syndrome (p. 800). The commonest tumours are adenocarcinomas (50%), carcinoid tumours (30%), lymphomas (15%) and sarcomas (5%).

TABLE 15.32 Aetiology of small • • • • • •

bowel ischaemia

Arterial atheroma Arterial thrombosis Arterial emboli (usually from the heart) Vasculitis due to collagen disorders External compression of arteries (e.g. tumours, aneurysms) ? Venous thrombosis

795

TABLE 15.33 Features of gut carci no ids according to embryological origin Embryological origin

Usual primary site

Principal active substance

Diagnosis

Treatment

Foregut

Stomach

Histamine 5-hydroxytryptophan

Normal or raised urinary 5-HIAA

Surgery H1 and H2-receptor antagonists

Mid-gut

Terminal ileum

5-hydroxytryptamine

Raised urinary 5-HIAA

Surgery Cyproheptadine, methysergide and somatostatin Embolization of hepatic metastases

Hind-gut

Colon and rectum

None

Histology

Surgery only

Adenocarcinomas Aetiology and pathology The tumours usually occur in the upper small bowel and are more common in patients with coeliac and Crohn's disease. They present as ulcerating obstructing neoplasms and metastasize to regional lymph nodes and the liver. Clinical features and investigation Patients usually present with abdominal pain, and intussusception may occur. Chronic blood loss is frequent and there may be melaena. The diagnosis can sometimes be made by small bowel enema and, occasionally, endoscopically (if in the duodenum) or by colonoscopy (if in the terminal ileum). Management Surgical excision is the treatment of choice but only 70% are resectable. The regional lymph nodes are resected where possible. Metastatic lesions respond poorly to cytotoxic chemotherapy.

Carcinoid tumours 1 Gut carcinoid tumours are rare; their behaviour is to some extent dependent on the part of the gut from which they are embryologically derived (Table 15.33). Histology shows sheets of neuroendocrine cells which are usually of low-grade malignancy. Immunocytochemistry shows positive silver staining for amines, and midgut tumours are often also positive for gut-regulatory peptides such as neurotensin. Foregut tumours usually originate in the stomach and predominantly secrete histamine. Appendiceal carcinoid tumours are commonly found in appendicectomy specimens but do not metastasize or cause clinical problems. Terminal ileal carcinoids are those most likely to metastasize. They

1 796

MCQ 15.11

2

MCQ 15.12

cause the carcinoid syndrome and predominantly secrete 5-hydroxytryptamine. Hindgut tumours do not produce the syndrome and behave similarly to colonic adenocarcinomas.

Carcinoid syndrome Aetiology The carcinoid syndrome only occurs when the liver is bypassed and cannot metabolize tumour products. Symptoms therefore arise when there are hepatic metastases which drain direct into the hepatic vein. Symptoms can also be seen in the absence of hepatic metastases with primary pulmonary, testicular and ovarian tumours whose venous drainage is directly into the systemic circulation. Clinical features The most characteristic symptom of the carcinoid syndrome is a brick-red flush, usually of the face and upper trunk. Provoking agents include stress (via noradrenaline), alcohol and food (possibly via gastrin). Other symptoms include secretory diarrhoea, weight loss, wheezing, dyspnoea and right hypochondrial pain. This is due to the marked hepatomegaly which is usually the main clinical sign. Fibrosis of right heart valves (giving both stenosis and regurgitation) may be present. Midgut carcinoid tumours produce large amounts of 5hydroxytryptamine (5-HT, serotonin; see Table 15.34). This substance is thought to play a part in the pathogenesis of carcinoid syndrome symptoms, such as flushing and diarrhoea. Foregut tumours may secrete histamine and 5-hydroxytryptophan, producing a pink, weal-like flush which may itch and migrate. Pellagra due to nicotinic acid deficiency (resulting from tryptophan consumption by the tumour) may occur. The cause of the right-sided cardiac fibrosis is unknown, but serotonin has been suggested as a possibility. Investigation Functioning carcinoid tumours can be diagnosed by demonstrating raised 24-hour urinary 5-HIAA levels or by whole blood 5-HT. If the diagnosis is confirmed by urine 5-HIAA, but no liver metastases are demonstrable, a bronchial carcinoid should be suspected.

TABLE 15.34 Biochemical pathway for the synthesis and degradation of 5-hydroxytryptamine Tryptophan 5-hydroxytryptophan 5-hydroxytryptamine (5-HT, serotonin) 5-hydroxyindole acetaldehyde 5-hydroxyindole acetic acid* (5-HIAA) * 24-hour urinary 5-HIAA levels are raised in midgut and foregut carcinoids

Management Surgical removal of primary tumours may be helpful, but is rarely so in patients with terminal ileal tumours, where the primaries are usually small and multiple. Symptoms of the carcinoid syndrome may be controlled by 5-HT antagonists such as cyproheptadine. Methysergide, also a 5-HT antagonist, has the disadvantage of causing retroperitoneal fibrosis. The symptoms of histamine-producing gastric carcinoids can be blocked by a combination of H1and H2-receptor antagonists. Somatostatin or its analogues prevents flushing and diarrhoea, presumably by inhibiting the release of provoking agents from carcinoid cells. Diarrhoea may be helped by loperamide and codeine phosphate. Pellagra responds to large doses of nicotinamide. There is no definite role for cytotoxic drugs or radiotherapy, but hepatic arterial catheterization and embolization or surgical tumour debulking may help. In a carcinoid crisis, when the flushing is so severe that arterial hypotension develops, corticosteroids and plasma volume expansion may be necessary.

Lymphomas Lymphomas are the commonest gut tumours in children and a rare small bowel tumour in adults. Aetiology In the west most cases of primary lymphoma arise without any known predisposing cause, but coeliac disease may be complicated by a T-cell lymphoma. In the Middle East, immune proliferative disease of the small intestine, of unknown aetiology, frequently develops into a nonHodgkin's B-cell lymphoma which secretes free -heavy chains (Mediterranean lymphoma). Most cases in the west are non-Hodgkin's B-cell lymphomas. The histology usually shows diffuse infiltration of the bowel wall; nodular forms are rare. The lower small bowel is most frequently involved. The disease spreads early to involve local nodes, but distant dissemination is late. In the late stages of the disease extraintestinal lymphoma can spread to involve the gut.

Clinical features Presentation is often with subacute intestinal obstruction. Bleeding may occur and is usually chronic. Perforation is not unusual. When extensive, the disease may present as a fever of unknown origin.

15

Management The main treatment of primary lymphoma in the west is surgical resection. Further treatment is not required if there is no evidence of spread, but involvement of nodes or distant spread are indications for intensive combination chemotherapy. Local recurrences may respond to radiotherapy. In childhood the risk of CNS involvement is small, in contrast to other childhood lymphomas. The prognosis of localized resected gut lymphoma is good, with over 60% of patients alive at 5 years. It is not yet clear what impact modern chemotherapy will have on survival in more advanced cases. Malignant lymphoma complicating coeliac disease has a poor prognosis.

FURTHER READING ON THE SMALL INTESTINE Davies G R, Benson M J, Gertner D J, Van Someren R M N, Rampton D S, Swain C P 1995 Diagnostic and therapeutic push type enteroscopy in clinical use. Gut 37:346-352. Dieterich W et al 1997 Identification of tissue transglutaminase as the autoantigen of coeliac disease. Nature Med 3:797-801. Fredricks D N, Relman D A 1997 Cultivation of Whipple bacillus: the irony and the ecstasy. Lancet 350:1262-1263. Mustalahti K, Collin P, Sievanen H, Salmi J, Maki M 1999 Osteopenia in patients with clinically silent coeliac disease warrants screening. Lancet 354:744-745. Sulkanen S et al 1998 Tissue transglutaminase autoantibody enzyme-linked immunosorbent assay in detecting coeliac disease. Gastroenterology 115:1322-1328.

COLORECTAL DISEASE The colon and rectum act to reduce up to 1500 mL of fluid material per day, which passes through the ileocaecal valve to create a formed stool of 50-200 g. Important symptoms of colorectal disease are constipation, diarrhoea, blood per rectum, tenesmus, colicky abdominal pain and the symptoms of iron deficiency anaemia. Important signs are abdominal masses and abnormalities on rectal examination. Radiologically, the rectum and colon can be visualized by plain abdominal X-ray and double-contrast barium enema. Endoscopically the rigid sigmoidoscope, flexible fibreoptic sigmoidoscope and flexible fibreoptic colonoscope are used to view the mucosa directly and to take biopsies.

CONSTIPATION 2 The normal person opens their bowels with a frequency between two to three times a day and once every 2-3 days.

797

The normal daily stool weight in the west is 50-200 g, but up to 500 g is common in countries where a much higher fibre intake is consumed. Constipation can be considered to be present when defecation is twice a week or less and is associated with straining, although some patients may be constipated but pass hard faecal pellets several times a day after straining. Constipation is a common complaint in the western world, and vast quantities of laxatives are purchased annually to treat the symptom.

Aetiology and diagnosis Constipation is commoner in women than men and is often due to slow transit through the caecum and ascending colon. Patients often complain of alternating diarrhoea and constipation, where the underlying problem is constipation. In patients under 30 with mild symptoms investigation beyond a sigmoidoscopy is usually not indicated. Some of the many causes of constipation are listed in Table 15.35. Slow-transit constipation is a diagnosis of

exclusion where there is no cause other than a low-fibre diet. Constipation is common in old age, when impaired colonic muscle function may contribute to the problem. Anorectal problems are associated with constipation because the patient delays defecating to avoid pain. Some patients with obstructive defecation contract their anal musculature when it should relax. This problem can be associated with a past history of child abuse. Inflammatory proctitis may result in faecal loading proximal to the inflamed mucosa (best seen on plain abdominal X-ray); the patient usually complains of passing small amounts of faeces frequently. Hypothyroidism, hypopituitarism and hypercalcaemia may have constipation as one of their earliest features. A careful drug history should be taken. Peripheral and central nervous system diseases (apart from Hirschsprung's, which usually presents in early childhood) commonly have obvious manifestations before constipation develops. Constipation may be the presenting symptom of depression. In difficult cases colonic transit studies, using the Shapes' test, and proctography, which assesses anorectal coordination with X-ray screening, can be helpful in determining the physiological abnormality.

TABLE 15.35 Causes of constipation Slow-transit constipation Colonic obstruction Tumours Encarceration in hernias Volvulus Abnormal muscle function Old age Irritable bowel syndrome Diverticular disease Crohn's and ulcerative colitis Ischaemic colitis Systemic sclerosis Hirschsprung's disease Anorectal problems Ulcerative proctitis Anal tissure Thrombosed haemorrhoid Obstructed defaecation Neuropsychiatric disorders Depression Spinal cord injury Cauda equina lesions Multiple sclerosis Parkinson's disease Cerebral tumours Cerebrovascular accidents Anorexia nervosa

1

798

Fig. 15.21

Drugs Anticholinergics Antidepressants Anticonvulsants Antacids (aluminium and calcium salts) Diuretics Opiate analgesics Iron Metabolic and endocrine problems Diabetes Hypothyroidism Hypercalcaemia Pregnancy Uraemia Fever Hypokalaemia Porphyria Lead poisoning Proximal gastrointestinal disease Gastric carcinoma Reduced food intake

Management Wherever possible, the underlying cause of constipation is treated. In slow-transit constipation and where a lowresidue diet is being consumed, a high-fibre diet should be recommended. Patients should be encouraged to drink plenty of fluids and to take regular exercise. Diet sheets and the advice of a dietitian can be useful, particularly in men (Table 15.36). Bran is the best source of fibre as it absorbs a large amount of water and allows the passage of larger amounts of soft stool. Beans, dried fruits, some nuts and pasta also contain large amounts of fibre, and fruit and vegetables contain non-absorbable polysaccharides, such as cellulose and pectins, which are useful. Patients with obstructive defecation can be treated with relaxation and biofeedback, when they are taught to relax their anus during defecation. An approach to the treatment of constipation is summarized in Figure 15.20. Severe constipation is defined as opening the bowels less than once a week. Pharmacological preparations of bulk-forming agents such as methylcellulose, isphaghula husk, sterculia and, possibly, guar are helpful if patients cannot remedy the situation by diet alone. Osmotic laxatives such as the disaccharide lactulose, or magnesium sulphate or hydroxide, can be useful. If possible, the stimulant laxatives which increase intestinal motility (e.g. senna, cascara, castor oil, bisacodyl, docusate sodium and danthron) should be avoided, as it is thought they can cause ganglion degeneration and an acquired megacolon, thereby perpetuating constipation. Stimulant laxatives also tend to cause abdominal colic and hypokalaemia. Faecal softeners (e.g. liquid paraffin and dioctyl sodium sulphosuccinate) have a short-term role in softening stool in the presence of anal disease.

TABLE 15.36 Dietary fibre content of foods Fibre content

g fibre/100 g food

High (more than 10g/100g food) Bran Partially purified bran Haricot and kidney beans Dried apricots Desiccated coconut Almonds Potato crisps Lentils Spaghetti, macaroni, lasagne

44.0 26.7 25.0 24.0 23.5 14.3 11.9 11.7 10.0

Medium (5-1 Og/100 g food) Wholemeal bread Peas Peanuts Raspberries Muesli Sultanas Chestnuts Spinach

8.5 7.8 7.6 7.4 7.4 7.0 6.8 6.0

Low (below 5g/100g food) Cornflakes White bread Boiled potato White rice Cauliflower Lettuce Jam Grapes

3.0 2.7 2.4 2.4 1.8 1.5 1.1 0.9

reflex on anorectal manometry, and a megacolon above the narrow aganglionic segment on barium enema. Treatment is surgical, with an extended internal sphincterotomy or myectomy for short-segment disease or a resection of the aganglionic segment with anastomosis of normal colon to the anorectum (e.g. Duhamel's procedure) for longersegment disease.

15

Idiopathic meg a rectum and colon Rarely, patients can present with long-standing severe constipation due to a grossly dilated rectum or colon. Rectal examination and plain abdominal X-ray show large bowel distended by large amounts of solid faeces. Treatment is with laxatives (see Fig. 15.19) and sometimes with surgical excision.

Chagas' disease Chagas' disease is endemic in South America and is due to infection with the protozoon Trypanosoma cruzi (p. 354). Chronic myocarditis, megaoesophagus and megacolon are late symptoms of the disease. Destruction of the ganglia produces a dilated and atonic colon. Treatment is with bulking agents and laxatives, but occasionally panproctocolectomy and ileostomy may be necessary.

BENIGN TUMOURS OF THE LARGE BOWEL Neuropathic colon

Large bowel polyps

Neuropathic colon occurs as a result of a loss of Auerbach's and Meissner's plexuses, along with the associated intrinsic neurons. This results in failure of colonic motility and constipation.

Some polyps may progress to carcinomas, and early diagnosis and removal therefore has the potential to prevent colonic carcinoma. Colonoscopes allow the passage of wire snares which can be pulled tight around the stalk of polyps; a diathermy current can then be passed through the polyp, enabling its removal. Many laparotomies have been avoided by the use of this technique.

Hirschsprung's disease (congenital colonic aganglionosis) In this familial disorder, which occurs in about 1 in 4500 live births, the ganglion cells of the neural plexus of the colonic wall are absent. The loss extends for a variable length from the anal margin. In two-thirds of patients the rectum and sigmoid colon are involved, but much shorter segments, the whole colon or, rarely, the whole intestinal tract may be involved. Most cases present in childhood, either with acute intestinal obstruction in the neonatal period or with chronic constipation in later childhood. Occasionally the disorder can present in adults - even in those past middle age - but all will have a history of constipation dating back to childhood. Some, but not all, of these adults will have short or ultrashort segments of aganglionosis. Diagnosis is made by the demonstration of aganglionosis and hypertrophic nerve fibres in the neural plexus on rectal biopsy, an absent rectosphincteric inhibitory

Classification A classification of colonic polyps is shown in Table 15.37. Colonic carcinoid tumours are relatively rare and do not produce biologically active amines or peptides. Metaplastic polyps are usually small (<1 cm), whereas adenomas may grow to several centimetres in diameter. Small adenomatous and metaplastic polyps cannot be differentiated visually and, as subsequent management is different, all polyps must be assessed histologically. Inflammatory polyps are islands of regenerating mucosa which occur with severe ulcerative or Crohn's colitis. Hamartomas are heaped-up areas of normal tissue arranged in a disorganized way; they are commonest in children but may be seen in patients of any age. Peutz-Jeghers syndrome is a dominantly inherited disease associated with pigmentation of the skin and mucous membranes, O and

799

FIG. 15.19 Treatment of constipation (After Gattuso & Kamm 1993 Alimentary Pharmacology and Therapeutics 7: 487-500)

hamartomatous polyps in the stomach and small and large intestines. These polyps only rarely undergo malignant change. Clinical features and investigation Many polyps are asymptomatic. When symptoms do occur, the most common is the passage of blood per rectum; altered bowel habit, colicky abdominal pain and, rarely, anorexia and weight loss may also be seen. For nonmalignant polyps the only physical signs are anaemia due to blood loss or mucocutaneous pigmentation (in PeutzJeghers syndrome). A double-contrast barium enema shows most polyps (Fig. 15.20). Colonoscopy is performed when the barium enema is equivocal, and is also essential for biopsy and treatment. If dysplastic or frankly malignant polyps are removed, long-term colonoscopic follow-up is required.

Familial adenpmatous polyposis (polyposis coli) Familial adenomatous polyposis is an autosomal dominantly inherited condition in which affected individuals develop multiple (usually more than 100) adenomatous colonic polyps. A variant of this condition, associated with epidermoid cysts and osteomas, is known as Gardner's syndrome. Most patients develop carcinomatous change in their polyps before the age of 40. Panproctocolectomy with ileostomy formation, or ileoanal anastomosis with a pelvic ileal pouch, is therefore recommended in affected individuals in their late teens. Family screening for affected siblings is essential and genetic markers will soon be available (see Recent Advances box, p. 802). Some patients also develop adenomas of their small intestine and stomach, and these may rarely become malignant. Periampullary carcinoma is an important complication.

CARCINOMA OF THE LARGE BOWEL O 1 800

MCQ 15.13

Colorectal carcinoma is primarily a disease of western Europe, Australasia and North America. Carcinoma of the

15

FIG. 15.21 Age-specific incidence of carcinoma of the large bowel in the western world

FIG. 15.20 Demonstration of colonic polyps Double-contrast barium enema showing many small colonic polyps.

syndrome, both of which are inherited as autosomal dominant traits, and in some other patients (e.g. familial adenomatous polyposis and hereditary non-polyposis colorectal cancer). Adenomatous polyps and ulcerative and Crohn's colitis are well established precursors.

Pathology TABLE 15.37 Histological classification of colonic polyps Potentially malignant

No malignant potential

Adenomas Tubular Villous Tubulovillous

Metaplastic (hyperplastic) polyps

Carcinoid Hamartomas Peutz-Jeghers Juvenile

Connective tissue polyps Lipomas Fibromas Leiomyomas Inflammatory Ulcerative colitis Crohn's disease

colon affects the sexes equally (Fig. 15.21) but carcinoma of the rectum has a higher incidence in men. There were 19625 deaths from carcinoma of the colon in the UK in 1992, and it is therefore second only to carcinoma of the bronchus as a cause of death from malignant disease.

Aetiology The aetiology is unknown, although clearly there are factors associated with a western lifestyle. For example, the incidence is low in Japan but higher in Japanese who have moved to the USA. Diet has been implicated, but its role is controversial. Increasing dietary calcium and the ingestion of non-steroidal anti-inflammatory drugs and aspirin, but not increasing dietary fibre, appear to have protective effects. Altered colonic bacterial flora and changes in bile acid secretion may be important in pathogenesis. Genetic factors are important in familial polyposis and Gardner's

The pathology is a malignant epithelial tumour of the rectum or colon. Macroscopically there are three main appearances: polypoid, ulcerative and annular lesions. The primary site is most commonly the rectum, followed by the sigmoid colon and the right side of the colon. These tumours then spread outwards through the wall of the bowel and invade local tissues, lymphatics and blood vessels. Staging of the tumour by Dukes' classification is important in predicting prognosis (Fig. 15.22). Microscopically, the tumour is nearly always an adenocarcinoma.

Clinical features Many tumours are initially asymptomatic or their symptoms (rectal blood loss, constipation) are misinterpreted by the patient, resulting in a delay in diagnosis. The change in bowel habit may be constipation, diarrhoea, or one alternating with the other. Colicky abdominal pain is usually associated with colonic obstruction, whereas a constant pain implies local invasion. Tenesmus suggests a rectal carcinoma, but anal pain suggests local invasion down towards the anus. Air and faeces being passed via the urethra or the vagina imply local invasion anteriorly from the rectum, with fistula formation; posterior invasion may result in sacral pain. Tumour bleeding may cause anaemia. Liver metastases may give rise to hepatomegaly, with jaundice as a late sign. Lymphatic spread is usually to para-aortic nodes and may cause extrahepatic biliary obstruction. Ascites may occur as a result of peritoneal carcinomatosis. The tumour may be palpable, and if it is obstructing the bowel lumen there will be proximal faecal loading. Rectal examination and sigmoidoscopy are essential as part of the initial

801

RECENT ADVANCES IN COLORECTAL CARCINOMA Genetics There have been great advances in the understanding of the genetic basis of colorectal carcinoma. There is a lot of evidence that colon cancers are associated with an accumulation of quantitative and qualitative alterations in gene expression. There are two main types of genetic change. First, alterations in pro-oncogene expression are described. Mostly these take the form of alterations of myc and ras oncogene products. Sometimes it is not clear if the changes are the cause of malignant transformation or the result of increased proliferative activity. Ras gene mutations are seen in 58% of adenomas more than 1 cm in diameter and in 47% of colorectal carcinomas. Chromosomal abnormalities are the second type of genetic change seen in colorectal cancers. These take the form of allellic deletions of putative tumour suppressor genes. Deletions at 17p and 18q are seen in more than 70% of colorectal carcinomas. The best worked-out example of allellic loss is that from 5p, which is seen in familial polyposis coli and some sporadic colon cancers. Screening Considerable research effort has been devoted to screening for colorectal carcinoma. Colorectal cancer fulfils two of the four main conditions for successful screening: it is a common major health problem and it can be treated successfully, at least in its early stages. It is less clear whether the other two conditions, namely a readily acceptable good screening test and costeffectiveness, can be achieved. In the absence of anything better so far, American data suggest that patients over the age of 50 with an average cancer risk should at least have an annual faecal occult blood test (with or without rectal examination) and a 3-5-yearly flexible sigmoidoscopy (to 60cm from the anal margin). Mathematical modelling shows that this screening programme would halve the probability of death from colorectal cancer in a 50-year-old man.

assessment. The fibreoptic sigmoidoscope can visualize the whole of the left side of the colon. Patients may present with large bowel obstruction or perforation, in which case urgent surgery is required.

Investigation If colorectal carcinoma is suspected, a colonoscopy or

1

802

Fig. 15.22

FIG. 15.22 Dukes' staging of carcinoma of the colon A Tumour involves mucosa and submucosa only, good prognosis. B Tumour has penetrated muscle, moderate prognosis. C Tumour has spread to lymph nodes, poor prognosis. D Distant metastases are present. The corresponding 5-year survival rates are also shown.

double-contrast barium enema is carried out. If abnormalities on a barium enema are equivocal, a colonoscopy is essential. Investigations are necessary to determine the extent of spread of the tumour by performing abdominal and pelvic imaging with ultrasound, CT 1 or MRI. For rectal carcinomas local spread is best assessed by per-rectal ultrasound. Raised serum hepatic alkaline phosphatase may indicate hepatic metastases. Serum Carcinoembryonic antigen (CEA) is elevated in some patients at diagnosis (36% in Dukes' A and B tumours) and can be of use in monitoring response to treatment and diagnosis of recurrence.

Management A laparotomy is indicated unless a carcinoma is localized within a resectable polyp. For right-sided tumours a right hemicolectomy is performed, and a left heniicolectomy for left-sided tumours. Very low rectal tumours are usually treated with abdominoperineal resection of the tumour and rectum. There is some interest in treating very small rectal tumours by local diathermy or laser techniques. These techniques may also be used palliatively in advanced inoperable lesions causing obstruction or bleeding. For operable lesions the role of pre- or postoperative radiotherapy is still being assessed. There is now evidence that adjuvant chemotherapy postoperatively improves the prognosis in patients with Dukes' B or more advanced tumours. Embolization of hepatic metastases can be helpful for pain, as can external beam irradiation.

The prognosis depends on the extent of spread at the time of surgery. The overall 5-year survival rate in the UK is approximately 25% (80% for Dukes' stage A, 60% for stage B and 20% for stage C). Most patients with Dukes' stage D die within a year. Early diagnosis is therefore critical. In patients with Dukes' stage A tumour there is a greater risk from new primary tumours than from metastatic spread, and 3-yearly colonoscopic surveillance should be performed.

15

OTHER MALIGNANT COLORECTAL TUMOURS Malignant colorectal tumours other than adenocarcinomas constitute less than 5% of primary malignant colorectal neoplasms. They behave in a similar way to adenocarcinomas, and include carcinoids, lymphomas, leiomyosarcomas, fibrosarcomas and melanomas. Squamous carcinoma of the anus may also invade the rectum and be clinically indistinguishable from a rectal adenocarcinoma.

DIVERTICULAR DISEASE (DIVERTICULOSIS) Incidence and aetiology Colonic diverticula are herniations of mucosa and submucosa through the wall of the large bowel, usually at the point where arteries pass through the submucosa. The most common site is the sigmoid colon, but colonic diverticula may occur throughout the large bowel and can be very numerous. They are rare before the age of 30, but occur in about 50% of people by the age of 70. They are uncommon in the Middle and Far East and in Africa. Diverticula occur because of a weakness in the bowel wall and increased intracolonic pressure. The former is associated with an age-related reduction in strength of colonic connective tissue. The latter is thought to be due to reduced colonic contents resulting from a low fibre intake.

Clinical features Uncomplicated diverticulosis may be asymptomatic or be associated with colonic symptoms similar to those of irritable bowel syndrome (p. 817). Symptoms may arise as a resut of the complications of diverticular disease, the most important of which is an inflammatory mass (diverticulitis). This presents with abdominal pain, guarding tenderness and fever, and sometimes as an emergency with ileus, septicaemic shock, pericolic abscess or perforation. Diverticulitis can result in stricture formation. In diverticular disease there may be profuse colonic bleeding or a chronic iron deficiency anaemia. The differential diagnosis will then include other causes of chronic blood loss, such as a carcinoma.

FIG. 15.23 Double-contrast barium enema showing widespread diverticula, worst in the descending and sigmoid colon

Investigation Anaemia suggests blood loss, and a raised white cell count and ESR suggest inflammation. If patients are acutely unwell, a plain abdominal X-ray may show subdiaphragmatic gas due to perforation. When the problem is not acute a double-contrast barium enema is useful to show the extent of the diverticula (Fig. 15.23). If the patient is persistently unwell, with a pyrexia, ultrasound should be performed to detect an abscess following a localized perforation. A difficult diagnostic problem is the presence of a carcinoma in a segment of colon affected by diverticular disease. The barium enema is often difficult to interpret, and so colonoscopy is indicated.

Management There is no specific treatment for uncomplicated diverticular disease. A high-fibre diet may prevent further diverticula developing. The patient should be reassured that complications are unlikely to develop. Antispasmodic drugs such as mebeverine may help some patients with colicky pains. Broad-spectrum antibiotics are indicated for diverticulitis. Surgery is indicated for severe haemorrhage, local abscess, perforation and stricture causing obstruction.

803

PNEUMATOSIS COLI Pneumatosis coli is a rare syndrome where cysts of gas (comprising air and variable amounts of hydrogen and methane) up to 2 cm in diameter form in the submucosal and subserosal surfaces of the colon (and occasionally the small intestine). It can occur as a result of a peptic ulcer. In some patients there may be no evidence of a mucosal break, and most have chronic obstructive airways disease. Most patients are asymptomatic, but symptoms can include bloody diarrhoea, lower abdominal pain and increased rectal flatus. The cysts may be palpable rectally and sigmoidoscopy usually shows them as multiple blue swellings. Biopsy causes deflation, and the biopsy specimen often floats on the surface of the formol saline fixative. Plain abdominal X-ray shows multiple translucent cysts along the course of the colon and may be used to follow progress.

is reassured and encouraged to take a high-fibre diet to avoid constipation. The anus is kept clean by washing twice daily, without the use of strong soaps, ointments etc. If the problem is persistent and there is no obvious treatable cause, local 1% hydrocortisone and oral antihistamines may help.

FAECAL INCONTINENCE Faecal incontinence is usually due to weakness of the smooth muscle of the internal anal sphincter or to impacted stool in the rectum. It affects 7% of healthy adults over 65. The most common cause is childbirth, but it also occurs after surgery and in patients with neurological disease, particularly multiple sclerosis. It can be defined by anal manometry and ultrasonography. Antidiarrhoeal drugs such as loperamide and codeine are often effective in patients without faecal impaction. In more severe cases specialist investigation and surgery may be required.

Management Treatment is symptomatic, but breathing high concentrations of oxygen in a hyperbaric chamber accelerates resorption of the cysts. This is usually effective within 5 days, but there is a tendency to relapse.

PRURITUS ANI Itching around the anus is a common symptom and can have a number of causes (see Table 10.31, p. 433). A careful history to identify an aetiological factor is followed by anal inspection, rectal examination and, if necessary, proctoscopy or sigmoidoscopy. In the UK many patients use proprietary ointments and creams for their 'piles', and these treatments commonly produce contact dermatitis and pruritus. Unless there is a thrombosed pile or hygiene is poor, pruritus rarely complicates haemorrhoids. Investigation of infections requires the laboratory examination of anal smears and, sometimes, faeces for threadworms and infections such as Candida. Tight-fitting clothing and obesity cause local warmth and moisture, and predispose to skin infection and inflammation. In some patients no cause can be identified; some of these have an obsessive and neurotic attitude, which may be the primary problem.

Management Treatment is directed at the underlying cause. The patient

1

804

MCQ 15.14

2

MCQ 15.15

INFLAMMATORY BOWEL DISEASE 1 2 Inflammatory bowel disease can be defined as chronic inflammatory disease of the gut of uncertain aetiology. It is divided into two types: • Crohn's disease, which affects the gut from mouth to anus and is characterized pathologically by noncaseating giant cell granulomata; • Ulcerative colitis, which affects only the large bowel. In Crohn's disease small aphthoid ulcers, larger ulcers and strictures are seen macroscopically. Histology shows the whole bowel wall to be infiltrated by lymphocytes and plasma cells. In contrast, ulcerative colitis (UC) is primarily a superficial mucosal inflammation. In both diseases the large bowel may initially be the only site of involvement, and differentiation between them is then less important as the presentation, complications and management are very similar. It is possible that the two diseases are different responses to the same aetiological agent.

CROHN'S DISEASE Crohn's disease is a granulomatous disease that most commonly affects the terminal ileum and right side of the colon. It is named after Dr Burrill Crohn of New York, who described 52 cases in 1932. Crohn's disease is common in the western world but rare in underdeveloped countries. The annual incidence of new cases appears to be rising in all countries studied (England, Wales, Scotland, Scandinavia and North America) and is currently 3-6 per 100000 population. It occurs equally in the sexes. The initial presentation can be at any age but is most common in early adult life.

CASE STUDY 15.4 BLOODY DIARRHOEA IN A 23-YEAR-OLD AFRO-CARIBBEAN WOMAN History A 23-year-old female secretary of Afro-Caribbean descent was seen in clinic with a 3-week history of diarrhoea with bleeding, abdominal pain, anorexia and weight loss. She was opening her bowels 6-8 times a day and twice at night. The stool was liquid and dark brown, containing fresh and altered blood and mucus. She had lower abdominal cramping pain, which was associated with the urge to defecate and was relieved by defecation. She had lost 6 kg in weight over the 3 weeks. There was nausea but no vomiting. Her symptoms started while on holiday in Spain, but none of her friends who went with her were ill. However, further questioning revealed that her stools had been looser than normal and she had mild abdominal discomfort over the 3 months before her holiday. There was no relevant previous medical history and her only medication was the oral contraceptive pill. She had been treated with loperamide and ciprofloxacin for 1 week, with no effect on her symptoms. There was no relevant family history and she was a non-smoker. Examination The patient was pale and tired, with a temperature of 38°C and pulse of 95 beats/minute. Her abdomen was slightly distended, with generalized tenderness to deep palpation. There was no guarding or rebound tenderness and bowel sounds were normal. Perianal inspection was normal and rectal examination revealed bloody liquid stool on the glove.

Questions l. What is the differential diagnosis? 2. Does the drug and social history help with the differential diagnosis?

Investigations Haemoglobin 7.9g/dL, MCV 70 fl, MCH 64 pg,WCC 12.5 (neutrophil leukocytosis), platelets 550, serum albumin 30 g/L; the rest of the routine biochemistry was normal; CRP 15 mg/L; stool microscopy and culture, negative; plain abdominal X-ray, no dilatation or evidence of perforation, but the air-contrast appearance suggested a colitis extending from rectum to mid-transverse colon; rigid sigmoidoscopy, inflamed rectal mucosa with contact bleeding and muco-pus in the lumen. Question 3. What histological changes could be seen in the rectal biopsy? Rectal biopsy - typical appearances of acute ulcerative colitis. Management A diagnosis of acute colitis was made on the basis of initial sigmoidoscopy. Question 4. How is the severity of colitis assessed? , I She was admitted because the colitis was severe, as indicated by significant anaemia and hypoalbuminaemia, fever, tachycardia and nausea. She was treated with intravenous fluids and hydrocortisone 100 mg qds and kept nil by mouth. Her fluid balance and urine output were monitored and her stools were charted. She had daily plain AXR, full blood count, blood urea and electrolytes until she was significantly better. After 24 hours she was improved with no nausea, less abdominal pain and diarrhoea and normal temperature. At 48 hours she had no further blood PR. After 3 days she was passing three semiformed blood-free stools a day and had no abdominal pain. She started a low-lactose light diet without any relapse in her symptoms.

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She was changed from hydrocortisone i.v. to prednisolone 40 mg daily by mouth. After 6 days she was discharged on prednisolone 30 mg daily and iron supplements, feeling well and passing two soft stools a day. At review in clinic 1 week later she was still improving. She was started on Asacol (mesalazine) 800 mg t.d.s. and told to progressively reduce the prednisolone dosage over the next 2 months so that the drug could be stopped. After 3 months she was well on Asacol. Iron and prednisolone had been stopped. Her hemoglobin was 12.5 g/dL and her albumin and CRP were normal. Colonoscopy showed a quiescent colitis from the proximal transverse colon to the anal margin. Multiple biopsies confirmed the diagnosis of ulcerative colitis. Discussion The sudden onset of bloody diarrhoea on holiday in Spain suggested an infective colitis. This could have been caused by bacteria, such as Salmonella, Shigella or Campylobacter species. Viral gastroenteritis does not cause bleeding and amoebic dysentery is not a disorder likely to be acquired in Spain. However, stool microscopy and culture were negative. She had no diarrhoeal contacts as far as she knew, and no response to ciprofloxacin. Other causes of bloody diarrhoea needed to be considered, and particularly in a young adult, inflammatory bowel disease (Table 15.17). Close questioning revealed that her bowel had not been right before her holiday. The confirmation of colitis was made at sigmoidoscopy. This examination must be performed gently and carefully, with minimal air insufflation to minimize the risk of precipitating toxic megacolon. The plain AXR is performed in all severe colitics to exclude toxic megacolon. In addition, the colitis and its extent can often be seen, as the air in the colon shows a featureless colon with

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CASE STUDY 15.4 CONTINUED oedematous mucosa. Rectal biopsy confirmed ulcerative colitis, but it is possible that the exacerbation of her symptoms was precipitated by a concurrent enteral infection. She was a non-smoker, which is more common in ulcerative colitics than in patients with Crohn's disease. Questions 5. Why was she started on a low-lactose diet? 6, What are the therapeutic options if she had not responded to corticosteroids? Her colitis was severe (see Table 15.42) and required in-patient treatment. Mild or moderate attacks can be treated on an outpatient basis. All severe colitics are given i.v. fluids and are kept nil by mouth. Ill patients must be started on an intravenous corticosteroid and, if infection is suspected and cannot be excluded, antibiotics must also be

given. Similarly, very ill patients with ulcerative colitis or Crohn's colitis who are toxic and/or have guarding and rebound tenderness should be given antibiotics. Patients can be fed orally after 3-4 days if they are recovering, rapidly as in this case. However, patients with very severe fulminating colitis and/or toxic megacolon need 5 days' intensive treatment without oral feeding. If at 5 days they are no better, or if they relapse on refeeding, emergency colectomy should be considered. These severely ill patients may need parenteral nutrition. Ciclosporin intravenously may help acutely ill non-responding ulcerative colitics who do not have a toxic megacolon. If food is tolerated, intravenous corticosteroids are replaced by oral medication. Lactose intolerance due to primary lactase deficiency is a problem in many populations and can cause troublesome diarrhoea and flatulence, particularly in patients

recovering from colitis. Seventy-five per cent of adult Afro-Caribbeans have primary lactase deficiency, so it was sensible to start feeding her with a low-lactose diet. After discharge prednisolone is gradually reduced and, as the drug has no role in maintaining remission, is stopped. Reduction of the dose and cessation of therapy can lead to relapse, but it is unusual not to be able to stop prednisolone completely. This is in contrast to Crohn's colitis. 5-Aminosalicylic acid preparations have no role in the treatment of moderate or severe acute colitis but have a major role as maintenance treatment because they reduce the risk of relapse. Colonoscopy allows assessment of the extent of disease and confirmation of its nature. Sometimes it is not possible to distinguish ulcerative colitis from Crohn's colitis even on histology (indeterminate colitis). Colonoscopy can be left until the acute attack has settled.

CASE STUDY 15.5 ABDOMINAL PAIN, WEIGHT LOSS AND DIARRHOEA IN A 23-YEAR-OLD ASIAN WOMAN History A 23-year-old South Asian (Indian) housewife presented with a 6-month history of right iliac fossa pain, anorexia, weight loss of 6 kg and diarrhoea. The pain was episodic and occasionally severe but was not associated with eating, defecation or micturition. She had no upper GI symptoms. She opened her bowel 3-5 times a day with a soft or watery stool of normal colour containing no blood or mucus. She did not awake at night to defecate. She had no musculoskeletal or urinary symptoms. She had not had a period for 3 months, although she did not think she was pregnant. There was no relevant previous medical history and she had never been pregnant. She

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was taking no regular medication. There was no family history. She was a non-smoker who had been born in England. She had been to India on one occasion as a 12-year-old. Examination She was thin and pale, with tenderness but no guarding to deep palpation in the right iliac fossa. No masses were palpable. Perianal inspection and rectal examination were normal. Questions 1. What are the possible diagnoses? 2. What blood investigations are necessary?

Investigations Haemoglobin 9.5g/dL; MCV 69 fl; MCH 22 pg; WCC normal; platelet count 456 x 109/L. Biochemical profile normal except for serum albumin - 29g/L. C-reactive protein, 40mg/L (n = < 5). Serum iron was low and TIBC was raised; serum B12 and folate were normal. Endomysial antibodies were absent. TSH was normal. Question 3. What is the most likely diagnosis and how would you confirm it? Pregnancy test was negative. Stool microscopy was negative. Flexible sigmoidoscopy was normal. A small

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CASE STUDY 15.5 CONTINUED bowel follow-through showed the typical radiological appearances of Crohn's disease affecting the ileocaecal area. A colonoscopy was later performed which showed an inflamed contracted caecum. Biopsies from the caecum and terminal ileum showed the typical features of Crohn's disease with non-caseating granulomas.

Question 4 Was a colonoscopy absolutely necessary in this patient?

Management A diagnosis of ileocaecal Crohn's disease was made. In view of the severity of her illness she was started on prednisolone 40 mg daily, as well as iron supplements. After 1 month she was much better, with loss of diarrhoea, lessening of the abdominal pain, return of appetite and weight gain of 8 kg. She looked slightly Cushingoid and was no longer tender in the right iliac fossa. Her haemoglobin had improved to 11.0, her serum albumin to 33g/L and her CRP was normal. She was able to progressively cut down her prednisolone dose to 10 mg daily over the next 8 weeks without relapse. She did not attend follow-up appointments and was re-referred as an urgent appointment 18 months later, when she was admitted with a 4-week history of increasingly severe attacks of colicky central abdominal pain associated with nausea and vomiting. There was no diarrhoea and between attacks she felt reasonably well. She had lost 2 kg in weight. On examination she was not ill but was in pain. Her abdomen was slightly distended, with diffuse mild tenderness but no guarding. Bowel sounds were loud. Her blood tests were normal.

Questions 5. What is the diagnosis? 6. What single test would you do next? A plain abdominal X-ray showed distended small bowel with fluid levels on the erect film. A diagnosis of subacute intestinal obstruction was made and was treated with i.v. fluids and analgesics. She was not vomiting and so a nasogastric tube was not inserted. Her pain settled over the next 24 hours and she was able to tolerate liquids and then a light diet, she had a small bowel meal which showed an extensive tight stricture involving the terminal ileum. She was started on prednisolone and discharged. Her attacks of pain persisted and 6 weeks later she was admitted electively for a right hemicolectomy and ileal resection. She made a good postoperative recovery. Prednisolone was stopped and she was started on mesalazine (as Pentasa) 2 g daily. Six months later she was very well on mesalazine. Question 7. What is the rationale for mesalazine use? Discussion Although the commonest cause of abdominal pain and diarrhoea continuing for several months in a young adult is irritable bowel syndrome, this diagnosis is not the most likely one. Weight loss is unusual in IBS, so special care must be taken to exclude other causes. Crohn's disease may present in this way. The absence of blood per rectum and of typical colonic pain (abdominal pain worse before and relieved by defecation) suggested that colitis or another colonic disorder was less likely. Apart from weight loss there were no typical features of malabsorption, although their absence does not exclude such a

disorder. There was nothing to suggest an infective aetiology. Malignancy was unlikely, although small bowel lymphoma (which is rare) can present like this in younger adults and children. Thyrotoxicosis must be considered in patients presenting with diarrhoea and weight loss, although abdominal pain is not usually a feature. The blood tests showed iron deficiency anaemia, hypoalbuminaemia and raised CRP. Therefore, the diagnosis of IBS was unsustainable. These tests with the clinical features suggested inflammatory bowel disease, particularly Crohn's disease of the small bowel. However, infection and malignancy remained possibilities. The barium study of the small bowel showed appearances typical of ileocaecal Crohn's disease. However, these are not diagnostic and tuberculosis and lymphoma may give similar appearances. In practical terms Crohn's disease is by far the most likely cause of these radiological appearances, and therefore the patient can be treated as a presumptive case of Crohn's disease. Tuberculosis was an unlikely diagnosis, although the patient was of Indian origin; she was born in Britain and had only been to India once 10 years previously on holiday. There was no family history of TB. A colonoscopy is not essential but does allow a definitive diagnosis. It would be indicated if there was a higher suspicion of another cause for the clinical and radiological features. The patient's disease was active, as indicated by her gastrointestinal and systemic symptoms and by the presence of anaemia, hypoalbuminaemia and raised inflammatory markers (CRP). The main treatment for active Crohn's disease remains corticosteroid therapy. Her initial response was encouraging and, unlike many patients with Crohn's disease, she was able to stop therapy without relapse.

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CASE STUDY 15.5 CONTINUED On her return to hospital 18 months later she had developed typical symptoms of subacute intestinal obstruction. This was confirmed by plain abdominal X-ray during an attack of pain. Subacute obstruction in Crohn's disease does not require emergency surgery and the symptoms will settle with 'drip and suck' and

analgesia. A terminal ileal stricture was later shown on a small bowel meal. Stricture can be due to mucosal oedema secondary to active Crohn's disease or to scarring as a result of previous disease. The normal blood tests and the lack of response to corticosteroids suggested the latter. The treatment of choice was ileal

Aetiology

SUMMARY 7 Clinical presentation of Crohn's disease

The aetiology is unknown but evidence suggests that the cause is largely environmental. For example, when a population migrates from an area of low to one of high incidence, the incidence in that population subsequently rises. A 1995 report from North Tees suggested 7.3 cases/ 100000/year for Crohn's and a rise to 22 for ulcerative colitis. Prevalence rates of up to 100 in 100000 for ulcerative colitis and up to 147 in 100000 for Crohn's are recorded. The following theories have been put forward: • Infection. No infectious agent has yet been shown to transmit the disease or produce a similar granulomatous reaction in animals. At present there is interest in the possible role of Mycobacteria, Campylobacter and measles. • Immunological. The characteristic granuloma of Crohn's disease suggests a possible immunological origin. Both food and bacterial antigens have been implicated, but there is no clear evidence for either. As with other inflammatory bowel diseases, minor, nonspecific, immunological changes have been reported. • Dietary. A high intake of refined sugars and a low intake of fibre have been suggested as aetiological factors, but the evidence that they are primary factors is weak. • Genetic. There is a higher incidence of both Crohn's disease and UC in relatives of patients with Crohn's disease. Concordance rates in twin pairs and siblings are high, with a relative risk of about 25 in patients with inflammatory bowel disease. • Smoking. In direct contrast to UC, patients with Crohn's disease are more likely to be cigarette smokers than are appropriate controls. • Others. Oral contraceptives, detergents, mercury and psychological trauma have all been proposed as aetiological agents, but with little firm foundation.

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resection with right hemicolectomy: 80% of patients show endoscopic if not clinical or biochemical evidence of relapse 6-12 months after resection. There is now good evidence that mesalazine in a dose of at least 2g/day as maintenance therapy after resection reduces the risk of relapse.

Fig. 15.23

2

Fig. 15.24

General Fever Malaise Weight loss Amenorrhoea In children: failure to thrive, growth retardation, delayed puberty Terminal ileal disease Abdominal pain Diarrhoea (with or without steatorrhoea) Right iliac fossa tenderness or mass Signs of small intestinal obstruction Colonic disease Abdominal pain Diarrhoea Blood and mucus per rectum Tenesmus Abdominal tenderness Anal disease Skin tags, fissures and abscesses Incontinence Fistulae between anal canal and skin

Mouth

Cobblestone mucosa Aphthous ulcers Glossitis Stomatitis Fistula formation Entero-enteric or enterocutaneous Urinary frequency, dysuria, haematuria and pneumaturia Faeces per vaginam and per urethram Complications due to nutritional deficiencies Anaemia Oedema due to hypoproteinaemia Gallstones Tetany Osteomalacia Vitamins A and K deficiency Water-soluble vitamin deficiency Ion deficiencies (potassium, magnesium and zinc)

Pathology At laparotomy, Crohn's disease is seen as thickened bowel with associated enlarged lymph nodes. Microscopically the inflammation is transmural, in contrast to ulcerative colitis, where only the mucosa is usually involved. The other hallmark of Crohn's is the microscopic finding of noncaseating granulomata. As a result of transmural inflammation there may be local abscesses or fistulae between two pieces of bowel (entero-entero or enterocolonic) or between the bowel and the skin (enterocutaneous), usually in the anterior abdominal wall or around the anus. 1

Fistulae may also form between the bowel and bladder or vagina.

Clinical features The commonest initial presentation is with terminal ileal disease, often with coexistent oral and anal involvement. Less common initial presentations are acute right iliac fossa pain simulating acute appendicitis, and acute colitis identical to that of UC. General symptoms When the disease is active the majority of patients have a mild fever and general malaise. Loss of appetite and malabsorption contribute to weight loss. In prepubertal and pubertal children there may be no history of diarrhoea or abdominal pain. Children usually present with non-specific symptoms: failure to thrive, decreased growth velocity, delayed puberty and symptoms of anaemia. Gastrointestinal symptoms The gastrointestinal symptoms depend primarily on the site of disease. As a result of stricture formation, many patients with ileal disease complain of colicky abdominal pain, usually in the right iliac fossa. Diarrhoea, usually modest and containing excess fat, is usual. Disease in the right side of the colon produces similar symptoms, although colonic disease alone does not cause steatorrhoea. It is often combined with ileal disease. Left-sided colonic disease results in diarrhoea without steatorrhoea, but with blood per rectum. Urinary frequency and dysuria may result from inflamed bowel adjacent to the urinary tract (especially the right ureter and bladder). Pneumaturia (air in the urine), and faeces via the urethra or vagina indicate a fistula from the bowel to the genitourinary tract. Complications due to nutritional deficiency The complications of nutritional deficiency may cause symptoms. Anaemia may be due to blood loss or reduced

SUMMARY 8 Investigation of Crohn's disease Sigmoidoscopy and rectal biopsy Stool culture and microscopy Abdominal and chest X-ray Small bowel enema or meal Barium enema Colonoscopy Upper gastrointestinal endoscopy (when indicated) Full blood count and acute-phase reactants, e.g. ESR, CRP or orosomucoids Serum iron, iron binding capacity, folate and B12 Liver function tests, including serum albumin Radiolabelled white blood cells (when indicated)

absorption of iron, folate and vitamin B12. Oedema secondary to hypoproteinaemia is a consequence of both protein loss into the lumen of the gut (protein-losing enteropathy) and reduced dietary intake. Gallstones are due to terminal ileal bile acid malabsorption, which results in cholesterol-supersaturated bile and causes cholesterol gallstones. Hyperoxaluria and renal oxalate stones can occur in patients with steatorrhoea. Vitamin D and calcium malabsorption can result in hypocalcaemia (manifest as tetany) or, when long-standing, pseudofractures (Looser's zones) or fractures due to osteomalacia (p. 962). Night blindness and spontaneous bleeding may rarely occur as a result of vitamin A and K malabsorption. Angular cheilitis, glossitis and even scurvy can result from vitamin B and C deficiency. Hypokalaemia results in malaise and muscle weakness, and hypomagnesaemia can cause tetany. Zinc deficiency can cause a rash similar to that seen in zinc-deficient children with acrodermatitis enteropathica.

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Non-intestinal manifestations Both Crohn's disease and UC may be associated with nonintestinal manifestations (Table 15.38). Acute large joint arthritis, seen commonly, affects the knees and ankles. Erythema nodosum and pyoderma gangrenosum usually affect the limbs, particularly the legs (p. 407). If urticaria and erythema multiforme are seen they should be assumed initially to be due to sulphasalazine. If there are ophthalmic symptoms, an assessment with a slit lamp is needed to exclude uveitis. Sacroiliitis occurs in up to 10% of patients. The association with ankylosing spondylitis is rare. Abnormal liver function tests occur in about 10% of patients with colitis and are usually asymptomatic. The commonest lesions are pericholangitis and fatty infiltration. Primary sclerosing cholangitis (p. 858) is the most common clinically significant problem. Cholangiocarcinoma and autoimmune chronic active hepatitis are rare. Cholesterol gallstones, secondary to bile acid malabsorption, are common in patients with terminal ileitis or resection. Acute colitis is associated with an increased risk of venous thromboembolism. Signs Physical examination of a patient with Crohn's disease should start with a search for nail changes (including clubbing, leukonychia and koilonychia), anaemia, pyrexia, tachycardia and mouth ulcers. 0 In the abdomen there may be operation scars, evidence of fistulae and signs of intestinal obstruction, with visible peristalsis. Palpation may reveal a mass, most commonly in the right iliac fossa, due to disease in the terminal ileum and the right side of the colon. Auscultation may suggest intestinal obstruction. Perianal inspection, sigmoidoscopy and rectal biopsy are essential. Sigmoidoscopy may show ulceration, a granular inflamed mucosa, spontaneous bleeding and increased mucus formation. Even in the absence of obvious inflammatory changes, the rectal biopsy may demonstrate diagnostic granulomata.

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TABLE 15.38 Non-Intestinal manifestations of inflammatory bowel disease Affected part

Manifestation

Reflecting acute illness Joints Skin

Eyes

Acute large joint arthritis Pyoderma gangrenosum Erythema nodosum Vasculitis Conjunctivitis Episcleritis Uveitis

TABLE 15.39 Differential diagnosis of Crohn's disease Symptoms

Differential diagnosis

Terminal ileal disease

Tuberculosis Yersinia Tumours, especially lymphoma and primary carcinoid Irritable bowel disease

Colitis

Ulcerative colitis Infective colitis Ischaemic colitis Irritable bowel syndrome

Weight loss and diarrhoea

Carcinoma (especially of the large bowel in older people) Other causes of malabsorption, e.g. coeliac disease Hyperthyroidism Anorexia nervosa (with or without surreptitious purgative abuse) Addison's disease Hypopituitarism

Venous thromboemboiism Not reflecting acute illness Joints Liver

Sacroiliitis Ankylosing spondylitis Fatty change Pericholangitis Primary sclerosing cholangitis Carcinoma of bile duct (cholangiocarcinoma) Autoimmune chronic active hepatitis

Investigation The diagnosis is confirmed by demonstrating the characteristic granulomatous histology, often by rectal biopsy. In the presence of active disease the haemoglobin is usually low and the neutrophil count and acute-phase reactants are raised. The serum albumin is low if there is widespread disease. Stool culture and microscopy should be performed; infections, particularly Yersinia (p. 816) and Campylobacter (p. 324), may mimic Crohn's disease. A plain abdominal X-ray will determine whether there is colonic dilatation. A chest X-ray may reveal tuberculosis, which may present with ileal disease similar to Crohn's disease. A small bowel enema or meal shows involvement of the small bowel, which is characterized by stricture formation, rose-thorn ulcers, proximal dilatation and fistula formation (Fig. 15.24A). The colon and caecum (and often the terminal ileum) are visualized by a double-contrast barium enema (Fig. 15.24B). Multiple aphthous ulcers, seen at colonoscopy or barium enema, are typical of early Crohn's colitis. Colonic changes include thickening of the wall, deep ulcers (rose-thorn and collar-stud types) and skip lesions, with areas of normal bowel interspersed between diseased segments. Colonoscopy allows direct inspection 1 and biopsy of the colon and terminal ileum. A useful technique is to label the patient's white cells in vitro with an isotope such as indium-Ill. After reinjecting them into the patient, the localization and activity of the

1

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Fig. 15.25

disease can be assessed by determining the site of uptake using a gamma camera.

Differential diagnosis The differential diagnosis of Crohn's disease is shown in Table 15.39. In many parts of Africa, India and the Far East, ileocaecal tuberculosis is quite common and Crohn's disease is rare. The barium radiological appearance is similar to that of Crohn's disease; however, in the case of tuberculosis, caseating granulomata are found on histology, acid-fast bacilli may be seen on microscopy, and Mycobacteria are isolated on culture of the biopsy. Yersinia can present with an acute ileitis in young people, but symptoms and signs disappear within 3 months. Some patients with Crohn's disease may be wrongly diagnosed and treated for anorexia nervosa. Addison's disease and hypopituitarism can also present as weight loss and diarrhoea.

Complications • Acute colonic (toxic) dilatation, indistinguishable from that seen with UC and sometimes complicated by perforation and haemorrhage. • Subacute small bowel obstruction, due to stricture formation and obstruction by a food bolus. • Fistula formation. • Renal stones. • Carcinoma of the colon may complicate long-standing (usually more than 20 years) Crohn's colitis. Small intestinal carcinomas rarely complicate Crohn's disease.

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FIG. 15.24 Barium enemas demonstrating Crohn's ileitis and colitis A Small bowel enema showing stricture formation and ulceration of the terminal ileum, typical of Crohn's ileitis. B Barium enema showing deep ulceration of the distal colon, suggesting Crohn's colitis.

• Amyloid may occur in the bowel and other organs, and may regress with resection of diseased bowel. • Perforation may occur in acute toxic megacolon or silently in acute disease during steroid therapy. • Severe colonic haemorrhage.

Management Crohn's disease can cause considerable morbidity, but with joint medical and surgical specialist care the overall quality of life should be good. Life expectancy for most patients is virtually the same as for normal individuals, but patients with extensive disease and with onset before 20 years of age still have higher mortality than normal.

Medical Management of patients with Crohn's disease depends on the site, severity and extent of disease (Table 15.40). Smoking may adversely affect prognosis and should be stopped. In general, patients should be encouraged to take a balanced diet with an adequate amount of fibre. Dietary fibre should only be restricted when there is stricture formation, as it may then contribute to intestinal obstruction. Replacements are given if there is evidence of haematinic, fat-soluble vitamin or mineral deficiency.

Active ileitis and colitis Active ileal disease causing diarrhoea, abdominal pain and a right iliac fossa mass is usually treated with a 3-month course of oral prednisolone (starting at 30-40 mg/day). If the disease is resistant, azathioprine (2mg/kg) or 6mercaptopurine may be used. Clinical trials have shown that 5-aminosalicylate preparations are of minor value when the disease is restricted to the ileum. An elemental diet (a solution of essential amino acids, carbohydrate, fat, vitamins and trace elements) may also be of value in the treatment of active ileal disease. Active colonic disease is also treated with prednisolone. Sulphasalazine, which is 5-aminosalicylic acid bound to a sulphonamide (sulfapyridine), may be of some use in Crohn's colitis, although its main role is in the prevention of relapse in UC. However, because of the numerous and potentially serious side-effects (Table 15.41), mostly due to the sulfapyridine, 5-aminosalicylic acid preparations have been developed. One of the enteric-coated preparations uses an acrylic-based resin outer coat (mesalazine) which, like the semipermeable membrane of the slow-release preparation of sulfasalazine, is pH dependent and allows the release of 5-aminosalicylic acid into the ileum and colon. Azodisalicylate consists of two molecules of 5aminosalicylic acid bound by an azo bond which is split by lower intestinal bacteria. Another option is the use of

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TABLE 15.40 Medical treatment of Crohn's disease Symptoms

Treatment

Nutritional deficiencies

Good balanced diet Folicacid Vitamin B12 Iron Vitamins A, D, E and K Potassium, zinc and calcium

Ileal disease

Prednisolone Elemental diet Azathioprine/6-mercaptopurine 5-aminosalicylate drugs

Colonic disease

Prednisolone Sulfasalazine Azathioprine/6-mercaptopurine 5-aminosalicylate drugs

Severe active ileitis and/or colitis

Intravenous hydrocortisone Intravenous fluids or total parenteral nutrition Antibiotics

Anal disease and fistulas

Metronidazole Azathioprine Elemental diet/total parenteral nutrition and nil by mouth

Non-responsive active disease with or without fistulae

Infliximab

Non-intestinal manifestations

Local measures Prednisolone (if acute illness)

CROHN'S DISEASE

TABLE 15.41 Role and side-effects of salicylate drugs used In Crohn's disease and ulcerative colitis Drug

Side-effects

Sulphasalazine

Prevention of relapse in UC Skin rashes Marrow suppression Some use in ileal and colonic Crohn's disease Haemolysis Male subfertility Gastrointestinal symptoms Orange urine

5-aminosalicylic acid (mesalazine)

Headache Diarrhoea Nephrotoxicity

Alternative to sulfasalazine

Azodisalicylate (olsalazine)

Headache

Alternative to sulfasalazine

5-aminosalicylic acid enemas

Headache

Alternative to Sulfasalazine enemas

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RECENT ADVANCES IN TUMOUR NECROSIS FACTOR- (TNF- ) ANTIBODY IN

Role

TNF- is a cytokine which is thought to have a major role in the initiation and propagation of the inflammatory response and apoptosis in patients with Crohn's disease and rheumatoid arthritis. Mouse-derived monoclonal antibodies (e.g. infliximab and CDP571) have subsequently been raised and assessed in these diseases. The respective antibodies, IgG 1 and IgG4 do not cause an immune response in humans but do neutralize human TNF- . If the antibodies are infused into patients with active Crohn's disease there is a beneficial effect at 2 and 4 weeks on symptoms and laboratory markers of inflammation, but by 6 months, the effects have disappeared. Endoscopic and biopsy studies have shown a significant healing of endoscopic inflammation and ulceration and a reduction in the inflammatory cell infiltrate. A randomized double-blind placebo-controlled trial of three doses of infliximab in patients with fistulae showed an improvement in fistula healing. The most common sideeffects of infliximab were headache, nausea, upper respiratory tract infection and fatigue. Tubercluosis may occur. TNF-a antibodies are a promising new treatment for patients with severe Crohn's disease who do not respond to other agents. 5-aminosalicylic acid enemas. The new 5-aminosalicylate preparations are as effective as sulphasalazine and are replacing it. Resistant patients may respond to azathioprine or 6-mercaptopurine. Patients with severe active ileitis and/or colitis have constitutional symptoms and require hospital admission. Intravenous hydrocortisone sodium succinate (usually l00mg 8-hourly) is usually given for about 5 days and then oral prednisolone is substituted. Intravenous fluids are needed, and if the patient is malnourished total parenteral nutrition should be started. If there is a possibility of infection or abscess the patient is treated with intravenous broad-spectrum antibiotics (e.g. ampicillin, gentamicin and metronidazole). Anal disease Anal disease with sinuses, abscesses or fistulae can be treated with metronidazole for several weeks, but the patient should be warned to report any symptoms suggestive of drug-induced peripheral neuropathy. Resistant anal disease may respond to dietary measures or require surgical resection with the formation of a stoma. In severe cases an elemental diet will greatly reduce stool frequency and help healing. Enterocutaneous and enteroenteric fistulae usually require surgery.

MCQ 15.16

Non-intestinal manifestations Disorders reflecting acute illness settle with removal of the

affected bowel (usually colon), but those due to the chronic illness do not. Severe joint, skin or eye disease requires prednisolone. The treatment of sacroiliitis and ankylosing spondylitis is described in Chapter 22, page 1147.

Surgical Surgery is required for a severe acute attack unresponsive to treatment, persisting active disease resistant to corticosteroids, symptomatic strictures, non-healing fistulae and complicating carcinoma. Most Crohn's patients will at some time require intestinal surgery. Limited resections and end-to-end anastomoses are performed as necessary, usually to relieve obstruction or fistula formation. Strictureplasties may relieve obstruction without the need for small bowel resection. Occasionally, panproctocolectomy with the formation of an ileostomy is indicated for severe colitis. Restorative proctocolectomy with pouch formation is generally thought to be contraindicated in Crohn's colitis. The complications of ileostomy are discussed on page 815. In patients with small intestinal resections, oral 5aminosalicylic acid preparations reduce the number of endoscopic recurrences.

ULCERATIVE COLITIS

1

Ulcerative colitis (UC) is a chronic inflammatory condition of unknown aetiology affecting the colon and rectum. Like Crohn's disease, it is most common in the western world (Fig. 15.24) and its incidence appears to be increasing (see p. 804). It is slightly more common in women than in men. Most patients present in early adult life, but all ages can be affected.

Aetiology and pathology Aetiological factors are similar to those for Crohn's disease (p. 808). There is evidence that relapses can be associated with stopping smoking cigarettes; the explanation for this is not known. UC primarily involves the mucosa; only in very severe disease is the muscularis mucosae penetrated. Microscopy shows plasma cells and neutrophils, particularly in the crypts of Lieberkiihn, which can break down to form 'crypt abscesses' communicating with the luminal surface. If the disease is confined to the rectum (proctitis) it is clinically less severe and there is no increased long-term risk of carcinomatous changes. The extent of disease varies from patient to patient, but in almost all cases the rectum is involved.

Clinical features Acute attack The usual presenting symptom is the passage of frequent loose, small-volume brown motions, with fresh blood and

TABLE 15,42 Ulcerative colitis: clinical features of mild, moderate and severe attacks Clinical feature

Mild

Diarrhoea Blood per rectum Mucus Abdominal pain Tenesmus Anorexia Weight loss Acute extracolonic manifestations Fever Tachycardia Anaemia Distended abdomen Abdominal tenderness Sigmoidoscopy

+ + + +

Abnormal plain abdominal X-ray High ESR High neutrophil count Hypoproteinaemia

+ + ± Fine granularity

+ + -

Moderate

15

Severe

++

+++

++

+++

++

+++

+

++

+

++

+

++

+

++

+

++

+

+

+

+

+

++

±

+

±

+

Coarse granularity Spontaneous bleeding -

Ulceration Pseudopolyps Mucopus +

+ + +

++ ++ ++

mucus either on the surface of the stools or intermixed with them. Blood per rectum alone or diarrhoea alone are common first symptoms. Attacks can be usefully divided into mild, moderate and severe (Table 15.42). Patients with mild attacks open their bowels up to five times a day, with moderate attacks up to 10 times a day, and with severe attacks over 10 times a day. The faeces become increasingly soft with more severe relapses. Cramping abdominal pains are common in attacks of moderate severity, whereas rectal pain and a painful feeling of incomplete evacuation (tenesmus) are common in the more severe cases. Fever and tachycardia indicate severe disease - usually widespread and active - rather than infection. Anaemia, if present, is usually hypochromic and microcytic and is due to blood loss. Sigmoidoscopy and rectal biopsy are essential for the assessment of proctocolitis. In proctitis the mucosa becomes oedematous, diffusely reddened and granular, when it loses its normal 'wet' appearance. The blood vessels and mucosal folds are lost, and contact bleeding and spontaneous haemorrhages may be present. 'Pseudopolyps' are islands of residual mucosa around which mucosa has been destroyed. Sigmoidoscopy in active proctitis should be brief; no attempt should be made to insert the instrument far into the rectum and only a little air insufflated. Colonic blood loss causes anaemia, whereas protein loss

813

TABLE 15.43 Investigation of an acute attack of presumed ulcerative colitis • • • • • • •

Sigmoidoscopy and rectal biopsy Full blood count and acute-phase reactants Liver function tests and plasma albumin Stool microscopy and culture Plain abdominal X-ray Barium enema or colonoscopy (delay until after acute attack) Radiolabelled white cell scan (selected cases)

leads to hypoproteinaemia and peripheral oedema. With acute colonic dilatation the patient becomes ill and febrile, with abdominal tenderness and reduced bowel sounds. Signs of peritonitis (abdominal rigidity, extreme tenderness, guarding and absent bowel sounds) suggest colonic perforation, a complication with a mortality rate approaching 50%. Emergency colectomy may therefore be necessary in acute colonic dilatation to avoid this complication. Chronic ulcerative colitis Following recovery from an acute attack, patients may return to a normal bowel habit. Acute exacerbations of varying severity usually occur intermittently. In some patients these periods of remission may be very short, so that treatment becomes almost continuous. Other patients have persistent symptoms, which typically become worse when their prednisolone dose is reduced. Development of malignant change Patients with total colitis for more than 10 years are at an increased risk of developing carcinoma of the colon, hence the need for regular colonoscopic screening. Non-intestinal manifestations The non-intestinal manifestations of UC are similar to those of Crohn's disease (p. 809 and Table 15.38).

Investigation The relevant investigations in UC are shown in Table 15.43. Stool microscopy and culture are necessary to exclude infection. A plain abdominal X-ray may demonstrate colonic dilatation, usually best seen in the transverse colon (Fig. 15.25). Barium enemas or colonoscopies can precipitate toxic dilatation and should therefore be avoided in acute disease. When used, they show loss of haustra, dilatation of the lumen and superficial ulceration. 1

1 814

Figs 15.26-15.28

FIG. 15.25 Plain abdominal X-ray showing a dilated transverse colon outlined by air (arrowed) - the toxic megacolon of colitis

Management Acute attack In mild attacks of distal disease, corticosteroid or 5aminosalicylic acid enemas are usually effective. In mild but more extensive disease, oral 5-aminosalicylic acid preparations or prednisolone are effective. In moderately severe attacks, oral prednisolone (30-40 mg daily) is the usual therapy, with the dose then being tapered off over 3 months. In severe attacks intravenous hydrocortisone (l00mgt.d.s.) is given. Antibiotics and total parenteral nutrition are indicated in sick toxic patients. Intravenous, followed by oral, ciclosporin can lead to remission in 70% of very severe cases not responding to intravenous corticosteroids, but relapse may occur on stopping treatment. 5-aminosalicylic acid compounds (e.g. mesalazine, 800mgt.d.s.) reduce symptoms in patients with mild attacks. Some patients benefit from the exclusion of dietary milk products. Maintenance treatment Numerous studies have shown that 5-aminosalicylate preparations reduce the relapse rates of patients in remission (see Table 15.41). Azathioprine can also be helpful. There is no indication for steroids in patients in remission. Management in pregnancy Most patients with inflammatory bowel disease improve during pregnancy, although a minority (about 20%) have relapses. There is no contraindication to the use of 5aminosalicylate preparations, azathioprine and prednisolone in any trimester. Patients tend to relapse

postpartum because of a fall in plasma steroid levels. They should be warned of this possibility and the disease treated vigorously if it occurs.

15

Management in childhood Children should be treated actively in the same way as adults to maximize growth. Prednisolone should be used sparingly because, although it reduces disease activity, it tends to inhibit growth. Particular attention should be paid to diet. In medically resistant disease a colectomy should be performed. Surgery The standard operation for UC has been panproctocolectomy with ileostomy. However, subtotal colectomy is now usually performed and, at a second operation, a pelvic pouch is constructed from the terminal ileum to act as a reservoir and anastomosed to the anus (restorative proctocolectomy). Inflammation of the pouch ('pouchitis') is a complication. There are three major indications for surgery: 1. Patients with severe acute disease, especially where the colon is dilated more than 6cm on plain abdominal Xray and the patient is toxic with a pyrexia and tachycardia. The operative mortality becomes much higher (50%) if patients perforate their colon and develop a faecal peritonitis (compared with 3% for elective and 10% for urgent operations). Acute severe colonic bleeding is also an indication for surgery. 2. Patients with chronic severe extensive disease which persistently requires high-dose corticosteroid treatment. Patients usually feel dramatically better after colectomy, which also avoids the development of further complications (apart from chronic liver disease). 3. In patients with total colitis for more than 10 years there is a significant risk of carcinomatous change (Fig. 15.26). Carcinomas may be multifocal and are often preceded by the development of epithelial cell dysplasia. After 10 years' total colitis, regular colonoscopies are therefore indicated. Severe dysplasia or carcinoma are indications for total colectomy. Complications of an ileostomy Complications of ileostomy are usually minimal, apart from minor problems with the abdominal wall around the stoma. There may be high fluid outputs (more than 1L/day), especially if there has been small bowel surgery or Crohn's disease. This can be helped by avoiding hyperosmolar food and by the use of drugs that slow intestinal motility (e.g. loperamide, codeine phosphate). Impotence due to damage to the sacral nerves is unusual. Dehydration, oliguria and hyponatraemia can occur in hot weather, with poor oral intake of fluids. Reduced urine output can lead to urate stones. However, most patients with an ileostomy have excellent health. Psychological problems can be severe and patients require sensitive counselling by medical and nursing staff. Many hospitals have full-time stoma nurses, who care for

FIG. 15.26 Barium enema findings with pancolitis Long-standing UC with disease throughout the colon, mucosal ulceration (white arrows at right-hand side) and loss of haustrations. There is an 'apple-core' lesion of the ascending colon (single white arrow) typical of carcinoma.

patients' equipment and basic medical and psychological needs, both in and out of hospital. Many patients also find it helpful to meet other stoma patients. Colitis and stoma societies and self-help groups are of great value in helping patients to lead a normal life. Prognosis Less than 1 % of patients suffering from UC die within a year of presentation. In contrast, after their first attack settles, 10% of patients will have at least 15 subsequent asymptomatic years. Up to 25 % of patients require colectomy within 5-10 years of developing the disease. Death can be avoided by performing colectomy before advanced carcinoma develops. Overall, the majority of patients have a normal life expectancy.

INFECTIVE, MICROSCOPIC, ISCHAEMIC AND RADIATION COLITIDES

PSEUDOMEMBRANOUS COLITIS Pseudomembranous colitis is usually due to a toxin produced by Clostridium difficile and nearly always follows the use of broad-spectrum antibiotics, e.g. amoxycillin, and cephalosporins. It is much more commonly hospital than

815

community acquired. The symptoms develop 4 days to 6 weeks after starting the drugs.

Clinical features and investigation The patient develops cramping abdominal pains and diarrhoea with mucus and, sometimes, blood. Sigmoidoscopy reveals diarrhoea, proctitis and, sometimes, multiple yellow elevated plaques (pseudomembranes) up to 20mm in diameter. Investigations may demonstrate Cl. difficile toxin in the faeces. A rectal biopsy is usually diagnostic and shows necrotic foci with inflammatory cells migrating through to the lesion ('the summit lesion') and pseudomembranes.

Management The treatment of choice is vancomycin for 7-14 days, but metronidazole is also effective. Colestyramine (cholestyramine), an anion-exchange resin, can be used to bind the toxin and reduce diarrhoea. Supportive measures, which often include intravenous fluids, are important. The prognosis is usually good, except in the elderly or if there is a delay in making the diagnosis. Relapse can occur.

tuberculosis is ingested to cause disease. The affected bowel becomes ulcerated and may alternate with normal bowel (skip lesions). The radiological and macroscopic appearances can be very similar to those of Crohn's disease. Histology shows caseating granulomata, and acidfast bacilli may be seen. Clinical features and investigations There is a gradual onset of abdominal pain, anorexia, weight loss, diarrhoea and fever. Intestinal obstruction, perforation and haemorrhage can occur, and if there is extensive small intestinal involvement malabsorption can be a feature. In tuberculous colitis there may be blood and mucus in the stool. Perianal tuberculosis may cause ulceration, fistula and abscess. Tuberculous intestinal lesions are shown on small bowel meal and/or barium enema. These are not specific, and so colonoscopy with biopsy or even laparotomy with biopsy is indicated to obtain a histological diagnosis. The differential diagnosis for small intestinal tuberculosis includes Crohn's disease, yersiniosis and lymphoma, and for large bowel tuberculosis, Crohn's disease, ulcerative colitis, infective colitis and carcinoma.

Tuberculous peritonitis YERSINIA Yersinia enterocolitica and pseudotuberculosis are organisms which may cause an acute ulcerative inflammation of the ileum, appendix and colon. They may be associated with erythema nodosum and an acute arthritis. Barium studies show a swollen terminal ileum with tortuous folds and filling defects, giving a cobblestone appearance or a colitis. Some patients may have a laparotomy because a mistaken diagnosis of acute appendicitis is made. The condition is self-limiting and resolves completely within 3 months. Tetracycline or cotrimoxazole are indicated in patients with severe systemic symptoms.

ABDOMINAL TUBERCULOSIS This is rare in the west but relatively common in developing countries, particularly the Indian subcontinent. Tuberculosis can affect any part of the gastrointestinal tract, but is commonest in the ileocaecal area, proximal colon and peritoneum. Fifty per cent of patients have evidence of previous or active pulmonary tuberculosis.

Intestinal tuberculosis

Tuberculous peritonitis is usually due to haematogenous spread from pulmonary tuberculosis and is rarely associated with intestinal tuberculosis. It presents with progressive ascites, accompanied later by anorexia, weight loss, fever and minor abdominal pain. Oedema, hepatosplenomegaly and generalized lymphadenopathy may appear late. A dry form of the disease can occur which presents with palpable abdominal masses due to multiple intra-abdominal adhesions. Other causes of ascites, particularly malignancy and cirrhosis, must be considered in the differential diagnosis. M. tuberculosis organisms are rarely seen in ascitic fluid (5%), which is an exudate and may contain numerous lymphocytes, but culture is positive in about 80% of cases. Sometimes diagnosis is made by biopsy and culture of peritoneal tissue obtained at laparoscopy or laparotomy. Management Standard antituberculous chemotherapy (see p. 645) leads to complete resolution of abdominal tuberculosis and should be continued for 12 months. Occasionally, longterm problems are caused by intestinal strictures or intraabdominal adhesions.

COLLAGENOUS (MICROSCOPIC) COLITIS

Either the human or the bovine form of Mycobacterium

1

816

Fig. 15.29

Collagenous colitis is a rare cause of chronic watery diarrhoea. Macroscopically the colon looks normal, but microscopically there is a thickening of the subepithelial layer by collagenous bands and an inflammatory cell infiltrate of the lamina propria. The aetiology is unknown, but some patients also have coeliac disease. Treatment can be

difficult, but regimens used in UC, such as maintenance mesalazine and courses of prednisolone for acute relapses, can help. Symptoms may last for months or years, but spontaneous resolution can occur.

GAY BOWEL SYNDROME Homosexuals have an increased incidence of diarrhoea from infections such as Shigella, Salmonella, Campylobacter, Giardia, amoebae and Cryptosporidium. They also commonly develop perianal warts (condylomata acuminata). These patients may have a proctitis due to gonococcal or herpes simplex type 2 infection and, occasionally, anal syphilis (see Chapter 9). The acquired immune deficiency syndrome (AIDS) can be associated with fulminant bowel infections as well as the development of plaques of Kaposi's sarcoma throughout the bowel (p. 449). Eating and swallowing may be painful owing to oral and oesophageal Candida infection.

ISCHAEMIC COLITIS Aetiology and pathology Ischaemic colitis usually affects the region of the splenic flexure or the rectosigmoid area. Rarely, ischaemia of the superior mesenteric artery may affect the ascending and proximal transverse colon. Atheroma is a more common cause than embolus, but aetiological factors are otherwise similar to those seen in small bowel ischaemia (p. 795).

Clinical features and investigation The patient is usually elderly and presents with bloody diarrhoea and abdominal pain. Examination shows mild peritonism and the rectal mucosa may be normal or show a non-specific proctitis. Sometimes a plain abdominal Xray shows a dilated colon with 'thumb printing', due to oedema of the bowel wall, which is confirmed by a barium enema. 1

Management In most patients the symptoms resolve with analgesia and intravenous fluids. Perforation is rare. A late complication is stricture formation.

RADIATION COLITIS Damage to the transverse colon may occur during upper abdominal radiotherapy and damage to the sigmoid colon and rectum during pelvic irradiation. In the acute phase

(during or immediately after treatment) the symptoms are bloody diarrhoea, tenesmus and abdominal pain. These are treated with a low-residue diet and rectal steroids if there is a proctitis. Later complications include the development of a chronic proctitis or colitis, with telangiectatic lesions which may bleed, benign ulcers and stricture formation. The proctocolitis and ulcers may sometimes improve with rectal or systemic steroids.

15

FUNCTIONAL BOWEL DISORDERS Incidence In the UK it is estimated that the prevalence is 10-22% of adults; 14-50% of these patients visit their GP with these symptoms. Patients with functional bowel disease make up 25-50% of new patients in gastroenterology outpatient clinics. These patients have abdominal symptoms with no evidence of underlying organic pathology. Many individuals do not seek medical advice, presumably because they understand the nature of their symptoms and may be able to attribute them to a particular cause; they thereby learn to avoid or live with them. Others will consult their GP, sometimes because of the discomfort experienced but often out of fear that the symptoms might indicate more serious disease. Some will then be referred to a specialist. This may be because of the severity or intractability of the symptoms, or because the presence of atypical features causes concern. More often, however, the referral will be made in order to reinforce the reassurance already given and, hopefully, to make treatment more effective. Specialists therefore tend to see a selected sample of patients who will often form the basis of clinical studies. Because the cause or causes are not known, and because the range of symptoms is wide and relates to the whole of the gastrointestinal tract, it is sensible to consider all the manifestations of functional bowel disorder as a single entity associated with multiple factors. At different times the same patient may experience either predominantly lower gastrointestinal symptoms (irritable bowel syndrome, IBS) or upper gastrointestinal symptoms (functional or non-ulcer dyspepsia). Functional bowel disorders commonly present in the third and fourth decades, with a slight predominance in women. In retrospect many patients can recall intermittent symptoms in childhood, often at times of stress, to which various labels may have been applied, e.g. bilious vomiting, grumbling appendix, abdominal migraine. Symptoms first presenting in the mid-40s onwards should be regarded more seriously, and as possibly indicating organic disease. Many of these older patients will none the less be found to have sigmoid diverticular disease, which has pathophysiological features in common with IBS. However, there is no convincing evidence that IBS in young adults progresses to diverticular disease in the middle-aged. Surveys of the general population show that symptoms of IBS are common: 30% of such a sample of 301 appar-

817

TABLE 15.44 Organic vs functional disorders in a sample of 2000 gastroenterology outpatients* Diagnosis

Number of patients

Definite non-organic Spastic colon Painless diarrhoea Painless constipation Depression and pain Anxiety and Gl symptoms Functional dyspepsia Others

888 449 107 39 50 24 77 59

Definite organic Peptic ulcer (Duodenal ulcer) (Gastric ulcer) Oesophagitis Carcinoma of stomach Postgastrectomy Inflammatory bowel disease (Crohn's disease) (Ulcerative colitis) Coeliac disease Infective diarrhoea Carcinoma of colon Gallstones Hepatitis Cirrhosis Alcoholism Other

980 197 (135) (62) 188 13 14 168 (57) (111) 26 21 28 48 11 21 16 229

* After Harvey, Salih and Read 1983. Lancet 1: 632-634. The study was based on 2000 new attenders at a gastroenterology outpatient clinic over a period of 5 years. Of these, 57 had a non-gastroenterological diagnosis and 75 remained undiagnosed.

ently healthy people had either abdominal pain, constipation or diarrhoea. When 2000 new attenders at a gastroenterology outpatient clinic in Bristol were prospectively studied over a 5-year period, about half turned out to have functional disorders. It is interesting to contrast these patients with the remainder found to have organic disease, as many of the organic conditions have to be considered in the differential diagnosis of functional bowel disorders (Table 15.44).

Aetiology Many aetiological factors have been postulated for functional bowel disorders. Whether the bowel is inherently irritable, or is normal until irritated, cannot be determined. No clear pattern of inheritance of functional bowel disorders has been demonstrated; although it may sometimes appear to be familial, this can probably be explained by common environmental factors.

1

818

Fig. 15.30

Motility disturbance 1 Hyperreactivity of the gut, both in the sense of provoking reflex contraction and of a lowering of the threshold to stimuli causing pain, has been demonstrated in many ways, including balloon distension studies. Pressure transducer studies have shown that some patients have increased frequency and strength of small intestine motility.

Previous gut infection The postinfective variant of IBS may comprise up to a third of all patients. Damage to the epithelium by microorganisms, their toxins or bile acids may allow stimulation of mast cells or paracrine cells initiating the syndrome. Dietary factors Many patients with IBS have diets high in refined carbohydrates and low in fibre. Food intolerance is often suspected by patients: in different studies its estimated frequency varies between 6% and 60%. Although exclusion diets, with recurrence of symptoms when the suspected food is reintroduced, would seem to support this possibility, relatively few double-blind studies have been undertaken. True allergy, in an immunological sense (using such criteria as a rapid reaction to small doses of antigen accompanied by raised IgE levels and positive skinprick tests) is exceedingly rare. The usually transient cows' milk intolerance of infants is the best-known example. Alternative non-immunological mechanisms have been postulated to account for some apparent reactions, which require large amounts of the suspect food and come on so slowly that the offending food may not be recognized. It has been suggested that changes in gut flora to give high counts of facultative anaerobes (analogous to changes produced by antibiotic therapy) may enhance the production of toxic metabolites from undigested food residues. Psychological The psychosomatic mechanisms postulated seem to be borne out by the frequently found evidence of stress and

SUMMARY 9 Contributory factors in functional bowel disorders • • • • •

Motility disturbance Altered sensory threshold Previous gut infections Altered gut flora Dietary Fibre deficiency Food intolerance Immunological ('allergy') Non-immunological Food additives • Psychological Anxiety Depression

CASE STUDY 15.6 ABDOMINAL PAIN AND CHANGED BOWEL HABIT IN A 47-YEAR-OLD MAN History A 47-year-old white Caucasian housewife presented to clinic with a 4-month history of altered bowel habit and worsening abdominal pain. Before her illness she opened her bowels once a day with a formed stool. Now her bowel habit was erratic, with a few days of constipation during which she passed hard pellet-like stools with difficulty once a day, alternating with several days of opening her bowel up to five times a day, with a semiformed stool containing mucus. She saw spots of blood on the toilet paper after straining when constipated. She never awoke at night to defecate, but on 'diarrhoea' days she opened her bowels several times during the first 2 hours after getting up, and had tenesmus. She had episodes of severe colicky left iliac fossa pain, which tended to occur before and was partially relieved by defecation. She had abdominal bloating, low back pain and urinary frequency. She had no upper gastrointestinal symptoms. Her appetite was poor but she had not lost weight. She felt tired. She had had a hysterectomy for uterine fibroids 5 months previously. There was no other relevant history and she was on no medication. Her mother had died of bowel cancer at the age of 62. Examination This revealed a tense, anxious but not ill middle-aged woman. Her abdomen was slightly distended with gas and her sigmoid colon was tender and palpable in the left iliac fossa. Questions 1. What is the most important disease that must be excluded? 2. What other disorders should enter the differential diagnosis? 3. What investigations are necessary?

Investigation The full blood count, biochemical profile, C-reactive protein, urinalysis, MSU and pelvic ultrasound were normal. Colonscopy showed a 5 mm stalked polyp in the sigmoid colon 30 cm from the anal margin. The rest of the colon, from anal margin to caecum, was normal. The polyp was excised by diathermy snare. Questions 4. What are the advantages of colonoscopy in the investigation of suspected colonic disease? 5. What types of polyp can be present in the colon? Histology showed that the polyp was metaplastic and not adenomatous. Biopsies from the rest of the colon were normal. Management A diagnosis of irritable bowel syndrome (IBS) was made. Question 6. Outline the management of

IBS.

The benign nature of the disorder was explained and she was advised to take a high-fibre diet. An antispasmodic, mebeverine, and additional fibre (sterculia) were prescribed. On review in 2 months she was a little better, although she still found the abdominal pain troublesome. She remained very tense and was concerned about her continuing symptoms. Amitriptiline 25 mg nocte was started and on review 2 months later she was much more relaxed and largely symptom free. She was more positive about the future. Six months later she was well off all treatment. Discussion In a middle-aged woman the presenting symptoms raised the

15

possibility of colonic cancer, particularly with the family history of the disease. She had blood on the toilet paper but the amounts were small and the nature of the bleeding suggested that it was from the anal canal rather than from higher up. The location of the pain and the type of bowel irregularity suggested a colonic disorder. The nature of the change in bowel habit, which did not include persistent diarrhoea, suggested that she did not have inflammatory bowel disease. There were no worrying symptoms such as weight loss or vomiting. Many of the features suggested irritable bowel syndrome (IBS), namely erratic bowel habit, increased frequency of defecation without liquid stools, mucus PR, tenesmus and early morning stool frequency. The absence of nocturnal defecation supported the diagnosis of non-organic disease. The easing of abdominal pain after defecation is seen in both non-organic and organic colonic disease. From middle life onwards colonic diverticulosis may occur, but the symptoms are similar to those of IBS and may have a similar aetiology. Patients with IBS may have non-gastrointestinal symptoms, such as malaise, tiredness, backache and urinary frequency. Headache, dysuria and dyspareunia can also occur. In IBS investigations are normal because the bowel is not diseased, although its motility is disturbed. In this case a colonoscopy was essential to exclude serious colonic disease, especially carcinoma. Sigmoidoscopy and barium enema are probably as good in the diagnosis of cancer, but in a patient with a family history of colon cancer identification of adenomatous polyps is essential, and so colonoscopy is preferred to barium radiology. Moreover, colonoscopy allows biopsy of lesions and the excision of polyps. The aetiology of IBS is unclear (see p. 818), but life events and the patient's psychological response to

819

CASE STUDY 15.6 CONTINUED

them may be important. This patient had had a hysterectomy just before the onset of IBS symptoms. Explanation and reassurance are vital in the management of IBS. The patient must realize that improvement is gradual and episodic, and is almost never rapid. The role of stress in precipitating and exacerbating symptoms must be explained. She was started on a highfibre diet, which may be beneficial in most cases of IBS, especially those with pure constipation or constipation alternating with increased stool frequency. In the early stages of treatment additional fibre in the form of sterculia is helpful, being less associated with gas

formation than methylcellulose or isphagula. However, in some patients diarrhoea, bloating and pain are exacerbated by extra fibre. She was started on an antispasmodic, although evidence for their benefit is largely anecdotal. The placebo response is a major feature in the treatment of IBS. In the present case the psychological state of the patient inhibited the response to treatment, and she improved greatly after the introduction of the tricyclic amitriptyline. This drug has been found to be of particular benefit in functional gastrointestinal disorders associated with anxiety and/or depression. Benzodiazepines were used in the past with benefit, but

anxiety. None the less, attempts to modify autonomic nervous activity pharmacologically have met with limited success, perhaps partly because the less accessible enteric nervous reflexes may be at fault. Much remains unexplained. It is not known what determines which of the various symptom patterns will develop in an individual patient, nor what makes some individuals accept the situation without recourse to orthodox, or even complementary, medical advice. A study screening consecutive non-complaining blood donors showed that the psychoneurotic symptomatology in the non-complaining IBS subjects more closely matched that of IBS patients than that of the remaining blood donors. It is not clear whether the differences between patients and the normal population are quantitative or qualitative.

Clinical features 1 The descriptive names given to functional bowel disorders indicate many of the symptoms - spastic colon, mucous colitis (in fact a misnomer, as the colon is not inflamed), and functional dyspepsia. Globus hystericus is difficulty with swallowing which has a non-organic basis. Most patients will experience alteration of bowel habit, many will have pain and bloating, and distension and excess flatus are common in the predominant lower gastrointestinal IBS (Table 15.45).

1 MCQ 15.17 820

their potential for addiction has severely limited their use. The prognosis for IBS is good for most patients: follow-up studies show that 80% of patients are well on no treatment 5 or more years later. The remainder have recurrent attacks or persisting symptoms Of varying severity. Good prognosis is associated with a short history, onset after bowel infection, constipation and male gender. The patient was found to have a metaplastic polyp at colonoscopy which, unlike adenomatous ones, has no malignant potential and is of no significance.

TABLE 15.45 Symptoms more commonly associated with functional than organic disease. The probability of functional bowel disease inireases the more these symptoms are present The criteria Ire better for women than men and are less predictive with increasing age Upper abdominal symptoms (non-ulcer dyspepsia) Oral flatulence and aerophagy Morning nausea and vomiting Symptoms worse with stress Intestinal symptoms (irritable bowel syndrome) Borborygmi Abdominal distension or bloating Pain relief with bowels open More frequent stools with the onset of pain Looser stools with the onset of pain Passage of mucus per rectum Increased rectal flatulence Sensation of incomplete rectal evacuation Urgency of defecation Straining to finish defecation Proctalgia fugax Oesophageal symptoms (irritable oesophagus) Globus

Irritable oesophagus This is a recurring retrosternal pain which may be severe and associated with globus, dysphagia, reflux-like symptoms or dyspepsia. Anxiety levels are high and angina is suspected, but cardiac and gastro-oesophageal tests are normal. Patients often have associated irritable bowel symptoms.

Non-ulcer dyspepsia (p. 782) Pain after food, with nausea, distension, belching and regurgitation, in patients who have had negative gastroscopy and gallbladder studies, are the hallmarks of nonulcer (or functional) dyspepsia, though the symptoms may overlap those of IBS. Unlike IBS, which does not progress to any other condition, up to 20% of patients with nonulcer dyspepsia may subsequently develop demonstrable peptic ulceration or oesophagitis. Fifty per cent of patients have Helicobacter pylori in their stomachs.

Pain It has long been recognized that pain arising from the gut is not always localized to the midline. In addition to 'classic' subumbilical griping, pain in many other sites and radiations, sometimes extra-abdominal, can occur. This can lead to a wide differential diagnosis (Table 15.46). Although not feasible as a routine diagnostic procedure, it can be useful to perform studies in which a balloon attached to a colonoscope is inflated at different sites as it is withdrawn from the caecum. This not only confirms that colonic distension can produce pain at both conventional and unconventional sites, but may also exactly reproduce a patient's pain. The severity and quality of pain may vary considerably, even mimicking biliary colic and other acute

TABLE 15.43 Differential diagnosis of typical and atypical IBS and functional dyspepsia Functional bowel disorder

Differential diagnosis

Typical IBS

Inflammatory bowel disease (Crohn's>ulcerative colitis) Colorectal cancer Diverticular disease Infective diarrhoea Malabsorption (coeliac disease) Endocrinopathies Thyrotoxicosis Hypothyroidism Carcinoid syndrome

Atypical IBS Right iliac fossa pain Right hypochondrial pain Lett hypochondrial pain Back pain Loin pain Menstrual exacerbation Dyspareunia

Appendicitis, Crohn's disease Gallstones Ischaemic heart disease, chronic pancreatitis Pancreatic disease Spinal osteoarthritis Renal disease Endometriosis Pelvic inflammatory disease

Functional dyspepsia

Peptic ulcer Oesophagitis Gastric cancer Ischaemic heart disease

Irritable oesophagus

Gastro-oesophageal reflux Oesophageal dysmotility Angina

abdominal emergencies. Palpable and tender bowel in the left iliac fossa is a relatively non-specific finding, but evidence of spasm (by feeling transmitted pressure waves in the reservoir bulb on sigmoidoscopy) or the reproduction of pain by the above procedure are particularly helpful in making a positive diagnosis. Proctalgia fugax is a transient shooting pain in the rectum, seen in IBS patients.

15

Constipation Constipation may be the predominant presenting symptom in functional bowel disorders, but often alternates with diarrhoea and may be associated with pain. The stools may be pellet- or ribbon-like and be commonly associated with the passage of mucus. Rectal bleeding must always be fully investigated, even if only to confirm that it is due to haemorrhoids. Although some patients may have large amounts of dry stool in the rectum with little awareness of its presence, others, despite not having a bowel action for several days, may have an empty rectum with greatly delayed colonic transit. Constipation dating back to childhood commonly emerges in the history, when 'potty training' may have been at fault, the urge to defecate repeatedly ignored, and purgatives regularly administered.

Diarrhoea Diarrhoea is often a distressing symptom because of the uncertainly and anxiety it may generate in an already anxious patient. The fear of faecal incontinence is a real one and, as the diarrhoea frequently occurs during the morning, the journey to work may be dreaded. Eating may precipitate the urge to defecate. The stool may vary between liquid and semiformed. There is often much flatus, and another uncertainty is thus whether the urge to pass wind may result in passage of diarrhoea and consequent soiling. The patient may be greatly relieved to be asked about this, as he or she may be too embarrassed to volunteer the symptom. A sense of wanting to evacuate when there is nothing there (tenesmus), or of incomplete defecation, is also particularly common. Although the patient may think large amounts are being passed, stool weights are in fact within the normal range. Diarrhoea occurs less commonly at other times of the day, but unlike inflammatory bowel disease or other organic diarrhoeas does not usually disturb sleep. Rumbling and gurgling (borborygmi) accompany diarrhoea and flatus.

Associated symptoms Other associated, non-specific symptoms may confuse the diagnosis. Sweating, tremor, hyperreflexia and tachycardia in association with diarrhoea are usually due to anxiety rather than thyrotoxicosis; a marked sinus arrhythmia, indicating autonomic overactivity, is frequently present. Gynaecological symptoms, e.g. increased severity of pain premenstrually, low back pain and dyspareunia, are common and often lead to unnecessary gynaecological

821

investigation. Headache, low back pain and fibromyalgia syndrome occur. Some patients have urinary symptoms, especially frequency ('irritable bladder'). Psychological symptoms are common, and underlying stress and disorders of mood and personality are frequently invoked as major factors in pathogenesis. None the less, the results of formal studies have often been conflicting. The perennial problem of whether anxiety provokes symptoms or vice versa cannot be clearly resolved, although the vicious circle of symptoms (anxiety -> more symptoms —> more anxiety) is real enough. Although depression may present with predominantly functional bowel symptoms (which regress with antidepressants), this is not as common as was once thought. Even if there were initially other reasons for a patient's anxiety, the symptoms frequently reinforce it. An important part in history taking is to ask the patient what they consider the cause to be. Frequently a fear of cancer, which they were reluctant to voice, will be revealed. Many will also be worried about inflammatory bowel disease, a worry perhaps reinforced by a previous vague diagnosis of mucous colitis or peptic ulcer.

Examination The patient often shows signs of anxiety, including sweaty hands and a tachycardia. There are no signs of masses or organomegaly. The abdomen may be diffusely and nonspecifically tender and the patient's response to the tenderness may be exaggerated. Sigmoidoscopy shows normal rectal mucosa, but air insufflation may reproduce the pain.

Prognosis Morbidity from functional bowel disorders can be considerable. There have been few long-term studies, but in one such, of 77 of 91 patients recalled after 6 years 29 had no bowel problems and many of the 44 who still had IBS symptoms found the condition easier to cope with. In view of the difficulties in making a positive diagnosis, it is notable that only four patients had a new diagnosis made, invariably prompted by a change in the clinical picture.

Investigation and management

822

The first problem that arises in the management of functional bowel disorder is the confidence with which one can make the diagnosis and the extent to which further investigation should be undertaken. The need for a full history and examination (including sigmoidoscopy) is self-evident; the history may be further supplemented at the follow-up appointment, which should be given to every patient. Many important psychological and social factors may then be disclosed to a doctor who has earned the patient's confidence. All investigations should be ordered at the first visit and the patient told that they are expected to be normal. To go on asking for 'just another test' counters the essential reassurance given. In hospital practice the stool

should be examined for pathogens and parasites if the history is of recent diarrhoea, especially after foreign travel. A barium enema or colonoscopy to exclude other colonic disease is not necessary in all patients, particularly if they are young with typical symptoms. Sometimes, however, the patient will require this investigation for complete reassurance. The most important diagnoses to exclude are inflammatory bowel disease in young adults and colorectal tumours in older patients. Patients with dyspepsia or chest pain may need upper GI endoscopy to exclude upper GI disorders and provide reassurance. The less typical the clinical presentation the more the exclusion of other diseases may be necessary, but a positive diagnosis should be made rather than arriving at one purely by exclusion. Such a minimalist approach is therapeutically effective and safe, with the proviso that fuller investigation or even reinvestigation is undertaken in the following circumstances: • Patients over 40 years of age presenting with symptoms for the first time; • Any change in the pattern of symptoms, or the development of new symptoms which sound organic; • The presence of additional symptoms which are not part of IBS, such as weight loss, rectal bleeding or fever. At the end of the first consultation the physician should be able to make a positive diagnosis and suggest an explanation for the cause of the symptoms. Even if the symptoms are bizarre, their existence should not be questioned. Patients can be specifically reassured that the physician does not think that they have cancer, peptic ulceration or intra-abdominal inflammatory conditions. The patient should be asked what they feared might be the cause, and then be reassured by pointing out how common the problem is and the generally good prognosis. After identifying any provocative factors, the doctor should suggest modifications in the patient's lifestyle that might be beneficial. The constipated may need to increase dietary fibre intake as well as adequate daily fluid. Smoking and excess alcohol consumption should be stopped and the effects of other medications reviewed. At a subsequent interview the results of normal tests can be used to reinforce the fact that there is no serious underlying cause for the symptoms. Patients should be encouraged to return if symptoms alter or complications such as weight loss develop.

Medication Drugs play only a minor role in management. When properly conducted, all drug trials in IBS and functional dyspepsia have shown very high rates of response to placebo (often over 50%). Antispasmodics Anticholinergic drugs may relieve pain but are limited in dosage by their side-effects. The directly acting smooth muscle relaxant mebeverine is widely used, and in some studies has been shown to be superior to placebo. An old

remedy, peppermint oil, in a new colonic-release capsule, is probably as effective. Opiate analgesics should always be avoided. Antidiarrhoeals Disabling morning diarrhoea can be treated with codeine phosphate on rising, repeated if necessary. If this is not effective, loperamide can be substituted. Constipation should be avoided. Laxatives and purgatives Only bulking agents should be encouraged. Many constipated patients may have been using purgatives for many years and these should be stopped, despite the fears and reluctance of patients to abandon them. Simple suppositories, or even periodic enemas, may have to be given temporarily while attempts are made to re-educate the bowel. Psychotropics Long-term use of benzodiazepine or other tranquillizers must be avoided, but they may be necessary as a short-term measure to combat periods of stress. Tricyclic antidepressants, especially amitriptyline or selective serotonin reuptake inhibitors (e.g. fluoxetine) may be helpful, particularly if diarrhoea is present, as the anticholinergic side-effect tends to have a constipating effect. Prokinetics The postprandial distension and nausea of non-ulcer dyspepsia is often greatly helped by metoclopramide syrup or tablets before meals. If this is ineffective, or if the drug is not tolerated because of somnolence or dyskinetic movements, domperidone should be substituted. Antiadd drugs. Simple antacids, H2-receptor antagonists or proton pump inhibitors may be helpful in patients with dyspepsia. Helicobacter pylori eradication This may benefit some patients with non-ulcer dyspepsia and Helicobacter in their stomachs. Calcium channel blockers and nitrates These may help some patients with oesophageal symptoms. 5 HT-3 antagonists These may benefit some patients with abdominal pain and diarrhoea.

SELF-INDUCED BOWEL DISEASE Self-induced bowel disease may be a variant of Munchausen's syndrome, where patients deliberately invent symptoms (p. 239), or be a result of drug abuse. Both problems are rare, and tend to occur in young females. The diagnosis is often well disguised. Invention of symptoms The patient who is inventing symptoms most commonly presents with severe abdominal pain or with gastrointesti-

nal bleeding (sometimes fictitious and sometimes simulated by the ingestion of animal blood). The history may be convincing but background information is vague. Examination often reveals an abdomen with multiple scars from when surgeons have been misled in the past. If this diagnosis is suspected, investigations should be minimal and the treatment is observation and reassurance. Psychiatric support rarely helps.

15

Laxative abuse The patient abusing laxatives usually presents with profuse watery diarrhoea secondary to purgative abuse. There may be several litres of watery diarrhoea a day, with consequent weight loss, dehydration and hypokalaemia. The diagnosis may be suggested by the appearance of pigment deposition in the rectal mucosa at sigmoidoscopy (melanosis coli). It may be confirmed by chemical analysis that purgatives such as phenolphthalein, bisacodyl, sennosides, danthrone or magnesium are present in the faeces or urine, or by finding the patient surreptitiously taking them. Confrontation should be avoided, and psychiatric treatment is often disappointing. Some patients may also abuse diuretics.

DISEASES OF THE PERITONEUM

PERITONITIS Acute bacterial peritonitis This follows perforation of an abdominal viscus or abdominal diverticulum as a result of ulceration, inflammation, ischaemia, trauma or (rarely) malignancy, or follows infection in the female genital tract. The patient develops an acute abdomen, with severe abdominal pain, nausea, vomiting, fever and tachycardia, followed by shock. Septicaemia and multiorgan failure can occur. On examination in the early stages there may be guarding, rebound tenderness and scanty bowel sounds. Later the abdomen becomes rigid and extremely tender, with absent bowel sounds. There is often a neutrophil leukocytosis and there may be metabolic acidosis. A plain erect abdominal or chest X-ray shows free gas under the diaphragm. Treatment requires a laparotomy if there is a ruptured viscus. Preoperatively the patient will need nasogastric suction, intravenous fluid and electrolytes, oxygen, opiate analgesia and broad-spectrum antibiotic therapy, including cover for anaerobic organisms (e.g. amoxicillin, gentamicin and metronidazole).

Primary (spontaneous) peritonitis This is acute or subacute bacterial inflammation of the peritoneum. It occurs in patients with cirrhotic or malignant ascites, immune deficiency states and after splenectomy, and in children with nephrotic syndrome or urinary tract infections. The commonest organism is Streptococcus pneu-

823

moniae. Pneumococcal vaccination or lifelong penicillin therapy will reduce the risk to splenectomized patients.

Tuberculous peritonitis (see p. 816) Chemical peritonitis develops when a sterile but irritant fluid, e.g. bile, blood or pancreatic secretions, leaks into the peritoneal cavity. Granulomatous peritonitis can be caused by infections (tuberculosis, fungi, parasites), secondary adenocarcinoma, sarcoidosis, Crohn's disease or foreign bodies (e.g. starch). Vasculitic peritonitis occurs when there is gut involvement in SLE, polyarteritis nodosa, systemic sclerosis, dermatomyositis or Henoch-Schonlein purpura. Familial Mediterranean fever is characterized by recurrent episodes of acute self-limiting serositis, especially involving the peritoneum (see p. 1263).

PERITONEAL MALIGNANCY Secondary carcinoma is the commonest cause of peritoneal malignancy. Most cases result from adenocarcinoma of the stomach, colon, pancreas, ovary, lung or breast. Primary mesothelioma is rare, slightly more common in men, and usually associated with asbestos exposure. About 50% of patients have signs of asbestosis on chest X-ray.

Clinical features and investigations The main symptoms are abdominal pain, nausea, vomiting, weight loss and abdominal swelling due to ascites. The ascitic fluid has a high protein content, may be bloodstained, and may contain malignant adenocarcinoma or mesothelial cells. Laparoscopy or laparotomy is sometimes necessary to make a diagnosis. Differential diagnosis includes tuberculous peritonitis, cirrhosis and Budd-Chiari syndrome.

Management and prognosis The prognosis is poor in secondary carcinoma and mesothelioma. Radiotherapy or chemotherapy may sometimes help in palliation of secondary carcinoma. Patients' symptoms may be helped by regular paracentesis.

FURTHER READING ON COLORECTAL DISEASE

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Ferzoco L B, Raptopoulos V, Silen W 1998 Acute diverticulitis. N Engl J Med 338:1521-1526. Halligan S, Fenlon H M 1999 Virtual colonoscopy. Br Med J 319:1249-1252. Jones E M, MacGowan A P 1998 Back to basics in management of Clostridium difficile infections. Lancet 352:505-506. Kamm M A 1998 Faecal incontinence. Br Med J 316:528-532. Midgley R, Kerr D 1999 Colorectal cancer. Lancet 353:391-399. Present D H et al 1999 Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med 340:1398-1405

Rodriguez L A G , Ruigomez A 1999 Increased risk of irritable bowel syndrome after bacterial gastroenteritis: cohort study. Br Med J 318:565-566 Satsangi J, Parkes M, Jewell D P, Bell J I 1998 Genetics of inflammatory bowel disease. Clin Sci 94:473-478.

THE PANCREAS The pancreas is a retroperitoneal organ which, along with the common bile duct, drains through the medial wall of the second part of the duodenum via the ampulla of Vater. The pancreas has exocrine and endocrine functions. Duodenal release of the hormone secretin results in acinar bicarbonate secretion. The pancreatic enzymes trypsin and chymotrypsin break down proteins, lipase digests fats, and amylase acts on starch. These enzymes are released in response to cholecystokinin and the activity of the parasympathetic nervous system. The endocrine cells of the pancreas are localized to the islets of Langerhans and make up about 1% by volume of the pancreas. The most numerous endocrine cells are the (3 cells secreting insulin but also present are a cells secreting pancreatic glucagon, D cells secreting somatostatin and PP cells secreting pancreatic polypeptide. With disorders of the pancreas, exocrine function is usually lost before endocrine function.

Clinical features of pancreatic disease The symptoms of pancreatic disease include pain (severe, epigastric or central abdominal, and often radiating through to the back), steatorrhoea (indicating lipase deficiency), weight loss, nausea, vomiting, and those of hyperglycaemia. Patients with acute pancreatitis may present with an acute abdomen. Other features include anaemia, jaundice due to common bile duct obstruction or associated liver disease, an abdominal mass, ascites and pleural effusion (usually left-sided).

Investigation of pancreatic disease General A full blood count is done to look for anaemia and for the white cell count (high in acute pancreatitis and abscesses etc., low in Schwachman's syndrome; see p. 827). A serum amylase is only indicated if a diagnosis of acute pancreatitis or continuing pancreatic obstruction due to an abscess or pseudocyst is being considered. Pancreatic proteases play a role in making vitamin B12 available for absorption in the terminal ileum, and a deficiency may result in megaloblastic anaemia. Three-day faecal fats are useful to assess the degree of steatorrhoea, and very high levels (more than 100 g fat per day) are typical of pancreatic insufficiency. Tube pancreatic function tests Tube pancreatic function tests involve the passage of a thin catheter into the second part of the duodenum. The duodenal contents are then aspirated for measure-

15

CASE STUDY 15.7 EPIGASTRIC BACK PAIN IN A 68-YEAR-OLD MAN A 68-year-old white Caucasian male coalminer presented with a 3-month history of epigastric pain. The pain had become increasingly severe and was worse with eating. It radiated through to his back. His appetite had become reduced and he had lost 12kg and now weighed 68kg. He was a lifelong smoker, smoking 15 cigarettes a day. He drank about 25 units of alcohol a week. Examination He looked thin and unwell. There was early jaundice and rectal examination showed him to have steatorrhoea. Examination of the heart and lungs was normal. Abdominal examination showed erythema ab igne (CD Figure 15.29) over the upper abdomen and epigastric tenderness. Question 1. What is the most likely cause of the pain and why? Investigations Haemoglobin 13.8 with a normal white cell and platelet count. Urea and electrolytes normal. Liver function tests showed a bilirubin of 85 umol/L with a cholestatic pattern of liver enzymes showing an alkaline phosphatase of 910 IU/L, an ALT of 105 U/L and -GT of 272 U/L.

ducts and gallbladder were all dilated. A CT scan confirmed the findings. Endoscopic retrograde cholangiopancreatography (ERCP) (CD Fig. 15.30) was performed and showed strictures in the head of the pancreas, with proximal dilatation of both the bile duct and the pancreatic ducts. An imaging wire was passed through the bile duct stricture and the stricture was brushed for cytology. A plastic stent was then placed through the bile duct stricture and produced good drainage of bile. Cytology of the brushings showed adenocarcinoma cells. Questions

3. What further investigations are needed? 4. What is the treatment of choice? A CT scan was performed (Fig. 15.31, p. 832) and showed that the tumour was invading the superior mesenteric artery and the portal vein. The patient was reviewed at a joint radiological and surgical meeting and it was decided that a Whipple's procedure to remove the tumour was not practical. Six weeks later the plastic stent was removed and replaced by an expanding metal stent to allow long-term relief from jaundice and itching.

Question

Question

2. What further investigations are indicated?

5. What further treatment is indicated?

An abdominal ultrasound showed a 3 cm solid mass in the head of the pancreas. The bile duct, intrahepatic

The aim of treatment in this patient is palliation. In particular, pain needs to be controlled by analgesics,

ment of bicarbonate and pancreatic enzymes, after stimulation by an intravenous pharmacological dose of cholecystokinin and secretin, or by a Lundh test meal, which consists of a 500 mL standard mixture of fat, protein and carbohydrate.

including opiates if necessary. Non-steroidal anti-inflammatory drugs may help. The patient needs to be advised about diet and given supplements if necessary. Patients with a blocked pancreatic duct have problems with fat malabsorption because of lack of pancreatic lipase. They may benefit from taking pancreatic enzyme supplements and substituting dietary fat with carbohydrate. Discussion Severe epigastric pain radiating to the back and associated with weight loss is commonly due to carcinoma of the pancreas in older patients. Epigastric pain after eating commonly occurs in patients with gastric ulcers, gastric cancers and pancreatic disease, whereas duodenal ulcer pain is often improved by eating. Alternative diagnoses are carcinoma of the stomach, benign gastric ulceration or chronic pancreatitis. All patients under the age of 80 should be considered for surgery, but advanced disease is usually present at the time of presentation. If patients are treated palliatively the prognosis is very variable and depends on tumour growth and the development of metastases. Some patients only survive a few weeks, whereas others can survive 5 years. When a pancreatectomy is performed for carcinoma of the head, body or tail of the pancreas, the 5-year survival rate is under 10% because the tumours spread early to adjacent lymphatics and the liver. The 5-year survival rate for carcinoma of the ampulla of Vater is higher, probably because they present earlier.

Tubeless pancreatic function tests Tube tests are uncomfortable for patients, and oral tests (Fig. 15.27) are fortunately now available. In the PABA test, pancreatic chymotrypsin cleaves N-benzoyl-

825

L-tyrosyl-p-aminobenzoic acid; the resulting paraaminobenzoic acid (PABA) is absorbed and the urinary PABA is measured in a 6-hour collection. To exclude possible intestinal malabsorption, a trace dose of 14C-PABA or para-aminosalicylic acid (PAS) is given at the same time and urinary radioactivity or PAS measured. The test is invalidated by paracetamol and cotrimoxazole and is dependent on normal gastric emptying and renal function. A similar test involves the cleavage of fluorescein dilaurate by pancreatic esterase, and subsequent measurement of urinary fluorescein.

FIG. 15.27 Tubeless pancreatic function tests A The PABA test involves chymotrypsin cleavage of N-benzoyl-tyrosyl and the subsequent measurement of PABA in urine or plasma. B The fluorescein test involves esterase cleavage and the subsequent measurement of fluorescein in urine. If either test is abnormal, the basic chemical (i.e. PABA and fluorescein) should be given on a separate day to exclude a problem with intestinal malabsorption.

Imaging techniques The pancreas is relatively difficult to image because of its retroperitoneal location. Plain abdominal X-ray is often unhelpful, but pancreatic calcification may be seen with chronic pancreatitis and a 'sentinel loop' of dilated duodenum may be seen over the pancreas in acute pancreatitis. Ultrasound, CT or MRI are useful in delineating abnormal anatomy and can be used to direct needle biopsies. Endoscopic retrograde pancreatography (ERP) is usually combined with cholangiography (ERCP). ERP is particularly useful in demonstrating abnormalities due to chronic pancreatitis or carcinoma. Angiography may help to diagnose pancreatic tumours and to assess operability.

SUMMARY 10 Investigations of pancreatic disease CONGENITAL PANCREATIC ANATOMICAL ABNORMALITIES

General Full blood count Liver function tests and serum proteins Serum amylase Blood glucose Serum B12 Three-day faecal fat excretion Tube pancreatic function tests Cholecystokinin-secretin test Lundh meal Tubeless pancreatic function tests PABA test Fluorescein dilaurate test Imaging techniques Plain abdominal X-ray Ultrasound CT scan ERCP Angiography

1

826

MCQ 15.18

2

MCQ 15.19

Embryologically the pancreas is derived from an anterior and a posterior bud, which normally fuse and drain into the medial wall of the duodenum. Developmental abnormalities include: 1. Accessory pancreatic tissue, which is separate from the body of the pancreas. This is found in about 10% of autopsies, with ectopic tissue most commonly located in the wall of the stomach and intestine. Rarely it may ulcerate and cause gastrointestinal bleeding, or be the site of carcinomatous change. 2. Annular pancreas, where the second part of the duodenum is encircled by pancreatic tissue. This is a rare abnormality which usually presents in the first months of life with duodenal obstruction; it requires a bypass gastrojejunostomy. Mild cases are asymptomatic, but the condition may present for the first time in adults with abdominal pain and vomiting, sometimes associated with peptic ulcer or obstructive jaundice. 3. Pancreas divisum, caused by failure of the two pancreatic ducts to fuse. Most of the gland is drained through the accessory ampulla. It is associated with an increased incidence of acute pancreatitis. Sphincterotomy of the accessory ampulla may reduce the number of attacks.

TABLE 15.47 Pancreatic and intestinal complications of cystic fibrosis Effect

Complication

Pancreatic insufficiency

Enzyme deficiency Diabetes mellitus Intestinal obstruction Volvulus Peritonitis following perforation Polyhydramnios in utero Intussusception Intestinal obstruction

Meconium ileus

Meconium ileus equivalent

CONGENITAL PANCREATIC FUNCTIONAL ABNORMALITIES Cystic fibrosis 1 Cystic fibrosis is the most important congenital disease of the pancreas. The pancreatic and intestinal effects of the disease are summarized in Table 15.47. Other complications include cirrhosis of the liver (Ch. 16), pulmonary disease (Ch. 13) and male infertility due to atrophy or absence of the vas deferens, seminal vesicles and epididymis. Cystic fibrosis is characterized by hyperviscous secretions containing excessive sodium, mucus and protein from exocrine glands, which result in the plugging of ducts leading to destruction of glandular tissue (Table 15.47). Diagnosis is made by demonstrating excessive sodium in sweat. Pancreatic insufficiency The destruction of pancreatic exocrine acini is often rapid. The patient develops steatorrhoea and oedema secondary to hypoproteinaemia. A good response is seen with the introduction of pancreatic enzyme supplements taken with each meal, and proton pump inhibitors and H2-receptor antagonists can help by raising duodenal pH to increase pancreatic enzyme activity. High-strength protease preparations can result in fibrous strictures of the colon. Supplements of vitamins A, D, E and K also have a role in the presence of steatorrhoea. With severe malnutrition, dietary supplements of easily absorbed medium-chain triglycerides and protein hydrolysates in the form of milkshakes or cooking additives may be helpful. Diabetes mellitus due to the destruction of pancreatic endocrine tissue is a late event. Meconium ileus In cystic fibrosis the meconium protein content at birth is about eight times the normal level. As a result, neonates with cystic fibrosis often present with intestinal obstruction, which may be complicated by a volvulus or peritonitis due to a perforation. Instillation of high-osmolarity

diatrizoate (e.g. Gastrografin) causes the plug to shrink and allows its passage down the gut. If a perforation or volvulus has occurred, surgery is usually needed. Fetal meconium ileus in utero causes maternal polyhydramnios.

15

Meconium ileus equivalent 'Meconium ileus equivalent' is, as the name suggests, a problem similar to meconium ileus, but it occurs later in life and is complicated by the presence of faeces. A highfibre diet to soften the stool, and laxatives, are effective in mild cases. N-acetylcysteine can be used as a mucusclearing agent. In severe cases diatrizoate is usually effective in shrinking the faecal mass; surgery should be avoided if possible, because of the high mortality from intestinal and pulmonary complications. Prognosis The prognosis is variable, but many affected children are now surviving into their 30s and 40s.

Macroamylasaemia Macroamylasaemia is a condition of unknown aetiology characterized by large molecular weight amylase in the serum. It accounts for 2.6% of elevated serum amylase levels. The amylase may be bound to immunoglobulins or glycoproteins, and is too large to be excreted by the glomerulus like normal amylase. Consequently, very high serum amylase levels occur. The diagnosis can be confirmed by chromatography and by showing low urinary amylase and normal plasma trypsin and lipase levels. It is important to make the diagnosis to avoid mistaking the condition for acute pancreatitis. There is an association with coeliac disease. No therapy other than reassurance is needed for macroamylasaemia.

Schwachman's syndrome Schwachman's syndrome is the association of pancreatic enzyme deficiency, neutropenia, short stature and metaphyseal dysostosis. Sometimes there is also anaemia, thrombocytopenia and low intelligence. It is inherited as an autosomal recessive. The usual presentation is with steatorrhoea and failure to thrive in young children; a normal sweat sodium and chloride excludes cystic fibrosis. The pancreatic insufficiency is treated with pancreatic enzyme supplements and H2-receptor antagonists or proton pump inhibitors. Infections should be treated aggressively in the presence of neutropenia, which is associated with a deficiency of white cell precursors. The prognosis is usually good.

ACUTE PANCREATITIS 2 Acute pancreatitis is an acute inflammatory condition of the pancreas which results in necrosis of exocrine tissue. It

827

causes abdominal pain and is associated with high plasma and urinary pancreatic enzyme levels. The incidence is 10 per 100000 per annum in the UK and North America, and in Copenhagen in 1970-80 was 28.1 per 100000 in people over the age of 20. The median age is 53 years, with an equal sex incidence.

Aetiology Pancreatitis occurs as a result of pancreatic duct obstruction, bile and duodenal content reflux and direct action of toxins. In the UK about 80% of cases are due to gallstones or alcohol abuse. In some parts of the world (e.g. South America) alcohol abuse is the most important factor. Gallstones are thought to block pancreatic enzyme outflow, but may be passed via the ampulla of Vater before investigations are undertaken. In this situation gallstones are usually found in the gallbladder or in the common bile duct. The mechanism by which alcohol causes acute pancreatitis is controversial. It may be due to a rise in pancreatic duct pressure or to a direct action on acinar cell membranes. ERCP may cause acute pancreatitis, possibly as a result of increased pressure in the pancreatic duct. Exploratory laparotomy, other intra-abdominal operations and translumbar aortography may also be complicated by acute pancreatitis. Patients with a Polya partial gastrectomy with a 'blind' duodenal loop are at increased long-term risk. Acute pancreatitis due to viral infection (e.g. mumps) is rare, and is caused by viral destruction of acinar cells. Pancreatic tumours may cause pancreatitis by ductular obstruction. Many drugs have been reported as possible causes. It is often stated that types I, IV and V hyperlipoproteinaemia and hypercalcaemia are causes of acute pancreatitis, but studies have suggested that these associations are doubtful.

SUMMARY 11 Aetiology of acute pancreatitis • • • • • • • • •

Gallstones in common bile duct Alcoholism latrogenic - usually post-ERCP Trauma Viral - mumps and coxsackie B Pancreatic tumours Drugs, e.g. corticosteroids, oral contraceptives, thiazide diuretics Possibly hyperlipidaemia and primary hyperparathyroidism Idiopathic

1

828

MCQ 15.20

TABLE 15.48 Complications of acute pancreatitis Early Clinical Cardiac failure Renal failure Respiratory failure (ARDS) Hyperglycaemia Anaemia Jaundice Disseminated intravascular coagulation

Biochemical Uraemia Hypocalcaemia Hypoalbuminaemia Abnormal liver function Hyperglycaemia Metabolic acidosis Hypoxaemia

Late Pseudocyst Abscess Pancreatic duct stricture Ascites/pleural effusion Diabetes mellitus

Clinical features The main symptom of acute pancreatitis is severe abdominal pain. Its usual site is epigastric or hypochondrial, but it may occur around the umbilicus. In about half the patients it radiates through to the back. The onset is usually sudden, such that the main differential diagnosis is intestinal perforation. The pain settles within 48 hours in most cases. The other common initial symptom is vomiting. Examination reveals a patient in great pain with severe abdominal tenderness, and often guarding and rigidity. Bowel sounds are usually reduced. Extra-abdominal signs may include fever, tachycardia and hypotension. In severe cases, complications (Table 15.48) may supervene.

Investigation The diagnosis is made by finding a serum amylase at least four times the upper limit of normal. A smaller rise in serum amylase may be seen in patients with perforated peptic ulcer, intestinal obstruction, other intra-abdominal emergencies, diabetic ketoacidosis, after opiate analgesia, macroamylasaemia and renal and hepatic failure. If the serum amylase is less than four times the upper limit of normal, or if it is thought that the high amylase may be due to macroamylasaemia, a high amylase:creatinine urinary excretion, serum lipase or serum trypsin may be used as confirmatory evidence of acute pancreatitis. A plain abdominal X-ray may show a 'sentinel loop' of air-filled duodenum lying over the pancreas. It may also show evidence of ascites or intestinal ileus, which may complicate acute pancreatitis. Ultrasound or CT may demonstrate an oedematous enlarged gland, gallstones, and complications such as pseudocysts. The differential diagnosis of acute pancreatitis includes gastric or intestinal perforation, peptic ulcer disease, acute cholecystitis, intestinal obstruction, acute mesenteric ischaemia, ruptured aortic aneurysm and myocardial infarction.

indicator of a severe attack and is independent of the Glasgow Score. Initial treatment is to restore fluid and electrolytes by intravenous infusion. A central venous pressure line is helpful to monitor fluid replacement. Analgesia should be maintained with pethidine or buprenorphine; morphine is contraindicated because it causes spasm of the sphincter of Oddi. A sedative such as diazepam may be helpful. Nasogastric suction is indicated initially, and should be continued until there is evidence that gastric emptying is normal and any intestinal ileus has resolved. Neither drugs such as cimetidine, anticholinergics, glucagon, aprotinin (a trypsin and kinin inhibitor), antibiotics, somatostatin and calcitonin, nor peritoneal lavage or parenteral nutrition, have been shown to have overall benefit in clinical trials. Early endoscopic sphincterotomy is indicated in severely ill jaundiced patients with stones in the distal common bile duct.

15

Complications of acute pancreatitis

FIG. 15.28 Management steps in acute pancreatitis

TABLE 15.49 Indicators of severe acute pancreatitis • • • • • • • • •

White blood cell count over 15 x 109/L Glucose over 10mmol/L Urea over 16 mmol/L Pa02 below 8.0 kPa Calcium below 2.0 mmol/L Albumin below 32 g/L LDH over 600 units/L AST over 100 units/L Over 55 years of age

Management (Fig. 15.28) Acute pancreatitis may have a self-limiting short course, be associated with the development of late complications, or be very severe and result in early death from circulatory collapse. In order to predict severity and prognosis, a number of indicators are helpful (Table 15.49); if more than three of these are present there is a risk of early death or complications (Glasgow coma scoring system). A serum CRP >210mg/L in the first 4 days is an

The treatment of these severe problems (Table 15.48) is supportive (usually in an intensive care unit), with fluids, cardiac inotropes, oxygen, ventilation, dialysis, calcium and insulin as necessary. Pseudocysts are collections of pancreatic juice in the lesser sac, and may need surgical or endoscopic drainage into the stomach. Pancreatic abscesses are usually due to Escherichia coli infection and require surgical drainage and antibiotics. Persistent high serum amylase levels suggest pseudocyst or abscess formation. Ascites and pleural effusions due to a fistula from the pancreatic duct system into the peritoneal or pleural spaces are characterized by very high amylase concentrations in the fluid aspirate. The effusions can often be treated with drainage via a cannula, but sometimes surgical closure is required. The overall mortality rate is about 10% per attack; this rises with age and other indicators of severity. The mortality of initial attacks is more than 10 times higher than that of recurrent attacks, and is twice as high with gallstones as with alcoholism. The recurrence rate is greatly reduced by successful treatment of gallstones or alcoholism.

CHRONIC PANCREATITIS 1 Chronic pancreatitis is associated with the destruction of pancreatic exocrine tissue which persists even when the underlying cause has been removed. Inflammation is followed by fibrosis and atrophy. Chronic relapsing pancreatitis is a variant in which symptoms, such as pain, are intermittent. The disease may be further classified according to its aetiology and whether steatorrhoea or diabetes mellitus is present. Steatorrhoea implies loss of lipase due to advanced acinar damage; diabetes mellitus indicates severe loss of islet tissue and advanced disease.

829

In 1978-79 the prevalence of chronic pancreatitis in Copenhagen was 27.4 per 100000 adult population per year, with a 3:1 male preponderance. The median age at onset was 39. The annual incidence in Minnesota in 1960-69 was 3.5 per 100000 population. The incidence rises in areas with high alcohol intakes.

SUMMARY 12 Aetiology of chronic pancreatitis • • • •

Alcohol Gallstones Hereditary Pancreas divisum

• Hyperlipidaemia • Hypercalcaemia • Idiopathic

Aetiology Alcohol is by far the most important factor in cases where a cause can be identified. Protein precipitates have been found in the pancreatic juice of alcoholics with chronic pancreatitis, and it is suggested that these form plugs which block the small pancreatic ducts and cause acinar damage. Gallstones are a common cause of acute pancreatitis but a rare cause of the chronic form. In the hereditary form of chronic pancreatitis the children in affected families usually present in adolescence. It is inherited as an autosomal dominant, but penetrance is variable. Pancreas divisum, which occurs when the ventral and dorsal embryological buds do not join, is a rare cause of chronic pancreatitis, as are hyperlipidaemia and hypercalcaemia. The disease may also occur in primary biliary cirrhosis, sclerosing cholangitis, and with choledochal cysts. In the tropics, chronic pancreatitis associated with malnutrition may be seen in young adults. In a significant number of patients no cause can be found.

Clinical features The main symptom of chronic pancreatitis is upper abdominal pain. 1 This is usually severe and chronic, although in about 10% of patients pain is not a feature. Radiation to the back is common, and sometimes the pain can be relieved by leaning forward. It may be exacerbated by eating. Anorexia, nausea and vomiting may be prominent. Steatorrhoea occurs with very high faecal fat output, and is associated with weight loss despite a good appetite. After 8 years of symptoms, about 70% of patients have Steatorrhoea. If there is gross Steatorrhoea deficiencies of vitamins A, B12 (see p. 824), D, E and K may occur. Coexistent alcoholic cirrhosis, or thrombosis of the portal or splenic vein as a complication of pancreatitis, may cause oesophageal or gastric varices. Gastric outflow obstruction due to swelling of the pancreatic head or a pseudocyst, and pancreatic ascites due to a fistula from the pancreatic duct to the peritoneum, occasionally occur. Biliary obstruction secondary to swelling of the pancreatic head is seen particularly in alcoholics, and can cause obstructive jaundice. About a third of patients develop diabetes mellitus. Calcific pancreatitis is associated with

1

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Fig. 15.31

SUMMARY 13 Investigations for chronic pancreatitis Biochemical

Radiological

Faecal fat estimation and other tests for malabsorption Secretin-cholecystokinin test Lundh test PABA test Liver function tests Blood glucose Serum amylase (only useful in acute attacks)

Plain abdominal X-ray Ultrasound, possibly CT scanning Endoscopic retrograde pancreatography (ERP)

alcohol abuse and has a high risk of diabetes mellitus and Steatorrhoea.

Investigation Biochemical Serum amylase levels are not usually raised in chronic pancreatitis. Although faecal fat excretion may be very high (more than 100g/24h) this is not diagnostic of pancreatic disease, as amounts approaching this level may be seen in patients with small bowel disease. Low pancreatic enzyme and bicarbonate outputs can be measured by pancreatic function tests (p. 824). Mild abnormalities of liver function tests are common. Rarely, the head of the pancreas may swell and cause an obstruction to the lower end of the common bile duct; this results in jaundice and cholestatic liver function tests. Radiological A plain abdominal X-ray may show pancreatic calcification which is diagnostic (Fig. 15.29A). Ultrasound, CT and ERCP may show abnormal anatomy, including duct dilatation, calcification and tissue damage (Fig. 15.29B).

Management It is important, whenever possible, to treat the underlying cause, although this may not prevent progression and pain. Mild analgesia is rarely effective. Codeine, pethidine or buprenorphine may control pain, and destruction of the coeliac ganglion with injection of 100% alcohol may give relief. Surgery in the form of total or subtotal pancreatectomy should be considered in patients with severe pain, preferably before addiction to opiates has developed. However, the results are variable and often poor if patients

SUMMARY 14 Treatment of chronic pancreatitis • Treatment of aetiological problem. No alcohol • Pain Simple analgesics Avoid opiate analgesics (if possible) Coeliac ganglion block Surgery • Steatorrhoea Low-fat/high-carbohydrate diet Enzyme supplements H2-receptor anatagonists/Proton pump inhibitors MCTs/fat-soluble vitamins • Diabetes mellitus Diet Oral hypoglycaemics Insulin • Metabolic complications Protein supplements Vitamin B12

15

Prognosis The prognosis, if not the quality of life, of patients with chronic pancreatitis is generally good. Patients rarely die directly of complications and most survive 20 years from the onset. Pain may settle spontaneously; this may reflect 'burning out' of the pancreas and be complicated by Steatorrhoea and diabetes. Sometimes patients whose pain is poorly controlled become dependent on narcotics.

TUMOURS OF THE EXOCRINE PANCREAS FIG. 15.29 Chronic pancreatitis A Plain X-ray showing pancreatic calcification. B ERCP in chronic pancreatitis showing a dilated main pancreatic duct with associated dilated side branches.

continue to abuse alcohol. A minority of patients require regular methadone. Steatorrhoea and the resulting malnutrition may be helped by a low-fat, high-carbohydrate diet. Pancreatic enzyme supplements should be taken with food. They can be inactivated by acid, and therefore intraduodenal pH can be raised by H2-receptor antagonists or proton pump inhibitors. Food may be cooked in, or be supplemented by, midchain triglycerides (MCTs), as these can be absorbed directly without lipolysis. Supplements of vitamins A, D, E and K should be prescribed as necessary. Diabetes mellitus requires standard treatment. A particular problem is variable absorption of carbohydrate owing to exocrine deficiency or after surgical procedures, as this may result in poor control of blood glucose ('brittle diabetes'). Protein supplements may help raise plasma proteins, and parenteral vitamin B12 is occasionally required.

The overall incidence of carcinoma of the pancreas is about 10 per 100000 per year, but this rises to 100 per 100000 in those over 65 years of age (Fig. 15.30). It accounts for 5.5% of cancer deaths and is the fourth most common cause of such deaths in men. The incidence is rising throughout the world, with particularly high rates seen in Afro-Americans and New Zealand Maoris. In England and Wales in 1995-1997 there were 5000 deaths per year due to carcinoma of the pancreas.

Aetiology and pathology The aetiology is unknown. The disease is twice as common in cigarette smokers and in females with diabetes mellitus; chemists and non-oven coke workers also have an increased incidence. There is no definite association with alcoholism, coffee drinking or acute or chronic pancreatitis (except of the rare familial chronic type). However, there may be an increased incidence in chronic calcific pancreatitis. In cases where a histological diagnosis is established the tumour is almost always an adenocarcinoma, usually arising from the ductular epithelium. It may be mucin producing. About 5% of tumours arise from the acinar cells

831

FIG. 15.30 Age-specific incidence of pancreatic carcinoma per 100000 population in the UK It is commoner in males and the incidence increases with age.

and, rarely, sarcomas may occur. The tumour metastasizes to local lymph nodes adjacent to the vascular supply and, by invasion of blood vessels, to the liver and distant sites. Sixty-five per cent of tumours occur in the head of the pancreas, 30% in the body and 5% in the tail. The tumour infiltrates locally into the duodenum and the retroperitoneal space. It may involve the portal vein, causing thrombosis and splenomegaly, and may also seed into the peritoneal cavity causing ascites.

FIG. 15.31 CT scan of abdomen This demonstrates a dilated gallbladder (filled with contrast medium following an ERCP) and a large tumour mass in the head of the pancreas (arrowed).

SUMMARY 15 Symptoms and signs of carcinoma of the pancreas Symptoms

Signs

Weight loss Abdominal pain Jaundice Vomiting Steatorrhoea Pruritus Diabetes

Hepatomegaly Jaundice Palpable pancreatic mass Palpable gallbladder Thrombophlebitis Ascites

Clinical features Symptoms tend to occur late and are often non-specific. Consequently there may be a delay in diagnosis, and the majority of patients already have inoperable large tumours and/or metastases by the time the diagnosis is made. The most important symptoms are epigastric pain radiating through to the back, weight loss and jaundice. Jaundice and pruritus indicate obstruction to the common bile duct or multiple hepatic metastases. Left upper quadrant pain can occur in tumours of the tail of the pancreas. Vomiting may be due to gastric or duodenal invasion or peritoneal metastases. Haematemesis and melaena may also occur as a result of invasion of the stomach or intestine. Steatorrhoea may occur as a result of bile duct obstruction. The development of diabetes may predate all other symptoms. Hepatomegaly and/or jaundice are found in the majority of patients at presentation, and the coexistence of a palp-

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Fig. 15.32

able distended gallbladder suggests the presence of a carcinoma obstructing the lower end of the common bile duct (Courvoisier's sign). This is, however, an unreliable sign, as it can also occur with cholelithiasis and is often absent with pancreatic cancer. Thrombophlebitis at remote sites, or deep venous thrombosis, occurs in about 10% of patients as a paraneoplastic syndrome (Ch. 6, p. 154). Carcinoma of the ampulla of Vater presents early with obstructive jaundice.

Investigation A full blood count and liver enzyme tests may show anaemia and an obstructive jaundice, but these are nonspecific and do not help to make the diagnosis. In experienced hands ultrasonography can be diagnostic; it also allows the passage of an ultrasound-directed needle to biopsy from the tumour for histology. CT scanning (Fig. 15.31) has an equal or greater accuracy and is of great help if ultrasound is negative or equivocal. Endoscopy may allow a direct view and biopsy of ampullary lesions, and

TABLE 15.50 Pancreatic endocrine tumours Peptide

Cellular source

Title

Clinical syndrome

Pancreatic glucagon

celI

Glucagonoma

Insulin Somatostatin

celI D cell

Insulinoma Somatostatinoma

Gastrin

G cell

Gastrinoma (Zollinger-Ellison syndrome)

Pancreatic polypeptide Vasoactive intestinal polypeptide

Pancreatic polypeptide cell Nerves

P Poma VIPoma (Verner-Morrison syndrome)

Adrenocorticotrophic hormone Parathyroid hormone Growth hormone releasing hormone

Unknown Unknown Unknown

Cushing's syndrome Ectopic hyperparathyroidism Pituitary acidophil hyperplasia

Necrolytic migratory erythema Diabetes mellitus Hypoglycaemia Diabetes mellitus Steatorrhoea Cholelithiasis Duodenal ulcers and malabsorption secondary to hyperacidity in the duodenum None Watery diarrhoea, hypokalaemia and achlorhydria (WDHA syndrome) Cushing's syndrome Hypercalcaemia Acromegaly

ERCP often demonstrates main duct lesions and gives information about the biliary tree. 1 In the case of ductular lesions, pancreatic juice may be aspirated for cytology. Laparoscopy and biopsy under direct vision are helpful in some difficult cases. Selective angiography may help to make the diagnosis and is important in determining resectability. Management The surgical treatment of carcinoma of the pancreas is very unsatisfactory owing to the organ's inaccessibility, the frequency of local spread and metastases. Radical surgery may be performed for localized tumours and a small number of patients are cured. The prognosis for ampullary tumours is considerably better than for those elsewhere in the pancreas. However, even in operable cases the 5-year survival is less than 15%. Hepatic metastases and portal vein thrombosis are contraindications for surgery. Nonsurgical palliation is now usual, the procedure of choice being to stent the biliary obstruction at ERCP to relieve jaundice. Alternatives are percutaneous stents or biliary drainage. For most patients with carcinoma of the pancreas, treatment is directed to symptomatic relief. Analgesics and coeliac plexus block may be needed. There are few cytotoxic drugs that are effective in pancreatic carcinoma, although responses are sometimes seen with alkylating agents, nitrosoureas and 5-fluorouracil.

PANCREATIC ENDOCRINE TUMOURS The islet cells of the pancreas are the primary site for a number of rare functioning endocrine tumours (Table

15

15.50), which may be benign or malignant and can produce characteristic syndromes. These tumours are important because surgical cure by resection may be possible. The symptoms caused can be predicted by the known physiological action of the hormone produced, the exception being pancreatic polypeptide, which is secreted by many of these tumours and can be used as a tumour marker. Multiple endocrine neoplasia type 1 (MEN type 1) is inherited on an autosomal dominant basis and is the association of hormone-synthesizing parathyroid adenomas (parathyroid hormone), pituitary adenomas (prolactin, growth hormone) and pancreatic endocrine tumours. MEN type 2a (see p. 938) is similarly inherited, and is the association of hormone-synthesizing parathyroid adenomas (parathyroid hormone), phaeochromocytomas (catecholamines) and medullary carcinoma of the thyroid (calcitonin). Occasional islet cell tumours are non-functioning.

Investigation Diagnosis of these tumours is by demonstrating a high plasma level of the appropriate peptide by radioimmunoassay. The tumours can often be demonstrated by ultrasound or CT scanning. On occasions it is necessary to sample blood along the portal vein and to demonstrate a peak of hormone secretion corresponding to the site of tumour venous drainage. Arteriography can also be used, and is helpful in demonstrating multiple primary tumours (common with gastrinomas) and hepatic metastases.

Management Treatment is surgical resection if possible, and this often results in cure. In the presence of metastatic disease the cytotoxic drugs streptozotocin and 5-fluorouracil can

833

produce worthwhile remissions. The symptoms of most of the tumours may be helped by somatostatin therapy. The rash of the glucagonoma syndrome can be improved by zinc, and the hypoglycaemia of insulinomas by diazoxide. The symptoms of gastrinomas are controlled by high-dose proton pump inhibitors, and the diarrhoea of VIPomas by a variety of agents, including corticosteroids, metoclopramide and trifluoperazine.

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FURTHER READING ON THE PANCREAS Baron T H, Morgan D E 1999 Acute necrotizing pancreatitis. N Engl J Med 340:1412-1417. Glazer G, Imrie C W, Mann D V 1998 United Kingdom guidelines for the management of acute pancreatitis. Gut 42 (suppl 2):S1-S13. Mergener K, Baillie J 1997 Chronic pancreatitis. Lancet 350:1379-1385.

16

Liver and Biliary Tract Disease

disease and chronic hepatitis in countries with well-developed liver transplant programmes continue to die without having access to transplantation. The factors limiting the application of liver transplantation include cost, the limited availability of organs, and the lack of effective strategies to prevent the recurrence of alcoholic and viral disease.

STRUCTURE AND FUNCTION

John O'Grady

ANATOMY

Introduction 835

Chronic hepatitis 863

Structure and function 835

Primary biliary cirrhosis 866

Investigations in liver disease 839

Haemochromatosis 868

The jaundiced patient 845

Wilson's disease 869

Unconjugated hyperbilirubinaemia 846

Other causes of cirrhosis 870

Acute hepatitis 846 Drug-induced jaundice 852 Acute liver failure 853 Jaundice in pregnancy 855 Acute alcoholic hepatitis 855 Cholestatic jaundice 856 Cirrhosis 859

Complications of cirrhosis 871 Hepatocellular carcinoma 875 The liver in systemic disease 877 Non-viral infections involving the liver 879 Congenital biliary and hepatic disorders 881 Liver transplantation 881

Chronic alcoholic liver disease 861

INTRODUCTION Liver disease occurs worldwide and the majority of cases are due to either chronic viral hepatitis or alcohol. However, there is a considerable geographical variation. Hepatitis B is particularly common in the Far East, but there is some evidence to suggest that active vaccination programmes will reduce the prevalance of infection there. Alcohol is the dominant aetiology in the west, but it is now clear that viral hepatitis pays a significant role there too, in the form of hepatitis C. As yet, there are no major strategies aimed at reducing the incidence of liver disease in the west. The common liver diseases lead to premature death by means of liver failure, or the development of hepatocellular carcinoma. Liver transplantation is changing the profile of liver disease, but the impact is greatest in the west and it is having its greatest benefit in those diseases that are relatively uncommon. The majority of patients with alcoholic liver

The classic division of the liver into right and left lobes has now been complemented by the description of eight segments defined on the basis of blood supply. The caudate lobe is segment 1, segments 2-4 make up the left lobe, and the right lobe contains segments 5-8 (Fig. 16.1). The liver has a dual blood supply: from the hepatic artery, which is usually a branch of the coeliac axis, and from the portal vein, formed from the mesenteric and splenic veins (Fig. 16.2). The total liver blood flow is about 1300mL/min, i.e. one-quarter of the resting cardiac output. The hepatic artery supplies about 25% of the total liver blood flow but 50% of the oxygen; the remaining 75% of the volume and 50% of the oxygen comes from the relatively deoxygenated low-pressure portal vein supply. Both vessels run in the free edge of the lesser omentum to the liver hilum before dividing into major right and left branches. The hepatic veins drain directly into the inferior vena cava, which runs in a groove along the back of the liver between the functional right and left lobes. The three large hepatic veins (right, middle and left) enter just below the diaphragm, but there are a number of smaller veins draining the posterior aspect of the right lobe which enter the vena cava directly. These assume importance in two clinical situations: they may be the only remaining draining vessels if there is thrombosis of the main hepatic veins (the Budd-Chiari syndrome), and they are particularly difficult to dissect during a right hemihepatectomy. The biliary system collects bile, stores and concentrates it in the gallbladder, and delivers it to the duodenum when required. The main right and left hepatic ducts join in the hilum of the liver to form the common hepatic duct. The gallbladder lies on the undersurface of the right lobe of the liver, with its fundus usually projecting slightly below the lower edge. The cystic duct runs upwards and backwards to join the common hepatic duct, and the resulting common bile duct then runs with the hepatic artery and portal vein in the free edge of the lesser omentum to pass behind the first part of the duodenum and the head of the pancreas before turning to the right to enter the duodenum. This part of the duct is often completely buried in the pancreas, and it is here that it is susceptible to obstruction by pancreatic tumours. The pancreatic and bile ducts usually share a common channel for the last 2-7 mm, which opens through a small papilla on the inner wall of the

835

FIG. 16.1 The liver is divided into eight segments according to the vascular tree This subdivision has replaced conventional anatomy (see Fig. 16.2) for the purposes of planning hepatic surgery.

FIG. 16.2 A simplified view of the gross anatomy of the liver and its major relationships Hepatic veins (A); hilar lymph nodes (B); portal vein (C); splenic vein (D); pancreatic duct (E); bile duct (F); inferior mesenteric vein (G); superior mesenteric vein (H).

duodenum (the ampulla and papilla of Vater). In this part of the duct the choledochal muscle is thickened to form the sphincter of Oddi.

efferent veins. Although the concept of the acinus as a functional unit has proved useful in understanding patterns of liver injury, it is still useful for descriptive purposes to refer to the lobule as the classic structural unit of the liver. Each lobule is centred on an efferent (or central) vein, surrounded by radially orientated sinusoids and with five or six portal tracts at the periphery.

Microanatomy At a microanatomical level the liver consists essentially of a series of channels, or sinusoids, that run between plates of hepatocytes. These are lined by endothelial cells which contain unusually large fenestrations, allowing the sinusoidal part of each hepatocyte surface to have free access to almost all the constituents in plasma (Fig. 16.3). The space of Disse contains specialized cells, including Kupffer cells and stellate cells. The Kupffer cells are fixed macrophages and are an important barrier to gut-derived infections. The normal function of stellate cells is unclear, but they appear to be important in the pathogenesis of fibrosis. Specialized phagocytic cells (Kupffer cells) are also present in the sinusoids. Biliary canaliculi form between the contiguous surfaces of hepatocytes, and both here and on the sinusoidal surface there are extensive microvilli in the cell membrane to increase the capacity for transmembrane transfer. Branches of the hepatic artery, portal vein and bile duct within the liver are carried in portal tracts. The smallest of these, carrying terminal branches, supply groups of sinusoids which together form a functional unit, the acinus. Blood from each acinus then passes into a number of

1

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MCQ 16.1

PHYSIOLOGY Essentially the liver has four quite distinct functions: • It supplies bile salts and bicarbonate to assist in digestion. • It acts as a buffer between the gut and the systemic circulation. • It maintains stable levels of amino acids and glucose in blood. • It synthesizes a large number of specialized proteins, carbohydrates and lipids. • It is a major excretory pathway for larger and more hydrophobic physiological metabolites, foreign substances and drugs.

Bile acid metabolism and secretion The primary bile acids, cholic and chenodeoxycholic acids, are synthesized from cholesterol in the liver, conjugated with taurine or glycine to form bile salts, and then excreted by an active transport mechanism into the bile canaliculi and eventually into the duodenum. In the distal ileum there is another active transport system which ensures the conservation of bile salts when they have fulfilled their

16

FIG. 16.4 Enterohepatic circulation of bile acids Bile salts entering the duodenum via the bile duct (A); absorption of bile salts in the terminal ileum (B); secondary bile acids formed by bacterial degradation (C); uptake and re-excretion of bile salts by liver (D).

FIG. 16.3 The microanatomy of the liver A The classic liver lobule is centred on the central vein with the portal tracts at its periphery. The concept of the functional lobule emphasizes the portal tracts as the points of entry of the arterial and portal venous blood, with the sinusoids then extending from there to the 'central veins'. B A liver sinusoid with liver cell plates separated from the lining endothelial cells by the space of Disse. The Kupffer cells straddle the blood-filled centre of the sinusoid. C The endothelial cells, riddled with fenestrations, allow macromolecules to pass between the blood and the hepatocytes. The biliary canaliculi run between the hepatocytes in the liver cell plates.

digestive function (Fig. 16.4). This system of enterohepatic circulation is extremely efficient. The entire body pool of bile salts is circulated through the gut about twice during each main meal, and only about 5% is newly synthesized in the liver. The small fraction reaching the colon is modified by bacteria, which perform 7a-dehydroxylation, producing the secondary bile acids deoxycholic and lithocholic acids. All bile salts are powerful detergents, solubilizing lipids by enclosing them in bile salt aggregates called micelles. These are organized so that hydrophobic groups are orientated into the lipid-rich interior whereas the hydrophilic hydroxyl and carboxyl groups are on the outside. Cholesterol and lecithin in bile itself are carried in such micelles, and if the concentration of these molecules

rises too high relative to the concentration of bile salts, the bile becomes supersaturated. Precipitation of cholesterol may then occur, particularly if a nidus for crystal formation is present. This is the pathophysiological basis for gallstone formation, which is discussed further on page 856. The active transport of bile salts is the main driving force for bile secretion and its failure may be an important cause of intrahepatic cholestasis. Bile salts accumulate in cholestasis, whether owing to mechanical obstruction or to a defect in excretion, and deposition in the skin may account for the pruritus which is often a troublesome symptom. There is also a bile salt-independent contribution to bile secretion, which is probably driven by active sodium transport in the distal canaliculus. Bicarbonate is added in the small bile ductules and this process is stimulated by the hormone secretin. Cholecystokinin principally stimulates gallbladder contraction. 1

Protein metabolism The liver receives amino acids from the gut and the muscles and regulates their levels in plasma by controlling the rate of gluconeogenesis and transamination. It also converts ammonia into urea via the urea cycle. Ammonia is produced intrahepatically by deamination, in other tissues by nucleotide metabolism, and in the colon by bacterial action on proteins or urea. The liver is the major site of synthesis of almost all the plasma proteins, and for many is also the principal site of degradation. In an average 70kg adult total body protein is about 12kg and turns over at a rate of about 250g/day. There is a close relationship between the muscles, liver and gut with

837

SUMMARY 1 Liver physiology Normal function Bile acid metabolism Glucose and amino acid homeostasis Synthesis of plasma proteins, clotting factors, lipids Metabolism/excretion of bilirubin, ammonia/urea, drugs

Consequence in disease Fat malabsorption Encephalopathy Ascites, bleeding, xanthelasmata Jaundice, encephalopathy, drug toxicity

FIG. 16.5 Amino acid and protein metabolism in health Branched-chain amino acids (BCAA), marked in blue, constitute only 20% of the dietary intake, whereas aromatic amino acids (AAA), marked in black, make up 80%. The liver preferentially metabolizes AAA rather than BCAA, which are passed to the tissues (particularly muscles). The thickness of the blue and black lines represents the relative amounts of the amino acids in the different body compartments.

838

respect to amino acid fluxes (Fig. 16.5). Muscle contributes the biggest source of protein turnover - about 130g/day whereas dietary intake is about 90g/day. Only 23% of amino acid nitrogen absorbed into the portal bloodstream after a meal is passed on to the peripheral tissues, and in exercising this gate function the liver is responsible for extensively modifying the blood amino acid composition. The aromatic amino acids - phenylalanine, tyrosine and methionine - are preferentially processed to urea, whereas the branched-chain amino acids - valine, leucine and isoleucine - are selectively passed to the periphery, where they are predominantly metabolized by muscle. This selectivity is lost in severe liver disease, and it is possible that the resulting change in the ratio of the plasma concentrations of these two groups of amino acids may alter cerebral neurotransmitter metabolism and contribute to the pathophysiology of portosystemic encephalopathy (p. 873). Of the many proteins synthesized in the liver, albumin and prothrombin are of particular interest in relation to

liver disease and are discussed as liver function tests on page 839. Because albumin is also the most important mediator of the plasma colloid osmotic pressure, the fall in albumin concentration that accompanies chronic liver disease is relevant to the pathophysiology of ascites, one of the frequent complications of cirrhosis (p. 871).

Carbohydrate metabolism The liver acts as a gate for the large amounts of glucose delivered from the gut during digestion, by storing it as glycogen, and is also the main source of glucose during starvation. Initially, glycogenolysis is the principal metabolic pathway used, but as the glycogen stores become depleted, gluconeogenesis assumes a greater importance. The main substrates for this pathway are lactate, pyruvate, glucogenic amino acids (mainly alanine from muscle) and glycerol (from lipolysis in fat stores). In the fed state about 160g/day of glucose are needed for those tissues with an obligatory requirement for this substrate, principally the brain and haemopoietic tissues. During prolonged starvation the brain adapts to ketone bodies as an alternative energy source, and the total body requirement for glucose drops to about 40g/day. Although blood glucose levels may directly influence carbohydrate metabolism in the liver, the principal instruments for metabolic control are the hormones insulin, glucagon, catecholamines and glucocorticoids (Fig. 16.6). The fall in insulin levels during starvation releases glycogenolysis and gluconeogenesis from the inhibitory effects of this hormone, with glycogenolysis being particularly sensitive. The increasing glucagon and catecholamine levels act directly to stimulate glycogenolysis. In the periphery, the relative excess of glucocorticoids compared to insulin leads to increased release of amino acids into the circulation, and high glucagon levels stimulate alanine uptake by the liver. In liver disease the supply of glucose by gluconeogenesis is generally well preserved, and hypoglycaemia is only usually a problem in severe (acute) liver failure. Glucose intolerance is more common, but is rarely a clinical problem.

Lipid metabolism The major plasma lipids, cholesterol, cholesterol esters, phospholipids and triglycerides, are highly insoluble in water and are carried in macromolecular complexes of lipid and a protein carrier (apoprotein) called plasma lipoproteins. Only the intestine and the liver synthesize and secrete plasma lipoproteins. There are four main classes, which differ in size and density and have different proportions of the main lipids: • Chylomicrons are made in the mucosal cells of the small intestine during dietary fat absorption, and are the main carriers of triglyceride. • Very low-density lipoproteins (VLDL) are produced in the liver and intestine and have a core which contains

TABLE 16.1 Non-hepatic causes of impaired liver function tests Cause

Nature of abnormality

Haemolysis

Isolated hyperbilirubinaemia

Adolescence, Paget's disease, osteomalacia, bone tumours

Isolated elevation in (bone) alkaline phosphatase

Enzyme-inducing drugs (and alcohol)

Increased -glutamyl transpeptidase (GT) levels

Malnutrition, maiabsorption, protein loss and chronic illness

Decreased serum albumin

Fat maiabsorption, disseminated intravascular coagulation (DIC), warfarin therapy

Prolonged prothrombin time

Myocardial infarction, myositis

High serum aspartate aminotransferase (AST) levels

16

Drug metabolism

FIG. 16.6 The main routes of carbohydrate metabolism in the fed state and fasting

50-60% triglyceride. Their apoprotein content is low (about 10%). • Low-density lipoproteins (LDL) are formed in the plasma by catabolism of VLDL. They have a higher protein content (22%) and lower triglyceride proportion (10%) than VLDL. • High-density lipoproteins (HDL) are made to some extent within the plasma, but are also synthesized in the liver and intestine. They have the highest protein content (50%) and lowest triglyceride proportion (5%). Hypercholesterolaemia is a feature of any liver disease in which there is obstruction to bile flow, whether this is intra- or extrahepatic. The increase is due to a rise in free cholesterol levels. Although total plasma phospholipids are often normal, lecithin levels are increased as a result of regurgitation back into the blood from the obstructed biliary tree. Although the elevated free cholesterol levels may also be due to regurgitation, there is some evidence to suggest that the increased plasma lecithin stimulates hepatic cholesterol synthesis. A marked increase in LDL levels, and the appearance of an abnormal lipoprotein, lipoprotein X, is due to the lipids providing increased substrate drive. Among the clinical effects of these lipid changes are the yellowish plaques of cholesterol deposited in the skin (xanthomata) in long-standing biliary obstruction, and the appearance of 'target' red cells in the peripheral blood film, probably a reflection of altered membrane fluidity.

The liver is an important site for the clearance of many drugs. In general, the more lipophilic and the higher the molecular weight, the more likely the drug is to be cleared by the liver rather than the kidney. Such hepatic clearance usually involves metabolic biotransformation with or without conjugation. In liver disease, alteration of drug handling can have clinically important consequences (Ch. 1).

INVESTIGATIONS IN LIVER DISEASE LIVER FUNCTION TESTS Blood tests often described as 'standard' liver function tests are not true tests of liver function but reflect present or previous liver cell damage and biliary obstruction. Although they are useful in differential diagnosis and may be the first indication of liver disease, they are rarely of diagnostic value alone. Most of these tests are not specific indicators of liver damage, and the influence of disease in other organs needs to be carefully considered when evaluating their significance (Table 16.1).

Serum bilirubin The main source of bilirubin is the reticuloendothelial system, where haemoglobin from effete red blood cells is split to haem, then to bilirubin. This is lipophilic and is carried in the plasma, tightly bound to albumin. Uptake into the hepatocytes is mediated by a carrier system in the liver cell membrane, and by ligands in the cytosol (Fig. 16.7). Bilirubin is then converted to a water-soluble

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TABLE 16.2 Clotting factors synthesized in the liver Fibrinogen Vitamin K-dependent factors (II, VII, IX and X) Labile factors (V and VIII) Contact factors (XI and XII) Fibrin-stabilizing factor (XIII)

SUMMARY 2 Liver function tests All non-specific, so consider disease in other organs Synthesis Albumin: long half-life, so slow response = chronic liver disease Prothrombin time: short half-life, so fast response = acute and chronic liver disease Excretion Bilirubin: conjugated bilirubin elevated in liver disease, whatever the cause FIG. 16.7 The formation and metabolism of bilirubin The main sites of congenital defects leading to jaundice are indicated. Failure of uptake into hepatocytes: probably the main abnormality in Gilbert's syndrome (A). Failure of conjugation, the main abnormality in more serious cases of unconjugated hyperbilirubinaemia in childhood (e.g. Crigler-Najjar syndrome) (B). Failure of excretion can occur in some rare congenital causes of conjugated hyperbilirubinaemia, such as Dubin-Johnson syndrome (C).

compound by conjugation with glucuronic acid, and excreted as the diglucuronide into bile. Conjugated bilirubin refluxing back into the blood can be excreted by the kidney, but the water-insoluble unconjugated bilirubin cannot. Hence jaundice without bilirubinuria, indicating high serum levels of unconjugated bilirubin, is a feature of haemolysis (increased formation), failure of bilirubin uptake, or conjugation in the liver. Excess conjugated bilirubin in serum occurs with cholestasis. In hepatitis there is intrahepatic cholestasis in addition to liver cell injury, but conjugated bilirubin is found in the plasma as conjugation is preserved even with severe liver damage. Tests reflecting synthetic function

Serum albumin Serum albumin levels are used to assess the liver's ability to perform a high-volume synthetic function. The half-life of albumin is about 21 days, and inability to maintain serum albumin levels between 35 and 50 g/L indicates impending liver failure in the context of chronic liver disease. Serum albumin levels are often normal in acute liver failure. 1

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Case 16.1

Alkaline phosphatase: sensitive indicator of cholestasis -GT: not so sensitive but elevated with enzyme induction, including alcohol Cell damage AST/ALT: released from damaged liver cells = active liver inflammation

Other conditions causing low serum albumin levels need to be considered; they include urinary loss and, less commonly, severe malnutrition or hypercatabolism. Coagulation studies Analysis of coagulation factors is used to assess the liver's ability to synthesize important proteins immediately. The half-life of coagulation factors can be as short as 7 hours, and consequently these tests are used to identify massive liver injury, as seen in acute liver failure. The one-stage prothrombin time (Table 16.2) is a functional assessment of several coagulation factors and is widely used in acute and chronic liver disease. It is subject to significant methodological variation between laboratories and countries, and some aspects of this are overcome by reporting the result as an international normalized ratio (INR). Individual clotting factors can also be measured and, of these, Factor V assays are particularly useful. In chronic liver disease the prothrombin time or INR tends to parallel changes in serum albumin levels. In cholestasis the prothrombin time is often prolonged, even though synthetic liver function is intact. This is because several of the factors evaluated in the test are dependent for their activity on vitamin K, one of the fat-soluble vitamins which is poorly absorbed when bile salts are not reaching the intestine. Giving vitamin K parenterally

(10 mg daily for 3 days) is therefore a clinically useful test of liver synthetic function. The prothrombin time corrects completely in cholestasis but remains abnormal in severe hepatitis or chronic liver disease.

Tests reflecting cholestasis Serum alkaline phosphatase Different isoenzymes are found in bone, liver, intestine and placenta, and serum electrophoresis can be useful to identify the source of elevated levels. The liver isoenzyme is located mainly in the bile canalicular region of the hepatocyte surface membrane, and high serum levels are a sensitive indicator of segmental or global biliary obstruction, whether within or outside the liver. Much of the rise is due to increased production of the enzyme in areas of the liver proximal to an obstruction, together with reflux of a high molecular weight form of the liver type of isoenzyme, the 'biliary isoenzyme'. This is associated with vesicular structures which may be actual fragments of the canalicular membrane. Although high plasma bilirubin levels often accompany high alkaline phosphatase levels, bilirubin values can be normal in spite of markedly raised serum alkaline phosphatase levels. This usually indicates a patchy or incomplete obstructive lesion, with bilirubin being excreted by the non-obstructed areas. This pattern is a feature of space-occupying lesions in the liver, e.g. granulomata, cysts and abscesses, as well as secondary deposits. Serum y-glutamyl transpeptidase Serum y-glutamyl transpeptidase (y-GT) is a more liverspecific enzyme than alkaline phosphatase and also reflects cholestasis. However, it is less sensitive to biliary obstruction, and an important clinical point is its sensitivity to enzyme-inducing drugs, such as phenytoin, and alcohol, both of which can cause quite marked elevations in serum levels in the absence of significant liver damage. A useful practical guide to interpretation is to compare the levels of y-GT and alkaline phosphatase in serum. In cholestasis the alkaline phosphatase is usually higher than the -GT, whereas the reverse is usually true in alcoholic liver disease or in patients taking enzyme-inducing agents. 1

tion of the circulatory disturbance often results in a very rapid fall in AST levels.

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Serum alanine aminotransferase Although more liver-specific, changes in levels of serum alanine aminotransferase (ALT) tend to parallel those of serum AST. However, ALT levels tend to be somewhat higher than AST levels, and this may be important when screening for necroinflammatory activity in patients with chronic hepatitis. ALT is predominantly a cytosolic enzyme, whereas 80% of AST is located in mitochondria.

SPECIAL INVESTIGATIONS Imaging techniques Ultrasound scanning Ultrasound scanning is often the first specialized investigation in patients with liver disease. It enables a rapid assessment of liver and spleen size, vessel size and patency, and the calibre of bile ducts (Fig. 16.8), cysts and tumours. It is particularly good at detecting gallstones, as they are very echogenic. Ultrasound is also widely used to screen for hepatocellular carcinoma in patients with cirrhosis. The sensitivity and diagnostic accuracy of ultrasound has been increased by new techniques enhancing patterns of vascularity. Liver scintiscanning This is now nearly obsolete in the investigation of liver disease. Liver scintiscanning is obtained by gamma camera imaging of the upper abdomen after the intravenous injection of technetium-99m-labelled sulphur colloid, which is taken up by Kupffer cells in liver sinusoids. Liver and spleen size can be accurately assessed. In cirrhosis,

Tests reflecting liver cell injury Serum aspartate aminotransferase Serum aspartate aminotransferase (AST) is found in particularly high levels in the liver and in skeletal and cardiac muscle; serum levels can rise after injury to any of these tissues. High levels in liver disease are classically associated with liver cell necrosis in acute or chronic hepatitis, but membrane damage without cell death may also allow enzyme to leak out into the circulation. Thus, high levels of serum AST can occur in conditions such as acute left ventricular failure and septicaemia, in which hypoperfusion and anoxia lead to transient liver cell injury. Correc-

FIG. 16.8 Ultrasound of the liver demonstrating dilated intrahepatic and common bile ducts

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effective hepatic (sinusoidal) blood flow is reduced, and other parts of the reticuloendothelial system, notably the spleen and bone marrow, show markedly increased isotope uptake. Acute alcoholic hepatitis and Wilson's disease may yield a 'whiteout' because of complete failure of uptake of colloid by the Kupffer cells. Computed tomography (CT) CT is capable of providing high-resolution sectional views of the liver and surrounding structures in the upper abdomen (see Figs 16.22, 16.28B). Contrast enhancement is of value in further defining the nature of abnormal areas. The technique is best used in cases where ultrasound has failed to provide the expected morphological information, and for the examination of retroperitoneal structures. Magnetic resonance imaging (MRI) The role of MRI in the evaluation of liver disease is increasing (Fig. 16.9). It frequently complements the ultrasound and CT scans in the assessment of focal lesions, particularly since the availability of contrast-enhancing techniques, e.g. with manganese. MR cholangiography (MRCP) is being increasingly used to define anatomy and pathology, and MR angiography and venography (Fig. 16.10) are rapidly being developed.

FIG. 16.9 MR scan outlining a large cyst in the liver

Positron emission tomography (PET) The role of this emerging investigative technique has yet to be defined, but it may prove valuable in the management of patients with malignant disease. Contrast radiology Although ultrasound scanning is the best technique for detecting gallstones and dilated bile ducts, radiological contrast studies are of great value in further defining the morphology of the biliary tree. Oral cholecystography This investigation is also becoming obsolete. Oral cholecystography may be used as a screening procedure in patients with suspected gallbladder disease, but ultrasound is usually preferred. Like all procedures which rely on the excretion of contrast material by the liver, poor results are obtained in the presence of liver disease, particularly cholestasis. Percutaneous transhepatic cholangiography In percutaneous transhepatic cholangiography (PTC) a very fine flexible needle is introduced into the liver substance until a bile duct is punctured. Contrast medium is then injected to fill the biliary system. More widespread use of ERCP has meant that PTC is now used selectively.

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Fig. 16.1

FIG. 16.10 MR venography outlining patient hepatic veins and portomesenteric venous system without the need for catheterization

Endoscopic retrograde cholangiopancreatography (ERCP) Endoscopic retrograde cholangiopancreatography involves cannulation of the ampulla of Vater via an endoscope, followed by the injection of contrast medium into the bile ducts. It allows excellent pictures of the biliary tree to be obtained (Fig. 16.11) and is the procedure of choice in most patients in whom biliary disease is suspected. Prophylactic broad-spectrum antibiotics are used immediately before the procedure in those with biliary obstruction to prevent ascending cholangitis.

The diagnostic information gained at ERCP may be increased by the extraction of bile for culture, brushing of the biliary epithelium for cytological analysis, and biopsy of suspicious lesions. Therapeutic interventions include the extraction of gallstones and dilatation and/or stenting of benign or malignant strictures. 1

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Vascular studies Hepatic angiography following selective catheterization of the hepatic artery defines the vascular anatomy of the liver. It is used in the investigation of focal lesions and in conjunction with lipiodol injection, and CT is the most sensitive technique for the detection of small hepatocellular carcinomas. The patency of the portal vein is defined during the venous phase. Angiography is almost mandatory prior to major liver surgery. Therapeutic applications of angiography include embolization of bleeding points, e.g. following trauma or liver biopsy, and transcutaneous arterial chemoembolization (TACE) of hepatocellular carcinoma. Hepatic vein catheterization is used to indirectly measure portal vein pressures in the diagnosis and management of portal hypertension. Occasionally splenic puncture is required to determine the portal pressure accurately. Thrombosis of the hepatic veins in the BuddChiari syndrome is most reliably defined by contrast venography.

New techniques Endoscopic ultrasound is likely to have a significant impact on the investigation of biliary and pancreatic disease. Laparoscopic cholangiography is being assessed as an alternative to ERCP.

Liver biopsy Percutaneous needle biopsy of the liver has been increasingly accepted as part of the routine investigation of patients with liver disease. In experienced centres it is an extremely safe procedure, the overall mortality in one of the largest published series (79381 liver biopsies) being 0.015%. Nevertheless, it is an invasive procedure which needs to be approached with care. The guidelines for the use of liver biopsy issued by the British Society of Gastroenterology are shown in Table 16.3.

FIG. 16.11 Endoscopic retrograde cholangiopancreatography A ERCP demonstrating a normal duct system in a patient who has had a previous cholecystectomy (arrow). B ERCP in a patient immediately following cholecystectomy (note T-tube). There is a stone at the lower end of the common bile duct, which is dilated.

Indications and contraindications These are listed in Table 16.4. The patient must be able to understand the instructions, particularly to hold his or her breath at the appropriate moment. Determination of the patient's blood group is a sensible precaution, with some serum being saved for cross-matching should transfusion be required. The contraindications (Table 16.4) are not absolute, but in the presence of any of these risk factors the chance of complications is considerably increased.

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TABLE 16.3 Guidelines for the use of liver biopsy • Establish a clear indication for the biopsy (diagnosis of primary liver disease, diagnosis of multisystem disease affecting liver, e.g. sarcoidosis, pyrexia of unknown origin, malignant disease, metabolic disease; monitoring of response to therapy) • Review ultrasound scan of the liver performed within 4 weeks of biopsy to detect abnormal anatomy • Review prothrombin time and platelet count performed within 7 days of biopsy prothrombin time - proceed if <4s prolonged; give fresh frozen plasma if 4-6s prolonged platelet count9 - proceed if >60 x 109/L; give platelet infusions if 40-60 x 10 /L do not proceed if either parameter exceeds these limits • Screen for other contraindications (most important are ascites and biliary obstruction; unusual causes include amyloid, hydatic cyst and large haemangioma) • Obtain informed consent • Prophylactic antibiotics should be given to those with valvular heart disease and those at risk of bacteraemia • No more than two passes should be made • Keep the patient under observation for at least 6 hours after procedure

Technique Sedation is rarely necessary, except in young children, when general anaesthesia is often used. The lateral intercostal route is usually preferred, although an anterior approach can be useful in specific lesions in the left lobe, particularly when combined with ultrasound guidance. Two different types of technique are used: one in which the biopsy is aspirated into the lumen of a large-bore needle (the Menghini needle), and one where a core of liver tissue is cut out by a needle sheath sliding over a notched introducer (the TruCut needle). The latter is often preferred because it preserves the integrity of the specimen in hard fibrotic or cirrhotic livers, although technically the Menghini is easier to use. After the biopsy the patient is advised to lie on the right side for 2 hours, and during this time quarter-hourly pulse and blood pressure measurements are recorded. Complications Bleeding at the site of liver puncture is inevitable and usually causes mild pain, either locally or at the right shoulder tip because of diaphragmatic irritation. Persistent bleeding into the peritoneum or biliary tree (haemobilid) is much rarer and more serious, and angiography and embolization or even laparotomy may be required to secure haemostasis. Sudden transient hypotension immedi-

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MCQ 16.2

TABLE 16.4 Indications and contraindications for liver biopsy Indications For diagnosis of Primary liver disease Multisystem disease commonly affecting the liver, e.g. sarcoidosis, lymphoma Pyrexia of unknown origin and disseminated infection, e.g. tuberculosis Malignant disease Metabolic disease, e.g. glycogen storage disease For assessment of Progression of disease and response to treatment Contraindications Clotting defect Prothrombin time more than 6s prolonged Platelet count less than 40 x 109/L Ascites Hydatid cyst Risk of dissemination Haemangioma or amyloid Increased risk of bleeding Biliary obstruction Risk of biliary leak, cholangitis and peritonitis

SUMMARY 3 Complications of liver biopsy • • • • • • • •

Bleeding Sudden transient hypotension Perforation of colon/puncture of kidney or pancreas Pneumothorax Perforation of gallbladder Biliary peritonitis Cholangitis Septicaemia

ately after the biopsy, probably due to vagal stimulation, is not uncommon. Occasionally it may be dramatic and lead to loss of consciousness, but rapid recovery can be confidently anticipated. Perforation of the colon, or puncture of the kidney or pancreas, is rare but can usually be managed conservatively. Pneumothorax may occur in patients with obstructive airways disease and hyperinflated lungs, and in those who have been unable to cooperate at the time of the biopsy. Biliary peritonitis may follow puncture of the gallbladder or biliary tree or may be due to bile leaking from an appropriate puncture site in the liver. Biliary peritonitis can usually be avoided if biopsies are not performed in patients with biliary obstruction. It is a potentially very serious complication with a high mortality; early laparotomy is indicated. The introduction of a needle into an obstructed biliary tree also carries a high risk of cholangitis and septicaemia, another reason for avoiding biopsy in these patients.

FURTHER READING ON LIVER BIOPSY Grant A, Neuberger J 1999 Guidelines for the use of liver biopsy in clinical practice. Gut 4(Suppl 4): 1-11

THE JAUNDICED PATIENT

Differential diagnosis Four broad categories of disease cause jaundice: • • • •

Prehepatic (unconjugated hyperbilirubinaemia) Hepatitis Intra- or extrahepatic obstructive jaundice Chronic liver disease.

The initial aim should be to use the clinical history, physical examination, liver function tests and special investigations to establish a working diagnosis in terms of one of these broad groupings. This will then determine the next steps to be taken in establishing the final diagnosis and treatment. The organization of this chapter reflects this clinical approach.

Clinical features Although the jaundice itself is often the dominant feature of the illness for the patient, it is important to explore the first symptoms in detail as these often contain the most reliable clues to the diagnosis (Table 16.5). A prodromal 'flu-like' illness with anorexia and myalgia is characteristic of acute viral hepatitis, and usually starts from a few days to 2 weeks before the onset of jaundice. A longer history of mild malaise and anorexia (often 3-6 months in duration), associated with weight loss of more than 3kg, is common with carcinoma of the pancreas. Biliary colic with pain referred to the right scapula and shoulder a day or two before the jaundice suggests the passage of a stone down the common bile duct. Generalized itching is another symptom of considerable importance. It often precedes or parallels the jaundice in patients with biliary obstruction, but is usually absent or delayed in acute hepatitis, only becoming of major clinical

importance in those with an unusually prolonged cholestatic phase during recovery. Important exceptions to this general rule are acute alcoholic hepatitis, where cholestasis is sometimes a dominant early feature, and hepatitis associated with some drugs and chemicals, in which the dominant feature is a disturbance of biliary secretion rather than hepatocellular damage. Pale stools and dark urine are to be expected in jaundice due to obstruction, and in acute and chronic hepatitis. This finding is therefore of no help in differential diagnosis. In contrast, normal-coloured urine and stools in the presence of obvious jaundice strongly suggests a prehepatic cause. In addition to these general features specific risk factors should be identified, including homosexuality, drug addiction, foreign travel, contact with jaundiced patients and alcohol intake. It is essential to take a complete drug history. Drug-induced hepatitis can mimic a viral hepatitis, including a prodromal illness, or can present with all the features of a pure obstructive jaundice. 1

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Physical examination In contrast to the history, which may point strongly to the diagnosis, the physical examination usually gives less specific information. Tender hepatomegaly is often present in both acute hepatitis and obstructive jaundice, and minor splenomegaly is present in a small proportion of patients with viral hepatitis. The finding of a palpable gallbladder is well recognized as a classic sign of carcinoma of the head of the pancreas, but is not often present. If the jaundice is due to hepatic metastases, hard, irregular and sometimes tender hepatomegaly is usually a prominent feature. Cutaneous stigmata of chronic liver disease, such as spider naevi, liver palms, leukonychia and Dupuytren's contracture, should be looked for carefully, as these are important clues that an apparently acute episode may instead be a manifestation of chronic liver disease. Conversely, in acute alcoholic hepatitis there may be signs suggestive of chronic liver disease, including splenomegaly, ascites and florid cutaneous stigmata, but no histopathological features of cirrhosis.

Liver function tests

TABLE 16.5 First symptoms before jaundice Symptom

Meaning

A few days of a 'flu-like' illness Months of malaise and anorexia Biliary colic Rigors Itching before jaundice Any medication

Acute viral hepatitis Carcinoma of pancreas Stone in common duct Biliary obstruction with sepsis Biliary obstruction or cholestasis Think of this as the cause

Although it is generally true that the ratio between the serum AST (or ALT) and alkaline phosphatase helps to distinguish between hepatitic (ratio high) and cholestatic (ratio low) types of jaundice, there is a large 'grey area' and the results of these tests are best regarded as an extension to evidence from the history and examination, rather than being diagnostic in their own right. A prolonged prothrombin time is an exception, the response to parenteral vitamin K clearly distinguishing between a hepatitic and a cholestatic cause. In isolated hyperbilirubinaemia the determination of conjugated and unconjugated serum

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CASE STUDY 16.1 A 56-YEAR-OLD MAN WITH PAINLESS JAUNDICE A 56-year-old man presented with a 3-week history of jaundice which was preceded by the development of pale stools, dark urine and pruritus. On direct questioning he denied pain or fever. His weight had decreased by 4kg to 78kg. He was otherwise well. He had no significant past medical history apart from osteoarthritis of the hips, and he used diclofenac intermittently as analgesia. His alcohol consumption was 12-20 units per week and he had smoked 20-30 cigarettes daily for over 30 years. Physical examination confirmed the presence of jaundice but revealed no cutaneous stigmata of chronic liver disease. There was some skin

excoriation secondary to scratching. The liver could not be palpated but the gallbladder was palpable. There was no splenomegaly or ascites. The remainder of the examination was normal. The laboratory investigations were: haemoglobin 13.6g/dL, white cell count 7.8 x 109/L, platelets 182 x 109/L, prothrombin time 26 s (control 13s), serum bilirubin 474umol/L, aspartate aminotransferase 54IU/L, alkaline phosphatase 1293IU/L and serum albumin 39g/L.

Queition 1. What is the diagnosis?

bilirubin levels is of considerable value in confirming a diagnosis of prehepatic jaundice.

Special investigations The most useful special test in the jaundiced patient is an ultrasound scan. The aim is to determine whether or not the intrahepatic biliary system is dilated, which is one of the most reliable indicators of extrahepatic obstruction. If duct dilatation is detected it is usual to proceed to ERCP (p. 842). If the ducts are of normal calibre and the history is consistent with an acute hepatitis, then the specific diagnosis should be established with the appropriate virological tests. Liver biopsy is only indicated if there is real doubt as to the diagnosis, or if chronic liver disease is suspected.

UNCONJUGATED HYPERBILIRUBINAEMIA The two principal diagnostic categories are haemolysis and congenital defects in bilirubin uptake or conjugation.

HAEMOLYTIC JAUNDICE

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The diagnostic features of haemolytic jaundice are acholuric jaundice (jaundice without bilirubinuria), unconjugated hyperbilirubinaemia and a raised reticulocyte count. The differential diagnosis, further investigation and treatment are discussed on page 1214.

This is one of the few situations where a clinical diagnosis of the cause of jaundice can be made with confidence. The symptoms and the biochemical profile are typical of obstructive jaundice. In that context, the absence of pain and the palpable gallbladder make carcinoma of the head of the pancreas the most likely diagnosis. Gallstones would be expected to cause severe pain, although this may not be true in elderly patients. An ultrasound of the abdomen confirmed dilation of the gallbladder with no evidence of gallstones. A CT scan located a tumour in the head of the pancreas.

DEFECTS IN BILIRUBIN UPTAKE OR CONJUGATION The commonest defect in bilirubin uptake or conjugation (see Fig. 16.7) is Gilbert's syndrome, probably owing to defective uptake of bilirubin into hepatocytes and secondary deficiency of hepatic glucuronyl transferase. The condition is of no functional significance but is frequently the cause of much diagnostic confusion, with 'recurrent hepatitis' being the most common misleading label. The tendency for the bilirubin to rise or jaundice to become clinically apparent in association with intercurrent infections or starvation can erroneously consolidate the association between symptoms and Gilbert's syndrome. The finding of unconjugated hyperbilirubinaemia and a normal reticulocyte count, with no other abnormalities on the standard tests of liver function, is sufficient to make the diagnosis with confidence. A full explanation to the patient is all that is required for successful management. More serious congenital defects in bilirubin conjugation, such as the Crigler-Najjar syndrome (Fig. 16.7), can produce higher unconjugated bilirubin levels in the blood and kernicterus in infants, but are rare.

ACUTE HEPATITIS The term 'viral hepatitis' is often used rather loosely to mean infection with one of the hepatotropic viruses, although jaundice can occur as part of a systemic infection with several other viruses (Table 16.6) or as a reaction to drugs or alcohol. The general features of hepatitis

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TABLE 16.6 Viral causes of hepatitis Virus Hepatotropic viruses Hepatitis A vims (HAV) Hepatitis E virus (HEV) Hepatitis B virus (HBV) Hepatitis Delta virus (HDV) Hepatitis C virus (HCV) Other viruses which can cause hepatitis Epstein-Barr virus (EBV) (infectious mononucleosis)

Cytomegalovirus (CMV)

Herpes simplex and H. zoster

Lassa fever, Marburg virus and Ebola virus

Features

RNA virus; faecal-oral transmission; 1-month incubation RNA virus; faecal-oral transmission; 1-2 month incubation DNA virus; blood and sexual transmission; 3-month incubation RNA virus; blood (and sexual?) transmission; needs HBV RNA virus; blood (and sexual) transmission; 2-month incubation

DNA herpes-type virus, close contact and aerosol transmission; liver function tests abnormal in most cases but jaundice in only 15% DNA herpes-type virus; blood and close contact transmission, behaves like EBV infection Rarely involves the liver, but may cause severe liver damage in immunosuppressed patients Rare diseases; imported from Africa; severe organ damage, including liver

described earlier are similar whichever virus is responsible, but there are major differences in epidemiology and prognosis between the various hepatotropic viruses. Serological identification of the responsible agent is therefore of considerable help in management. Treatment is generally supportive, and in controlled clinical trials neither bed rest nor low-fat diets, which are often advised, have been shown to be of any value in speeding recovery. Similarly, although abstinence from alcohol is usually advised for about 6 months after recovery from the acute illness, there is no hard evidence that this makes any difference to the outcome. There is anecdotal evidence that vigorous exercise in the prodromal phase may increase the severity of the illness.

ENTERICALLY TRANSMITTED HEPATITIS VIRUSES Hepatitis A virus Virology Hepatitis A virus (HAV) is an RNA virus whose major polypeptides are similar to those of the enterovirus group (Fig. 16.12). Serologically the diagnosis of acute HAV infection is usually made by testing for the presence of specific IgM anti-HAV antibodies, which are present in

FIG. 16.12 The structure of the hepatitis A virus

serum for about 80 days after the acute illness. Although the mechanisms leading to cell necrosis have not been defined in detail, the role of immunological processes appears more important than direct viral cytotoxicity. Epidemiology HAV is transmitted by the faecal/oral route and rarely, if ever, parenterally. It may be endemic or sporadic, and epidemics sometimes occur. Childhood acquisition, often asymptomatic, is the norm in parts of the Mediterranean, the Middle East and India. In contrast, in northern Europe the vast majority of children reaching adulthood have no evidence of immunity to hepatitis A. They are then at risk of acquiring hepatitis A while travelling in endemic areas or with changes in eating habits, e.g. developing a taste for uncooked shellfish. The incubation period is about 1 month (2-7 weeks). Carriers have not been detected. Clinical features Acute hepatitis A is usually a mild illness preceded by a typical prodrome. This may be so similar to 'flu', with prominent myalgia, that the patient does not connect the prodrome with the jaundice, and should be asked about a preceding febrile illness. The patient is most infectious during the prodrome and less so during the first week of the clinical illness. Acute liver failure is a rare complication, and progression to chronic liver disease does not occur. Hepatitis A may follow a biphasic clinical course or, more frequently, may be followed by a protracted cholestatic phase. Aplastic anaemia, particularly in children, is a rare complication with a high mortality.

Hepatitis E virus This is an RNA virus which resembles the calciviruses in the size (7.5kb) and organization of its genome. It is spread by the faecal/oral route and first came to attention because of a major waterborne hepatitis epidemic in India, initially thought to be due to hepatitis A. It is common in the Indian subcontinent. The incubation period is about 6 weeks and the clinical illness it produces is in most respects like any viral hepatitis. However, there is an unusually high mortality among pregnant women who become infected. It does not produce chronic hepatitis. Diagnostic tests for the

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virus and antibodies to its antigenic components are now available in specialist laboratories.

PARENTERALLY TRANSMITTED HEPATITIS VIRUSES Hepatitis B virus

1

Virology Hepatitis B vims (HBV) is a member of an unusual group called the HepaDNA viruses. It has an outer and an inner

protein coat, with double-stranded DNA and a DNA polymerase in the nucleocapsid (Fig. 16.13). The main antigenic protein of the outer coat, the hepatitis B surface antigen (HBsAg), is produced in excess during viral replication, and forms large numbers of smaller empty particles in the serum. The complete core protein coat reacts antigenically as hepatitis B core antigen (HBcAg). The open reading frame for the core gene of the virus has two start codons (positions 1814 and 1901 in Fig. 16.14). Transcription from the second one leads to production of the core subunits, which self-assemble to make the viral capsid, whereas transcription from the first start codon inserts a signal peptide

CASE STUDY 16.2 A YOUNG MAN WITH JAUNDICE RECENTLY RETURNED FROM INDIA A 23-year-old university student presented with jaundice, which he had noticed the previous day. He had been unwell for the previous 6 days, with nausea, vomiting and dark urine. However, these symptoms had improved once the jaundice appeared. He had recently travelled to India. He drank 20 units of alcohol per week and had used 'Ecstasy' most weekends for the previous 2 years. He was a sexually active heterosexual and had had numerous partners since the age of 17. There was no history of previous illnesses requiring hospitalization. Physical examination confirmed the presence of jaundice. His temperature was 38.2°. There were no cutaneous stigmata of chronic liver disease. The liver was palpable 3 cm below the costal margin and was tender. There was no clinical evidence of splenomegaly or ascites. His mental state was normal, with no evidence of drowsiness or confusion. The initial laboratory investigations were: haemoglobin 14.5 g/dL, white cell count 3.6 x 109/L, platelets 223 x 109/L, prothrombin time 16s (control 13s), serum bilirubin 176fimol/L, aspartate aminotransferase 1462IU/L, alkaline phosphatase 121 IU/L.

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MCQ16.3

Question 1. What Is the most likely jdiagnfosis? The very high serum transaminase level indicates hepatitis, and in this age group this is most likely to be viral or drug related. He has a number of risk factors for hepatitis. Recent travel to India puts him at risk of hepatitis A and hepatitis E. Hepatitis B would also have to be considered on the basis of multiple sexual partners. Hepatitis C is unlikely as his recreational drug usage was confined to 'Ecstasy', and it is unusual for hepatitis C to cause clinical episodes of jaundice. 'Ecstasy' can cause jaundice but this is usually seen within the first few months of use. There is no reason to link alcohol to this episode of jaundice. The viral serology indicated that he was HAV IgM positive, HBsAg negative and HEV IgG negative. This established the diagnosis as acute hepatitis A. This was also the most likely diagnosis because of the fever that was present. He was due to attend the surgery 4 days after the initial consultation to review the results of investigations, but he did not arrive. Later that day he was

found unconscious by a flatmate and was taken directly to hospital. Physical examination confirmed he was unresponsive except to painful stimuli. The laboratory investigations were: haemoglobin 14.1 g/dL, white cell count 3.2 x 109/L, platelets 116 x 109/L, prothrombin time 101 s (control 13s), serum bilirubin 354 |imol/L, aspartate aminotransferase 434 IU/L, alkaline phosphatase 109 IU/L. Question 2. What complication has developed? The high prothrombin time and the impaired conscious level indicate that he has developed acute liver failure. This occurs in only about 0.1% of cases of acute hepatitis A infection. The prothrombin time was over 100 seconds and this indicated that he was unlikely to survive. Consequently, he was transferred to a specialist unit and underwent liver transplantation the following day. He made a full recovery. Question 3. What else should be done? His household contacts should be vaccinated against hepatitis A.

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FIG. 16.13 The hepatitis B virus. A Structure; B genome

in front of the core protein, which leads to self-cleavage in the endoplasmic reticulum and the secretion of a soluble protein into the blood known as the hepatitis B 'e' antigen (HBeAg). This seems to be of crucial importance in establishing immune tolerance to the core protein, particularly in infants. Its presence in blood, with HBsAg, is also used as an indication of active viral replication in the liver and as a marker of infectivity. Each of these antigens can elicit a corresponding antibody response (anti-HBs, anti-HBe and anti-HBc). In an acute HBV infection the appearance of these antigens and antibodies in serum, and changes in serum AST levels, follow a well-defined pattern (Fig. 16.15). In most cases, HBV infection is detected by finding HBsAg in serum. The diagnosis of acute, as opposed to chronic, HBV infection is best made by testing serum for IgM-class anti-HBc antibodies. Epidemiology The main route for HBV infection is by parenteral inoculation, although direct transmission by blood transfusion is now very uncommon following the development of sensi-

FIG. 16.15 The main serological changes in (A) acute HBV and (B) chronic HBV infection The break in the x-axis of B has been used to indicate the very variable length of time that can elapse between the establishment of the chronic carrier state and the spontaneous cessation of viral replication.

tive serological tests to detect infectious blood donations. The virus has a wide global distribution (Fig. 16.16). Chronic carriers are especially prevalent in the Middle and Far East and in sub-Saharan Africa, where they may constitute 10-30% of the population. In the Far East vertical transmission from mothers to their children is the usual route of infection, whereas in Africa horizontal spread in early childhood, possibly through scarification rituals, is more common. In northern Europe and the USA, where chronic carriers are less common and where the screening of blood donations is accepted practice, the main reservoirs

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FIG. 16.16 The distribution of HBV infection in the world as judged by the prevalence of hepatitis B surface antigen in different populations

for the virus are urban homosexual communities and intravenous drug abusers. The virus seems to be readily transmitted by rectal intercourse.

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Immunopathology Recent evidence suggests that the complete hepatitis B virion has an area of its surface protein coat that resembles the IgA molecule and that this can bind to IgA receptors on hepatocytes. This probably explains the hepatotropism of HBV. During replication of the virus, viral antigens, principally HBsAg and HBcAg, appear on the surface membrane of infected hepatocytes and trigger a cytotoxic T-lymphocyte response (Fig. 16.17). This is largely directed at HBcAg and leads to cytolysis, seen clinically as acute liver damage (jaundice and AST elevation), and histologically as spotty necrosis of hepatocytes scattered throughout the liver lobules. Released virions are then neutralized by antibodies probably directed at the region responsible for hepatocyte binding. Complete recovery involves a coordinated T-cell and antibody response to different viral antigens. Failure of these complex mechanisms results in about 5% of apparently normal adults not clearing the virus, and becoming chronic carriers (Fig. 16.15). The carrier state is commoner in infancy and childhood and in those with an associated immunodeficiency, whether this is congenital, due to drugs (as in immunosuppressed transplant recipients), or secondary to other diseases. The human immunodeficiency virus (HIV) is the most dramatic of these associated virus infections, and AIDS and HBV infection often coexist in male homosexuals. In the case of HBV, an effective vaccine made by purifying HBsAg from the plasma of carriers and a recombinant HBsAg vaccine are available for those at increased risk. These include sexual and family contacts of carriers, as well as healthcare workers and children born to carrier mothers. In many of the developing countries in the Far East, extensive country-wide vaccination programmes have been in force for over a decade, and the incidence of HBV carriers has shown a marked fall. In Africa vaccination pro-

FIG. 16.17 The immunopathology of hepatitis B Liver cell damage in HBV infection is due to an immune attack by T cells against viral antigens expressed on the surface of infected hepatocytes. The T cells recognize the foreign viral antigens as small peptides bound to class I histocompatibility antigens (HLA class I).

grammes are less well developed, but HB vaccine is now being included in the childhood vaccination programme. Clinical features The prodromal illness may be particularly severe, with arthralgia, urticaria and occasionally a full 'serum sickness' syndrome with associated glomerulonephritis. Acute liver failure is a rare complication, and the main clinical concern is the relatively high rate of progression to a chronic carrier state. The resulting liver lesions are described on page 864. Careful follow-up with repeated serological tests is an essential part of the management. Although persistence of HBsAg for more than 6 months is the usual criterion for chronicity, persistence of HBeAg in serum for more than 8 weeks may give an earlier indication of failure to clear the virus normally.

Delta virus Virology This is a small RNA virus with a genome that does not code for its own protein coat; instead, it borrows HBsAg provided by a concurrent HBV infection (Fig. 16.18). Serologically, Delta infection can be detected by testing for anti-Delta antibodies in serum. These appear early in the course of the infection but may not persist. Epidemiology Delta infection is absolutely dependent on a helper function of HBV, and so is only found in two settings: either there is a dual acute infection of HBV and Delta virus, or Delta virus infects an existing HBsAg carrier. Like HBV it is spread by the parenteral route or via intimate contact. It is endemic in countries around the Mediterranean basin, and in northern Europe and the USA is found mainly in drug abusers.

16

SUMMARY 4 Clinical aspects of viral hepatitis Type Faecal/oral spread A E (Enteric non-A, non-B) Parenteral/sexual transmission C (Parenteral non-A, non-B) B

D (Delta)

Incubation period

Clinical features

Outcome

Vaccines

4 weeks 6 weeks

Mild often subclinical High mortality in pregnancy

No chronic disease No chronic disease

Widely available None

8 weeks

Mild otten subclinical

None

12 weeks

Variable severity

4-12 weeks

Severe in HBV carriers

20-40% progress to chronic disease Neonatal 90% carriers Childhood 10-40% carriers Adult 1-10% carriers Carrier on chronic HBV; Recovery in most coinfections

36 nm

FIG. 16.18 The Delta virus The Delta virus is a strange structure. It borrows its coat from the hepatitis B virus (HBsAg), so HBV must also be present in hepatocytes. The infective material of Delta is a small circular strand of RNA.

Immunopothology Clinical evidence and studies in primates suggest that the Delta virus is directly cytopathic to the cells it infects. The contribution of immune responses to cell damage and recovery is not known. Clinical features Coinfection produces an acute hepatitis that is clinically indistinguishable from HBV infection alone, although there is some suggestion that the illness may be more severe. Recovery from the HBV infection is always associated with the disappearance of Delta. Infection in an HBsAg carrier can produce a severe acute hepatitis, and in some cases acute liver failure. Chronic Delta infection is also more likely to occur and has a bad prognosis (p. 865).

Hepatitis C virus Hepatitis C, an RNA virus, was discovered in 1989. It belongs to the Flavivirus family and is quite common

Widely available and in national programmes None

throughout the world. There are significant geographical variations in the distribution of the four main genotypes of the virus which influence both the virulence of the infection and its responsiveness to current antiviral therapy. The results of epidemiological studies suggest that the carrier rate varies from about 0.05 to 0.2% in northern Europe, through 1 or 2% in the Mediterranean to 5% or more in the Far East. It is an important cause of chronic liver disease, cirrhosis and hepatocellular carcinoma. It is transmitted mainly by parenteral inoculation. Blood transfusion was one of the most important sources until the introduction of reliable blood tests for the detection of carriers around 1990-91. Drug abusers remain an important at-risk group. Sexual and neonatal transmissions can occur but are uncommon. Acute infection is not usually associated with a recognized clinical episode of hepatitis, even in adults. About 85% of cases become chronic carriers and 20-40% of these will develop chronic liver disease over a period of 20-30 years. Standard liver function tests screen for necroinflammatory activity but not for fibrosis. The assessment of the severity of the infection is best determined by measuring viral load in blood and by liver biopsy.

NON-HEPATOTROPIC VIRUSES Epstein-Barr virus Liver function tests are often abnormal in glandular fever, but jaundice occurs in less than 10% of cases. The Epstein-Barr virus (p. 287) does not seem to infect hepatocytes and liver cell necrosis is minimal. Recovery is almost always uneventful, although fatigue, as part of a postviral syndrome, can be troublesome for a few months.

Cytomegalovirus In adults cytomegalovirus (p. 288) can produce an illness like glandular fever, with accompanying jaundice in some cases, but recovery is usually rapid. Liver biopsy, although

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not required to make the diagnosis (which is made serologically), may show the characteristic eosinophilic nuclear inclusions in infected hepatocytes.

Herpes simplex Herpes simplex (p. 286) is a rare cause of severe acute hepatitis, that usually affects immunosuppressed patients. There is usually a local oral lesion, but the striking feature is disseminated infection with encephalitis or myocarditis, in addition to hepatitis.

DRUG-INDUCED JAUNDICE The continued production of new drugs has been accompanied by an increasing problem with drug-induced liver damage (Table 16.7). It is generally stated that about 10% of cases of jaundice in hospital practice are due to medication. There are two main types of adverse reaction: predictable or dose-dependent (type A), and idiosyncratic or dose-independent (type B). In the former, liver damage is dose-dependent and relatively common, and can usually be reproduced in laboratory animals. Idiosyncratic cases are infrequent, not related to dose and not usually reproducible experimentally. Recognition of these cases is important for two main reasons: withdrawal of the drug usually leads to rapid recovery, and repeat prescription, which may be associated with a more severe reaction, can be avoided. The liver damage produced by drugs can mimic almost any acute or chronic hepatic or biliary disorder. In most cases liver damage is predominantly hepatitic or cholestatic.

TABLE 16.7 Examples of drugs causing liver damage Drug Antituberculous Para-aminosalicylic acid (PAS) Isoniazid (INAH) Rifampicin Pyrazinamide and ethionamide Other antibiotics Tetracycline Sulphonamides including co-trimoxazole Erythromycin Ketoconazole Nitrofurantoin Psychotropic drugs Monoamine oxidase inhibitors Phenothiazines Tricyclic antidepressants Analgesics Paracetamol Aspirin Non-steroidal analgesics Steroid drugs and hormones 17-alkyl/ethynyl substituted steroids (including contraceptive pill)

DRUG-INDUCED HEPATITIS Paracetamol- and halothane-induced liver damage are two examples of drug-induced hepatitis; both are potentially fatal. Paracetamol is a predictable hepatotoxin, but the liver damage induced by halothane occurs idiosyncratically.

Paracetamol

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Paracetamol is safe in normal therapeutic doses but produces a severe hepatitis if taken in overdose (more than 10g or 20 tablets). Liver damage is due to the formation of highly reactive metabolites (Fig. 16.19). At normal dose levels these are inactivated by conjugation with glutathione. When a large amount of drug is taken, insufficient glutathione is available for detoxification and the metabolites damage the cell by binding to cellular macromolecules. Compounds acting as -SH donors can prevent this process. The most effective and non-toxic of these is 7V-acetylcysteine given intravenously (p. 28).

Anaesthetic agents Halothane Immunosuppressive drugs Azathioprine Methotrexate Corticosteroids Cardiovascular drugs Methyldopa Perhexilene Thiazide diuretics Oral hypoglycaemic drugs Chlorpropamide

Comments Idiosyncratic type; 1% get drug hepatitis in first 2 months Raised transaminases in 10%; 1% jaundice in first 2 months Up to 4% develop hepatitis; ?increases isoniazid toxicity Late-onset hepatitis in 1%

Microvesicular fatty liver Idiosyncratic; mimics viral hepatitis Cholestasis; especially estolate Hepatitis in 0.1% Cholestasis and chronic hepatitis Viral hepatitis lookalike in 1-2% after about 4 months Mixed cholestatic and hepatitic picture in 1-2% after 2-4 months; can persist Rare cholestatic hepatitis Predictable liver necrosis in overdose (more than 10g); /V-acetylcysteine antidote Acute anicteric hepatitis, especially in children; may cause Reye's syndrome Considered one of common causes, given scale of usage Predictable (dose/duration-dependent) Cholestasis, especially the 19-nortestosterones; increased risk of adenoma Commonly produces minor increase in transaminases, very rarely fatal hepatitis Rare Cholestasis Long continued treatment, as in psoriasis, may cause fibrosis and cirrhosis Fatty infiltration Acute and chronic hepatitis starting after 2-5 months Rare hepatitic illness, looks like alcoholic liver damage Cholestatic hepatitis; may be prolonged Cholestatic hepatitis in 5%, with granulomatous reaction

damage by direct hepatotoxicity. The agents include androgenic and anabolic steroids, progestogens and oestrogens. The cholestatic effect is dose related and the obstructive jaundice resolves following the cessation of treatment. Histologically there is evidence of centrilobular cholestasis without obvious hepatocellular damage. The exact mechanism is unknown.

16

Chlorpromazine Chlorpromazine is a rather dramatic example of an agent causing an idiosyncratic reaction. About 1-2% of those taking this drug develop a severe cholestasis, which may persist for weeks after the drug has been withdrawn. The reaction has been described following only one dose. The mechanism responsible is unknown.

FIG. 16.19 Paracetamol overdose Paracetamol is normally sale to take because the metabolites are inactivated by conjugation. After an overdose the conjugating material, particularly glutathione, is used up and reactive metabolites damage the liver cell proteins.

Halothane Halothane is an example of an unpredictable (idiosyncratic) hepatotoxin. Significant liver damage is very rare (1 in 30000 halothane anaesthetics), but when it occurs it is often fatal. It is more common after repeated halothane anaesthesia. The clinical picture is very similar to viral hepatitis, with a prodromal illness starting a few days after the surgical procedure. In about one-third of cases unexplained pyrexia has been noted following a previous halothane anaesthetic. Progression to acute liver failure is common, although the exact frequency of this complication is difficult to assess because of uncertainty about the diagnosis in mild cases. The mechanism of liver damage is thought to be immunological. A reactive metabolite, produced during oxidative metabolism of halothane, alters the normal antigens on the liver cell membrane. In patients with halothane hepatitis these new antigens have been shown to stimulate an immune response, which may produce the liver damage. The idiosyncrasy seems to be related to the ability of the immune system to recognize these subtle antigenic alterations.

DRUG-INDUCED CHOLESTASIS The cholestatic jaundice induced by C17-substituted testosterone derivatives and chlorpromazine is an example of predictable and idiosyncratic hepatotoxicity.

C17-substituted testosterone derivatives C17-substituted testosterone derivatives produce liver

ACUTE LIVER FAILURE

Pathophysiology Severe liver damage leads to secondary disturbance of function in other organ systems. This complex development is recognized clinically as acute liver failure. Encephalopathy is the commonest and most obvious complication. Although the exact cause is unknown, potential factors include the release of toxins from the damaged liver, failure to detoxify metabolites, and alterations in cerebral neurotransmitters owing to amino acid imbalances (p. 873). Renal failure and cardiovascular instability are also common and carry a particularly bad prognosis.

Epidemiology Acute liver failure is a rare complication of almost any of the causes of acute hepatitis. In most countries viral hepatitis (A, E, B and Delta) is the most common cause, but in the UK about half the cases are due to paracetamol poisoning, with most of the remainder being associated with hepatitis A or B, or seronegative hepatitis (also known as non A-E hepatitis). Hepatitis C virus seems to be a very rare cause of acute hepatic failure. A small proportion are due to medications such as isoniazid and rifampicin. In areas around the Alps and the Rocky mountains, ingestion of the poisonous mushroom Amanita phalloides is an important cause. The recreational use of Ecstasy may cause acute liver failure. Other less common causes include Wilson's disease, autoimmune hepatitis, Budd-Chiari syndrome, hyperthermia, and a range of conditions associated with pregnancy.

Clinical features Patients develop the signs of acute liver failure within 8-12 weeks of the onset of the illness and have no previous history of liver disease. This distinguishes acute liver failure

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TABLE 16.8 Grades of coma in liver failure Grade

Clinical features

I

Slowness of mentation and affect, fluctuant mild confusion; reversed sleep rhythm; slurred speech Accentuation of grade I; inappropriate behaviour; drowsiness Marked confusion; sleeps most of the time but rousable; incoherent speech Unrousable; may or may not respond to noxious stimuli

II III IV

from rapidly progressive chronic liver disease. The first signs of the disease often relate to the encephalopathy, with the appearance of mild confusion, irrational behaviour or even euphoria. Progressive deterioration in mental condition then follows, leading to coma. The usual grading of the level of coma is according to a four-stage model (Table 16.8). In some rapidly progressive cases jaundice may never be apparent and the whole illness, from first symptoms to death, may last less than a week. The classic signs of encephalopathy, including fetor hepaticus and liver flap, are usually absent. In the early stages of grade IV coma hyperventilation is common, and the pupils are dilated and react sluggishly to light. Hypertonia and grasp reflex are readily elicited, and in deep coma decerebrate postures are seen. Terminally, the oculovestibular reflex is lost and hypotension, cardiac arrhythmias and respiratory arrest occur. The prolongation of prothrombin time is the most important of the liver function tests and is very influential in determining prognosis. However, extreme prolongations may be seen after paracetamol ingestion in patients who will survive, whereas modest prolongations are typical of syndromes that evolve over 4-12 weeks but ultimately lead to death in the vast majority of cases. The serum bilirubin increases with time and aids the determination of the prognosis. However, the range of serum transaminase levels seen is great and, as it bears no relationship to the clinical outcome, is of limited value. An early and often extreme acidosis is very suggestive of paracetamol toxicity.

Complications and management The complications and management of acute liver failure are listed in Table 16.9. Treatment consists of skilled supportive therapy based on a sound knowledge of the expected course of the disease and its complications. Admission to an intensive care area is essential and early ventilatory support is frequently required. Intravenous nutritional support is with 10% dextrose. Serum sodium and potassium levels are measured daily and any abnor-

1

854

MCQ 16.4

2

Fig. 16.2

TABLE 16.9 Complications and management of acute liver failure Problem

Treatment

Cerebral oedema Nutrition, fluid and electrolytes Renal failure

Mannitol infusions given promptly reverse pressure rises 10% dextrose into a central vein; extra potassium needed; low sodium is usually dilutional Common problem; half have 'functional renal failure', others acute tubular necrosis. Attention to fluid balance may help, but dialysis may be needed H2-receptor antagonists significantly reduce risk, and are given routinely Common late complication. Intubate early to protect airway

Gastrointestinal haemorrhage Respiratory failure

malities corrected. Hypoglycaemia and hypokalaemia are early life-threatening abnormalities which must be detected and corrected quickly. Erosive oesophagitis and gastritis leading to severe gastrointestinal haemorrhage used to be a major problem, but prophylaxis has proved effective. Renal failure is common, and haemodialysis or other forms of renal support may be needed. Coagulation disorders are also common, owing to failure of synthesis of clotting factors and, in some cases, the occurrence of disseminated intravascular coagulation (p. 1275). Cerebral oedema is an important cause of death, and mannitol infusions are useful in reducing increased intracranial pressure. The other major causes of death are sepsis and cardiovascular instability, which are unresponsive to antimicrobial agents and vasopressor drugs, respectively. Liver transplantation is a common treatment for the most severe cases, but it is essential to have a method of rapidly assessing prognosis to avoid transplanting those who will survive even though they appear to be desperately ill. Liver assist devices are being developed as a means of supporting patients until a liver becomes available for transplantation or until spontaneous recovery occurs. These use human hepatocytes from a tumour cell line or animal liver cells which restore some degree of liver function, but they await evaluation in controlled clinical trials. Combined medical and surgical management strategies are achieving survival rates of 40-90%, depending on the underlying aetiology. Survivors rarely develop cirrhosis or chronic liver disease, probably because of the remarkable regenerative capacity of the liver. 1

FURTHER READING ON HEPATITIS Da Villa G, Picciottoc L, Elia S, Peluso F, Montanaro F, Maisto T 1995 Hepatitis B vaccination: universal vaccination of newborn babies and children at 12 years of age versus high risk groups. A comparison in the field. Vaccine 13(13):1240-1243. Heathcote E J, Shiffman M L, Cooksley W G E, Dusheiko G M, Lee S S, Dalart L, Reindollar R, Reddy R K, Wright T L, Lin A, Hoffman J, De Pamphilis J 2000 Peg interferon alpha-2a in patients with chronic hepatitis C and cirrhosis. N Engl J Med 343:1673-1680.

RECENT ADVANCES LIVER ASSIST DEVICES A new generation of extracorporeal liver assist devices has started to emerge that have the potential to do for hepatology what haemodialysis did for renal failure. The devices currently under evaluation use either pig cells or cells from a human tumour cell line - Hep 3CA cells - to provide basic functions. The volume of cells used varies from 20 g of porcine cells to 200-400 g of Hep 3CA cells. The porcine cells are usually in series in the extracorporeal circuit with a charcoal filter designed to protect them from harmful toxins. Patients are treated intermittently for about 6 hours per day with the porcine cells, or continuously with the Hep 3CA cells for up to 10 days. The clinical evaluation of these systems is in progress. Preliminary results are sufficiently encouraging to proceed to formal controlled trials. The application of an effective device might initially be to 'bridge' very ill patients to liver transplantation by stabilizing their condition. However, if the devices are powerful supplements of liver function they may be effective in salvaging patients with acute or chronic liver failure without recourse to transplantation. These devices also have theoretical roles in extending the boundaries of feasibility for liver resection and the scope for using marginal donors in liver transplantation.

Hoofnagle J H, Di Bisceglie A M 1997 The treatment of chronic viral hepatitis. N Engl J Med 336:347-356. Makin A J, Wendon J, Williams R 1995 A 7-year experience of severe acetaminophen-induced hepatotoxicity (1987-1993). Gastroenterology 109(6):1907-1916. Mellor J, Holmes E C, Jarvis L M, Ya L, Simmonds P 1995 Investigation of the pattern of hepatitis C virus sequence diversity in different geographical regions: implications for virus classification. The International HCV Collaborative Study Group. J Gen Virol 76(pt 10):2493-2507. Tillman H, Trautwein C, Walker D, Michitaka K, Kubicka S, Boker K, Manns M 1995 Clinical relevance of mutations in the precore genome of the hepatitis B virus. Gut 37(4):568-573. Zeuzem S, Feinman V, Rasenack J, Heathcote E J, Lai M-U, Gane E, O'Grady J, Reichen J, Diago M, Lin A, Hoffman J, Drunda M J 2000 Peg interferon alpha-2a in patients with chronic hepatitis C. N Engl J Med 343:1666-1672.

JAUNDICE IN PREGNANCY CHOLESTASIS OF PREGNANCY Cholestasis of pregnancy is a rare condition in which pruritus, with or without painless jaundice, occurs in the last trimester of pregnancy. Some women taking the oral contraceptive pill seem to develop a similar condition, suggesting that it represents an unusual response to high oestrogen levels. The itching usually responds to cholestyramine. The symptoms disappear following the

birth, and liver function tests return to normal. The cholestasis tends to recur with each pregnancy.

16

ACUTE FATTY LIVER OF PREGNANCY Acute fatty liver of pregnancy is a serious but rare condition. It presents in the last trimester with a prodromal illness which is similar to acute viral hepatitis, and which starts about a week before the jaundice appears. The histological changes are quite distinct from those of viral hepatitis. There is a widespread, centrilobular microvesicular fatty change in hepatocytes. The aetiology is unknown, although identical changes are rarely seen following tetracycline treatment. Urgent delivery of the baby is essential and in most cases this triggers rapid resolution of the condition. Acute liver failure can occasionally develop but with optimal treatment the prognosis is good and liver transplantation is rarely required.

HELLP SYNDROME AND TOXAEMIA The HELLP syndrome is a combination of encephalopathy, elevated liver enzymes and thrombocytopenia. It also occurs in the last trimester and can be difficult to differentiate from acute fatty liver of pregnancy. Patients with toxaemia (pre-eclampsia or eclampsia) may develop infarction of the liver secondary to obliteration of small arteries and arterioles. These patients are characterized by especially high serum transaminases and can develop acute liver failure.

ACUTE ALCOHOLIC HEPATITIS Clinical features The term 'alcoholic hepatitis' has two quite different meanings. To the histopathologist it indicates certain specific features found in some patients with alcoholic liver disease, particularly perinuclear eosinophilic hyaline inclusion bodies (Mallory's hyaline) in hepatocytes in, or near to, areas of spotty parenchymal necrosis. An associated inflammatory infiltrate consists largely of polymorphonuclear leukocytes. There may or may not be associated fibrosis or cirrhosis. Although some patients with these changes on liver biopsy are entirely asymptomatic, the pathological features are important as they indicate a greatly increased chance of the development of cirrhosis. This progression occurs in 90% of patients with features of alcoholic hepatitis on liver biopsy if they continue to drink, whereas complete regression is the rule in 90% of those who subsequently remain abstinent. 0 To the clinician, the term 'alcoholic hepatitis' is also used to describe an acute illness associated with alcohol abuse,

855

in which deep jaundice, abdominal pain, fever, marked polymorphonuclear leukocytosis, and elevated prothrombin time are the principal features. Cutaneous stigmata of chronic liver disease are common, even in the absence of cirrhosis. Cholestasis is often prominent and may lead to a mistaken diagnosis of extrahepatic obstructive jaundice, and possibly a laparotomy, which can be fatal. The mortality of the condition is high (30-60%). Both the clinical illness and the pathological changes are commoner and more severe in women, and in people of northern European origin (including America). Although the histological changes can be found in southern European patients, the severe acute clinical illness is uncommon. There is no definite relation to the pattern of drinking or the type of alcoholic drink.

Management Trials of specific drug treatments have proved disappointing, although recent studies support the use of prednisolone 30-40 mg for periods of up to 4 weeks. Abstinence remains the most effective therapy (p. 251).

CHOLESTATIC JAUNDICE As with the diagnosis of acute hepatitis, a good history is the key to identification of cholestatic (including obstructive) jaundice. Although pale stools and dark urine are common to both, the early appearance of itching and, more rarely, high fevers with rigor (ascending cholangitis), is a general pointer to extrahepatic bile duct obstruction. The commonest causes are outlined in Table 16.10 and the specialized investigations that may be required to identify the site and cause of the obstruction are described on pages 842 and 843. An essential early investigation is an ultrasound scan of the upper abdomen. The presence of dilated bile ducts is an almost certain indication of major duct obstruction. Gallstones, which are echo dense, are also detected easily, but it can be more difficult to comment with certainty on the pancreas and other retroperitoneal structures. In some cases a CT scan may be helpful. The final determination of the site of obstruction is best made by ERCP or PTC.

GALLSTONES 1 Pathophysiology Mixed cholesterol stones Mixed cholesterol stones are the commonest variety in the western world, and consist largely of cholesterol crystals

1

856

MCQ 16.5

TABLE 16.10 Causes of cholestatic jaundice Intrahepatic Metabolic/unknown cause Pregnancy Contraceptive pill Methyltestosterone Parenteral nutrition Lymphoma Benign recurrent intrahepatic, and postoperative cholestasis Extrahepatic Benign Gallstones in bile duct Post-traumatic stricture Sclerosing cholangitis Biliary atresia Choledochal cyst Acute and chronic pancreatitis Retroperitoneal fibrosis Ascending cholangitis Haemobilia

Liver damage Primary biliary cirrhosis Late viral hepatitis Alcoholic hepatitis Biliary hypoplasia Secondary deposits

Malignant Carcinoma of the gall bladder Carcinoma of the bile duct Hilar lymphadenopathy Carcinoma of the ampulla of Vater Carcinoma of the pancreas

with a variable proportion of calcium salts. The main constituents of bile are cholesterol, phospholipids and bile salts. The ratio between cholesterol and the other constituents is crucial in maintaining cholesterol in solution. Bile supersaturated with cholesterol can develop because of an increased cholesterol concentration, or a decreased bile salt content. These changes in the constituents can be due to altered rates of secretion, either congenital or acquired, or changes in the relative proportions during concentration and storage of bile in the gallbladder. Pigment stones Pigment stones consist of bilirubin and salts such as phosphates and carbonates. They are common in the Far East. Increased delivery of bilirubin in chronic haemolytic anaemias is a frequent cause in the UK, whereas in the Far East parasitic and bacterial infection of the bile is the usual causative factor. These organisms promote the formation of insoluble deconjugated bilirubin by the release of enzymes such as glucuronidase.

Epidemiology The epidemiology of gallstone disease is changing. Cholesterol gallstones occur more often in women than in men (Fig. 16.20), and the prevalence increases with age, obesity and parity. Other suggested risk factors are diet (a vegetarian diet appears protective), a positive family history, low social class, and the use of oral contraceptives. There

FIG. 16.20 The increasing prevalence of gallstones with age in both men and women

are marked racial differences in prevalence, with Native Americans being particularly susceptible. There is a predisposition to cholesterol stone formation in patients with chronic liver disease, in whom there is reduced excretion of bile salts, and also in patients with a resection or disease of the terminal ileum. In these cases there is reduced bile salt reabsorption from the gut and a consequent fall in bile salt excretion into the bile.

Detection Only 10% of cholesterol gallstones contain enough calcium salts to be visualized on plain X-ray of the abdomen. Ultrasound is the investigation of choice to detect stones in the gallbladder. Several studies have shown that, using ultrasound, stones can be detected with an accuracy of more than 95%.

Clinical features Stones in the gallbladder are a common incidental finding and, if they remain there, may never give rise to symptoms. Stones in the biliary tree may cause biliary colic. Impaction in the cystic duct followed by infection produces acute cholecystitis, whereas passage down the common bile duct produces biliary colic, obstructive jaundice and cholangitis.

ACUTE CHOLECYSTITIS The presenting symptoms of acute cholecystitis are malaise, anorexia and pyrexia, with pain in the right hypochondrium sometimes radiating to the right shoulder. There is guarding and rigidity in the right upper quadrant. Tenderness on inspiration over the gallbladder area (Murphy's sign) is usually present. Jaundice suggests stones in the common bile duct. A polymorphonuclear leukocytosis is usually present but does not help in the differential diagnosis, which includes acute appendicitis and pancreatitis. There are two different approaches to treatment: either

early cholecystectomy or initial broad-spectrum antibiotic therapy (e.g. cephalosporin with metronidazole), fluid replacement and analgesia, followed by elective cholecystectomy several weeks later. Exploration of the common bile duct, with operative cholangiography, should be undertaken if there is jaundice, dilatation of the duct, or evidence on previous investigations of stones in the common bile duct. Complications include empyema and perforation of the gallbladder, and liver abscesses following portal pyaemia. Perforation is particularly frequent in the elderly. The signs are those of generalized peritonitis, unless previous episodes of cholecystitis have led to dense adhesions, when a localized abscess may be produced. Empyema results from infection of obstructed bile in the gallbladder, which fills with pus. There is a very tender mass in the right hypochondrium, with fever and sometimes Gram-negative septicaemia. Treatment is by emergency drainage of the biliary system under broad-spectrum antibiotic cover.

16

STONES IN THE COMMON BILE DUCT Although the classic symptoms of biliary colic followed by jaundice might be expected to accompany the passage of a stone down the common bile duct, it is important to realize that a substantial proportion of patients with biliary obstruction due to gallstones may present with painless jaundice. Cholangitis and Gram-negative septicaemia are frequent and dangerous complications, and the diagnosis must be established quickly. Ultrasound is again of great value in demonstrating a dilated biliary system, and may also show the stone in the common bile duct. It is usually necessary to proceed to cholangiography (PTC or ERCP, p. 843) to confirm the diagnosis, but antibiotics should be given first to minimize the risk of cholangitis. Treatment is usually surgical, involving exploration of the duct, the removal of stones and temporary T-tube drainage. It is best to start antibiotics, to give intramuscular vitamin K, and to correct fluid balance or electrolyte abnormalities before surgery. Many broad-spectrum antibiotics have been shown to be effective in this prophylactic setting and cephalosporins, with their low incidence of toxic reactions, are usually favoured. Mannitol infusion has been shown to reduce the incidence of postoperative renal failure. In the elderly or in bad-risk patients endoscopic sphincterotomy, followed by the removal of any remaining stones with a basket or balloon via the endoscope, is an alternative procedure and in many centres this is becoming the preferred treatment for all cases.

ACUTE CHOLANGITIS In any patient with obstructive jaundice the biliary system can become infected, often with dramatic clinical conse-

857

quences. Rigors usually accompany a high fever, and this in the presence of jaundice is sometimes known as Charcot's intermittent biliary fever, or more simply ascending cholangitis. Vascular collapse and renal failure are common complications, reflecting the high incidence of Gram-negative septicaemia. Urgent broad-spectrum antibiotic therapy, after taking blood cultures, is essential and must be coupled with early relief of the biliary obstruction. A combination of antibiotics active against aerobic and anaerobic organisms is usually chosen.

CHRONIC CHOLECYSTITIS Chronic inflammation of the gallbladder is usually found in association with gallstones, but whether or not this produces symptoms, and what these are, is a subject of continuing debate. The diagnosis of chronic cholecystitis is almost certainly made too frequently. The symptoms are often vague, with 'flatulent dyspepsia', fullness in the upper abdomen and excessive eructations (belching). In a sizeable minority of cases treatment by cholecystectomy does not alter these complaints. Other conditions, such as the irritable bowel syndrome (p. 817), can produce identical symptoms. Nausea is the commonest single symptom and is often triggered by fatty food. Gallstones are best detected by ultrasound, but are common in older women and should not be used as the sole criterion for making a diagnosis of chronic cholecystitis. Careful investigation of the upper gastrointestinal tract by endoscopy is often helpful in excluding another treatable cause, such as a gastric ulcer or gastritis. In the elderly, medical dissolution of gallstones with bile salts is an alternative to cholecystectomy, but the rate of dissolution is slow and the stones usually return after withdrawal of treatment. The biliary tree, including the gallbladder, can be infected by Cryptosporidium, particularly in an immunocompromised host, including those infected with HIV. Up to 10% of AIDS patients with cryptosporidiosis have biliary involvement, with right upper quadrant abdominal pain, nausea and vomiting. The infection is very difficult to control.

BENIGN BILE DUCT STRICTURE Benign bile duct stricture is almost always a consequence of prior surgical intervention. The bile duct may have been cut and repaired, or stenosis may develop after interference with its blood supply, or be secondary to local sepsis.

1

858

Figs 16.3, 16.4

2

Fig. 16.5

Clinical features The usual history is of recurrent episodes of obstructive jaundice, fever and rigors, as a result of ascending cholangitis. After many months of recurrent symptoms progressive fibrosis and secondary biliary cirrhosis may develop.

Diagnosis and management Good-quality cholangiography is essential for diagnosis and planning treatment. Antibiotic cover for these procedures is a sensible precaution. Surgical relief of the obstruction offers the best chance of long-term relief of symptoms, but it is often difficult to find suitable sites in the biliary tree for an adequate bypass anastomosis. Fat malabsorption is common and should be treated with replacement of the fatsoluble vitamins A, D and K. Sequential use of antibiotics can reduce the number of disabling and potentially dangerous attacks of ascending cholangitis.

PRIMARY SCLEROSING CHOLANGITIS (PSC) In primary sclerosing cholangitis, short strictures from in the intrahepatic and extrahepatic biliary system. There is a close association with inflammatory bowel disease, especially ulcerative colitis. About 70% of patients with PSC have ulcerative colitis and up to 10% of patients with ulcerative colitis develop PSC. The precise pathogenetic mechanism is unknown, but it is probably (at least in part) autoimmune. Episodes of ascending cholangitis and jaundice are common. ERCP shows a characteristic beaded appearance of the bile ducts, and liver biopsy typically shows concentric, onion-skin fibrosis around the bile ducts. 1 Drainage procedures are rarely possible. Ursodeoxycholic acid may improve the biochemical abnormalities and some of the clinical symptoms, but it has not been shown to prolong survival. Corticosteroids and penicillamine have been tried, but are of no proven benefit. The disease is slowly progressive and secondary biliary cirrhosis usually develops. Cholangiocarcinoma (bile duct cancer) develops in 10-15% of cases. There is no reliable method of detecting this malignant transformation which is a contraindication to liver transplantation. Otherwise transplantation is a very successful intervention in advanced disease.

Carcinoma of the pancreas A full discussion is given on page 824.

CANCER OF THE BILE DUCTS AND GALLBLADDER Incidence and aetiology Tumours of the bile duct and gallbladder have an equal sex incidence and occur most frequently over the age of 60

16

FIG. 16.22 CT scan of the liver showing a carcinoma of the gallbladder infiltrating the liver parenchyma FIG. 16.21 The steep rise in the incidence of gallbladder cancer with age

(Fig. 16.21), when they are commoner than hepatoma. Known aetiological factors include liver flukes (Opisthorchis felineus and Clonorchia sinensis} and gallstones. The risk of these tumours in patients with long-standing gallstones is about 2%.

inoperable. With gallbladder cancer, ultrasound and CT (Fig. 16.22) may show a mass but the diagnosis is frequently made at laparotomy. With bile duct cancer PTC is usually carried out before surgery, and will show the dilated proximal ducts and the upper limit of the block. ERCP may be used to demonstrate the distal extent.

Pathology

Management

The distal common bile duct and the hilum are the commonest sites (50% of cases). Of the remainder, 20% arise from the small intrahepatic biliary ducts, and 30% from the proximal extrahepatic duct. Gallbladder cancers usually arise in the body (95% of cases). Bile duct cancers are adenocarcinomas, which usually provoke a fibrous reaction. Gallbladder cancers are usually adenocarcinomas (85%), with occasional squamous and anaplastic forms. The tumours infiltrate locally and metastasize to regional lymph nodes. They spread to involve the liver by both local infiltration and metastases.

Gallbladder cancer often cannot be resected, and a biliary decompression operation is undertaken when technically possible. Resection may involve removal of part of the liver as well as the gallbladder. Only 20% of carcinomas of the biliary tree are operable, and major resections carry a high operative mortality (10-15%). Biliary bypass procedures are effective in palliation and may be accomplished during PTC or ERCP, with the passage of a cannula (stent) through the site of the obstruction. Radiotherapy can be used to reduce tumour size, and may relieve obstruction and pain for a considerable time.

Clinical features Bile duct tumours grow slowly and cause obstructive jaundice with pruritus. The jaundice may fluctuate if the tumour sloughs and obstruction is temporarily diminished. The gallbladder may be distended if the tumour is distal to the junction of hepatic and cystic ducts. Intrahepatic tumours may not cause jaundice until they are very large. Right upper quadrant pain is common. Carcinoma of the gallbladder causes similar pain, with obstructive jaundice occurring later.

Diagnosis and investigation The presentation with pain may lead to a diagnosis of gallstones. A palpable mass usually means the tumours are

CIRRHOSIS

Definition Cirrhosis (Table 16.11) is an irreversible change in liver structure, the essential features being disorganization of the lobular architecture, the presence of regeneration nodules and increased fibrosis. 0 The size of the regeneration nodules can be smaller than of a normal liver lobule (micronodular cirrhosis), or they can embrace several portal tracts and central veins (macronodular cirrhosis). These are not separate varieties. The nodules tend to be small when there is active, continuing liver cell destruction, and larger when there is low-grade inflammation and

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TABLE 16.11 Classification and distribution of cirrhosis Common causes Alcohol The commonest cause in the western world ' Chronic hepatitis Chronic virus infection (HBV, Delta, HCV) The commonest cause in the Middle and Far East Autoimmune Almost restricted to north European Caucasians

Primary biliary cirrhosis Broad geographical spread, 90% female Schistosomiasis Equatorial and in the Middle and Far East; fibrosis is usual, but cirrhosis is found in S. japanicum

Rare but potentially reversible causes Wilson's disease Drug-induced (hepatolenticular degeneration) Methotrexate, methyldopa, isoniazid, perhexiline Early copper chelation can reverse liver damage Galactosaemia and fructosaemia Genetically determined Haemochromatosis metabolic disorders; diet can Venesection removes iron, prevent cirrhosis improves liver function Biliary atresia Constrictive pericarditis, Early protoenterostomy can congenital venous web prevent cirrhosis Two examples of chronic venous congestion, often completely reversible Rarities Secondary biliary cirrhosis Cystic fibrosis Glycogen storage disease Indian childhood cirrhosis

Sclerosing cholangitis Neonatal hepatitis syndrome deficiency 1antitrypsin Veno-occlusive disease

necrosis. The most important pathological distinction is from portal fibrosis, which is a reversible increase in collagen deposition in and between portal tracts.

Classification Table 16.11 gives a classification of cirrhosis based on aetiology. In the developed countries of the west, alcohol is the commonest cause (about 80% of cases in the UK), but this is relatively less frequent in Africa and Asia. Cirrhosis due to chronic viral infection dominates the picture in the Middle and Far East, and in many places in Africa, but both these main causes are common in southern Europe. Whatever the cause, cirrhosis produces common complications (pp. 871-875).

1

860

Fig. 16.6

Presentation and general clinical features If the process causing the cirrhotic transformation is inactive, presentation is usually delayed until portal hypertension and liver cell failure produce symptoms of ascites, haematemesis from bleeding varices, or encephalopathy. In older males, primary hepatocellular carcinoma (primary hepatoma) is a frequent complication, usually associated with an underlying inactive macronodular cirrhosis. In some cases the disease is detected at an asymptomatic stage during routine physical examination or biochemical screening. Some of the causes of cirrhosis produce more florid liver damage, and may present with jaundice, pruritus or symptoms of other organ involvement before cirrhosis has become established. On examination, cutaneous stigmata of chronic liver disease are usually prominent. Spider naevi are restricted to the upper half of the body. Possible causal mechanisms are inappropriate vasodilatation or high oestrogenic activity, which are normal features of pregnancy and sometimes found in females taking oral contraceptives. Leukonychia is a manifestation of low serum albumin levels and is not specific for liver disease. The term 'liver palms' refers to a blotchy erythema of the thenar and hypothenar eminences, and may be a visible manifestation of a widespread disturbance in vasomotor tone. Dupuytren's contracture is due to a thickening of the palmar fascia and is particularly common in alcoholic liver disease. A flapping tremor of the outstretched hands (asterixis), best seen when the wrists are extended, is a feature of hepatic encephalopathy. Feminization in males, with gynaecomastia, testicular atrophy and loss of body hair, is particularly common in alcoholic liver disease and haemochromatosis. It is not due to high oestrogen levels alone, but also to more complex gonadal and hypothalamic dysfunction. Female patients with cirrhosis may develop amenorrhoea. Examination of the abdomen usually reveals hepatosplenomegaly, although in advanced cirrhosis the liver may become very small. Ascites may be present, and striae may be a sign of previous abdominal distension. Patients with portal hypertension may have dilated veins on the abdominal wall.

FURTHER READING ON CIRRHOSIS Cabrera J, Maynar M, Granados R et al 1996 Transjugular intrahepatic portosystemic shunt versus sclerotherapy in the elective treatment of variceal haemorrhage. Gastroenterology 110(3): 832-839. Fernandez J, Navasa M, Gomez J, Colmenero J, Vila J, Arroyo V, Rodes J 2002 Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxes. Hepatology 35:140-148. Henrikson J H 1995 Cirrhosis: ascites and hepatorenal syndrome. Recent advances in pathogenesis. J Hepatol 23 (Suppl 1): 25-30. Laffi G, Foschi M, Masini E et al 1995 Increased production of nitric oxide by neutrophils and monocytes from cirrhotic patients with ascites and hyperdynamic circulation. Hepatology 22(6): 1666-1673.

16

FIG. 16.23 Deaths resulting from chronic alcoholic liver disease in the UK

Wong F, Logan A, Blendis L 1996 Hyperinsulinemia in preascitic cirrhosis: effects on systemic and renal hermodynamics, sodium homeostasis, forearm blood flow, and sympathetic nervous activity. Hepatology 23(3): 414-422.

CHRONIC ALCOHOLIC LIVER DISEASE

Epidemiology Chronic alcoholic liver disease is the commonest cause of cirrhosis in Europe, and is increasing in prevalence in most countries (Fig. 16.23). In district general hospitals in Britain, 80% of all cases of cirrhosis are associated with alcohol abuse. In the USA, deaths from cirrhosis, mostly alcohol-related, increased by 72% between 1950 and 1974, making it the fourth commonest cause of death in white male adults. This was associated with a sharp increase in alcohol consumption over this period, but a reversal in trend saw a reduction of 40% over the subsequent 15 years.

Pathology There is a striking range of histopathological changes produced by alcohol. The most consistent is increased fat deposition (steatosis), 1 which is almost invariably present in those drinking more than 80 g (one bottle of wine or 3 pints of beer - 6 units, p. 248) of alcohol per day. Although a large proportion of the cytoplasm of affected hepatocytes is occupied by a single large triglyceride inclusion, liver function is surprisingly normal. The fatty change is rapidly reversible during abstinence. In most cases isolated steatosis does not progress to cirrhosis, although in some there may be slowly increasing fibrosis around central veins, leading to stellate scarring and incomplete septum formation. It is possible that this could eventually lead to cirrhosis. The particular histological changes seen in alcoholic hepatitis (p. 855) are thought to be of fundamental importance in determining progression to cirrhosis.

The perinuclear eosinophilic inclusion bodies (Mallory's hyaline), one of the most obvious features, are probably condensed and disorganized fragments of the cytoskeletal framework of the hepatocyte. They are not specific to alcoholic liver disease, but may also be seen in Wilson's disease, primary biliary cirrhosis, Indian childhood cirrhosis and perhexiline-induced liver injury. Collagen deposition is another striking feature of alcoholic hepatitis. It can be pericellular, in the space of Disse, and around central veins (central hyaline sclerosis). This latter lesion is particularly associated with rapid progression to cirrhosis, and is commoner and more severe in women than in men. Collagen bridges eventually develop between central veins and portal tracts, isolating groups of hepatocytes which form the regeneration nodules characteristic of cirrhosis.

Pathogenesis The metabolism of ethanol to acetaldehyde and acetate is normally dependent on the enzymes alcohol dehydrogenase and acetaldehyde dehydrogenase (Fig. 16.24). These oxidation reactions are associated with the formation of NADH from NAD and alter the redox state of the cell. This in turn has profound effects on lipid and carbohydrate metabolism, one of which results in steatosis. In habitual drinkers a microsomal mixed-function oxidase, the microsomal ethanol oxidizing system (MEOS), is increased by enzyme induction, and is also responsible for the production of acetaldehyde. Breakdown of acetaldehyde may then become the rate-limiting step in ethanol metabolism, and it is thought that this toxic metabolite may be responsible for the liver cell injury. The direct correlation, in populations, between alcohol intake and risk of cirrhosis obscures the wide individual variation in susceptibility, for which there is at present no satisfactory explanation. Retrospective analyses of lifetime alcohol consumption in patients with cirrhosis have shown that women develop the disease about twice as fast as men, and that individuals who have inherited the histocompatibility antigen HLA B8 have a much shorter history of

861

CASE STUDY 16.3 PROGRESSIVE ABDOMINAL SWELLING IN A 45-YEAR-OLD WOMAN WITH A HISTORY OF DRINKING 5 UNITS OF ALCOHOL EACH DAY A 45-year-old woman attended her doctor with a swollen abdomen after a friend jokingly told her she looked pregnant. She had had amenorrhoea for 5 months but assumed that she was perimenopausal. Her only other complaint was tiredness, which she attributed to a stressful secretarial job in a large business. She had a previous history of deep venous thrombosis while taking the oral contraceptive pill. Her alcohol intake was constant at about 35 units per week. She did not smoke and had no risk factors for hepatitis. Physical examination revealed palmar erythema, facial telangiectasia and 11 spider naevi. The abdomen was distended with fluid, the liver could not be palpated and the spleen was palpable 4cm below the costal margin. The remainder of the examination was normal. The laboratory investigations were: haemoglobin ll.lg/dL, white cell count 11.7 x 109/L, platelets 86 x 109/L, prothrombin time 17s (control 13s), serum bilirubin 34umol/L, aspartate aminotransferase 54IU/L, alkaline phosphatase 99IU/L and serum albumin 26g/L. Question 1, What is the most likely diagnosis? The most likely diagnosis is ascites and portal hypertension secondary to chronic liver disease. The splenomegaly and low platelet count point towards long-standing portal hypertension and the low serum

albumin suggests cirrhosis. The past history of venous thrombosis should prompt consideration of the Budd-Chiari syndrome (hepatic vein thrombosis), but this would normally be associated with hepatomegaly rather than a small liver. The cirrhosis could be due to many causes, although the alcohol intake was sufficiently high to consider it the most likely aetiology. Question 2. What further investigations are required? A range of blood tests should be performed to look for other causes of cirrhosis. Serum immunoglobulin levels could point to autoimmune hepatitis if the IgG is elevated, or alcoholic cirrhosis if the IgA is increased. Of the autoantibodies, the antinuclear factor (ANA), antismooth muscle (ASM) and antiliver kidney microsomal (LKM) antibodies are most suggestive of a diagnosis of autoimmune hepatitis. Chronic viral hepatitis B and C should be excluded by the appropriate serological tests. Other routine investigations include serum ferritin, 1-antitrypsm phenotype and serum caeruloplasmin (in patients under the age of 40 years). An ultrasound of the liver should be performed to assess the size and shape of the liver, confirm the presence of ascites and splenomegaly, screen for hepatocellular carcinoma and assess the patency of the portal vein. A liver biopsy is performed once it can be

heavy drinking. This particular HLA antigen is strongly associated with organ-specific autoimmunity, and there is other evidence suggesting that immune reactions against Mallory's hyaline, or against new antigens on the surface 1 862

MCQ 16.6

2

MCQ 16.7

carried out with minimal risk (absence of ascites, near normal coagulation and platelet count >50 x 109/L). In this case the liver biopsy showed micronodular cirrhosis consistent with a diagnosis of alcoholic liver disease.

Question 3. How should this case be managed? Abstinence from alcohol is extremely important. A low-salt diet should be instituted and fluids restricted to 1.5L per day. Spironolactone is commenced in an initial dose of 50-100 mg daily and the dose titrated to achieve a weight loss of 0.5 kg per day. Frusemide is added if the desired response is not achieved with doses of Spironolactone in the order of 300-400 mg daily. A paracentesis is often performed at the start of therapy to reduce the length of time required to control the ascites. A sample of the ascites should be sent for analysis to exclude infection (white cell count >400/mL) and determine protein content (confirm it is a transudate and initiate antibiotic prophylaxis if the protein level is very low). In this case, abstinence was easily achieved. She was a regular consumer of alcohol but did not exhibit physical or psychiatric signs of dependency. The ascites responded rapidly to dietary manipulation and diuretics, and she remains well 7 years after presentation.

of hepatocytes, induced by acetaldehyde, could be responsible for liver cell damage.

Diagnosis The presenting features of cirrhosis and alcoholic hepatitis have already been discussed. However, some cases with significant liver damage are asymptomatic, and liver biopsy is the only way reliably to assess the degree of liver injury.

TABLE 16.12 Classification of chronic hepatitis Type Autoimmune Classic LKM positive type

Chronic virus infection Hepatitis B Delta hepatitis FIG. 16.24 The metabolism of ethanol Ethanol metabolism takes place largely in the mitochondria. The main product is acetaldehyde (A), which may itself be damaging. Hydrogen ions (B) are an important by-product which can drive many metabolic reactions in the liver cell cytosol, to create harmful effects (C, D).

Recognition of alcohol abuse is crucial, so that disease can be detected at a stage where abstinence can still lead to complete resolution of tissue damage. Important points in the history and examination are discussed on pages 845 and 860. A high mean corpuscular volume and serum -GT are important clues from laboratory tests.

Management Malnutrition is common in those with alcohol addiction, and should be treated with vitamin supplements and a high-protein diet. Fits are best controlled with diazepam, and delirium tremens prevented and treated with clomethiazole (chlormethiazole) or chlordiazepoxide. Other causes of confusion and coma, such as Wernicke's syndrome, subdural haematoma, hypoglycaemia and hepatic encephalopathy, must be excluded. Abstinence is the key to successful long-term management (p. 251). Ninety per cent of patients with alcoholic hepatitis alone will show complete regression of the liver damage, and those with cirrhosis who remain abstinent have a much better prognosis than those who continue to drink. O

CHRONIC HEPATITIS 2 Chronic hepatitis is a syndrome consisting of several different diseases with similar histological appearances on liver biopsy (Table 16.12). The portal tracts are enlarged and contain a chronic inflammatory cell infiltrate of lymphocytes, plasma cells and macrophages. The cells extend beyond the edges of the portal tracts through the limiting plate of periportal hepatocytes, and there is 'interface

Hepatitis C

Drug-induced

Metabolic Wilson's disease

Distribution

Features

Northern Europe, USA, Australia, South Africa Europe

Female/male ratio 7:3; high litre antinuclear antibodies Female/male ratio 1:1; high litre liver/kidney microsomal antibodies

Mediterranean, Middle and Far East Mediterranean and Middle East

Female/male ratio 1:9; low titre antinuclear antibodies Endemic in HBV carriers in Mediterranean; intravenous drug abusers in northern Europe Commonest post-transfusion hepatitis; also transmitted by blood products Examples are methyldopa, isoniazid, nitrofurantoin and dantrolene, usually like autoimmune chronic hepatitis

Wide distribution

A phenomenon of the developed world

Wide distribution

Haemochromatosis

Wide distribution, but not Brittany and Utah Mormons

Alcohol

Wide distribution, but particularly the developed world

16

Can mimic any liver disease, so easily missed Usually inactive fibrosis, but rarely resembles chronic active hepatitis, almost exclusively males affected Controversial as a cause of chronic hepatitis; may be in recovery phase of alcoholic hepatitis

hepatitis' of liver cells in this part of the lobule. Collagen deposition is prominent in areas of liver cell damage, leading to the formation of fibrous septa linking portal tracts to each other and to central veins. If the disease process continues unchecked, cirrhosis is an inevitable consequence.

AUTOIMMUNE Aetiology and pathogenesis Autoimmune chronic hepatitis was the first to be described. It is best considered as one of the organ-specific autoimmune diseases. There are two main subtypes. In the classic variety women are affected more commonly than men and antinuclear and/or smooth muscle antibodies are commonly found in the serum, whereas the other variety is characterized by the findings of a liver/kidney microsomal antibody in serum which reacts with one of the P450 microsomal liver enzymes. In both forms of the disease

863

serum globulin and IgG levels are high, and there is evidence of both cellular and humoral liver-specific autoimmune reactions directed at normal antigens on the surface of hepatocytes. HLA B8 and DR3 antigens are found in a high proportion of cases. Antibodies reacting with liver cell membrane components are almost always present, and probably damage hepatocytes in cooperation with cytotoxic lymphocytes bearing Fc receptors for the antibody molecules. There is a profound disturbance in immunoregulation associated with functionally abnormal suppressor T cells.

Clinical features Two-thirds of patients present with an illness indistinguishable from acute viral hepatitis. The remainder have symptoms due to an already established cirrhosis, such as ascites, haematemesis from bleeding varices, or encephalopathy. Half of those with an initial acute hepatitis remain jaundiced and have biochemical evidence of continued liver necrosis. The others appear to recover normally, but develop a second episode of jaundice some months later. Multisystem involvement is common, and includes arthralgia, ulcerative colitis, autoimmune thyroid disease and haemolytic anaemia. Cutaneous stigmata of chronic liver disease are often present, and more than 70% of patients already have cirrhosis when the diagnosis is first made.

cautiously withdrawn. However, relapse is very common (60-80%) and can be severe, necessitating prompt reintroduction of corticosteroids.

CHRONIC HEPATITIS B VIRUS INFECTION Worldwide, HBV is the commonest type of chronic active hepatitis, being particularly prevalent in the Mediterranean, the Middle and Far East, and tropical Africa. The serology and structure of HBV have been described earlier (pp. 848-850).

Clinical features Many patients are asymptomatic, the chronic virus infection being detected on screening for blood donations or the investigation of other diseases. When symptoms do occur they are often mild and non-specific, malaise being the commonest; some progress from an acute HBV infection. There is a striking male preponderance. The incidence of multisystem disease is lower than that found in the autoimmune variety. The liver function tests usually show a relatively mild hepatitic picture, with only moderately raised levels of serum transaminases.

Serological markers Investigations Liver function tests usually show a hepatitic picture with high serum transaminases. A marked elevation in the total globulin (more than 40g/L), with a high IgG, is a useful pointer to this subgroup. The diagnosis is made on liver biopsy, 1 and the presence of the appropriate non-organ specific autoantibodies indicates the correct classification.

Management The response to corticosteroids is excellent. The survival rate is greatly increased, with more than 60% alive at 10 years, although cirrhosis, if absent initially, may still develop. Azathioprine in a dose of l-2mg/kg is a useful adjunct to steroid therapy and may allow a lower dose of steroid to be used. This can be particularly important in older women who are prone to osteoporosis. Although serum transaminase levels are often used to monitor progress, liver biopsy is useful in establishing the activity of the disease during follow-up. If the disease has remained inactive for more than 2 years, steroid treatment can be

Fig. 16.7

864

Case 16.2

MCQ 16.8

There are two phases to the infection. Initially there is active viral replication, with HBsAg, HBeAg, HBV DNA, and the DNA polymerase of the virus detectable in the serum. In this phase the histological features of chronic hepatitis are most often present. After several years there may be a rather abrupt cessation of viral replication, with loss of serum HBeAg, HBV DNA and DNA polymerase. This change is often preceded by a rise in the levels of serum transaminases, but is frequently followed by a striking decrease in the activity of the disease, with a reduction in the extent of the inflammatory infiltrate in the liver. HBsAg levels in serum decrease because free viral DNA has been lost, but usually remain detectable in serum, probably because there has been integration of the viral genome into the hepatocyte DNA. The defect responsible for the failure to clear the virus after the initial infection has not been identified. Antibodies reacting with whole virions are absent, which may allow continued viral penetration of uninfected hepatocytes. Cellular immunity to HBeAg on the surface of infected liver cells, which is probably responsible for liver cell necrosis in acute HBV infection, is present and may be a component of the inflammatory liver lesion. On the other hand, factors must be present which interfere with effective clearance of infected cells. Autoimmune reactions to normal liver cell membrane antigens, similar to those found in 'autoimmune' chronic hepatitis, can be demonstrated, which could explain the similarity of the periportal histological

changes in two diseases with quite distinct aetiological backgrounds.

Management There is current interest in antiviral agents, particularly the -interferons, which appear to act by stimulating existing immune responses against the virus as well as by suppressing virus replication. Although immediate effects on viral replication can be convincingly demonstrated, only 20-40% of cases show long-lasting benefit. Treatment is particularly effective in those with pre-existing active liver inflammation. New nucleoside antiviral compounds have been developed which show considerable efficacy against HBV. They appear to suppress viral replication almost completely and are well tolerated. Lamivudine is the most widely used, and the main problem experienced to date is the emergence of viral mutants at a rate of about 7% per year of therapy. The clinical significance of these mutants is uncertain. Corticosteroids are of no benefit in the phase of active viral replication, and may be harmful. Liver transplantation has been used to treat patients with end-stage chronic liver disease or small hepatocellular carcinoma. Recurrence of HBV infection was problematic, but strategies have emerged to prevent reinfection in over 80% of cases. These rely on the suppression of viral replication before transplantation, e.g. with lamivudine, and passive immunoprophylaxis with anti-HBs (HBIg) indefinitely after transplantation. The results of transplantation are particularly good in patients with coexisting Delta virus infection because of a natural suppressing effect it has on hepatitis B virus replication, even in the presence of immunosuppressive medication.

CHRONIC DELTA VIRUS INFECTION The histological changes of chronic hepatitis are often present in chronic Delta virus infection (p. 850). The diagnosis is made by finding anti-Delta antibodies in serum or demonstrating Delta antigen in the nuclei of liver cells by immunofluorescence. Progression to cirrhosis seems to occur quite rapidly and the prognosis is poor. Little is known about the mechanisms of tissue damage, and no specific treatment has been shown to be effective.

CHRONIC HEPATITIS C VIRUS INFECTION GO The discovery of hepatitis C virus and tests for its serological and genomic detection have allowed a clear picture to emerge of a common cause of chronic liver disease throughout the world.

Clinical features The majority of carriers of the hepatitis C virus are rela-

tively asymptomatic and their life expectancy is not altered. The commonest symptom in these patients is fatigue, which can be severe even in patients with normal or near-normal blood tests and liver histology. Significant liver disease develops in 20-30% of patients who have necroinflammatory disease, fibrosis and ultimately cirrhosis. This process evolves over 20-30 years and is accelerated by moderate to high alcohol consumption. Once cirrhosis has developed, there is a 1.5-2% incidence of hepatocellular carcinoma per year. In the absence of this complication, 85% of patients are alive 10 years after the diagnosis of cirrhosis has been established. Extrahepatic manifestations and associations include porphyria cutanea tarda and cryoglobulinaemia-associated disease e.g. glomerulonephritis.

16

Serological markers Exposure to hepatitis C is confirmed by the detection of antibodies in serum. About 85% of patients with antibodies have HCV RNA in their serum and this is now the most commonly used confirmatory test. In the absence of HCV RNA testing, a RIBA test which screens for a range of antibodies is used to confirm exposure to hepatitis C. An IgM antibody test has not yet been developed, and therefore recent infections cannot be confirmed by serological testing.

Management Assessment of the activity of the liver disease in carriers can be difficult as the conventional liver function tests may be normal. However, if viral RNA is present, then liver biopsy should be performed to assess the need for therapeutic intervention. a-Interferon is effective in suppressing viral replication and normalizing serum transaminases in about 45% of patients who have precirrhotic disease. However, a sustained virological response occurs in only 9-29% of cases, depending on the dose and duration of interferon therapy. The response rate among patients with cirrhosis is negligible. Combination therapy using interferon 3 million units thrice weekly and ribavirin 1-1.2 g daily induces a sustained virological response in 45% of patients without cirrhosis. A new long-acting preparation of interferon, PEGylated interferon, in clinical trials yielded a virological response rate of 25% in patients with cirrhosis. Liver transplantation is an effective treatment for endstage disease but reinfection of the graft is almost inevitable. There are so far no effective prophylactic or therapeutic measures to modify the rate or impact of reinfection. The latter is very variable, but cirrhosis can develop 10 times more rapidly than in the immunocompetent individual, possibly because of the much higher viral loads seen in immunosuppressed patients. The overall results of liver transplantation are the same as for other aetiologies of cirrhosis up to 8 years after transplantation.

865

DRUG-INDUCED CHRONIC HEPATITIS Although rare, these cases are important as the disease almost always responds to drug withdrawal. All reported cases are examples of idiosyncratic reactions, which have not been reproduced experimentally. The drugs most frequently implicated are isoniazid, a-methyldopa, nitrofurantoin and oxyphenisatin. In many cases the disease is very similar to the 'autoimmune' type, with antinuclear and smooth muscle antibodies present in serum.

OTHER CAUSES The most important of these is Wilson's disease (p. 869), which can mimic the changes seen in viral or autoimmune cases. Because long-term survival on D-penicillamine is possible, it is clearly of great importance to exclude this condition in all cases of chronic active hepatitis in children and young adults. The histological features of chronic hepatitis can also be found in some cases of 1-antitrypsin deficiency, and in alcoholic liver disease.

PRIMARY BILIARY CIRRHOSIS Like autoimmune chronic hepatitis, primary biliary cirrhosis is a condition which is not necessarily associated with cirrhosis at presentation, although this frequently develops later in the course of the disease. The essence of the disease is a slowly progressive destruction of intra-hepatic bile ducts, possibly due to immune-mediated injury.

Incidence and aetiology In most series more than 90% of patients are women, with most being in middle age. In the UK the incidence is between 6 and 12 per million, with a prevalence of 40-80 per million. Familial cases are well described and a significant association with the HLA class II antigen HLA DR8 has been confirmed in a number of reports. This is a relatively rare antigen in both the controls and PBC patients, but the frequency of DR8 in PBC is two to six times higher than in controls. The antibodies in serum reacting with mitochondria, which are such a strong feature of the disease, are also found in family members, but in most cases there is no apparent liver or bile duct injury associated with this finding.

Pathology

866

Four stages in the histopathology of the disease have been described. They are not necessarily sequential, and there is considerable overlap between them.

RECENT ADVANCES HEPATITIS MUTANTS ESCAPE THE IMMUNE ATTACK Both HBV and HCV have proved capable of dodging the immune attack. Both viruses have a replication mechanism which does not faithfully copy their DNA or RNA, creating mutants with amino acid substitutions which can, in theory, alter their immune reactivity. In the case of HBV, the viral nucleocapsid (HBcAg) is one of the most important targets of the cellular immune attack on infected hepatocytes, and in acute viral hepatitis the vigorous polyclonal attack is able to eliminate all the viral species present. In chronic infection the immune tolerance gradually wanes and the T-cell response, when it occurs, is almost certainly oligoclonal, restricted to a small number of peptides. It follows that some of the mutants may be able to escape this restricted attack. Analysis of the HBV genome from patients with chronic active hepatitis B does show a variety of different mutants present in the peripheral blood, and in some experiments it has been possible to show that the mutants have core peptides which do not express amino acids that are key to stimulating existing cytotoxic T cells. In the case of HCV, one of the major epitopes on the cell surface to which neutralizing antibodies are made is in the middle of a hypervariable segment of the RNA genome. Changes in the amino acid sequence of this region alter the conformation of the surface determinant on the virion, and have been shown to escape from the neutralizing effect of the antibodies made to the original structure. These frequent changes in the virus surface conformation will almost certainly create considerable difficulties in designing a suitable vaccine against HCV. In both these instances, these changes in the viral genome are not only a successful ploy by the virus to ensure continued survival, but are also a source of frustration to those designing a therapeutic strategy to eliminate the viruses. 1. First stage. There is focal damage to the larger intrahepatic bile ducts, with a surrounding chronic inflammatory infiltrate of lymphocytes, plasma cells, eosinophils and macrophages. In some areas the infiltrate may be organized into an epithelioid cell granuloma, lying close to a damaged duct. 2. Second stage. Some of the larger ducts are replaced by lymphoid aggregates, and there is proliferation of smaller ductules. Fibrosis is present. 3. Third stage. Fibrosis extends beyond the edges of the portal tracts. There is often periportal cholestasis and accumulation of copper-binding protein. 4. Final stage. The features are those of an established cirrhosis. Ill-defined collections of lymphocytes and a paucity of bile ducts may be the only clues to the aetiology.

CASE STUDY 16.4 POOR CONCENTRATION AND REDUCED MENTAL ABILITY IN A 44-YEAR-OLD MAN WITH KNOWN HEPATITIS C INFECTION A 44-year-old man with an established diagnosis of cirrhosis secondary to hepatitis C was assessed in the outpatient clinic. He complained of tiredness, constipation, sleeping during the day and then being unable to go to sleep at night. He also said that his concentration was poor and he was no longer able to complete the crossword he did on a daily basis. He had acquired hepatitis C during a 7-month period of intravenous drug use while at university. He had consumed 40-60 units of alcohol per week consistently until the diagnosis of hepatitis C was made 3 years previously, but was now totally abstinent. His medication was spironolactone 300 mg, frusemide 40 mg and dihydrocodeine as required for analgesia. Physical examination revealed that he was not jaundiced but had palmar erythema, facial telangiectasia, spider naevi and gynaecomastia. A liver flap was not present. The liver was not palpable but the spleen was enlarged and extended 5 cm below the costal margin. There was no evidence of ascites. A number connection test was performed and this was completed in 54 seconds. The laboratory investigations were: haemoglobin 13.1 g/dL, white cell count 6.1 x 109/L, platelets 55 x 109/L, prothrombin time 19s (control 13s), serum bilirubin 24umol/L, aspartate aminotransferase 113IU/L, alkaline phosphatase 102IU/L and serum albumin 27 g/L. The afetoprotein was 34 lU/mL. An ultrasound examination showed a small liver with no focal lesion, a patent portal vein and splenomegaly.

Question 1. What is the clinical assessment? He has cirrhosis with impaired synthetic function (low albumin and prolonged prothrombin time). There is no evidence of a complicating hepatocellular carcinoma, as evidenced by the a-fetoprotein level and the ultrasound examination. The tiredness is characteristic of both cirrhosis and infection with the hepatitis C virus. The reversal of day/night sleep pattern is characteristic of early hepatic encephalopathy, and this diagnosis was further supported by the length of time required to complete the number connection test (normal less than 25 seconds). Constipation and dihydrocodeine were identified as two possible causes of the encephalopathy. The former was treated with lactulose and dihydrocodeine was discontinued. Three months later the patient was admitted to hospital in a coma. He responded only to painful stimuli. The other change on clinical examination was the presence of ascites. A therapeutic paracentesis was performed and the white cell count in the ascites was 650 per mL, with 90% neutrophils. An ultrasound examination of the liver showed no changes other than thrombosis of the portal vein. The only significant alteration in the blood tests was a haemoglobin of 9.3 g/dL, which represented a fall of 3.7 g/dL.

Immunopathogenesis Antimitochondrial antibodies are directed at an antigen on the inner membrane of the mitochondrium, and are unlikely to be of pathogenetic importance. However, they

16

Question 2. What is the cause of the coma and what precipitated it? Coma is typical of advanced hepatic encephalopathy and this is the most likely diagnosis, given the background history. He now has two of the most frequent causes of severe encephalopathy, infection and gastrointestinal haemorrhage. The white cell count in the ascites is diagnostic of spontaneous bacterial peritonitis, as it is above 400 per mL and is composed predominantly of neutrophils. A positive bacterial culture is achieved in no more than 70% of cases and is not necessary to substantiate the diagnosis. Spontaneous bacterial peritonitis does not usually present with classic signs of peritonitis, and a diagnostic paracentesis is mandatory to screen for this complication in all encephalopathic patients who have ascites. The possibility of gastrointestinal haemorrhage is suggested by the falling haemoglobin despite the absence of a history of haematemesis or melaena. Bleeding from oesophageal varices was confirmed and treated endoscopically. Bleeding oesophageal varices and spontaneous bacterial peritonitis are not random events occurring coincidentally, but are a common combination probably caused by bacterial translocation across the bowel wall into ascitic fluid. The thrombosis of the portal vein documented by ultrasound is a well recognized complication of cirrhosis and was the precipitant for the variceal bleed and the development of ascites.

are clearly an important feature of the disease. An attractive but unproven hypothesis is that they are cross-reactive antibodies generated by an immune response to an as yet unidentified bacterium which is in some way responsible

867

for the bile duct destruction. This hypothesis has been reinforced by the finding that the antimitochondrial antibodies are directed at the pyruvate dehydrogenase complex and cross-react extensively with the corresponding bacterial enzyme complex in Escherichia coli. Granulomas are usually indicative of a cellular immune reaction, but it is not clear what the antigenic stimulus could be. T cells sensitized to antigenic components in bile ducts may be responsible for their destruction. The disease in other organs may be an indication of a generalized disturbance in immunoregulation, but could also be due to an observed antigenic cross-reactivity between bile duct antigens and secretory duct epithelium in other organs.

Clinical features The disease is much commoner (9:1) in females than in males, and usually presents in the fifth and sixth decades. Pruritus is often the first symptom, and may lead to a dermatological consultation. Weight is usually well maintained and abdominal pain is unusual. Jaundice is a late feature. On examination there is often quite marked hepatosplenomegaly and skin pigmentation. Skin xanthomas are common. 1 With the increasing availability of automated biochemical profiles and screening tests for non-organ specific autoantibodies in serum, asymptomatic cases are being seen more frequently. In these patients minor hepatomegaly may be the only abnormality. The most striking serological feature is the presence of antimitochondrial antibodies in serum. These are of considerable help in the differential diagnosis, as they are found in 95% of patients with primary biliary cirrhosis but are usually absent in prolonged extrahepatic obstruction. 2 Associated diseases Disease in other organs is very common, and includes one or more of the components of the CRST syndrome (calcinosis, Raynaud's phenomenon, sclerodactyly, telangiectasia), autoimmune thyroiditis, renal tubular acidosis, rheumatoid arthritis and the 'sicca complex' (dry eyes and dry mouth).

Course and management In symptomatic cases average survival is 6 years, but it is difficult to give an accurate prognosis in individual cases. The bile duct destruction is slowly progressive, but bilirubin levels usually remain stable for several years before rising steadily in the last year or two of the illness. Steatorrhoea with malabsorption of fat-soluble vitamins can be a problem, and it is important to give supplements of

868

1

Fig. 16.8

4

MCQ 16.10

2

MCQ 16.9

0 Fig. 16.9

calcium and vitamins D and K. Cholestyramine usually controls pruritus. Corticosteroids are not usually given because of the likely exacerbation of osteoporosis in postmenopausal women. Ursodeoxycholic acid may alleviate symptoms and improve the biochemical profile, and consequently, is frequently prescribed. However, there is no evidence of an associated improvement in histological appearances or survival. Several other agents have been tried but all have failed to provide evidence, in controlled clinical trials, of a clear and clinically significant benefit. These include ciclosporin, an immunosuppressive drug which acts by interfering with the production of interleukin-2, an important stimulator of lymphocyte proliferation; colchicine, an antifibrotic agent; and D-penicillamine, which chelates copper, inhibits the synthesis of collagen and immunosuppresses. In advanced cases liver transplantation is a very successful therapeutic option, with survival rates of 90-95 % at 1 year. Patients are selected for transplantation if the prognostic models predict a survival time of 12-18 months, complications of end-stage liver disease develop and are difficult to control, or occasionally when the quality of life is very poor owing to severe lethargy or intractable pruritus. The latter is relieved immediately by liver transplantation and the overall quality of life in all patients is remarkably improved.

HAEMOCHROMATOSIS Increased iron deposition in hepatocytes is the hallmark of haemochromatosis. In idiopathic haemochromatosis this is due to a genetically determined increase in iron absorption. The inheritance is autosomal recessive and the responsible gene, called the HFE gene, is located on chromosome 6. The major mutation associated with clinical haemochromatosis is C282Y and a second minor mutation is H63D. The exact mechanism of the defect in control of iron absorption, however, is still not fully understood. The frequency of the haemochromatosis allele is very high (1:10) in European populations, and the frequency of homozygotes (1:100) makes this one of the commonest inherited disorders. Haemosiderosis - secondary iron overload - is usually due to a chronic haemolytic anaemia such as thalassaemia. The increased liver iron content is due to both increased iron release and repeated blood transfusions (p. 1231).

Clinical features There is a striking male preponderance, almost certainly because menstruation in women prevents a significant rise in iron stores. The disease usually presents in middle age. 'Bronzed diabetes' is a useful reminder of two of the important clinical features. The pigmentation is due to increased melanin in the skin, and is often seen best over the shins, where it gives a slate-grey appearance. Patients may present with diabetes, sometimes well before the liver

disease becomes symptomatic. It is associated with iron deposition in the pancreas. An arthritis, particularly affecting the knees and metacarpophalangeal joints, can also be a presenting feature, and is associated with the deposition of calcium pyrophosphate crystals in the affected joints. On examination, gynaecomastia, testicular atrophy and loss of body hair are often present, and seem to be due to a combination of partial testicular and pituitary failure, associated with iron deposition in these areas. Hepatomegaly is invariably present, but splenomegaly is uncommon. In younger patients congestive cardiomyopathy can be an unusual but troublesome complication. The rate of hepatocellular carcinoma is among the highest seen for the different aetiologies of cirrhosis.

Diagnosis Liver function tests can be entirely normal and haemochromatosis is a good example of a disease that must be considered before it can be diagnosed. The definitive diagnosis is established by detection of the genetic mutations, one of which is present in over 95% of cases. Liver biopsy allows demonstration of the iron deposition in liver cells, usually in a periportal distribution. 0 Extensive portal fibrosis develops before there is progression to a true cirrhosis, with regeneration nodules. Serum iron levels are high, with greater than 90% saturation of the total iron-binding capacity. Serum ferritin levels are a good reflection of total body iron content, but do not correlate precisely with the concentration of liver iron.

Management and prognosis The gradual depletion of body iron stores is best achieved by regular venesection, initially 1 unit weekly. Serum ferritin and a repeat liver biopsy are the most useful markers of complete removal of the excessive iron deposits. The severity of the associated diabetes tends to decrease, and there is a general improvement in malaise and a decrease in liver size. The changes of cirrhosis in the liver are not reversible, and one of the long-term risks is the development of primary hepatocellular carcinoma. Venesection is most effective when started early in the course of the disease, before the development of diabetes or cirrhosis, and investigation of the patient's relatives is an essential part of management. In 1935 the mean survival after diagnosis was 4.4 years, in 1969 the 5-year survival rate was 89%, and as more asymptomatic family members are picked up and treated it is becoming clear that the disease can be prevented if excess iron is removed at an early stage and the future accumulation of iron prevented. 4

WILSON'S DISEASE In this disease, genetically determined accumulation of copper in the liver, basal ganglia, kidneys and corneas can

16

FIG. 16.25 Wilson's disease The postulated block in copper metabolism in Wilson's disease is a failure to excrete copper trom lysosomes into bile. This leads to a build-up of the toxic metal in the liver and other tissues, particularly the basal ganglia in the brain.

produce a wide variety of liver lesions with or without associated extrapyramidal dysfunction. It is an autosomal recessive condition with an incidence of about 1 in 50000. The responsible gene, ATP7B, is located on chromosome 13 and codes for a copper carrier protein. A large number of mutations have been described in patients with Wilson's disease. Heterozygous individuals remain in virtually zero copper balance throughout their life and show no clinical features of the disease. Radiocopper studies indicate that the inherited defect in copper metabolism principally affects copper excretion from hepatic lysosomes into bile (Fig. 16.25). Pathologically and clinically the liver is often the first organ to be affected. The appearance of lipid droplets in the liver cell cytoplasm is the first abnormality, followed by increasing fibrosis and cirrhosis.

Clinical features Wilson's disease is a great mimic of many other liver diseases, and because of the excellent response to Dpenicillamine in the early stages it must always be considered and excluded in any child or young adult with chronic liver disease. In some cases there is a combination of fatty change, Mallory's hyaline and fibrosis, which may be wrongly attributed to the effects of social drinking. In others there is a mononuclear infiltrate in the portal tracts, with piecemeal necrosis of periportal hepatocytes, which can lead to a diagnosis of non-A, non-B or autoimmune chronic hepatitis. In children an 'acute hepatitis', sometimes progressing to acute liver failure, may be a presenting feature. This is usually accompanied by acute haemolysis. At the other extreme the disease may remain silent until a slowly progressive, inactive cirrhosis presents with haematemesis, ascites or encephalopathy. Neurological abnormalities may be absent in younger patients; when present, they are often subtle. They include deteriorating school performance, changes in personality, slurring of

869

speech, clumsiness, and difficulties with fine movements. 1 In adults, dysarthria and bulbar palsy may accompany more classic extrapyramidal signs and symptoms.

Diagnosis Brown deposits of copper in the margins of the cornea, called Kayser-Fleischer rings, are diagnostic. They are always present in patients with neurological symptoms, but can be absent in young patients presenting with liver disease. They are best seen on slit-lamp examination. Serum caeruloplasmin levels are typically low, but may also be decreased in chronic hepatitis and acute liver failure as well as in about 10% of healthy heterozygotes. Urinary copper excretion is high, and rises dramatically after a test dose of D-penicillamine. Liver copper levels are between 1.5 and 25 times the upper limit of normal, but are also increased in some conditions with chronic cholestasis, such as primary biliary cirrhosis. Because of the large number of genetic mutations identified, a clinically applicable genetic test has not yet been developed.

PAS-positive granules in periportal hepatocytes. Heterozygotes with an MZ phenotype have about half the normal circulating levels of 1-antitrypsin, but none can be detected in ZZ homozygotes. It is these ZZ individuals who are susceptible to the development of emphysema (p. 661) and cirrhosis, but the mechanisms responsible are not understood. The liver disease usually presents in infancy, with symptoms of the neonatal hepatitis syndrome (conjugated hyperbilirubinaemia with pale stools, dark urine and hepatomegaly). At this stage cirrhosis may already be present on liver biopsy, although varying degrees of hepatocellular damage and fibrosis are more usual. In those who survive cirrhosis usually develops, and about a quarter will die in early childhood. The clinical course in the remainder may be relatively long, although decompensation can occur in adolescence or early adult life. There is no specific treatment. Some adults with 1 -antitrypsin deficiency can present with cirrhosis without a history of jaundice in infancy. In these patients primary hepatoma is a recognized complication.

Management

CYSTIC FIBROSIS

The chelating agent D-penicillamine gradually depletes the copper stores and is the mainstay of treatment. In cases picked up early, and in those with a relatively inactive wellcompensated liver lesion, there is usually some improvement in liver function and no further progression of the disease. Patients who present with acute liver failure or decompensated cirrhosis show little response to chelation therapy, and have a poor prognosis. Interruption of maintenance therapy for 6-12 months, usually by adolescents or young adults questioning the need to take regular medication, can lead to liver failure which does not respond to the resumption of D-penicillamine. ©

Cystic fibrosis is considered in detail in Chapter 13. There is a generalized disorder of exocrine secretory glands, whose ducts become blocked with viscid, tenacious secretions. The liver can be involved in this process, with mild focal biliary obstruction due to inspissated bile being found in almost all cases. For unknown reasons, in some this process slowly progresses to a relatively inactive cirrhosis. This is present in about 10-15% of adolescents with cystic fibrosis, and can present with the complications of portal hypertension.

SECONDARY BILIARY CIRRHOSIS OTHER CAUSES OF CIRRHOSIS 1-ANTITRYPSIN

DEFICIENCY

1 -Antitrypsin, a protease inhibitor, is remarkably polymorphic, with more than 30 different variants now recognized. The inheritance of these alleles is autosomal and codominant, with the normal phenotype being designated MM. The clinically important variant is called Z. This codes for a defective protein core which has altered carbohydrate side chains and cannot be excreted from hepatocytes. It can be seen in liver biopsies as diastase-resistant

1 870

Case 16.3

2

MCQ 16.11

Secondary biliary cirrhosis can be a complication of any disease in which there is prolonged biliary obstruction. For example, it may arise as a long-term complication of biliary stricture owing to operative damage to the bile duct, or in sclerosing cholangitis (p. 858). There is slowly progressive portal fibrosis, often for several years before the development of true cirrhosis. If adequate biliary drainage can be restored during the earlier stages there may be substantial regression of the portal fibrosis and a fall in portal pressure.

HEPATIC VENOUS CONGESTION 'Cardiac cirrhosis' occurs in patients with chronic right heart failure. It is a progressive liver fibrosis caused by chronic centrilobular congestion. An important cause is constrictive pericarditis. Treatment, by surgical removal of

the pericardium, usually leads to resolution of the ascites and regression of the liver fibrosis. A congenital web in the inferior vena cava at or above the level of the diaphragm is another rare but correctable cause. A more dramatic cause of hepatic venous congestion is sudden occlusion of the main hepatic veins: the Budd-Chiari syndrome. The presenting features, of pain and tenderness over a large liver and tense ascites, are due to the marked elevation in portal pressure, the severe hepatic congestion and liver cell necrosis. In some cases the onset is more gradual, with refractory ascites being the dominant clinical feature. The occlusion of the hepatic veins is occasionally due to obstruction by tumour tissue extending up the vena cava from a hypernephroma, but is usually thrombotic. This may be initiated by trauma, or be due to a thrombotic tendency in diseases such as polycythaemia rubra vera, primary thrombocythaemia, paroxysmal nocturnal haemoglobinuria and chronic myeloid leukaemia. A thrombophilia screen may reveal deficiency of anti-thrombin III, proteins C or S, Factor V Leiden, or the antiphospholipid syndrome as the cause of the procoagulant state. A number of cases have been reported in young women taking the oral contraceptive pill, but since its oestrogen content has been reduced this association seems to have become less frequent. The patency of the main hepatic veins may be investigated by ultrasound, but radiological contrast studies are more definitive. Axial imaging of the liver usually demonstrates sparing and hypertrophy of segment I of the liver, also known as the caudate lobe. The treatment options include creation of a shunt (TIPSS, mesocaval or mesoatrial shunt), hepatic venoplasty or liver transplantation. The choice is influenced by the balance of acute versus chronic disease and the degree of hepatic reserve. Liver transplantation is the only option in patients presenting with acute liver failure.

temic shunt operation is usually performed to reduce portal vein pressure. The prognosis is good. Some cases are associated with congenital dilatation of the biliary tree, and the combination is known as Caroli's syndrome.

16

COMPLICATIONS OF CIRRHOSIS Although there is no specific therapy for many types of cirrhosis, skilled management of the complications can often provide prolonged relief from disabling symptoms.

ASCITES Pathophysiology There are two main hypotheses which seek to explain the formation of ascitic fluid in cirrhosis (Fig. 16.26). The first, sometimes referred to as the 'underfill theory', suggests that the reduction in plasma colloid osmotic pressure, due to a fall in serum albumin concentration together with raised portal pressure, leads to a net extravasation of capillary filtrate from the splanchnic circulation. This in turn reduces the circulating plasma volume and promotes secondary hyperaldosteronism, with retention of sodium and water in the kidneys. This theory predicts a normal or reduced cardiac output, decreased plasma volume and peripheral vasoconstriction. The observations that cardiac output is usually increased, that plasma volume is high and that there is peripheral vasodilatation in most patients with cirrhosis and ascites, prompted the development of an alter-

CHILDHOOD METABOLIC DISEASES Type IV glycogen storage disease, galactosaemia, fructosaemia and tyrosinaemia are all rare causes of cirrhosis in infancy and childhood (see Ch. 19).

CONGENITAL HEPATIC FIBROSIS Although this inherited condition is not a cause of cirrhosis, the presentation, with the symptoms and signs of portal hypertension, places it firmly in this context with respect to differential diagnosis. The basic hepatic architecture is preserved, but portal tracts are linked by broad bands of fibrous tissue. Increased numbers of bile ductules are seen in the portal areas, and some may appear cystic. The presentation is usually in childhood, with hepatosplenomegaly and haematemesis from bleeding oesophageal varices. Liver function tends to be well preserved, and a portosys-

FIG. 16.26 The pathophysiology of ascites formation in cirrhosis In addition to direct effects of the cirrhotic process leading to ascites, such as increased pressure in the'portal vein and decreased albumin lowering the plasma osmotic pressure, there is also an aldosterone-driven increase in sodium retention.

871

native view, sometimes known as the 'overflow theory'. This suggests that the primary abnormality is increased renin and aldosterone levels producing inappropriate sodium and water retention. The plasma volume and cardiac output are increased. The formation of oedema is a secondary event which is encouraged by the low colloid osmotic pressure in plasma, and tends to be localized to the ascitic compartment because of the portal hypertension. Although this theory fits better with the clinical measurements, it does not explain why there should be a primary increase in renin and aldosterone levels in some patients with cirrhosis. Renal haemodynamics are certainly altered, with a tendency for redistribution of blood flow from cortical to juxtamedullary nephrons, a tendency which is opposed in many patients by an increase in renal prostaglandin synthesis. These changes in renal haemodynamics may be part of a more general disturbance in vascular tone. There is evidence in cirrhosis of widespread and inappropriate vasodilatation. Although the cause of this is not understood it does provide a reason for the increased renin and aldosterone levels, driven by the necessity to fill the overexpanded vascular compartment.

Clinical features 1 Fullness in the flanks, with dullness on percussion which shifts with a change of position, is the earliest sign of ascites and is often asymptomatic. Ultrasound can reveal small amounts of fluid. Later the abdomen becomes tense and uncomfortable. At this stage a fluid thrill is more useful than shifting dullness in confirming the presence of fluid. It can be difficult to palpate the liver and spleen, although ballotting through the fluid may reveal them. A pleural effusion, particularly on the right side, may be present, and peripheral oedema often develops. Spontaneous bacterial peritonitis is a serious complication, with a high mortality. It can be asymptomatic, although fever, abdominal pain and a general deterioration in wellbeing, with encephalopathy and renal failure, may be accompanying features.

Management A diagnostic paracentesis is first performed to exclude bacterial peritonitis. The fluid should be clear or strawcoloured and any cloudiness should lead to suspicions of infection. Bacterial culture may be negative, and the most frequent abnormal finding is a polymorph count of more than 500 per mm3. The causative organisms are usually coliforms or streptococci, including anaerobes, and broadspectrum antibiotics should be started as early as possible.

1

872

Fig. 16.10

SUMMARY 5 Management of ascites Treatment Spironolactone Other diuretics

Salt restriction

Fluid restriction Paracentesis

Indication Main treatment Not alone; give with spironolactone if necessary Varies depending on response to diuretics and serum sodium 1.5Lor less if hyponatraemic 3-10L amounts with i.v. albumin

Problems Gynaecomastia K+ depletion; renal failure; encephalopathy Unpalatable diet leads to weight loss; Compliance Renal failure Hypotension

Tuberculous peritonitis is rare but should be considered, particularly in a malnourished alcoholic and when the ascitic leukocytes are predominately mononuclear. Diuretics Diuretics are the mainstay of treatment, but care is necessary as overdiuresis precipitates renal failure, electrolyte abnormalities and encephalopathy, which must be avoided. The diuretic of choice is the aldosterone antagonist spironolactone in a starting dose of l00mg per day. In addition to being a logical choice to combat the high aldosterone levels, it is also potassium sparing. Total body potassium levels are usually low, and hypokalaemia not only increases the risk of a cardiac arrhythmia, but also exacerbates encephalopathy. The rate of fluid loss is best assessed by changes in daily weight. A figure of 0.5kg per day is ideal, as the maximum rate of transfer of fluid from the ascitic to the vascular compartment is only about 700 mL per day. If a satisfactory response is not forthcoming in a few days, the daily dose of spironolactone should be increased in 100 mg increments to a maximum of 400 mg per day. Combination therapy in conjunction with a loop diuretic, e.g. furosemide (frusemide) 40-160 mg daily, is often effective. Measurement of urinary sodium concentration can be helpful in assessing the effectiveness of diuretic therapy. Strict control of sodium intake is not always necessary, but does allow lower doses of spironolactone to be effective. Large-volume paracentesis is once again in vogue in the management of severe ascites. Protocols that administer colloid intravenously at rates of 20-25 % of the volume of ascites drained have dramatically improved the safety of this approach. TIPSS or liver transplantation should be considered in intractable cases. The role for peritoneovenous shunts is now very limited. Hyponatraemia can be a problem, and is usually due to impaired renal free water clearance. Restriction of fluid intake is an appropriate therapeutic measure; sodium infusion simply increases fluid retention.

VARICEAL HAEMORRHAGE

Distortion of the lobular architecture in cirrhosis almost always produces raised portal venous pressure. Collateral veins open up between the portal and systemic systems. The most important clinically are those that run beneath the oesophageal mucosa, as they frequently rupture, producing life-threatening haematemesis (variceal haemorrhage).

Clinical features Evidence of portal hypertension may be detected on examination. Splenomegaly is almost invariable. Dilated collateral veins may be seen in the abdominal wall, and may radiate outwards from the umbilicus. In rare cases these may be especially prominent, forming a caput medusa. The obliterated umbilical vein may recanalize, and flow through it sometimes produces a venous hum heard best in the epigastrium or around the umbilicus.

Management Immediate measures The first priority is resuscitation. Blood transfusion is usually necessary, often with large quantities. The next step is to establish the source of the bleeding. Peptic ulceration is common in cirrhosis, and acute erosive gastritis and oesophagitis are often present, particularly in alcoholics. Early endoscopy is therefore helpful in demonstrating the likely bleeding site. The endoscopic signs of a recent bleed from a varix are a venous spurt of blood, or an adherent blood clot. Four treatment options are available: 1. Endoscopic ablation therapy Variceal banding has now largely replaced injection sclerotherapy as the treatment of choice for variceal ablation. The varices are individually sucked into a cylinder attached to the endoscope and bands are triggered to ligate the base of each varix. Five or six bands can be applied with each passage of the scope. Injection sclerotherapy, e.g. with ethanolamine, may be effective if brisk bleeding precludes good visualization of the varices. Bleeding gastric varices are injected with fibrin. 2. Pharmacology A range of drugs that cause splanchnic vasoconstriction have been used to control variceal bleeding. Terlipressin and octreotide (a somatostatin analogue) are now the drugs of choice, replacing the combination of vasopressin and glyceryl trinitrate. 3. Tamponade This is an effective short-term measure while other management strategies are put in place. A tube is introduced, e.g. Sengstaken-Blakemore balloon, which can be inflated to compress the varices, and a gastric balloon which anchors the lower end in the fundus of the stomach, and which may assist in reducing variceal flow by compressing gastric varices. It is very effective, but skill is needed in its introduction

TABLE 16.13 Child's classification of severity of cirrhosis

16

Points scored for increasing abnormalities Feature

1

2

3

Encephalopathy (grade) None 1 and 2 3 and 4 Ascites None Mild Moderate/severe Plasma bilirubin ( mol/L) less than 25 25-40 more than 40 Plasma albumin (g/L) more than 35 28-35 less than 28 Prothrombin time (sees 1-4 4-6 more than 6 prolonged) Total score: 5-6 = grade A; 7-9 = grade B; 10-15 = grade C

and in maintaining it in a safe position. Potential complications include perforation of the oesophagus and ischaemic damage to the oesophageal mucosa. 4. Shunts These may be fashioned either percutaneously in the form of a TIPSS or surgically. The former is preferred if liver transplantation is an option in the future management of the individual patient. The shunt approach is generally less popular, as several controlled trials have shown no benefit in terms of mortality at any stage. Reduced deaths from rebleeding are offset by an increased incidence of liver failure and encephalopathy, presumably owing to the reduction in liver blood flow and the increased amount of blood bypassing the liver after the shunt procedure. The mortality with each bleeding episode is about 35%. An episode of variceal bleeding is considered resolved once bleeding has stopped and oesophageal varices have been obliterated. The risk of rebleeding depends on the underlying aetiology, Child's classification, and the secondary prophylactic measures adopted. Patients with alcoholic liver disease who abstain are considerably less likely to rebleed than those who continue to consume alcohol. Rebleeding is also more frequent in patients with Childs C rather Child's A disease (Table 16.13). The 'state of the art' management of secondary prophylaxis involves the measurement of the portal pressure before and after the introduction of drugs to reduce the pressure, e.g. with propranalol and/or isosorbide mononitrate. The dose is then titrated to achieve an adequate reduction in the absolute portal pressures.

EXTRAHEPATIC PORTAL VEIN OBSTRUCTION

Although relatively uncommon, this is a condition with a good prognosis which often presents with variceal haemorrhage, and must be distinguished from cirrhosis. The cause of the portal vein obstruction is often not apparent and in many cases is thought to be due to portal vein thrombosis in infancy, possibly secondary to umbilical sepsis. Patients first present with haematemesis from

873

SUMMARY 6 Management of haematemesis in cirrhosis 1. Resuscitate: blood, blood substitutes 2. Identify the source of bleeding by endoscopy (haemorrhagic gastritis and ulcers common) 3. If varices bleeding, either: • Treat endoscopically - banding or sclerotherapy • Sengstaken-Blakemore tube (difficult to pass; can be dangerous) • Terlipressin 4. Long-term: • Banding or sclerotherapy • Shunts - TIPSS, or occasionally surgical • Liver transplantation

bleeding oesophageal varices in childhood, adolescence or early adult life. Clinically there are no cutaneous stigmata of chronic liver disease, and although splenomegaly is often marked the liver is usually impalpable. Liver function tests are normal and ascites does not occur. Liver biopsy is helpful in excluding cirrhosis, and ultrasound can often determine the patency of the portal vein. Direct confirmation of the diagnosis is best obtained from the venous phase of selective coeliac axis and superior mesenteric angiograms. These usually show a leash of collateral vessels in the porta hepatis, where the portal vein would normally be seen. In adults portal vein thrombosis can be a complication of intra-abdominal sepsis or carcinoma of the pancreas. Treatment is aided by the excellent liver function. Portosystemic shunts can be technically difficult, although if successful the risk of encephalopathy is much less than in patients with cirrhosis because liver cell function is not impaired. Endoscopic ablation is a suitable alternative.

ENCEPHALOPATHY This complication of cirrhosis is a sign of severe liver cell failure and usually has a poor prognosis. However, a treatable precipitating factor is often present, and its identification and correction is an important clinical objective.

Pathophysiology A reduction in functioning liver cell mass and the diversion of portal blood past the liver via portosystemic collaterals are the two important ingredients that predispose to the disturbance in cerebral function, but the precise

1

874

MCQ 16.12

mechanisms involved are not known. There are three main theories: 1. Toxic substances normally detoxified by the liver are thought to gain access to the systemic circulation and thus the brain, where they alter cerebral metabolism. 2. An alteration in the balance between cerebral neurotransmitters is postulated, with the formation of false neurotransmitters, possibly because of altered amino acid levels in the circulation, which in turn alter the levels of these neurotransmitter substrates in the brain. 3. The inhibitory GAB A receptor is upregulated by the benzodiazepine receptor, which is closely aligned to it in the form of a macroreceptor. Possible candidates as toxins in the first theory include ammonia, mercaptans, amines and indoles. All can be shown to induce encephalopathy in experimental animals, but in concentrations higher than those found in hepatic encephalopathy. Increased serum levels of the aromatic amino acids, and decreased levels of branched-chain amino acids, have promoted the concepts outlined in the second theory. There have been attempts to treat the encephalopathy by correcting the balance between the aromatic and branched-chain amino acids, but the place of this therapy in clinical practice is not established. Recently changes in the relative proportions of highand low-affinity receptors for some of the cerebral neurotransmitters have been demonstrated in animal models of hepatic encephalopathy, and this seems to be a fruitful area for further research. A functional increase in GABAergic tone has been demonstrated in experimental hepatic encephalopathy, and increased levels of benzodiazepine agonists, including diazepam, have been found in the body fluids and brain of patients with hepatic encephalopathy. Experimental use of the benzodiazepine antagonist flumazenil in individual patients with acute or chronic hepatic encephalopathy appears to be able to induce a transient and incomplete clinical and EEG improvement in about two-thirds of cases.

Clinical features The main difference between the encephalopathy of chronic liver disease and that of acute liver failure is the relapsing acute-on-chronic course and the consequent emphasis on the search for, and correction of, precipitating factors. The prodromal phase of an acute-on-chronic episode may be very gradual. Impairment of judgment can be an early sign. Anorexia is common and the reversal of sleep pattern may be troublesome. Fatigue, withdrawal, apathy and slowness of response often precede a more profound disturbance in consciousness (see Table 16.7). There may be spatial disorientation, with confusion as to place, time and person, and a flapping tremor of the outstretched, extended hands. A distinctive sweet smell of the breath, called fetor hepaticus, is detected with moderate to severe encephalopathy in patients with chronic liver disease.

Although not specific to liver disease, changes in the EEG can be helpful in identification and management. There is generalized slowing of the main components, with a resulting fall in the mean dominant frequency. Serial recordings are one objective way of following progress during treatment, although simple bedside tests are sufficiently reliable and sensitive in practice. A standardized number connection trail is a simple and semiquantitative method, and is now preferred to the classic assessment of constructional apraxia which involved copying a fivepointed star.

Management An important objective is to search carefully for a possible precipitating cause (Table 16.14). Intercurrent infections are the most common, and probably interfere with liver function in two ways: by exposing the liver to endotoxin and by reducing liver blood flow secondary to hypotensive effects in the systemic circuit. Spontaneous bacterial peritonitis is a common causative infection that is difficult to diagnose unless routine diagnostic paracentesis is performed. Empirical antibiotics are advised if the cause of the encephalopathy is uncertain. Increased absorption of nitrogen from the gastrointestinal tract occurs with excessive dietary protein, gastrointestinal bleeding and constipation. Diuretics may precipitate encephalopathy by causing dehydration or electrolyte imbalance. The other common precipitant of

encephalopathy is medication, especially narcotic drugs and benzodiazepines. Treatment of the encephalopathy itself is directed mainly at removing sources of ammonia. Ammonia production in the liver by deamination of amino acids can continue even though its further metabolic transformation to urea is impaired, and lowering the protein levels in the diet can sometimes be effective in improving the encephalopathy. However, care must be taken not to increase the catabolic state and thus exacerbate the long-term malnutrition which is often a feature of chronic liver disease. Ammonia is produced in the bowel by bacteria, and to reduce this the colon is emptied using a magnesium sulphate enema, and ammonia-producing colonic bacteria are reduced in number by giving oral lactulose. Lactulose is a synthetic disaccharide which is broken down into its constituent monosaccharides by bacteria in the colon, and then into lactic acid. This not only acts as a purgative, but also discourages the growth of ammonia-producing bacteria. Because of the change in pH, ammonia may also be fixed in the colon as ammonium ions. 1

16

HEPATOCELLULAR CARCINOMA Often referred to as hepatoma, hepatocellular carcinoma arises from the hepatic parenchymal cells.

Incidence, epidemiology and aetiology TABLE 16.14 Factors precipitating encephalopathy in cirrhosis Intercurrent infections Urinary tract Chest Upper respiratory tract Genitourinary tract Spontaneous bacterial peritonitis Septicaemia Dietary indiscretion High-protein meal Alcohol binge

In Africa and the Far East hepatocellular carcinoma is one of the commonest tumours, but is unusual in Europe and the USA (Fig. 16.27). Hepatocellular carcinoma usually arises in the cirrhotic liver, and in this setting is more common in males than in females. In Europe and North America the peak incidence is from 50 to 70 years of age, but in high-incidence areas patients are often in their 20s or 30s. When there is no

Gastrointestinal haemorrhage Blood acts as protein load, and hypotension impairs liver function (may be occult; melaena on rectal examination) Electrolyte imbalance Hyponatraemia or hypokalaemia (possibly due to vomiting, reduced free water clearance or effect of diuretics) Drugs Usual candidates are sedatives (increased end-organ sensitivity and reduced clearance) and diuretics (electrolyte imbalance) Primary hepatocellular carcinoma Worsening of encephalopathy may be the first indication

FIG. 16.27 The distribution of hepatocellular carcinoma in the world It almost parallels the distribution of HBV infection (Fig. 16.15).

875

underlying cirrhosis the sex ratio is equal, and the tumour usually presents in teenagers and young adults if of the fibrolamellar variety, and later if of standard morphology. Chronic viral hepatitis is closely associated with the development of hepatocellular carcinoma. In the west this is seen most commonly with hepatitis C, and this would appear to be the basis for the increasing incidence there of hepatocellular carcinoma. Chronic HBV infection is also strongly associated with the development of the tumour, particularly in areas with a high HBsAg carrier rate. The finding of subgenomic fragments of HBV DNA in liver cell and tumour DNA, even in some patients without serological markers of previous HBV infection, has led to the suggestion that the virus may be directly oncogenic. However, the pattern of integration of viral DNA appears to be random, and molecular mechanisms that could be responsible for oncogenesis have not yet been identified. Careful prospective studies of hepatoma development in patients with cirrhosis in the UK have shown that previous HBV infection, as detected serologically, is not a significant independent risk factor. Aflatoxin, a product of the fungal mould Aspergillus flavus, can induce liver damage and hepatocellular carcinoma in animals, and is a food contaminant in many tropical countries. Very rarely, hepatocellular carcinoma has been described following prolonged use of the oral contraceptive pill, and in individuals exposed to Thorotrast, an early radioactive X-ray contrast material.

Pathology The commonest microscopic pattern of hepatocellular carcinoma is the characteristic trabecular or sinusoidal pattern, which reproduces the normal relationship between clusters of liver cells and a flat endothelial cell covering (see Fig. 16.3). Fibrolamellar carcinoma is a distinct variant with a better prognosis. The tumour cells are large and polygonal and are arranged in trabeculae separated by parallel bundles of collagen which merge in places to form broader bands of fibrous tissue.

Clinical features In the UK there is usually a slow deterioration in wellbeing, with anorexia, weight loss and abdominal pain in a patient known to have cirrhosis. There may be no specific signs on examination, but hepatomegaly is usually present and there may be an arterial bruit and a friction rub over the tumour. In high-incidence areas the presentation is often more dramatic, with pain over the tumour, fever and weight loss. The deterioration in liver function is more profound in the patient with pre-existing cirrhosis. 1

876

Case 16.4

0 Fig. 16.11

Diagnosis 1 The most important biochemical marker of the tumour is oc-fetoprotein (AFP). This is a glycoprotein which can be thought of as a fetal albumin. It is synthesized by the fetal liver, but levels fall rapidly after birth. In adults it is present in serum in a concentration of less than lOng/mL. About 80% of patients with hepatocellular carcinoma arising in a cirrhotic liver, and 50% of those without an underlying cirrhosis, will show elevated AFP levels in serum. In a cirrhotic, patient levels above 500ng/mL are diagnostic of hepatocellular carcinoma. AFP is also greatly elevated in patients with germ cell tumours of the testis and ovary, but this is not a diagnostic problem. Some patients with hepatic metastases can also have elevated AFP levels, but not as high as those found in hepatoma. In viral cirrhosis levels of AFP can rise above the normal adult range, probably reflecting increased liver cell regeneration, but a rapid sustained rise in the serum levels on serial estimations is typical of hepatoma. Ultrasound, CT and MRI are all capable of visualizing hepatocellular carcinoma. Selective hepatic arteriography is a very useful diagnostic technique, and also provides information on the distribution of the tumour within the liver. There is usually a well-defined tumour circulation, with new vessel formation. Although the definitive diagnosis can only be made by histological examination of tumour tissue, in practice liver biopsy may not always be possible because of a prolonged prothrombin time. In these cases a working diagnosis is established from a combination of elevated AFP levels in serum and the demonstration of a tumour circulation on arteriography.

Management Hepatocellular carcinoma is usually a rapidly growing tumour which presents late. The prognosis is poor, with a mean survival of about 4 months. Resection is potentially curative but is only possible in those cases where the tumour is limited to one lobe of the liver. Most patients undergoing resection have normal unaffected liver tissue, but some progress is being made resecting tumours from patients with well compensated cirrhosis. The long-term outlook following successful resection is good, with local recurrence being much more common than distant metastases. On this basis it might be expected that liver transplantation would be another effective treatment, also applicable to those with cirrhosis. However, both tumour recurrence in the liver graft and distant metastases are commonly observed within 1-2 years of the procedure. It is not clear whether this is due to immunosuppressive therapy, or whether the tumours are often more advanced than initially suspected. Consequently, liver transplantation is reserved for patients with one or more tumours that do not exceed 4cm in diameter, and in this setting the outcome is excellent. The only cytotoxic drug to show any benefit so far is adriamycin (doxorubicin). About one-third of those

treated show a response, but in most of these survival is only prolonged by a few months. TACE (transcutaneous arterial chemoembolization) is effective in a minority of patients, and the mechanism of action is probably a combination of the effect of the cytotoxic drug and tumour ischaemia induced by the occlusion of small arterial vessels by the lipiodol. Direct injection of alcohol into the tumour may also temporize the progression of the disease.

LIVER METASTASES Many tumours metastasize to the liver, particularly those arising in the abdomen; in western societies this is the commonest cause of malignancy within the liver.

Clinical features Although the primary tumour may already have been identified, in some cases the metastatic tumour may be the cause of the presentation. In these cases, malaise, weight loss, pain over the liver and abdominal distension are the likely symptoms. Examination often confirms substantial weight loss and usually demonstrates a hard, enlarged liver with an irregular surface and edge.

Investigations The serum alkaline phosphatase is often elevated. Jaundice is usually a late occurrence and has a poor prognosis. Ultrasound and CT frequently confirm the presence of lesions in the liver, © and the definitive diagnosis can then be made on liver biopsy. Tumour tissue can be expected on liver biopsy in more than 70% of cases, and the success rate can be further enhanced by using ultrasound to indicate where the biopsy should be taken.

Differential diagnosis Because of the importance of the diagnosis of metastatic liver cancer, it is usually necessary to obtain histological proof of malignancy. The conditions most likely to be misdiagnosed are cysts, abscesses and granulomas. In areas where hepatoma is common, the pain, fever and rapidly enlarging liver make amoebic abscess and hydatid disease important treatable conditions to be considered in the differential diagnosis.

Management Treatment depends on the nature of the primary tumour. For certain tumours, such as small cell carcinoma of the lung, breast cancer and lymphoma, chemotherapy may be highly effective in producing regression of metastases

and symptomatic improvement. With other tumours, such as metastatic gastrointestinal and pancreatic cancer, chemotherapy is usually ineffective, although infusion of cytotoxic drugs such as 5-fluorouracil into the hepatic artery occasionally relieves pain and produces regression. It is questionable whether this complex procedure is more effective than intravenous administration. Pain in the liver is usually controlled by analgesics, but severe pain may be helped by external irradiation and even hepatic artery ligation or tumour embolization. Rarely, resection of an isolated metastasis may be feasible; colorectal metastases and carcinoid tumour (p. 796) are examples where this approach may be valuable. Symptoms of pain, nausea and anorexia are best treated by palliative measures, including analgesics, antiemetics such as metaclopramide, and corticosteroids.

16

LYMPHOMA The liver is often directly involved with infiltration of lymphoma cells. Liver biopsy can therefore be helpful in diagnosis. Documenting liver involvement is also important in staging the disease before deciding on appropriate therapy. Serum alkaline phosphatase levels may be increased and jaundice can occur. In Hodgkin's disease a cholestatic jaundice may appear before there is obvious lymph node involvement, and occasionally in the absence of any evidence of direct hepatic involvement.

THE LIVER IN SYSTEMIC DISEASE RHEUMATOID ARTHRITIS Increased serum alkaline phosphatase levels from the liver are frequently seen in rheumatoid arthritis. Histological changes on liver biopsy are often non-specific and unremarkable. Amyloidosis and primary biliary cirrhosis are well defined but infrequent associations. Nodular regenerative hyperplasia is sometimes found in Felty's syndrome (p. 1137).

SYSTEMIC LUPUS ERYTHEMATOSUS The early finding of lupus erythematosus (LE) cells in about 10% of cases of autoimmune chronic hepatitis, and the use of the term 'lupoid hepatitis' to describe these patients, created considerable confusion concerning the relationship between chronic active hepatitis and systemic lupus erythematosus (SLE). Although anti-DNA antibodies are frequently present in autoimmune chronic hepatitis, it is now clear that the two conditions

877

are quite distinct. In particular, clinically significant renal involvement, an important feature in SLE, is very rare in chronic autoimmune hepatitis. Furthermore, careful studies of liver involvement in SLE have in most cases shown only minor portal tract inflammation.

POLYARTERITIS NODOSA Chronic HBV infection has been reported in up to 40% of cases of polyarteritis nodosa, but this is not a consistent finding. The associated liver disease in these cases is usually very mild, with minor histological changes on liver biopsy. The appearance of characteristic arterial lesions in biopsy material can be of help in diagnosis.

SCLERODERMA There is a well-recognized association between scleroderma and primary biliary cirrhosis (PBC). In some cases of PBC the associated sclerosis is truly systemic, but in most it is limited to the skin of the terminal phalanges (sclerodactyly), and may be part of the CRST syndrome.

AMYLOIDOSIS The liver is often involved in systemic amyloidosis (p. 1263) but this rarely produces clinically significant liver disease. Rectal biopsy is safer than liver biopsy in establishing the diagnosis.

PORPHYRIA Porphyria cutanea tarda (Ch. 19) may be associated with alcoholic liver disease, and sometimes hepatoma; the accumulation of protoporphyrin in the liver in erythropoietic protoporphyria may eventually lead to cirrhosis and liver failure.

GRANULOMATOUS CONDITIONS The finding of granulomata in liver biopsy specimens is relatively common. Although they are a feature of some primary liver diseases, particularly primary biliary cirrhosis, they are more often a reflection of a systemic condition (Table 16.15). In the UK the most common causes are sar-

1 MCQ 16.13 878

TABLE 16.15 Causes of granulomatous liver disease Infections Bacterial Usually chronic intraceliular

and

infections Mycobacterial including tuberculosis* Brucellosis* Leprosy Listerosis Fungal Histoplasmosis Nocardia Candidiasis Actinomycosis Parasitic Schistosomiasis* Ascariasis Toxocara Amoebiasis Strongyloides Giardiasis Viral Cytomegalovirus Lymphogranuloma venereum Infectious mononucleosis Other Syphilis Q fever

Drug-induced Sulphonamides and derivatives Sulphonamide-containing antibiotics* antidiabetics such as chlorpropamide* Others e.g. Phenylbutazone* Allopurinol Hydralazine Carbamazepine Quinidine Multisystem diseases Collagen-vascular disease Polymyalgia rheumatica* Systemic lupus erythematosus Others Sarcoidosis* Whipple's disease Wegener's granulomatosis Granulomatous disease of childhood Miscellaneous Primary biliary cirrhosis* Crohn's disease* i.v. drug abusers Patients on haemodialysis Haemophilia After ileal bypass surgery Erythema nodosum

Neoplasms Hodgkin's lymphoma* Adenocarcinoma Hepatocellular carcinoma * Common causes of liver granulomata.

coidosis, tuberculosis and drug reactions. There is usually hepatomegaly, with a raised serum alkaline phosphatase but a normal serum bilirubin level. In up to 30% of cases the cause of the hepatic granulomata cannot be determined, in spite of rigorous investigation. Occasionally portal hypertension may develop, either because of a direct effect of the granulomata on liver blood flow or in association with increasing liver fibrosis. In these cases a trial of steroids is justified to try to halt the progress of the disease. Granulomatous hepatitis denotes the presence of focal parenchymal liver damage in association with multiple granulomata. In some cases of unknown aetiology there may be quite striking symptoms of a systemic illness,

including fever, malaise and weight loss. There is often a dramatic improvement on corticosteroid therapy. 1

NON-VIRAL INFECTIONS INVOLVING THE LIVER SCHISTOSOMIASIS Worldwide, schistosomiasis (p. 370) is a common cause of chronic liver disease. Adult worms live in small veins of the colon (Schistosoma mansoni) and the small intestine and colon (S. japonicum}. The liver damage is due to granulomatous reactions to eggs which have embolized to the liver and impacted in presinusoidal branches of the portal vein. Resolution of granulomata leads to severe periportal fibrosis in patients with heavy infections. Portal hypertension usually accompanies the developing fibrosis, but liver cell function is well preserved unless there is coexisting cirrhosis from another cause. Patients often present with haematemesis from ruptured oesophageal varices; gross splenomegaly is common and ascites occurs. The prognosis is fairly good. Diagnosis and management are discussed in Chapter 9.

LIVER FLUKES Fasciola hepatica is a flatworm which is common in sheep and, to a lesser extent, cattle worldwide (p. 375). It lives in the biliary tree and sheds its ova into the stools. The liver damage is caused by worms in the biliary system. In severe infections there is intermittent obstructive jaundice, with high fever, painful hepatomegaly and jaundice. Eosinophilia is common, and a complement fixation test is usually positive in high litre. The definitive diagnosis is made by finding ova in stool concentrates. The infection responds to treatment with praziquantel. Clonorchis sinensis is found in the Far East (p. 373). The worms inhabit the biliary system. Symptoms are usually mild, except in heavy infections, when there may be upper abdominal pain, tender hepatomegaly and diarrhoea. Praziquantel is an effective treatment. Late complications include obstructive jaundice, cholangitis, stones in the common bile duct and cholangiocarcinoma (pp. 858-859).

HYDATID CYSTS Hydatid cysts (p. 377) are formed in the liver by the larval stages of two tapeworms, Echinococcus granulosus and E. multilocularis, which normally live in dogs and wild carnivores, respectively. They may be asymptomatic or may present with pain in the right hypochondrium. If they are

very large they can cause abdominal distension and discomfort. Secondary infection in a cyst is a serious complication, presenting with fever and pain like other pyogenic liver abscesses. Ultrasound and CT are the most useful investigations and can be diagnostic if 'daughter' cysts are identified. Complement fixation and haemagglutination tests for antibodies to hydatid material can also be helpful in making a specific diagnosis, although negative results can occur, particularly in asymptomatic cases. Mebendazole and, more recently, albendazole have been used for treatment and have become the first line of therapy. Surgical removal of the cysts still offers the best chance of cure, but great care must be taken to prevent rupturing of the cysts, which leads to the dissemination of daughter cysts into the peritoneal cavity. This risk is minimized by injecting formalin, alcohol or hypertonic saline into the cyst before attempting removal. It is wise to leave asymptomatic cysts alone.

16

AMOEBIASIS In some cases of amoebic colitis, and in others without bowel symptoms, the organisms reach the liver through the portal venous system and form intrahepatic amoebic abscesses. Pain in the right hypochondrium, with tender hepatomegaly and fever, are the usual manifestations. A right-sided pleural effusion can also occur if an abscess has ruptured through the diaphragm. Ultrasound and CT scans are very useful investigations, and antibody tests are almost always positive. A week's course of metronidazole is a very effective treatment.

WEIL'S DISEASE The spirochaete Leptospira icterohaemorrhagica can be transmitted to humans from infected rats' urine. Those in contact with sewage and rat-infested water are at highest risk. The incubation period is 1-2 weeks. At first the illness may resemble the prodromal stage of viral hepatitis, with mild fever and malaise, but it is often more severe, with myalgia and high fever. This may progress to prostration, jaundice and renal failure. Headache, confusion and meningism are often present. Epistaxis, haematuria and petechiae occur. There is often a prominent leukocytosis, and the urine contains red cells and albumin. Identification of the causative organism in blood or urine is the definitive diagnostic test, although there is a rise in serum IgM antibody at the end of the acute phase of the disease. Although the jaundice may be deep, liver failure does not occur, and general toxaemia and renal failure are the usual problems in management. The organism is sensitive to benzyl penicillin and large doses are usually given. However, there is no convincing evidence that this contributes to the resolution of the disease unless adminis-

879

tered early, and skilled intensive care is essential. The reported mortality varies from 4 to 40%.

SEPTICAEMIA Cholestasis is not uncommon in severe sepsis. A rise in serum bilirubin occurs in 25-50% of cases, but serum transaminases and alkaline phosphatase are often normal. The pathogenesis is not understood, but there is no evidence of gross liver damage and there is usually rapid resolution with appropriate antibiotic therapy. In jaundice due to staphylococcal sepsis, treatment with fusidic acid should be avoided as this interferes with bilirubin excretion.

PYOGENIC LIVER ABSCESS O

Biliary tract disease Ascending cholangitis is the commonest cause and may be a complication of any obstruction in the biliary tract; it can also follow cholecystitis Portal phlebitis Any primary septic focus within the abdomen (diverticulitis, appendicitis, infected haemorrhoids, etc.) can cause thrombophlebitis in the local branches of the portal vein, and infect the liver Septicaemia Severe generalized sepsis can infect the liver via the hepatic artery Trauma Secondary infection of a damaged area of liver or a haematoma can lead to abscess formation Malignancy Some tumours develop areas of central necrosis, and pyogenic infection can then follow Extension of local infection e.g. subphrenic abscess and empyema of the gallbladder

The commonest cause of liver abscess worldwide is amoebiasis, but in the developed world pyogenic causes are of increasing importance. In the past pyogenic liver abscess was most commonly seen in children or young adults in association with appendicitis. However, as antibiotics have become more widely prescribed the condition is now most often seen in the elderly, owing to incomplete treatment of biliary tract disease or diverticulitis. In these patients the presenting symptoms are often non-specific and the diagnosis delayed.

Classically there is upper abdominal pain, swinging pyrexia, anorexia, malaise and weight loss. However, in many older patients the symptoms and signs may be much less dramatic, and pain and hepatomegaly may not be present. This is one of the causes of pyrexia of unknown origin.

Aetiology

Investigations

Possible causes of pyogenic liver abscess are listed in Table 16.16. Infection in any site drained by the portal vein can cause portal pyaemia, which can then seed the liver with abscesses. These are usually multiple and often concentrated in the right lobe. The primary site, particularly in diverticular disease, may be relatively silent. Direct spread of infection from the biliary tree is the presumed route of entry of the bacteria in those cases where abscess complicates biliary tract disease. Trauma and hepatic malignancy are uncommon causes.

A polymorphonuclear leukocytosis is usually present and the routine liver function tests often show a high serum alkaline phosphatase. The most useful investigation is an ultrasound scan. If there has been no previous antibiotic treatment, aerobic and anaerobic cultures of blood or direct aspirates of pus under ultrasound control will usually reveal the causative organism.

Bacteriology The dominant organisms isolated from hepatic abscesses have changed over recent years. Whereas aerobic Gramnegative organisms, especially E. coli, used to predominate, anaerobes, particularly Streptococcus milleri, are now found in up to 50% of abscesses. Mixed infections are identified in about one-third of cases.

1

880

TABLE 16,16 Causes of pyogenic liver abscess

MCQ 16.14

Presentation

Management Antibiotics are always needed and are best chosen according to the bacteriological findings. However, a combination of gentamicin (or a broad-spectrum cephalosporin), metronidazole and flucloxacillin will cover most of the likely organisms. In cases with very small multiple abscesses appropriate antibiotic treatment alone may be adequate, but in most cases drainage is also required. In a solitary abscess, or where the number is small, it may be possible to achieve satisfactory percutaneous drainage by repeated needle aspiration. In elderly patients the first line of treatment is usually closed aspiration combined with antibiotics instilled into the abscess cavity and given intravenously. When the abscesses are difficult to approach, open surgical drainage is used. Soft pliable drains are placed in the largest cavities and intensive broad-spectrum

antibiotic treatment is started. Whichever approach to drainage is used, the antibiotics need to be continued for 6 weeks to ensure resolution of the infection.

Prognosis Unfortunately, the diagnosis of pyogenic liver abscess is often delayed, and under these circumstances the mortality may be as high as 80%. With a high index of suspicion and early diagnosis the mortality has been as low as 10% in some series. Coexistent biliary tract disease, old age and multiple abscesses are associated with a poor prognosis.

CONGENITAL BILIARY AND HEPATIC DISORDERS CAROLI'S DISEASE Caroli's disease is a rare condition in which saccular dilations of the intrahepatic biliary tree predispose to ascending cholangitis. Symptoms usually begin in childhood or early adult life. Long-term antibiotic treatment reduces the frequency of attacks.

Large cysts, similar to those seen in polycystic kidney disease and often associated with them, may be found throughout the liver. Gross nodular hepatomegaly, often asymptomatic, is usual. Although pain, due to haemorrhage or infection in a cyst, can occur, the prognosis with respect to the liver lesions is excellent.

16

LIVER TRANSPLANTATION Liver transplantation is now an accepted and integrated component of the management of most of the conditions discussed in this chapter. However, the majority of patients with the common liver diseases, particularly alcoholic liver disease, are not transplanted, and most have rare conditions such as primary biliary cirrhosis. Guidelines have been developed by the British Society of Gastroenterology for the referral of adult patients for consideration for liver transplantation, and the salient points are outlined in Table 16.17. In chronic liver disease patients are considered for transplantation if there are major clinical complications that are not responding to standard therapy, available prognostic factors indicate that survival beyond 12-18

TABLE 16.17 Indications for liver transplantation in adults* CHOLEDOCHAL CYST Choledochal cyst is a gross dilatation or diverticulum of the common bile duct which obstructs normal bile flow and presents as cholestatic jaundice in childhood. The diagnosis is made on ultrasound and cholangiography. Treatment is by surgical resection and drainage, usually via a Rouxen-Y anastomosis.

Category Chronic liver disease Primary biliary cirrhosis Primary sclerosing cholangitis Autoimmune hepatitis Alcoholic cirrhosis Hepatitis C

BILIARY ATRESIA Originally thought to be a congenital anomaly, with failure of development of the extrahepatic biliary system, biliary atresia is now recognized as an acquired condition in many cases. There is gradual destruction of the common bile duct soon after birth, leading to deepening jaundice and secondary biliary cirrhosis. Early surgical intervention, using the Kasai technique to fashion a bypass anastamosis high in the porta hepatis, has proved remarkably successful in some cases. Liver transplantation has also produced promising results when used as primary therapy and in salvaging patients at various times after Kasai operations.

POLYCYSTIC DISEASE OF THE LIVER Polycystic disease of the liver may be a congenital anomaly related to biliary atresia, but rarely presents with jaundice.

Hepatitis B

Acute liver failure Paracetamol Other aetiologies Malignancy Hepatocellular carcinoma Neuroendocrine tumours Epithelioid haemangioendothelioma

Comment Bilirubin > 100 mol /L, liver failure Consider early to pre-empt cholangiocarcinoma Liver failure without reversible component with immunosuppression Liver failure after at least 6 months' abstinence Liver failure or hepatocellular carcinoma (see below) Liver failure if HBV DNA negative (spontaneously or with antiviral therapy), associated hepatitis D is favourable Medical criteria indicating a poor prognosis combined with favourable psychosocial assessment Medical criteria indicating a poor prognosis under the age of 60 years 1-2 nodules <5cm in diameter on radiological assessment Consider selected cases for palliation Must differentiate from angiosarcoma

* Modified from British Society of Gastroenterology Guidelines.

881

FIG. 16.28 MR cholangiography showing a tight stricture at the site of the biliary anastomosis in a liver transplant recipient

months is unlikely, or if quality of life is severely impaired by non-life threatening symptoms, e.g. fatigue, pruritus. Emergency liver transplantation is an essential component of the management plans for acute liver failure, and these patients should always be managed in specialist units with access to transplantation. Small hepatocellular carcinomas detected through routine surveillance in patients with cirrhosis account for the vast majority of cases undergoing liver transplantation for malignant disease. Liver transplantation continues to have a small role in the management of metabolic disease and normal liver morphology, e.g. Crigler-Najjar syndrome, hyperoxaluria, familial amyloid. There are remarkably few absolute contraindications to liver transplantation. Extrahepatic malignancy or infection and AIDS are the most obvious. Patients have been successfully transplanted as young as 5 days and over the age of 70 years. Each patient undergoes an assessment protocol to determine the risk/benefit profile, technical difficulties and comorbidity that may alter the outcome after transplantation. Most operations use whole organs from cadaveric donors. However, the liver may be reduced in size to match the recipient, may be split between two recipients, or only part of the liver be transplanted into the orthotopic position beside the native liver, having the potential to recover;

1 MCQ 16.15

882

this is known as auxiliary transplantation. The latter is used in the treatment of selected patients with acute liver failure and some metabolic disorders. Living related donation of either the right or the left lobe has now been established as an option for adult and paediatric recipients, respectively. The postoperative problems include technical complications, rejection, infections, complications of immunosuppressive therapy and disease recurrence. Arterial thrombosis and biliary complications, either leaks or strictures, are the most frequent technical problems. Acute rejection is usually easy to manage with increases in immunosuppression, and chronic rejection of the liver requiring retransplantation has now become rare. A very wide range of infections can be observed, including bacterial, fungal, viral and opportunistic. The need for long-term immunosuppression results in complications from the immunosuppression per se (e.g. lymphoma, increased risk of some other malignancies, opportunistic infections), as well as the side-effects of the constitutive drugs (e.g. nephrotoxicity, hypertension). The range of immunosuppressive drugs is now expanding (tacrolimus, ciclosporin, mycophenolate, sirolimus), giving more scope to customize immunosuppression regimens and minimize the attendant toxicity. The possibility of disease recurrence exists for the majority of transplantation indications, and ranges from being a significant problem (viral hepatitis, alcohol, malignancy) to one of academic interest (primary biliary cirrhosis). The results of liver transplantation are now generally excellent. Patients with primary biliary cirrhosis can expect a 90-95% 1-year survival rate, followed by a near-normal life-expectancy. The overall results for elective transplantation are 80-85% 1-year and 70-75% 5-year survival rates; individual programmes produce even higher rates. The equivalent figures for emergency transplantation are 70-75% and 55-60% 1- and 5-year survival rates, respectively. 1

FURTHER READING ON LIVER TRANSPLANTATION Chenard-Neu M P et al 1996 Auxiliary liver transplantation: regeneration of the native liver and outcome in 30 patients with fulminant hepatic failure - a multicenter European Study. Hepatology 23(5):1119-1127. Devlin J, O'Grady J G 1999 Indications for referral and assessment in adult liver transplantation: a clinical guideline. Gut 45 (Suppl VI); VI1-VI22. Devlin J, Wendon J, Heaton N, Tan K C, Williams R 1995 Pretransplantation clinical status and outcome of emergency transplantation for acute liver failure. Hepatology 21(4): 1018-1024.

17

Endocrine Diseases Anthony P Weetman

Historical introduction 883

The posterior pituitary gland 910

The physiology of hormone synthesis and action 883

The thyroid gland 912

Classification of endocrine diseases 888 The aetiology of endocrine diseases 888 Systemic effects of endocrine disorders 890 Endocrine function testing 891 The pituitary gland 892

The adrenal glands 925 Diseases of the adrenal cortex 929 Diseases of the adrenal medulla 938 The testes 939 The ovaries 945 Disorders of sex differentiation 949

The anterior pituitary gland 893

HISTORICAL INTRODUCTION Endocrinology emerged as a medical science in the 19th century. Berthold of Gottingen, in 1849, was the first to provide 'experimental proof for the existence of an internal secretion, by demonstrating that transplantation of the testis to another part of the bird's body prevented atrophy of the cock's comb, known to be caused by castration. In 1855, Thomas Addison described the clinical picture that resulted from destruction of the adrenal glands in humans. The first clear demonstration that an extract of a gland could correct a deficiency disease was provided by Murray and others, who showed that the administration of sheep thyroid extract would cure myxoedema and its childhood equivalent, cretinism, and the effects of thyroidectomy. In 1915 Kendall isolated the active principle and named it thyroxine. By then, the first demonstration of a hormone had been made, in 1902 by Baylis and Starling, who extracted the hormone they termed secretin from the duodenum, and found that it promoted pancreatic enzyme secretion. Adrenaline (epinephrine) was extracted from the adrenal glands at about the same time. By the mid19308, German chemists had isolated and later synthesized

testosterone and the main oestrogen, oestradiol, followed in the 1940s by the adrenal glucocorticoids, cortisone and cortisol. Because of its unusual chemical structure and high potency, the main mineralocorticoid, aldosterone, was not discovered until the mid-1950s. The major pathways of steroid synthesis were not completely identified, nor the inborn errors of steroid production recognized, until this time. From an early stage, clinical observation has had a major impact on the development of the science of endocrinology and the recognition of different hormones. This is particularly true of the pituitary gland and its subservient endocrine glands. Early this century, Harvey Gushing, the father of pituitary surgery, recognized that some features of pituitary disease were due to deficiencies, and others (for example in acromegaly) to hormone excess (in this case, growth hormone). Geoffrey Harris, working in Cambridge, was responsible for the concept that the anterior pituitary gland was controlled by secretions coming to it through a portal blood supply from the hypothalamus. Since the late 1960s we have seen the isolation and synthesis of several of these releasing hormones and their entry into clinical practice. Recently, the pace of development of our understanding of basic and clinical endocrinology has been truly staggering. Much has come from advances in methods for measuring the minute concentrations of hormones in body fluids. In many instances the concentration of active hormones in the circulation is in the range of picograms (10-12g) per mL. In the 1960s, initial bioassay and chemical methods gave way to protein-binding assays, of which the most widely used have been radioimmunoassays. These depend upon developing highly specific antibodies to hormones, coupled if necessary (e.g. for steroids) to a protein. A further essential development was the capacity to make radiolabelled hormones. Such methods have demonstrated, among other phenomena, the episodic nature of the release of certain hormones. Thus, administration of gonadotrophin-releasing hormone (GnRH) (initially to monkeys) showed the importance of pulsatile secretion of GnRH in transmitting the correct message. Continuous administration was found to switch of secretion of the hormones that it stimulates when given episodically. Recently, very sensitive bioassay methods have been developed, such as those using isolated cells; these are especially important for polypeptide hormones. Furthermore, immunoradiometric assays for many polypeptide hormones have now become available, with even greater sensitivity and specificity than radioimmunoassays.

THE PHYSIOLOGY OF HORMONE SYNTHESIS AND ACTION Hormones act in a classic endocrine fashion by exerting effects on a target organ at a distance from the endocrine

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cell by secretion into the bloodstream. Some hormones have additional biological actions. They may have paracrine effects on adjacent cells, usually within the endocrine organ itself, or may act as neurotransmitters. Most hormones are polypeptides, and general features of their synthesis and secretion are detailed below; the synthesis of thyroid hormones, steroid hormones and catecholamines depends on multiple enzymes and is described in the appropriate sections of this chapter.

HORMONE ACTION THROUGH CELL SURFACE RECEPTORS There are four main classes of cell surface receptors (Table 17.1). All endocrine receptors have a high-affinity hormone-binding region: binding of the hormone to this site alters the conformation of the receptor. They also have a region which couples to an intracellular signalling mechanism that mediates the function of the hormone.

Actions mediated by adenylate cyclase POLYPEPTIDE HORMONE SYNTHESIS

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After transcription from DNA, the mRNA precursor for a typical polypeptide hormone is subjected to posttranslational processing, particularly the excision of introns to form mRNA, which is translated into a precursor hormone. One type of precursor, a pre-hormone, consists of an aminoterminal signal sequence joined to the bioactive hormone (apoprotein), which requires no further proteolytic processing. The second type of precursor, the preprohormone, comprises an aminoterminal signal sequence followed by a prohormone (polyprotein) with one (or more) bioactive domains, which becomes available after post-translational modification of the prohormone. Such modification includes the removal of spacer sequences or cryptic peptides with no known function from prohormones, and glycosylation, sulphation or other modifications of amino acids. The signal sequence of polypeptide hormones is important in directing their transport into the cell's secretory pathway. Typically this pathway consists of the formation of transition elements from the rough endoplasmic reticulum, which are incorporated into the Golgi apparatus, leading to the formation of secretory granules. Such granules then fuse with the extracellular membrane to release the hormone. The regulation of polypeptide hormone gene expression can occur at various levels: RNA transcription or posttranscriptionalprocessing,translationand post-translational processing. As well as determining the amount of any hormone produced, these steps can create diversity of expression in a tissue-specific fashion. For instance, alternative exon splicing during post-transcriptional processing can generate different polypeptides; calcitonin and calcitonin gene-related peptide are generated in this fashion from the same RNA precursor in the thyroid and nervous systems, respectively. Post-translational processing of the pro-opiomelanocortin molecule generates a number of different peptides (see below) in different regions of the anterior pituitary, and these can be further modified by phosphorylation. Hormones in general exert their effects on the target organ in one of two ways. They may act on cell surface receptors, leading to intracellular signalling, or as transcription regulatory factors, by binding to intracellular receptors that usually cause gene transcription.

The first such effector mechanism to be recognized was the adenylate cyclase system, which, when activated, generates cyclic AMP (from ATP) as second messenger (Fig. 17.1). It is now recognized that hormones can either activate or inhibit this enzyme, depending upon whether they are linked to it via a stimulatory (Gs) or an inhibitory (G;) guanosine triphosphate (GTP)-containing coupling

TABLE 17.1 Classes of membrane receptor Receptor

Ligand

Signal system

G-protein coupled

Polypeptide hormones Neurotransmitters Prostaglandins

cAMP, cGMP Inositol triphosphate Ca2+

Receptor kinase

Insulin Growth factors

Protein tyrosine kinase Protein serine kinase

Receptor-linked kinase

Growth hormone Prolactin Cytokines

Receptor-associated tyrosine kinase

Ligand gated ion channel

Neurotransmitters Amino acids

Ion transport

FIG. 17.1 Mechanism of action of hormones that activate adenylate cyclase LTl The hormone (H) binds to the receptor (R), which alters the conformation of the regulatory coupling protein (Gs), allowing GTP to bind. B The binding of GTP causes the coupling protein to bind and activate adenylate cyclase (AC) in the membrane, generating cAMP. GTP breaks down to GDP and the activation then ceases.

protein. G protein consists of three subunits, , and . When the receptor is activated by the hormone, it associates with a Gs coupling protein; the -subunit dissociates and activates adenylate cyclase. The -subunit is also a guanosine triphosphatase (GTPase), and its activation leads to a simultaneous breakdown of GTP to GDP, switching off adenylate cyclase. Cyclic AMP, in turn, binds to and activates certain intracellular protein kinases, which then activate other enzymes and proteins by phosphorylation. The concentration of cyclic AMP is determined by the combined activity of adenylate cyclase and the enzyme that destroys cyclic AMP, phosphodiesterase. Hormones which act wholly or in part via the secondmessenger cyclic AMP include many polypeptide hormones such as adrenocorticotrophic hormone (ACTH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), parathyroid hormone, calcitonin and vasopressin. The effects of the catecholamine hormone adrenaline (epinephrine), mediated by the -receptor, are also produced by activation of adenylate cyclase. On the other hand, its -adrenergic effects are mediated, at least in part, by inhibiting adeny-

late cyclase (via the Gj coupling protein discussed above). This accounts in part for the mutually antagonistic a and (3 effects of adrenaline, at least in tissues that possess both types of receptors. Many of the effects of prostaglandins, which are not systemic hormones but do act via cell surface receptors, are also mediated by adenylate cyclase. A related G-protein coupled receptor system uses guanylate cyclase to generate a second messenger; atrial natriuretic peptide and nitric oxide signal through this type of receptor.

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Actions mediated by phosphatidyl inositols and calcium transport Many hormones act through cell surface receptors independently of adenylate cyclase, by inducing the transport or release of calcium and/or cleavage of cell membrane phospholipids to generate two further second messengers, inositol 1,3,4-trisphosphate (IP3) and diacylglyceroi (DG) (Fig. 17.2). These hormones include luteinizing hormonereleasing hormone, thyrotrophin-releasing hormone and vasopressin. In general, these ligands interact with G-

FIG. 17.2 Mechanisms of hormone actions mediated by calcium transport or release H Hormones that promote calcium transport into the cell (1). (2) Receptor (activated) hormone (H) binds to receptor (R) opens up Ca2+ channel; Ca2+ binds to calmodulin, which binds to secretory granule. (3) Secretory granule fuses with cell surface and releases product. E Hormones that act via cleavage of phosphatidyl inositol biphosphate (PIP2). (1) Hormone binds to receptor. (2) Receptor (activated) cleaves PIP2 to diacylglyceroi (DG) and inositol trisphosphate (IP3). (3) IP3 causes Ca2+ release from cytosolic pool; Ca2+ binds to calmodulin. DG binds and activates protein kinase C (PKC). PKC and Ca2+/calmodulin activate protein kinase and then phosphorylate proteins (often in a synergistic manner).

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FIG. 17.3 Mechanism of action of insulin Binding to subunit(s) alters conformation of the -subunit and switches on its protein kinase activity.

protein coupled receptors but instead of adenylate cyclase, the receptors are coupled to phospholipase C, which catalyses the generation of the second signals IP3 and DG. IP3 is believed to act principally by stimulating calcium release from a cytosolic pool of calcium and an influx of extracellular calcium. A transient rise in intracellular calcium activates intracellular proteins, notably calmodulin, which has four binding sites for calcium. Activated calmodulin stimulates certain protein kinases which, using ATP as a substrate, will then phosphorylate other proteins, thus activating them. Analogues of DG (the phorbol esters) will stimulate prolonged cell growth and proliferation and promote tumour growth. Some hormones act through more than one of these mechanisms, particularly depending on their concentration. There is a wide variety of possible combinations of different effects involving these simple organic compounds and calcium. An appreciation of the general structure of the system is of increasing importance, not only in endocrinology, but also in our understanding of tumour growth and development.

Actions mediated by tyrosine kinase activity A typical member of the receptor kinase family of receptors comprises an extracellular ligand-binding domain, a single transmembrane spanning domain, and an intracellular domain with intrinsic kinase activity. The insulin receptor is a well-characterized receptor kinase; it consists of four subunits, two a and two . The -subunit acts as a tyrosine kinase, which is capable of phosphorylating and thereby activating a number of intracellular enzymes (Fig. 17.3). This is also the signalling pathway used by a number of growth factors, including insulin-like growth factor-1 (IGF-1). Once insulin activates receptor kinase, insulin receptor substrate 1 is phosphorylated and this binds to

1

886

MCQ 17.1

a family of proteins with SH2 (src homology 2) domains. These in turn activate a cascade of intracellular enzymes, resulting in stimulation of glycogen synthesis and the other effects of insulin. It seems likely that the action of insulin in promoting glucose uptake depends upon a similar effect of altering the phosphorylation state of the glucose transporter molecule. The receptors for growth hormone, prolactin, leptin and certain cytokines are similar to the receptor kinases but have no integral kinase activity. Instead, the receptor interacts with membrane or intracellular kinases, such as those of the Janus (JAK) family.

HORMONE ACTION THROUGH INTRACELLULAR RECEPTORS Receptors for steroid hormones (including vitamin D) and thyroid hormones are located principally in the nucleus. In the presence of its ligand, the receptor binds with high affinity to specific promoter sites on DNA. Specific regions of DNA are then 'read' by the enzyme RNA polymerase, with synthesis of messenger RNA and specific important proteins (Fig. 17.4). Some hormones are made from the conversion of less active precursors in target tissues. The clearest example of this is dihydrotestosterone, which is synthesized from testosterone (the circulating form) by the enzyme 5ocreductase. This transformation is essential for many of the actions of testosterone.

CIRCULATION AND METABOLISM OF HORMONES Most polypeptide hormones have a relatively short halflife (minutes) in the circulation before they are degraded by proteases in the liver, kidneys, lungs and elsewhere. As implied above, some of the hormone is also internalized in target tissues. Exceptions to the short half-life are the glycosylated peptides - TSH, LH, FSH and human chorionic gonadotrophin (hCG) - where a coating of sugar residues partially protects the protein from degradation without apparently affecting its binding to the receptor. In some instances, such as FSH, the hormone is secreted episodically, but this is difficult to demonstrate because of its long half-life (several hours). LH, on the other hand, has a much shorter half-life and so episodic secretion is easily detected, with 'pulses' occurring up to once every 90-120 minutes. The steroid and thyroid hormones are partially protected from degradation by the liver and from renal excretion by circulating binding proteins, the most important of which are corticosteroid-binding globulin (CBG), sexhormone-binding globulin (SHBG), vitamin D transport globulin (or transcalciferin), and thyroxine-binding globulin (TBG). These proteins are less specific than the receptors; indeed, no general rules can be made for the relation

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FIG. 17.4 Mechanism of action of steroid and thyroid hormones A Hormone (H) binds to nuclear receptor (R). B Activated receptor now binds to specific promoter on DNA, allowing access of RNA polymerase. C and D RNA transcript is processed by removal of introns and splicing. E Messenger RNA (mRNA) is translated in cytoplasm by ribosomes which synthesize proteins.

between the affinity of a compound for its binding protein and its biological activity, except to say that these proteins generally bind biologically active compounds. In addition, a substantial fraction of many of these hormones bind to albumin and, in some cases, to other proteins with low affinity. Because the concentration of albumin is high, albumin binding is in some cases (e.g. oestrogens) quantitatively important. Hormone-binding proteins serve a damping role, reducing the fluctuations produced by the episodic secretion of hormones and reducing their rate of degradation. The small fraction (0.1-5%) of total hormone in free solution (unbound) is believed to be the 'biologically active' fraction, i.e. the amount available to activate cellular receptors. In the case of steroid hormones, it is probably also the unbound plasma steroid that is monitored as part of the feedback control mechanism. In the case of the IGFs there is a whole family of binding proteins, whose control is complex but which clearly has a major influence on the local availability and action of the growth factors.

INTERACTIONS BETWEEN DIFFERENT HORMONES Two hormones acting together may transmit information differing both qualitatively and quantitatively from that conveyed by either separately. For example, glucocorticoids and adrenaline (epinephrine) interact at the levels of both production and action. Glucocorticoids induce the last enzyme necessary for adrenaline (epinephrine) synthesis; they also promote production of the -adrenergic receptor and so enhance some target hormone responses to -adrenergic agonists (Fig. 17.5). The two hormones together enhance fetal lung maturation at birth. This may have therapeutic importance in treating respiratory distress syndrome and, in later life, bronchial asthma, when analogues of glucocorticoids and adrenaline act synergistically. Many of the symptoms and signs of thyroid hormone excess result from an augmented sensitivity to adrenaline from enhanced responsiveness to -adrenergic effects. The

FIG. 17.5 Interactions between glucocorticoids and adrenaline (epinephrine) at levels of production and action

mechanism which enhances (3 (and probably diminishes a) agonist activity is not yet clear. Many of these effects (excess sweating, tachycardia and tremor) can be blocked acutely by administering a -adrenergic blocking agent while the thyroid hormone excess persists. A third example of hormone-hormone interaction is that between oestrogens and progestogens. One effect of oestradiol (and its synthetic counterparts) is to induce production of the progesterone receptor, without which progesterone has little if any effect. The presence of progesterone receptors in breast cancer is among the best available evidence that the tumour is oestrogen dependent and amenable to an anti-oestrogen, such as tamoxifen. 1

FURTHER READING ON THE PHYSIOLOGY OF HORMONE ACTION Bidey S P, Best L C, Ray D W, Davis J R E 1998 Hormone receptors and intracellular signalling. In: Grossman A, ed. Clinical endocrinology. Oxford, Blackwell Science, 57-80. Postel-Vinay M-C, Kelly P A 1996 Growth hormone receptor signalling. Bailliere's Clin Endocrinol Metab 10: 323-336. Spiegel A M 1996 Mutations in G proteins and G protein-coupled receptors in endocrine disease. J Clin Endocrinol Metab 81:2434-2422.

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White A, Gibson S 1998 ACTH precursors: biological significance and clinical relevance. Clin Endocrinol 48: 251-255.

CLASSIFICATION OF ENDOCRINE DISEASES

THE AETIOLOGY OF ENDOCRINE DISEASES

HYPER-, HYPO- AND DYSFUNCTION

TUMOURS

Although excess and deficiency diseases form the basis of endocrine practice, it is an oversimplification to think of endocrine disease simply in terms of 'too much or too little hormone'. It is true that with some systems, e.g. the thyroid gland, normal production of the hormone(s) is relatively steady and the concept of pure excess or deficiency approximates to the truth. However, in other systems, e.g. the adult female reproductive system, there is an inbuilt and complex rhythm. Each of the major components of this system (hypothalamus, pituitary and ovary) secretes hormones and responds to those produced by other components. The interactions depend on both the circulating levels of hormone (often more than one) and the very important dimension of time. Here, the capacity for responses to become out of phase with one another is considerable, and many of the syndromes that we see with this system have features which suggest dysfunction rather than simple hyper- or hypofunction. As one abnormality may lead to another, with endocrine dysfunction we are, in some instances, still unable to dissect out the primary abnormality. Our only hope of doing so is to use the model of the normal system as a starting point.

Neoplasms of endocrine tissue are extremely common; they are usually benign and may secrete one or more hormones, or be apparently functionless. Such tumours cause problems for one of three reasons:

PRIMARY VS SECONDARY ABNORMALITIES It is essential to identify whether an abnormality of hormone production is primary or secondary. Adrenal or thyroid insufficiency, for example, may be due either to intrinsic disease of these glands, or to a failure of secretion of the trophic hormone (ACTH and TSH, respectively) by the pituitary. Pituitary deficiency in turn may also be intrinsic, or due to damage to the hypothalamus. The distinction may be important from the point of view of treatment and in predicting and treating accompanying features, including other hormone deficiencies.

TARGET ORGAN DISEASE

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quite common. Only recently have methods become available for examining such defects.

There are many instances of 'target organ' endocrine diseases. These generally involve receptor proteins with a binding site for the hormone, linked to an effector system. Although major disorders due to problems at this level are rare they are well documented and minor problems are

• They may present as a local space-occupying lesion. This is particularly true of tumours of the pituitary gland, because there is very little room for expansion without producing pressure effects on important surrounding structures. • By secreting a hormone, or hormones, they may produce the syndrome associated with excess of that hormone or of the gland that it controls. • They may destroy or compress the normal gland and lead to underproduction of other hormones (again, this applies almost exclusively to the pituitary gland). Malignant tumours of endocrine tissue share many of the properties common to other cancers. With some (such as the pituitary), distant metastases are rare. With endocrine tumours, hormone production may continue or be abnormal; for example, carcinomas of the adrenal cortex may secrete the normal product cortisol, or precursor steroids, or no steroids at all. The control mechanisms of hormone secretion for malignant tumours are generally more disturbed than are those of benign tumours. Occasionally, the properties of the normal gland can be used to treat the tumour; thus, for example, the uptake of radioactive iodine by the tumour can be used very effectively to treat metastases in papillary and follicular carcinomas of the thyroid gland. In some familial syndromes, in which tumours occur in more than one endocrine gland (so-called multiple endocrine neoplasia, MEN), an underlying fundamental defect in cell regulation is suspected (p. 938).

PRIMARY, SECONDARY AND TERTIARY HYPERFUNCTION Primary, secondary and tertiary hyperfunction can be readily appreciated in the case of the parathyroid glands (Fig. 17.6). Primary hyperparathyroidism exists when excess secretion of parathyroid hormone, not apparently secondary to any other process, leads to hypercalcaemia and other metabolic changes. It may be due to parathyroid adenoma or to 'primary hyperplasia'.

commonest inborn error of adrenal cortex function is 21hydroxylase deficiency (Fig. 17.32, p. 933), which is inherited as an autosomal recessive condition. In its extreme (salt-losing) form it is associated with blocks in the conversion of progesterone to aldosterone, and 17-hydroxyprogesterone to cortisol, leading to mineralocorticoid and glucocorticoid deficiency. Clinical disease results in part from deficiencies of these two hormones, and in part from the build-up of precursors and their androgenic by-products. Finally, excess ACTH secretion (in response to cortisol deficiency) and excess renin and angiotensin secretion (in response to aldosterone deficiency) also result. These tend to restore a new steady state, but at the expense of marked adrenal hyperplasia and even greater secretion of androgenic by-products. Recently, increasing numbers of 'target organ' endocrine diseases have been characterized, e.g. the androgen receptor defect (which causes testicular feminization) and 5a-reductase deficiency (which causes a particular form of male pseudohermaphroditism, see p. 949).

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FIG. 17.6 Primary, secondary and tertiary hyperparathyroidism.

AUTOIMMUNE ENDOCRINE DISEASE Secondary hyperparathyroidism is a physiological adaptation to hypocalcaemia. For example, in vitamin D deficiency, calcium malabsorption leads to hypocalcaemia and secondarily increased parathyroid hormone (PTH) secretion. This exerts effects on kidneys and bone which restore the plasma calcium level to normal while increasing phosphate excretion. In chronic renal failure other factors make this process less efficient (p. 1053), and so the parathyroid hyperplasia and PTH excess tends to be more prolonged and more extreme. If this secondary hyperparathyroidism leads to the development of an autonomous parathyroid tumour or tumours, tertiary hyperparathyroidism is said to have developed. After renal transplantation temporary hypercalcaemia is quite common. Although often referred to as tertiary hyperparathyroidism, it is usually due to the increased bulk of hyperplastic parathyroid tissue which has developed during prolonged renal failure, rather than to true autonomous tumour development.

ABNORMALITIES OF HORMONE BIOSYNTHESIS AND ACTION As the pathways of production and action of the major hormones have been defined, so defects in these pathways leading to specific clinical syndromes have been discovered. Often, logical and effective treatment of the condition has resulted. The defects may be inborn, due to single point mutations, or produced by pharmacologists developing new drugs. Most inborn errors occur in the peripheral rather than the central (hypothalamus and pituitary) endocrine glands. A single example illustrates some general principles. The

Autoimmunity is a frequent cause of destruction and malfunction of parts of the endocrine system. It is evident that both antibody-mediated and cell-mediated immunity may be involved, but the former is better understood. A wide range of antibodies may be involved, which can be directed at cell surface components, or at microsomes, mitochondria and other intracellular organelles. In many cases it is not clear which, if any, of the antibodies cause tissue damage and which are produced in response to cell destruction. The immune disturbance leads to: • Destruction of the gland, e.g. in autoimmune Addison's disease (where adrenal antibodies are generally present in plasma) or in primary myxoedema; • Lymphocytic infiltration of the gland, as in Hashimoto's thyroiditis (where a high titre of thyroid peroxidase (TPO) and thyroglobulin (TG) antibodies is invariably present); • Uncontrolled stimulation of the gland. In thyrotoxic Graves' disease antibodies are produced that mimic TSH sufficiently closely to bind to, and activate, the TSH receptor; • Blocking of the stimulatory hormone, e.g. some cases of autoimmune hypothyroidism. Different individuals vary greatly in their inherited tendency to develop autoimmune endocrine disease. The full basis for individual susceptibility is not known, but one factor is the histocompatibility complex HLA. Certain HLA alleles, for example HLA-DR3, confer susceptibility. Gender appears to be important, as these disorders are 3-10 times more common in women. Other genetic and environmental factors remain poorly defined. The term organ-specific autoimmune disease encompasses both endocrine and non-endocrine diseases, and

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includes autoimmune Addison's disease, Graves' disease, Hashimoto's disease, autoimmune hypothyroidism, myasthenia gravis, hypoparathyroidism, true autoimmune diabetes mellitus, pernicious anaemia, autoimmune ovarian failure and vitiligo (autoimmune skin depigmentation). As a general rule, individuals with one such disease are more likely than normal individuals to develop another.

FURTHER READING ON THE AETIOLOGY OF ENDOCRINE DISORDERS Weetman A P 1998 Endocrine autoimmunity and related conditions. Kluwer Academic Publishers, Dordrecht, 292pp

SYSTEMIC EFFECTS OF ENDOCRINE DISORDERS CENTRAL NERVOUS SYSTEM Local expansion of pituitary tumours commonly causes headache (due probably to tension on the diaphragma sellae) and damage to adjacent structures. 1 The optic nerves are particularly vulnerable to pressure, especially at the optic chiasm, and bitemporal hemianopia may result. Rarely, pituitary or suprapituitary tumours may cause hydrocephalus or damage in the region of the fourth ventricle, resulting in a syndrome of recent memory loss similar to Korsakoff s psychosis (p. 1439). Both hyper- and hypocalcaemia may precipitate any psychosis to which that individual is predisposed, or cause neuropsychiatric symptoms de novo. Hypocalcaemia may be associated with raised intracranial pressure, epileptic fits and, of course, tetany. Hyperfunction of both the adrenal cortex and the adrenal medulla may present with psychiatric manifestations. In Cushing's syndrome, the individual may present with depression or with a psychotic episode. Excess cortisol secretion may occur in severe depression per se, so it can be very difficult to establish whether or not the patient has Cushing's syndrome. Many of the symptoms and signs of emotional or physical stress result from the release of hormones, notably adrenaline, from the adrenal medulla. Tumours of the adrenal medulla (phaeochromocytomas) usually secrete noradrenaline (nonepinephrine), thus causing hypertension, but sweating and anxiety attacks are often an accompanying feature. Thyroid disease may also be accompanied by a variety of neuropsychiatric features. Thyrotoxicosis may present as anxiety, depression or behavioural disturbance, although

1 Figs17.1-17.5

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warm sweaty hands and a rapid pulse usually distinguish the condition from a simple anxiety state. Occasionally the patient appears unduly apathetic. Proximal muscle weakness is another common feature of thyrotoxicosis. Accompanying exophthalmos due to extraocular muscle infiltration may cause diplopia. Hypothyroidism may also present with depression. Its other neurological manifestations include carpal tunnel syndrome, myotonia and cerebellar dysfunction. Coma may be the presenting sign of a number of endocrine disorders. These (and other) manifestations of hyper- and hypoglycaemia are considered in Chapter 19. In profound hypothyroidism coma is likely to be caused by conditions that affect respiratory drive or by hypothermia. In severe hypopituitarism stupor leading to coma commonly follows a relatively minor disturbance (such as a trivial accident or infection). It is due in part to profound cortisol deficiency, in part to hypothyroidism, and is usually associated with hyponatraemia due to excess secretion of antidiuretic hormone (ADH) as a consequence of cortisol deficiency. In diabetes insipidus (DI) hypernatraemia may occur rapidly and produce convulsions or irreversible brain damage if access to water is restricted (e.g. postoperatively). Conversely, in the treated patient with DI, unlimited drinking may lead to cerebral dysfunction and fits from hyponatraemia (water intoxication).

CARDIOVASCULAR SYSTEM Hypotension, especially in the upright posture, commonly results from either glucocorticoid or mineralocorticoid deficiency, whereas hypertension, usually of mild degree, may result from mineralocorticoid excess. Phaeochromocytoma also causes hypertension, which can be episodic or sustained. Endocrine diseases leading to electrolyte disturbances such as hyper- or hypocalcaemia or hypokalaemia may present with dysrhythmias and/or characteristic ECG abnormalities. Prolonged hypercalcaemia and prolonged glucocorticoid excess are associated with an increased incidence of arterial calcification. Patients with primary hypothyroidism and angina are particularly vulnerable to worsening of their symptoms and even myocardial infarction when treated with thyroxine. In the elderly, thyrotoxicosis commonly leads to atrial fibrillation. Acromegaly is associated with cardiac enlargement, hypertension and a form of cardiomyopathy.

SKELETAL SYSTEM Skeletal manifestations of endocrine disease are commonly caused by osteoporosis, as in Cushing's syndrome, sex hormone deficiency or prolonged hyperthyroidism. Primary hyperparathyroidism may lead to calcification of articular cartilage, and present with calcium pyrophos-

phate crystal arthropathy (pseudogout, see p. 1171). The classic bone disease described by von Recklinghausen, osteitis fibrosa cystica, with giant cell tumours of bone due to primary hyperparathyroidism, is now very rare. Occasionally, Graves' disease is associated with finger clubbing and periosteal new bone growth (so-called thyroid acropachy). In acromegaly, periarticular overgrowth of new bone and increased cartilage quite commonly lead to osteoarthritis. In severe acromegaly and gigantism, skeletal abnormalities may be gross.

GENITOURINARY AND

REPRODUCTIVE SYSTEMS Conditions that affect sex hormone secretion in utero produce malformation of the external and internal genitalia (p. 939). Renal function may be disturbed by a number of metabolic disorders, some of which are endocrine in origin. For example, both hypercalcaemia and hypokalaemia may present with a form of (nephrogenic) diabetes insipidus and polyuria due to a water diuresis.

INTEGUMENTARY SYSTEM

Hirsutism and acne are common manifestations of androgen excess in the female. Mild hirsutism, skin atrophy, bruising and poor wound healing are features of Cushing's syndrome. Hyperpigmentation is common in Addison's disease. Vitiligo and mucocutaneous candidiasis occur in some autoimmune endocrine diseases. Of other endocrine disorders presenting with skin manifestations, the glucagonoma syndrome, which causes migratory necrolytic erythema, is probably the most striking (p. 833).

limitations of the assay method, including interference by drugs. The minimum number of tests should be made to answer a particular question. Old tests are rapidly being superseded by new and better methods.

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BASAL MEASUREMENTS Much can be learnt by basal measurements of so-called routine biochemistry (Table 17.2). Where endocrine disease involves hormones that control the electrolytes, these measurements are the mainstay. Thus, a parathyroid tumour is most unlikely unless the serum calcium level is raised, and a low serum phosphate further suggests the diagnosis. Aldosterone deficiency in Addison's disease is suggested by the finding of a high serum potassium level, usually associated with a low sodium and elevated urea owing to extracellular fluid depletion. In assessing posterior pituitary function, the most widely used test (fluid deprivation) depends upon assessing the renal response, mediated by ADH, to deliberate but controlled withholding of fluids. In most cases, and certainly to exclude diabetes insipidus, a simple study of the relationships of fluid loss to serum and urine osmolality suffices, without the need for difficult assays of ADH. Basal measurements of hormone levels or metabolites are most practical when they can be conducted on serum or urine samples collected at random. Nowadays, the widespread development and application of radioimmuno- and immunoradiometric assays have helped enormously, especially for hormones that are relatively stable in body fluids. This applies to the steroid hormones, thyroid hormones and most of the pituitary hormones. In most cases, serum is preferred to plasma; clotted blood can be left for 1-2 hours before centrifugation, and serum stored indefinitely

ALIMENTARY SYSTEM Thyrotoxicosis commonly causes diarrhoea and sometimes malabsorption. Hypothyroidism causes constipation. Conditions such as Addison's disease, hypopituitarism and diabetic ketoacidosis may present as apparent upper abdominal emergencies with epigastric pain and rigidity. Hypercalcaemia commonly causes vomiting, constipation and abdominal pain.

TABLE 17.2 'Routine' biochemical pointers in blood plasma to endocrine disorders Pointers

Condition

Hyperkaiaemia, hyponatraemia Hypokalaemia, metabolic alkalosis (high serum bicarbonate)

Addison's disease Conn's syndrome Cushing's syndrome (severe) Inappropriate ADH secretion Hypopituitarism Severe hypothyroidism Diabetes insipidus Diabetic ketoacidosis

Hyponatraemia, hypochloraemia

ENDOCRINE FUNCTION TESTING Endocrine function tests are used to establish or to refine the diagnosis, to monitor the response to treatment, to assess the prognosis, and to establish the pathogenesis of the condition, often in combination with endocrine gland imaging. Clearly, it is important to understand both the underlying physiology on which the test is based and the

Hypernatraemia, hyperchloraemia Hyperglycaemia, hyperchloraemia, metabolic acidosis (low serum bicarbonate) Hyperglycaemia, uraemia, hypernatraemia, hyperchloraemia Hypercalcaemia, hypophosphataemia, hyperchloraemia Hypocalcaemia, hyperphosphataemia

Diabetic hyperosmolar coma Primary hyperparathyroidism Hypoparathyroidism

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at -20°C. Economic and methodological considerations dictate that samples are assayed batchwise, so that the result is often not available at once. It may therefore be necessary to start treatment while the result is awaited. Urine sometimes has the advantage of reflecting integrated secretion and the 'free' (unbound) level (e.g. with cortisol). However, the major steroids in urine are metabolites several steps away from the biologically active compound.

FURTHER READING ON ENDOCRINE FUNCTION TESTING Jenkins R C, Ross R J M 1998 Protocols for common endocrine tests. In: Grossman A, ed. Clinical Endocrinology. Blackwell Science, Oxford, 1117-1134.

THE PITUITARY GLAND DYNAMIC FUNCTION TESTS The static nature of information obtained by basal measurements has led to the development of a whole range of dynamic function tests, where the system under study is deliberately driven, usually by interrupting negative feedback or by stimulation at one or more levels (Fig. 17.7). In testing anterior pituitary function there is a bewildering array of possible tests, not all of which are useful. For example, stimulation tests for ACTH (and so cortisol) with insulin hypoglycaemia, glucagon, vasopressin and CRH have all been devised, in addition to direct adrenal stimulation with synthetic ACTH (synacthen). With TSH and the thyroid hormones, marked episodic and diurnal variation - a problem inherent in assessing the ACTH-cortisol axis - is missing and, especially with new sensitive TSH assays, dynamic testing with TRH is not needed. Sometimes two or more tests can be carried out simultaneously, e.g. insulin, TRH and GnRH can all be given together to assess the extent of hypopituitarism. An example of a test used to monitor or predict response to treatment is the measurement of serum prolactin or growth hormone levels after a single dose of bromocriptine in patients with prolactinoma or acromegaly, respectively. In complex endocrine systems such as the ovulatory cycle, repeated samples over the cycle of more than one hormone may be necessary, and may be much more useful than contrived 'dynamic function' tests.

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FIG. 17.7 Principles of dynamic endocrine function testing Hypothalamic hormone A stimulates pituitary to produce pituitary hormone B, which then stimulates peripheral gland to produce C. Hormone C (or a synthetic analogue) inhibits production of A and/or B by negative feedback.

The pituitary gland is composed of two functionally separate lobes, the anterior and the posterior (pars nervosa), with an intermediate lobe which in humans is vestigial. The gland is derived from a downgrowth from the floor of the third ventricle and from Rathke's pouch, which is formed by invagination of part of the roof of the primitive nasopharynx. The pituitary gland is almost entirely enclosed in a bony box, the sella turcica; this has a floor and an anterior and posterior wall, the lateral extremities of which become the anterior and posterior clinoid processes. Immediately lateral to the pituitary gland are the two cavernous sinuses, with the third, fourth, fifth and sixth cranial nerves sandwiched between: the carotid syphon courses through the cavernous sinus (Fig. 17.8). Overlying the pituitary is a fibrous sheet, the diaphragma sellae, which is pierced by the pituitary stalk; this slender structure carries the nerve fibres to the posterior pituitary gland and the blood supply to both lobes, including the portal blood vessels draining from the median eminence of the hypothalamus.

FIG. 17.8 Gross anatomy and relations of the pituitary gland A View of pituitary gland, anterior clinoids, dorsum sellae and optic chiasm from above. B Schematic coronal cross-section through pituitary gland to show relation to important structures nearby.

17

TABLE 17.3 Terminology of hypothalamic and anterior pituitary hormones Hypothalamic hormone

Effect (stimulation or inhibition)

Gonadotrophin releasing hormone (GnRH) LH-releasing hormone/factor, LH-FSH releasing hormone (LHRH) Corticotrophin-releasing hormone (CRH) Arginine vasopressin (or antidiuretic hormone; ADH) Somatostatin (growth hormone/somatotrophin releaseinhibiting hormone) Growth hormone-releasing hormone (GHRH) Thyrotrophin-releasing hormone (TRH) Dopamine

The main hypothalamic and pituitary hormones are shown in Table 17.3.

+ +

SYNTHESIS AND SECRETION OF THE MAIN HORMONES

Luteinizing hormone (LH) Follicle-stimulating hormone (FSH) Adrenocorticotrophic hormone (ACTH, corticotrophin)

+

Growth hormone (GH, somatotrophin) + +

Thyroid-stimulating hormone (TSH, thyrotrophin) Prolactin

TABLE 17.4 Factors directly affecting anterior pituitary hormone synthesis and release Pituitary hormone

THE ANTERIOR PITUITARY GLAND

Pituitary hormone

ACTH

Stimuli

Inhibitors

CRH

Cortisol

Vasopressin (ADH) lnterleukin-1 (IL-1)* GH

GHRH

Somatostatin Insulin-like growth factor 1(IGF-1) Cortisol

TSH

TRH

T 3 ,T 4 Somatostatin

LH

GnRH Oestradiol (+ve feedback)

Oestradiol Progesterone Testosterone (male)

FSH

GnRH

Inhibin Oestradiol Progesterone Testosterone (male)

Prolactin

TRH Oestradiol**

Dopamine

Much is now known about how the synthesis and secretion of anterior pituitary hormones is controlled, and this is summarized in Table 17.4.

Adrenocorticotrophic hormone ACTH is synthesized in specific cells (the corticotrophs) from a large precursor molecule called proopiomelanocortin (POMC, Fig. 17.9). It is produced in both the anterior and the intermediate lobe of the pituitary, but the final processing differs in the two. Of the other ACTH-related peptides, B-lipotrophin (LPH), B-endorphin and a-melanocyte-stimulating hormone (MSH) are important. LPH and B-endorphin are synthesized and secreted with ACTH; the latter may have a role as an opiate in modifying the response to pain at times of stress. The synthesis and release of ACTH is controlled by corticotrophin-releasing hormone (CRH), which acts synergistically with vasopressin. There are at least two basic rhythms of ACTH secretion: episodes of secretion every 1-3 hours and at meal times are superimposed on a 24-hour rhythm, with lowest levels during the earliest hours of sleep and peak secretion just before wakening (Fig. 17.10). At any time, exposure to sudden physical or mental stress will overcome this rhythm and lead to a pulse of ACTH secretion. The adrenal cortex responds in turn with a pulse of cortisol secretion within minutes, so that the 24-hour plasma profile of cortisol is a somewhat dampened version of the 24-hour ACTH profile.

* Effect probably via CRH. **Increases prolactin synthesis, produces lactotroph hyperplasia but inhibits milk secretion.

The most important role of ACTH is to control the synthesis and secretion of the glucocorticoid cortisol. As would be expected from its relationship to MSH (see Fig. 17.9), ACTH possesses MSH activity and will directly stimulate the melanocytes of the skin and buccal mucosa when secreted in excessive amounts. This accounts for the increase in pigmentation to above normal (for that indi-

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FIG. 17.9 Relationship between pro-opiomelanocortin (POMC) and the various intermediates and end-products of its processing in the pituitary gland LPH = lipotrophin; NT = NH2 terminal peptide; MSH = melanocyte-stimulating hormone; CLIP = corticotrophin-like intermediate lobe peptide. FIG. 17.11 Control of growth hormone and IGF-1 secretion

FIG. 17.10 Plasma cortisol levels through the 24-hour cycle to show circadian variation, pulsatile secretion and influence of meals and stress

vidual) seen in Addison's disease (p. 930) and Nelson's syndrome (pp. 906 and 936). 1

relatively recently in evolution; their genes are located on chromosome 17. PRL is much less closely related and is encoded on chromosome 6. GH is synthesized in specific cells known as somatotrophs, where it is stored in granules and released episodically in response to peaks of hypothalamic secretion of GHRH (Fig. 17.11). The precise physiological interactions of GHRH with somatostatin, which inhibits its release, are complex. Much of the GH is secreted at night and episodically. Its secretion is inhibited by a rise in blood glucose (the basis of a useful suppression test) and stimulated by hypoglycaemic stress and by amino acids such as arginine (the basis of stimulation tests). GH controls the secretion of insulin-like growth factor-1 (IGF-1, somatomedin C), which functions as a hormone controlling the growth of cartilage and soft tissues. During puberty, the secretion of sex hormones appears to increase the pituitary secretion of GH, which is probably important in promoting growth before the sex hormones lead to closure of the epiphyses. GH also acts directly on tissues to control local production of IGF-1. The effects of IGF-1 are modulated by specific binding proteins, which are also under hormonal control.

Prolactin Growth hormone Growth hormone (GH), human placental lactogen (HPL) and prolactin (PRL) belong to a family of polypeptide hormones. GH and HPL both contain 191 amino acids, and PRL 199. GH and HPL are closely homologous (with 85% identical residues) and probably arose by gene duplication

1MCQ17.2

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PRL is produced in the lactotrophs, under stimulation by TRH and, more importantly, under tonic inhibition by dopamine. PRL has a basically nocturnal pattern of secretion and is also released in response to stress. Oestrogens probably act directly on the lactotrophs, increasing their number and activity. In pregnancy, PRL levels are high and so lead to hypertrophy of the breast epithelium (Table 17.5). However, high oestrogen and progesterone levels inhibit milk production until after delivery of the baby. During lactation, suckling stimulates the secretion of PRL via a reflex arc. High PRL levels have a contraceptive effect, probably by inhibiting cyclical gonadotrophin release.

TABLE 17.5 Action of hormones on the human breast Hormone Polypeptide hormones Prolactin Oxytocin Human placental lactogen Growth hormone Insulin Steroid hormones Oestrogens Progestogens Cortisol Androgens

Action

Milk protein synthesis and excretion in ducts and lobules Milk ejection. Contraction of myoepithelial cells Similar to prolactin Permissive' effects 'Permissive' effects

Increase duct and breast fat growth Inhibit prolactin-induced milk secretion Inhibit lactation (effect requires oestrogen) 'Permissive' effects Inhibitory effects on ?stroma

Luteinizing hormone and follicle-stimulating hormone LH and FSH are controlled by the same releasing hormone and are produced in the same cell type (the gonadotroph). They resemble TSH and hCG in being two-subunit polypeptides, and in possessing a sugar 'coat'. The ocsubunits of these peptides are identical, but the B-subunits differ greatly and confer the specificity. The ratio and absolute amount of LH and FSH secreted in response to a single pulse of GnRH vary greatly under different circumstances, being modified by age, sex hormone secretion by the gonads, and the preceding pattern of discharge of GnRH. Low-frequency discharge seems to favour FSH synthesis and release. In females, a rise in oestrogen level differentially reduces FSH and eventually promotes LH release ('positive feedback', see Fig. 17.37A). The gonads also produce a polypeptide hormone (inhibin) which feeds back to the pituitary to switch off FSH synthesis and secretion selectively.

Thyroid-stimulating hormone TSH promotes the synthesis and secretion of thyroid hormones, and the growth of the thyroid gland. The principal hypothalamic control is from thyrotrophin-releasing hormone (TRH), whose secretion, as with GnRH, is apparently pulsatile. The thyroid hormones feed back on both the hypothalamus, to regulate the synthesis of TRH, and the pituitary gland, inhibiting TSH release.

ANTERIOR PITUITARY HYPOFUNCTION Anterior pituitary hypofunction may develop rapidly or insidiously, and may affect all the pituitary hormones, a few, or only one. In progressive lesions LH and FSH are usually

lost first, followed by GH,TSH and, lastly, ACTH. We consider here those causes associated with partial or complete loss of all the anterior pituitary hormones, causing a state of so-called (anterior) panhypopituitarism. This will in some cases be associated with diabetes insipidus, where ADH secretion from the posterior pituitary is also impaired.

17

Aetiology The causes of panhypopituitarism are listed in Table 17.6. The commonest vascular cause is Sheehan's syndrome, in which hypopituitarism occurs following a pregnancy complicated by a period of shock and hypotension, commonly due to postpartum haemorrhage. The pituitary normally enlarges during pregnancy under the action of oestrogens on the lactotrophs, but the blood supply does not; it is therefore particularly vulnerable to a fall in blood pressure. There are usually no symptoms (such as headache) directly related to the infarction, but lactation does not occur and the symptoms of hypopituitarism soon follow. Menstrual periods do not return. Rarely, prolonged shock in other situations may precede the development of panhypopituitarism. Tumours, both within the pituitary (functioning or nonfunctioning adenomas) and suprasellar (e.g. the craniopharyngioma, which develops from Rathke's pouch), are the most common causes of panhypopituitarism. The clinical features include pressure effects on surrounding structures, including the optic chiasm and the hypothalamus. In the case of intrasellar tumours, panhypopituitarism is usually a late development, as some normal pituitary tissue remains. If the tumour is functional there may be additional features other than those from pressure on the remaining normal pituitary. A large prolactinoma, for example, may cause hypopituitarism and hyperprolactinaemia. Suprasellar tumours are more likely to affect the pituitary stalk, and thereby the posterior pituitary gland. If a large pituitary tumour becomes infarcted it will cause the syndrome of 'pituitary apoplexy' (severe headache, neck stiffness, vomiting), which may be followed by hypopituitarism if the normal tissue is compromised (see figs 17.14 and 17.15). Granulomatous conditions that may occasionally be responsible include eosinophilic granuloma (histiocytosis X, p. 1257) and sarcoidosis. Carotid aneurysms may occasionally damage the pituitary. Panhypopituitarism may develop long after pituitary irradiation (e.g. for a growthhormone-secreting tumour). This is usually a consequence of hypothalamic damage, and commonly affects growth hormone and gonadotrophin secretion before other hormones. In many cases of panhypopituitarism the aetiology is obscure; some may be autoimmune. In some cases there is an empty sella turcica and a defective diaphragma. It is still undecided whether the so-called 'empty sella syndrome' is a primary cause of hypopituitarism. Most subjects with an

895

TABLE 17.6 Causes of panhypopituitarism Cause

Mechanism

Associated features

Developmental abnormalities

Failure of hypothalamic or pituitary development Perinatal asphyxia

Severe cranial abnormalities Midline facial abnormalities GH deficiency predominant

Infection Encephalitis Bacterial meningitis

Hypothalamus or stalk damage, or pituitary destruction

History of encephalitis or bacterial meningitis

Granulomata Eosinophilic granuloma Sarcoidosis

Infiltration of pituitary/hypothalamus

Histiocytosis X (see p. 1257) Sarcoidosis (p. 682).

Hypotension, especially when the pituitary is enlarged, e.g. by pregnancy or tumour

Sheehan's syndrome from antepartum or postpartum haemorrhage Hypotension (surgical or traumatic) Pituitary enlargement/tumour Cranial nerve lesions Apoplexy simulates subarachnoid haemorrhage Ballooning of pituitary fossa

Vascular Infarction Haemorrhage

Pituitary apoplexy Subarachnoid haemorrhage

Aneurysms

Pressure

Tumour Suprapituitary (craniopharyngioma)

Pressure on stalk

Pituitary

Pressure or invasion of normal gland

Empty sella

Mechanism uncertain

Ballooning of pituitary fossa

Autoimmune

Antibodies or T-cell-mediated damage to pituicytes

Other organ-specific autoimmune disease

Trauma

Severe head injury causing stalk damage

Brain and cranial nerve damage

apparently empty sella have normal pituitary function and are detected by chance on CT scanning.

Local pressure effects of pituitary and suprasellar tumours The principal pressure symptoms are headache, which may be severe and persistent, and visual field disturbances. Bitemporal hemianopia is characteristic but may be preceded by loss of the upper outer quadrant (if the tumour is below the chiasm). The patient may notice loss of the lateral part of the visual fields; the defect will not at first be detectable by confrontation, but can be shown by formal perimetry with a Bjerrum's screen, and may be most obvious if a red object is used. Fundoscopy may reveal bi- or unilateral optic atrophy. Other field defects are also

1

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Figs 17.1-17.5

2MCQ17.3

Pressure on optic chiasm or brainstem Suprasellar calcification (craniopharyngioma) Large pituitary fossa Hormone excess if tumour functional

SUMMARY 1 Clinical features of hormone-producing pituitary tumours • Local symptoms are headache and visual disturbance; large tumours of any type may cause hypopituitarism. • In acromegaly the tumour is usually large, but is often small in Cushing's disease. • Incipient visual loss merits an immediate trial of bromocriptine if the prolactin is very high. • Macroprolactinomas occur equally in men and women. Microprolactinomas are generally detected in women.

quite common. More rarely, other cranial nerves (III, IV, V and VI) are involved. With extensive lesions a syndrome reminiscent of Korsakoffs syndrome with recent memory loss may occur if there is pressure on the floor of the third ventricle. Disturbances of appetite (causing hyperphagia) and thirst may also be seen. The latter causes particular problems if diabetes insipidus is also present, as the patient does not

SUMMARY 2 Summary of the Royal College of Physicians of London Working Party guidelines: recommendations for service provision and management of pituitary tumours

standard rates of growth. Panhypopituitarism in childhood is also associated with failure of pubertal development. Other common features of hypopituitarism in childhood include a tendency to hypoglycaemia and other general features discussed below.

Recommendations for service provision

Adult life

• All patients with pituitary tumours require evaluation and followup at a specialist centre. • Management plans should be agreed jointly between endocrinologist, neurosurgeon and radiotherapist. • A diagnostic register should be held in the specialist centre. • Patients should receive detailed education and be informed about self-help groups. • MRI scanning is preferable to CT.

In panhypopituitarism developing in adult life, patients usually feel unwell in a non-specific way. They appear pale without being anaemic, and the skin has a 'wax doll' appearance. They notice the cold, although features of hypothyroidism are often not as gross or obvious as in myxoedema. Women have amenorrhoea and men lose their sex drive and potency. Loss of secondary sexual hair and a decline in other secondary sexual characteristics is a feature in both sexes. The patients may present with a 'hypopituitary crisis' when challenged by trivial stress, which would normally be met by increased secretion of ACTH and cortisol. Acute abdominal pain may mimic an acute abdominal emergency. This syndrome responds rapidly to cortisol administration. Patients commonly develop hypoglycaemia, but because of an associated lack of adrenaline secretion (see Fig. 17.5, p. 887), they do not develop symptoms of 'classic' hypoglycaemia, i.e. a sympathetic response to the low blood sugar. They may therefore present with coma due to hypoglycaemia. Coma may also be due to hyponatraemia, as there is commonly an excess of ADH secretion (cortisol inhibits this secretion and the renal response to ADH). Manifestations of growth hormone deficiency include pallor, thin skin and hypoglycaemia. Those of ACTH (and thus cortisol) deficiency include malaise, somnolence, hyponatraemia, poor response to stress, hypoglycaemia, confusion, coma, hypotension and fever. Effects of sex hormone deficiency include delayed puberty, sexual infantilism, amenorrhoea and lack of breast development. Men show an abnormal 'puppy fat' distribution of body fat and lack of muscular development. Loss of secondary sexual hair is much more marked in panhypopituitarism than in conditions where there is only a lack of gonadal sex hormones. As with other causes of androgen deficiency in men, the patient's partner may complain more than he does. Loss of sex drive is also common in hypopituitary women. Features due to TSH deficiency include cold intolerance and dry skin, although hypothyroidism may be masked by other deficiencies. Diabetes insipidus is discussed on page 911; its effects are often less marked when cortisol is also deficient, as the latter is necessary for a water diuresis in ADH deficiency. PRL deficiency leads to failure of milk production, which is important only to the woman who is breastfeeding. ©

Objectives of treatment for all types of pituitary tumour: • • • •

Restoration of wellbeing Relief of pressure symptoms Treatment of any syndrome of hormone excess Recognition of or substitution for specific hormone system defects • Prevention of tumour regrowth • Reversal of increased long-term mortality. Comment The evaluation and management of diverse abnormalities of anterior pituitary function are not standardized. Alternative strategies are discussed in detail in this document for each disorder. Reference Clayton RN, Wass JAH 1997 Pituitary tumours. Recommendations for service provision and guidelines for management of patients. Royal College of Physicians, London.

drink enough to prevent hyperosmolarity. The occurrence of pressure effects depends mainly on the size of the tumour: for example, GH-secreting pituitary tumours (in acromegaly) are generally much larger than ACTHsecreting tumours (in Cushing's disease). Non-functioning tumours and prolactinomas are the two other intrasellar lesions that commonly cause pressure symptoms. Although pituitary tumours may be locally invasive, malignancy is very rare. 1

Clinical features of anterior pituitary hypofunction The clinical features of anterior pituitary hypofunction depend in part upon the age of onset.

Childhood If the onset of panhypopituitarism is before growth is completed, the patient will have the features of hypopituitary dwarfism, i.e. normal body proportions but failure to grow. The latter is detected and documented by careful measurements of height, using a stadiometer, recorded on standard growth charts (Fig. 17.12). From serial measurements, growth velocity (cm/year) can be calculated and related to

17

Investigation of suspected pituitary hypofunction If hypopituitarism is suspected in an ill patient, a clotted blood sample is taken for hormone analysis and glucocorticoid treatment commenced at once, most conveniently by

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FIG. 17.12 Hypopituitarism in childhood A Child aged 5 1 years (before GH therapy) and B aged 6 1 years, after 9 months' GH therapy, when he had grown 11 cm. C Height measurements of the boy illustrated in A and B before (black line) and during (blue line) GH treatment. Normal values for each centile are also shown (courtesy of Professor S M Shalet). [D] Height measurements in a boy with delayed puberty treated with androgens. Normal values for each centile are also shown (courtesy of Professor S M Shalet).

giving l00mg hydrocortisone intravenously, followed by 50 mg 6 hours later and then a normal regular replacement dose. If the patient does not have pituitary or adrenal insufficiency such treatment is unlikely to be harmful, and if they do it may be life-saving. There is a risk of precipating an adrenal crisis by starting thyroid replacement first (as this increases the metabolic clearance of cortisol). Much of value can be learnt from basal measurements of serum urea and electrolytes, LH and FSH, testosterone (in men), progesterone and oestradiol (in women), cortisol, thyroxine (T4), GH and PRL. These measurements help considerably to establish the diagnosis and possibly its cause. Dynamic hormone tests are often used as the 'gold standard' for assessing pituitary function (Fig. 17.13), although responses to TRH and GnRH actually add little to basal hormone measurement. For convenience, GnRH, TRH and insulin can be given simultaneously (Fig. 17.13). Insulin should be given in a low dose (0.15 units/kg) with close observation by a doctor throughout. An ECG should be done first, and this test should not be performed in the elderly or those with heart disease or epilepsy. Glucose for

1

898

MCQ 17.4

intravenous injection, or glucagon, should be available, and given early rather than late. GH and cortisol measurements are made serially over 2 hours. In many centres the short synacthen test is used to assess the cortisol response instead (see p. 929). Glucagon can also be used in adults to assess GH and cortisol reserve.

Investigations to establish the underlying cause of hypopituitarism The history and physical examination may point to a particular cause of hypopituitarism, such as previous infarction, meningitis or radiotherapy. Imaging Lateral and anteroposterior X-rays of the skull may reveal expansion of the pituitary fossa and erosion of the dorsum sellae and anterior or posterior clinoids (Fig. 17.14), although such changes do not indicate that the tumour responsible still exists - the fossa may be empty. For this reason, a CT or MR scan is essential (Fig. 17.15), and has now superseded other procedures. Angiography may be

17

FIG. 17.13 Responses in two patients to combined pituitary stimulation with insulin (0.15U/kg), GnRH (100ug) and TRH ( 2 0 u g ) given i.v. as a bolus at time 0 Patient 1 is a woman with amenorrhoea. She has normal responses despite previous operation for a functionless pituitary adenoma. Patient 2 is a man, also with a functionless pituitary tumour. He has absent responses for all except cortisol, which is blunted. The diagnosis is panhypopituitarism, requiring replacement therapy.

helpful if an aneurysm adjacent to the pituitary is suspected from the scans. The 'empty sella' syndrome, in which CT or MRI shows an absent pituitary gland, is usually a diagnosis of exclusion after the relevant radiological studies. In some cases the syndrome follows infarction of a tumour, whereas others are possibly due to the transmission of cerebrospinal fluid pressure to the pituitary fossa as a result of a defective diaphragma sellae. Hormone measurements Hormone measurements (PRL, GH, gonadotrophins, TSH) will indicate the nature of a functioning pituitary tumour, but there may still be major difficulties in diagnosis. For example, a modest elevation of PRL may be due simply to stalk damage, and not to prolactinoma. Levels more than about 10 times the upper limit of normal are, however, always due to a prolactinoma. Similarly, gonadotrophin levels are normally elevated after the menopause. Raised TSH is far more likely to be due to primary myxoedema than to a TSH-producing pituitary tumour. In the former, serum T4 levels will be low, whereas levels will be high with a TSH-producing tumour. A further clue is that there is an elevated level of the free a-subunit with TSH-producing tumours. 1

FIG. 17.14 Lateral skull X-rays in patients with pituitary tumours A Expansion of pituitary fossa and a 'double floor' due to asymmetrical enlargement. B Complete destruction of pituitary fossa and dorsum sellae.

Management of anterior hypopituitarism Although patients with hypopituitarism may have been ACTH- (and therefore cortisol-) deficient for many months or years without severe illness, they are nevertheless extremely vulnerable to even minor stress. A minor infection, illness or trauma may precipitate acute glucocorticoid deficiency, as may ill-advised prior treatment of hypothyroidism. As well as necessitating replacement therapy to deal with hormone deficiencies, pituitary tumours causing hypopituitarism may require treatment to relieve compressive signs and symptoms. Immediate The patient with pituitary collapse or coma should be given intravenous hydrocortisone (100mg repeated in 4 hours), which will generally lead to rapid improvement in the clinical condition, a rise in blood pressure and a fall in temperature. In some cases volume expansion may be necessary and, if the serum sodium level is very low (below 115 mmol/L) because of inappropriate ADH secretion (p. 911), slow correction to around 120mmol/L may be indicated by means of small amounts of hypertonic saline. Steroids should always be replaced before thyroid hormones, which can generally be given orally from the outset.

899

Sex hormone replacement therapy, particularly testosterone therapy in men, should be considered and generally instituted without delay, as this will greatly hasten the return of strength and wellbeing. Where occult posterior pituitary hormone deficiency coexists, it may be uncovered by glucocorticoid therapy. This should be suspected when there is marked and continuing water diuresis in the recovery phase, with low urine and rising serum osmolalities. It is best corrected with the synthetic ADH analogue desmopressin (DDAVP, p. 911). Long-term Steroid therapy There is no convenient way of mimicking the episodic secretion of glucocorticoids. Fortunately, however, this does not seem to matter, and oral treatment with hydrocortisone (cortisol) in a total daily dose of 20-40 mg given in two or, ideally, three divided doses (to approximate the normal diurnal variation) is usually satisfactory. Half the dose is given on waking in the morning and the last dose should be given no later than early evening (reversed for anyone working on a night shift). Cortisone acetate is generally equally effective. However, a possible disadvantage of cortisone over cortisol is that the plasma cortisol level rises to a peak more gradually on treatment with the former. In addition, some individuals, especially those with liver disease, have impaired conversion of cortisone to cortisol, and hydrocortisone is therefore now generally used. Prednisolone is a suitable alternative (5mg being roughly equivalent to 20mg hydrocortisone), but dexamethasone an even more potent halogenated glucocorticoid - should probably be avoided for long-term treatment because its much longer half-life means that glucocorticoid levels do not fall at night. Low levels then may be important to allow collagen repair. The patient should be given a card and wear a bracelet indicating the details of glucocorticoid replacement. As with Addison's disease (p. 931), dosage should be doubled temporarily to cover any stressful situation, and parenteral hydrocortisone will be required if oral steroids cannot be taken (e.g. during surgery, vomiting). Thyroid hormones Thyroid hormones are best replaced as oral thyroxine (100-200ug once daily). This is converted to the more active triiodothyronine (T3) in the tissues. Replacement can only be monitored by checking free T4 levels; TSH levels are obviously of no value, unlike in primary hypothyroidism.

1

900

Figs 17.1-17.5

2

MCQ 17.5

FIG. 17.15 MR scans of pituitary tumours

A Microadenoma (arrowed). B Macroadenoma with lateral and suprasellar expansion (arrowed) causing compression of the optic chiasm (courtesy of DrT Powell). 1

Sex hormone replacement In men testosterone is given in one of four ways, none of which is ideal. It may be implanted subcutaneously in the abdominal wall as fused pellets (600-800 mg every 4-6 months). More commonly, but with wider fluctuations in plasma testosterone levels, it may be given as testosterone esters - Sustanon (mixed testosterone esters) or Primoteston depot (testosterone enanthate) 250 mg i.m. every 2-4

weeks. Less effective is orally absorbed ester testosterone undecanoate (40-80mg twice daily), which also has the disadvantage of high price, and the capsules may cause gastrointestinal symptoms, perhaps because of the oleic acid vehicle. Transdermal delivery of testosterone via patches (e.g. Andropatch, each patch releasing 2.5 mg testosterone per 24 hours) has recently been introduced, but compliance is variable and the patches may cause skin irritation. However, these produce the most consistent physiological levels of testosterone. In women, where the uterus is present oestrogen therapy is indicated, combined with a cyclical progestogen to prevent endometrial hyperplasia (p. 948). In women who have had a hysterectomy oestrogen alone can be used (e.g. Premarin, which is an oral form of conjugated oestrogens, or Estraderm, which is a patch for transdermal delivery of oestradiol; gel preparations are available in some countries). Restoration of fertility In hypopituitary patients of either sex, restoration of fertility can usually be achieved by administering gonadotrophins. In men hCG (1500-2000IU i.m. three times weekly) is given to stimulate Leydig cell testosterone production, and after some 3 months or more this is combined with three times weekly i.m. injections of human menopausal gonadotrophins containing both LH and FSH (e.g. Pergonal 1 -l ampoule). Spermatogenesis should be evident after 3 months, but may take up to 12 months. Gonadotrophin therapy in women is much more complex, as FSH must be given early in the cycle and the follicular response followed by ultrasound scanning and serum or urinary oestrogen measurements (p. 948). When one or two follicles have achieved a diameter of 2cm, ovulation is produced by giving intramuscular hCG (5000 units). This treatment should only be undertaken in units with facilities for ultrasound and rapid oestrogen assays, and probably with access to egg retrieval and in vitro fertilization. An alternative treatment, effective in some cases of isolated gonadotrophin deficiency, is to administer GnRH in a pulsatile fashion through a pump connected to a subcutaneous needle. 2 Posterior pituitary hormone replacement Posterior pituitary hormone replacement is discussed on pages 910-912.

SUMMARY 3 Management of anterior hypopituitarism • Glucocorticoid replacement: hydrocortisone 10mg on waking, 5-10mg lunchtime and 5-10mg late afternoon; advice on steroid replacement in illness • Levothyroxine replacement: thyroxine 100-200ug daily • Sex hormone replacement: testosterone esters or patches in men (e.g. Sustanon 250mg i.m. every 3 weeks); oestrogen plus progestogen (e.g. Prempak-C) • Fertility: specialist treatment with gonadotrophins • Consider growth hormone replacement

Ablative treatment for pituitary tumours

17

Transfrontal surgery inevitably damages the normal pituitary and is generally ineffective in producing cure of large tumours. Transsphenoidal surgery, in good hands and performed via the midline approach, is effective in debulking large tumours and removing small ones, effecting a cure in more than half of the latter. Conventional external radiotherapy requires careful planning and dosing to avoid damage to the optic nerves; it is slowly effective but useful to contain aggressive tumours. The so-called 'gamma knife', coupled with sophisticated imaging, now offers the prospect of applying high-dose local radiation with great precision to pituitary tumours, but is not widely available. Specific types of hormone-secreting tumour and their management are considered below. It is important to note that compressive symptoms due to a prolactinoma respond rapidly to dopaminergic agonists, and an urgent prolactin should be requested before attempting surgery on a newly diagnosed pituitary tumour.

ISOLATED GROWTH HORMONE DEFICIENCY AND RELATED SYNDROMES GH deficiency only produces clinically obvious manifestations when it occurs in childhood. Although GH is secreted from early fetal life, it is not until infancy that its deficiency leads to impaired growth. The prevalence is about 1 in 10000.

Aetiology In most cases of isolated, non-iatrogenic GH deficiency the cause is unknown, but is believed to be due to a hypothalamic abnormality. There are, however, several genetic syndromes resulting in pituitary aplasia or hypoplasia, isolated GH deficiency or deletion of the GH gene. Patients in the latter group in particular may respond to injected GH as if it were a foreign protein and develop antibodies to it. In some cases of GH deficiency it may become apparent after GH therapy is initiated that TSH synthesis is also impaired; GH therapy accelerates the metabolism of TSH. Laron dwarfism is the term given to a syndrome that mimics GH deficiency, but in which GH levels are high and IGF-1 levels low. It is caused by a mutation in the GH receptor, which becomes unresponsive to GH. Some cases of short stature may be due to failure to respond to IGF1. In Pygmies the short stature and other somatic features appear to be due in part to low levels of IGF-1.

Clinical features Abnormally low rates of overall growth, leading to short stature, are associated with typical somatic abnormalities. In particular, the face appears baby-like, with persistence of a small nose, poorly developed nasal bridge and small chin.

901

The dentition may be delayed, with later crowding of teeth. Muscle development is poor, with excess subcutaneous fat, thin hair and skin, a small larynx and a high-pitched voice. Puberty is typically delayed until 18-20 years, when there is a small growth spurt. Even in patients with complete GH deficiency longitudinal growth occurs, but at only about one-third of the normal rate. There is a tendency to hypoglycaemia, which may be the most obvious feature in the neonate. GH deficiency developing in adult life may be associated with increased mortality and the value of GH therapy is becoming established (see below).

Management The diagnosis of GH deficiency is established by a combination of clinical observation (including serial measurements of growth and assessment of growth velocity) and provocative testing with clonidine, glucagon, arginine or, less frequently, insulin injection. Measurement of IGF-1, especially when combined with IGF-binding protein (IGFBP3) estimation, and assessment of the GH response to exercise or sleep are useful screening tests. If GH deficiency is found, CT or MR imaging of the pituitary is needed to exclude a pituitary or hypothalamic tumour (particularly craniopharyngioma), and the remainder of anterior pituitary function should be assessed. GH therapy is then initiated. GH isolated from cadaver pituitaries has been associated with some cases of Creutzfeldt-Jakob disease, leading to its withdrawal; biosynthetic GH is now available, although expensive. Treatment is with 0.5-0.7 units/kg/week (14-20 units/m2 body surface area weekly) as daily s.c. injections. Biosynthetic IGF-1 is necessary in Laron dwarfism. The response is monitored by frequent measurements of height, and calculation of growth velocity (Fig. 17.12, p. 898). There is an initial 'catch-up' period, followed by more steady growth. GH treatment improves growth in children with chronic renal failure and Turner's syndrome, but its use in idiopathic short stature (with GH deficiency) or in other conditions causing short stature is not generally recommended.

Growth hormone deficiency in adults The recent availability of recombinant GH has opened up the possibility of GH replacement in adults with GH deficiency. It seems likely that adult GH deficiency contributes to the increased risk of premature cardiovascular disease in hypopituitarism and causes increased fat mass, reduced muscle mass, low bone density, abnormal lipoprotein metabolism and impaired psychological wellbeing. GH deficiency should be tested for in patients with hypothalamic-pituitary disease, including GH deficiency in childhood, or in patients who have had cranial irradiation. 1

902

MCQ 17.6

2

Figs 17.6-17.10

Partial GH deficiency exists but can be difficult to distinguish from other causes of low GH levels, such as ageing. Short-term trials of GH therapy have shown modest improvements in body composition, exercise capacity and quality of life, although not all patients appear to benefit. Transient oedema is a frequent side-effect, but can be minimized by reducing GH dosage. Patients show variable sensitivity to GH; the usual starting dose is 0.15-0.3mg/day. Monitoring is performed using IGF-1 levels and simple anthropomorphic measurements. Absolute contraindications include active malignancy, intracranial hypertension and proliferative diabetic retinopathy. GH replacement is currently expensive and further work is required to establish the optimum treatment regimen, to identify which patients will benefit most from GH and to ensure that adverse side-effects (e.g. glucose intolerance) are avoided.

Growth retardation in other conditions It is often difficult to distinguish partial idiopathic GH deficiency from other states in which GH or IGF-1 secretion or action is secondarily impaired. These include psychological deprivation, hypothyroidism, growth failure due to inadequate nutrition (e.g. malabsorption due to coeliac disease) and chronic liver and kidney disease. Simple delayed puberty may also present with growth failure. In teenage boys with delayed puberty and short stature it is often justified to give a 3-6-month course of treatment with androgens (p. 943). The resulting growth spurt results in part from the androgens and in part from the augmentation of nocturnal GH secretion that they cause. 1

GROWTH HORMONE EXCESS The term acromegaly refers to the syndrome of GH excess when it develops in adult life. Gigantism is when its onset in childhood also leads to excessive height. At the turn of this century, Harvey Cushing recognized that acromegaly and gigantism were due to acidophil tumours of the pituitary gland that produce GH. He was the first clinician to distinguish features due to hyperpituitarism (hormone excess) from those due to hypopituitarism. Clinical GH excess is almost always due to a pituitary adenoma but, rarely, ectopic secretion of GHRH by a range of neuroendocrine tumours may lead to acromegaly by stimulating the pituitary gland to produce GH. Indeed, it was recognition of this syndrome that led recently to the extraction and purification of pancreatic-tumour-derived GHRH, which was rapidly shown to be present in identical form in the hypothalamus. Acromegaly is rare, with an annual incidence of 3 per million; gigantism occurs in less than 5 % of patients with acromegaly.

Aetiology The factors leading to the development of a GH-secreting adenoma are still uncertain. Most such tumours are mono-

clonal, suggesting a pituitary origin rather than excessive stimulation by the hypothalamus as their cause. Occasionally, mixed tumours secrete PRL and other hormones besides GH. Normally GH release is stimulated by dopamine, acting via GHRH stimulation. Paradoxically, the dopaminergic agent bromocriptine usually has a modest but significant inhibitory effect on GH secretion. In some cases, especially in individuals with mixed GH- and PRL-secreting tumours, this effect may be of therapeutic benefit. Somatostatin inhibits GH secretion, a phenomenon which has led to the use of the synthetic analogue octreotide.

17

Clinical features The clinical features of acromegaly and gigantism are due to a combination of GH excess, a local space-occupying lesion and other hormone deficiencies. Except where the tumour is large and growing rapidly, the latter usually occur late in the disease as a result of attempted treatment (radiotherapy or surgery), especially transfrontal surgery. Gigantism Gigantism is the most obvious and serious consequence of GH excess in childhood and adolescence. Normally, GH secretion occurs at a low level throughout childhood and increases with the rise in sex hormones at the time of puberty. With a GH-secreting tumour in childhood, however, inappropriate GH secretion occurs out of phase with the stage of puberty. The growth of cartilage at the epiphyseal plates is greatly stimulated due to the action of IGF-1 (p. 894). Normally this effect is held in check by an inhibitory action of sex hormones on the epiphyseal cartilage stem cell, ultimately leading to epiphyseal closure. The first feature of gigantism is therefore the onset of an inappropriate, continuing and excessive growth spurt, coupled with increased hand and foot size and general skeletal enlargement. Later, other features (increased skin and soft-tissue growth) become evident. In childhood, as in adult life, the pituitary tumour is often large at the time of presentation and may lead to local pressure effects. These include headache (owing to pressure on the diaphragma sellae) and visual field defects owing to pressure on the optic chiasm (pp. 892, 896) (see Figs 17.14 and 17.15). If pubertal failure results, either as a direct effect of a large tumour or as a result of treatment, epiphyseal closure will be delayed and the ultimate height attained even more extreme. Acromegaly There is a highly variable time between the onset of symptoms and signs and the diagnosis of GH excess in adults. This is dependent, among other things, on chance and the index of suspicion of any doctor who encounters the patient. In general, the greater the experience of the doctor, the more likely he or she is to make a confident and

FIG. 17.16 Typical appearances of acromegaly A Face showing enlarged supraorbital ridges, nose, lips and jaw. B 'Spade-like' hands. 0

correct diagnosis early. Clinical features due to the local tumour include headache and visual field defects (most commonly bitemporal hemianopia). Features due to GH excess may occur in many organs, but the most obvious involve the soft tissues, skin, and skeleton. Together, these give the classic acromegalic fades (Fig. 17.16A), with prominent supraorbital ridges, a large nose, a prominent lower jaw (prognathism) and thickening of the skin and soft tissues, including the lips and tongue. There is often a typical rather deep voice, due to thicken-

903

SUMMARY 4 Clinical features of acromegaly • Symptoms and signs are due to local tumour, growth hormone excess and deficiency of other hormones. • Prognathism, enlarged soft tissues, skeletal deformity and nerve entrapment occur. • Hypertension and diabetes mellitus contribute to mortality. • IGF-1 is a useful screening test. • Diagnosis is confirmed by failure of GH suppression after oral glucose.

ing of the vocal cords, enlargement of the sinuses and changes in other tissues in the nasopharynx and larynx. Dental malocclusion results from protrusion of the lower jaw, and the teeth may become more widely spaced or dentures may need to be changed. The wide 'spade-like' hands are caused by increased thickness and volume of skin and soft tissues and growth of periarticular cartilage (Fig. 17.16B); the feet are similarly affected. Ring, glove, shoe and hat sizes increase. In long-standing and severe acromegaly major skeletal deformities are common. Severe thoracic kyphosis and rib elongation lead to a barrel chest. In adult-onset acromegaly the growth of articular cartilage and soft tissues in and around a joint commonly leads to secondary osteoarthritis, which may be compounded by necrosis of articular cartilage. Neurological problems include carpal tunnel syndrome and muscle weakness. The age-related mortality rate of patients with untreated acromegaly is probably twice normal, largely attributable to cardiovascular disease hypertension, cardiac muscle hypertrophy, cardiomyopathy and ischaemic heart disease. The latter is particularly likely in acromegalics with diabetes mellitus. Overt diabetes due to insulin resistance occurs in about 10% of acromegalics, and about 50% have impaired glucose tolerance. Respiratory problems also contribute to the increased mortality. The prevalence of colonic polyps is increased in acromegaly, but it is unclear yet whether these confer an excess risk of malignancy. A common early complaint is increased sweating, owing to an increase in both number and activity of sweat glands. Macroglossia may lead to sleep apnoea, owing to obstruction of the airway at night, often presenting with daytime somnolence. Enlargement of the liver, spleen, pancreas and kidneys seldom causes problems, although the glomerular filtration rate may be increased because of the latter. About one-quarter of patients have a goitre, which is commonly multinodular. Patients with acromegaly have quite often been labelled as neurotic because many of the symptoms are rather vague. Impotence is a common complaint and only rarely

1

904

MCQ17.7

Minutes FIG. 17.17 GH response to oral glucose load in a normal subject (suppression) and a man with acromegaly (no suppression or paradoxical rise)

appears to be due to hypogonadism. Women commonly have menstrual irregularities, and some are hirsute. Galactorrhoea due to accompanying hyperprolactinaemia occurs in about one acromegalic woman in five. In some this is due to a mixed PRL- and GH-secreting tumour, in others to damage to the pituitary stalk. 1

Investigation Despite classic clinical features biochemical confirmation of the diagnosis is mandatory. Early signs of disease may be subtle and 'acromegaloid' features may occur without GH excess. GH suppression test. Baseline GH levels are of limited value in diagnosis because GH is normally secreted episodically. The definitive test remains the oral glucose load (50-75 g), with accompanying measurements of GH (Fig. 17.17). Normally, GH suppresses to below 4mU/L (2ug/L) within 2 hours after a 50 g oral glucose load, probably as an effect of central inhibition of GHRH secretion. In acromegaly levels either fail to suppress or show a paradoxical rise. About 30-40% of cases also show a paradoxical rise of GH in response to TRH or GnRH given intravenously, presumably because the tumour possesses receptors for these hormones, but these tests are not routine. Bromocriptine suppresses GH in the majority of acromegalics, though it is only clinically useful in a minority. An indication of its potential usefulness in an individual case is obtained from measurement of GH hourly for 4-6 hours after 5mg bromocriptine orally. Octreotide is now commonly used for GH suppression. A test dose (50-100 ug s.c.) with hourly GH measurement is a useful predictor of longer-term response. IGF-1 assay. Measurement of circulating levels of IGF1, especially combined with IGF-BP3, provides a useful screening test for acromegaly and is valuable in monitoring the effects of treatment. Levels do not fluctuate as with

17

CASE STUDY 17.1 DIAGNOSIS OF ACROMEGALY A 56-year-old woman presented with a gradual increase in tiredness over several months, accompanied by sweating and a change in her facial appearance. Friends had commented on the latter, and she had observed that she was developing a bigger nose and jaw. Comparison with photographs that she brought to the clinic confirmed that her face had indeed changed appearance over a 10-year period. Further inquiry revealed that her glove size had also increased, rings which she had previously been able to wear were now unwearable because of the increased size of her fingers, and her shoe size had increased from 6 to 71/2. She had put on 4 stones in weight in 2 years and had left-sided headaches. There was also a history of back pain and general stiffness and aches in the fingers. On examination, apart from the changes to the face and hands, the skin thickness was increased, as assessed by taking a pinch of the skin over the dorsum of the hand. The visual fields were full and the fundi were normal. The cardiovascular examination revealed that the blood pressure was 170/106, but there was no evidence of cardiac failure. There

were no other abnormalities on examination. Question 1, How would you investigate this woman to confirm the diagnosis of acromegaly? Discussion This lady has typical signs and symptoms of acromegaly. The only real differential diagnosis for the soft tissue changes in the extremities and face is pseudo-acromegaly, which can occur in insulin-resistant states, but the other features make this most unlikely. Visual field defects are only present in around 5% of acromegalics, whereas headache can occur in around 60%. Approximately 75% of acromegalics report arthralgia, due to osteoarthrosis secondary to bony overgrowth. Hypertension occurs in 25-50% of patients and is a major contributor to mortality from cardiovascular disease. If left untreated there is ventricular hypertrophy and impaired ventricular function, caused by the effects of growth hormone on the heart and muscle. To confirm the diagnosis of acromegaly, the gold standard is the

GH, and are almost always elevated in acromegaly and gigantism. Physiological increases in IGF-1 occur in pregnancy and puberty. GHRH assay. Ectopic secretion of GHRH is rare and usually causes pituitary hyperplasia, but this is difficult to distinguish from an adenoma radiologically and the diagnosis of a GHRH-secreting tumour is often retrospective. The diagnosis can be confirmed by measuring circulating GHRH and imaging the tumour (usually in the pancreas, lung, thymus or adrenal). Radiological investigations are given on pages 898-899.

use of the glucose tolerance test. This consists of giving 75 g of oral glucose and measuring the circulating growth hormone level over a 2-hour period. Normally growth hormone levels become undetectable (<2 ug/L) during this test, but in acromegaly the growth hormone is not suppressed and may even rise. In this case the basal growth hormone was 54ug/L and rose to 168ug/L 60 minutes after oral glucose. Simultaneous measurement of the glucose during this test will reveal glucose intolerance in around 50% of patients and 5% will have frank diabetes. Measurement of IGF-1 is a useful screening test, as elevated levels are strongly suggestive of acromegaly: in this patient the IGF-1 level was 723 ng/mL (reference range 123-463). The remainder of anterior pituitary function should be evaluated, and in this case was normal. The next step in the diagnosis is an MRI or CT scan of the pituitary to identify the pituitary tumour, which in this case was a 7 mm microadenoma. Treatment consists of surgical removal. Cure rates after transsphenoidal adenomectomy are 70-80%, and indeed this patient was cured by the procedure.

but the most widely used criteria are a mean serum GH level of below 2.5ug/L on repeated (3-5) samples during the day, normal IGF-1 or a normal response to glucose. The lower the GH level after treatment, the lower the mortality.

Management

Surgery Surgery (p. 901) is the usual first-line treatment. With intrasellar microadenomas (diameter < 1cm), the best centres now achieve at least 70% cure rates by transsphenoidal resection, without causing hypopituitarism, although the balance between endocrine benefit and penalty shifts unfavourably with increasing tumour size.

The aim of treatment of GH excess is to arrest and, where possible, reverse the local and systemic effects of the tumour. Except in the growing child, correction of GH excess is seldom urgent. Visual field defects, however, present an immediate and compelling indication for surgery. There is no consensus on what constitutes a cure,

Drug therapy Bromocriptine or cabergoline cause tumour shrinkage in only a minority of cases of acromegaly, but may be helpful when surgery is not thought desirable (e.g. in mild disease or the elderly) or when GH is effectively suppressed by these drugs. The usual doses needed are 10-30 mg of

905

bromocriptine daily in four doses or 0.5-2 mg cabergoline. Additional benefit with higher doses of bromocriptine has been reported. The clinical effect often exceeds the biochemical response, possibly because of a direct suppressive effect on IGF-1 secretion. The somatostatin analogue octreotide is expensive but more effective than bromocriptine. It is given in a dose of 50-100ug s.c. three times daily. It is especially helpful for headache in acromegaly and in patients who are not cured by other treatments. Octreotide causes mild (<20%) tumour shrinkage in about 40% of the cases treated. A long-term complication is the development of gallstones. Two long-acting Somatostatin analogues, lanreotide and Sandostatin-LAR, have recently been introduced which avoid the need for daily injections.

• Surgical removal of the pituitary tumour is first-line treatment, usually via the transsphenoidal route. • If tumour removal is inadequate, consider further surgery (microadenoma) or radiotherapy (macroadenoma). • Somatostatin analogues or, less successfully, dopaminergic agents control GH secretion when surgery is contraindicated or while waiting for radiotherapy to work.

Radiotherapy (p. 901) External radiotherapy can be used to produce tumour regression and is now usually used to treat persistent disease after surgery. It requires careful planning and megavoltage machinery. The treatment is remarkably safe but its effect is delayed, with a gradual and progressive benefit over 2-10 years. Octreotide may be useful while awaiting the full effects of radiotherapy. It is important that the total radiation dose does not exceed 45 Gy and that individual daily doses do not exceed 2 Gy, to avoid damage to surrounding tissues.

occurs as a result of selective enzymatic cleavage within the cells' hormone-containing granules; the relationship of the principal cleavage products is shown in Figure 17.9 (p. ••). It will be apparent that ACTH, B-LPH and B-endorphin are secreted simultaneously in response to CRH and other 'physiological' stimulants, such as insulin-induced hypoglycaemia. The principal hormonal action of ACTH is to stimulate cortisol secretion, particularly from the zona fasciculata. Its action is via cell surface receptors which activate adenylate cyclase. Receptor binding requires extracellular calcium. ACTH secretion is under synergistic control from several hypothalamic factors, shown in Table 17.4 (p. 893). Circadian rhythm (which affects both pulse amplitude and frequency), stress and food all modify ACTH secretion via their effects on these hypothalamic factors.

Complications of treatment

Isolated ACTH deficiency

The complications of surgery and radiotherapy vary greatly with the skill and technique of the operator. After surgery by the transsphenoidal route panhypopituitarism is quite rare, except where radical removal of a large tumour has been attempted, but isolated hormone deficiencies are more frequent. Postoperative diabetes insipidus is usually transient. If anterior hypopituitarism is suspected in the recovery period, full replacement therapy should be initiated and combined pituitary function tests conducted about 6 weeks postoperatively. After external radiotherapy the onset of hypopituitarism should be suspected if the patient complains of lassitude, lethargy and/or impotence. Regular follow-up with pituitary function tests should in any case be undertaken, and replacement therapy initiated as appropriate. 1

Isolated ACTH deficiency is very uncommon and may be difficult to diagnose. Patients are usually middle-aged at the time of presentation, with weakness, lethargy, hypoglycaemia and sometimes hyponatraemia. The diagnosis is confirmed by a low urinary free cortisol excretion, and low plasma ACTH and cortisol levels which do not rise normally in response to insulin hypoglycaemia or a short synacthen test. The defect may result from an autoimmune response against corticotrophs and may be associated with other organ-specific autoimmune disorders. Treatment is with glucocorticoid replacement.

ACTH DISORDERS Physiology ACTH is the most important hormone synthesized and secreted by the corticotrophic cells. Processing of POMC to produce the hormone ACTH (39 amino acid residues)

1

906

SUMMARY 5 Management of GH excess

MCQ 17.8

ACTH excess ACTH excess due to an ACTH-secreting adenoma leads to pituitary-dependent Cushing's syndrome (p. 932). 'Physiological' ACTH excess occurs when the adrenal glands fail, owing either to an inborn error of secretion or to destruction by disease. Under these circumstances the normal episodic and circadian fluctuations in ACTH secretion occur at much higher than normal levels. Rarely, hereditary unresponsiveness to ACTH, due to a mutation in its receptor, may cause glucocorticoid deficiency and very high ACTH levels. Nelson's syndrome is the name given to the hyperpigmentation, ACTH excess and pituitary expansion that may follow bilateral adrenalectomy for Cushing's syndrome due to a pituitary adenoma. It is presumed to result from removal of negative feed-back inhibition of a semi-

autonomous pituitary adenoma that was previously subject to some restraint by the high circulating levels of cortisol. Radiotherapy to the pituitary is used to prevent or treat Nelson's syndrome.

PROLACTIN DISORDERS

Physiology PRL is a polypeptide hormone of 199 amino acid residues, although dimeric and polymeric forms exist whose biological significance is uncertain. Secretion of prolactin PRL is synthesized and secreted by cells of the pituitary (lactotrophs), which are mainly located laterally in the gland (Fig. 17.18). Unlike other anterior pituitary hormones, PRL is secreted in the absence of stimuli, and the predominant influence of the hypothalamus is to restrain this by the secretion of dopamine. Besides causing TSH release,TRH also stimulates PRL secretion. PRL secretion is episodic and increases at night and with stress (e.g. venepuncture or breast examination), which must therefore always be excluded as a simple cause of mild hyperprolactinaemia. In females, PRL levels increase at the time of puberty. Androgens probably have a modest inhibitory effect.

In pregnancy, PRL levels rise about fivefold. Oestrogens, probably together with progesterone, cause hyperplasia of the lactotrophs and enhance PRL secretion while inhibiting its effect on the breast epithelium. The decline in sex hormones after delivery, coupled with the stimulus of suckling, is responsible for postpartum lactation. Postpartum, breastfeeding causes a marked increase in PRL secretion, as a result of a reflex involving sensory fibres from the breast, the dorsal nerve roots and the hypothalamus. This is probably important in maintaining milk production for weeks and months after delivery, when baseline PRL levels have declined to normal. Another reflex arc is responsible for suckling-induced oxytocin secretion, which is important in stimulating myoepithelial cells of the breast and so causing milk ejection from the ducts.

17

Action of prolactin and other hormones on the breast PRL has an action on the breast that is essential for lactation (Table 17.5, p. 895). Oestrogens promote ductal growth, whereas PRL and progesterone promote growth of the lobules and alveoli. Progesterone enhances the synthesis of B-lactalbumin, a non-catalytic subunit that converts the function of the enzyme galactose synthetase to lactose synthesis. Other hormones with important effects on the breast include insulin and cortisol (which are permissive or facilitatory), GH and placental lactogen. The decline in oestrogen and progesterone levels after delivery releases the brake on PRL-stimulated lobuloalveolar milk production.

Pathology PRL deficiency can occur with pituitary damage (Table 17.6, p. 896) and results in the failure of lactation. However, because of the unique predominance of inhibitory control over PRL secretion, damage to the pituitary stalk results in PRL excess as a result of diminished dopamine delivery, which contrasts with the failure of other anterior pituitary hormones, owing to loss of the appropriate hypothalamic releasing hormones. PRL excess. Hyperprolactinaemia and associated disorders are common, particularly in women. The low incidence in men is a reflection of the inhibitory effects of androgens both on the lactotrophs and on the breast.

HYPERPROLACTINAEMIA Aetiology

FIG. 17.18 Regulation of prolactin secretion

Unlike other anterior pituitary hormones, prolactin is secreted in the absence of stimuli and is normally under inhibitory restraint by dopamine.

The causes of hyperprolactinaemia are best considered in relation to PRL physiology. Table 17.7 lists the principal causes, most of which lead to only mild to moderate hyperprolactinaemia (levels up to 5-10 times normal). Pituitary tumours may lead to hyperprolactinaemia for one of two reasons: they may interfere with the pituitary stalk and so produce local dopamine deficiency, or they

907

TABLE 17.7 Classification of hyperprolactinaemia Cause

Example

Pituitary lactotroph excess Physiological Drug-induced Pathological

Pregnancy Oestrogens Tumour microprolactinoma macroprolactinoma mixed GH and prolactin tumour

Inhibition of dopamine secretion Thoracic sensory nerve stimulation Neurogenic Chest wall burns/incisions Suckling/nipple stimulation Pituitary stalk damage

Stalk section Stalk/hypothalamic tumour

Drug-induced

Methyldopa, reserpine, opiates, H2-receptor blockers

Inhibition of dopamine action Neuroleptic drugs Phenothiazines, e.g. chlorpromazine Butyrophenones, e.g. haloperidol Antiemetics

Metoclopramide

Endocrine disorders

TRH-mediated, e.g. primary hypothyroidism Miscellaneous, e.g. adrenal insufficiency, Cushing's syndrome, polycystic ovary syndrome

Impaired excretion

Renal failure

may secrete PRL. Pure prolactinomas are classified into two broad categories: the microprolactinoma, which is less than 1 cm in diameter and is associated with mild to moderate hyperprolactinaemia and no pressure symptoms, and the macroprolactinoma. In many instances, the diagnosis of microprolactinoma is presumptive, based on exclusion of other causes.

Clinical features and management The unwanted secretion of milk (galactorrhoea) is common in women, but in only about one-third of cases is it due to PRL excess. If treatment is required dopamine agonists (see below) may be effective, even when PRL levels are normal. Increased secretion of PRL from any cause has an inhibitory effect on cyclical ovarian function, probably

908

1

MCQ17.9

4

MCQ 17.11

2

MCQ 17.10

3

Case 17.1

owing to direct inhibition of GnRH secretion in hypothalamic neurons. Erratic and anovulatory cycles or amenorrhoea result. Treatment with a dopaminergic drug such as bromocriptine results in a drop in PRL and the resumption of normal ovulatory cycles. This restores normal oestrogen levels, which prevent premature osteoporosis and cardiovascular disease in women. It should be remembered that the commonest cause of hyperprolactinaemic amenorrhoea is, of course, pregnancy. 1

Microprolactinoma Clinical features Around 5-10% of the adult population have a microprolactinoma, but few of these ever come to medical attention. Classic presentations are with erratic menstrual cycles or amenorrhoea, with or without galactorrhoea. In some patients infertility or decreased libido is the main complaint, usually associated with amenorrhoea (primary or secondary). Frequently, presentation follows cessation of the pill (post-pill amenorrhoea) or pregnancy. Patients with microprolactinoma never present with visual field defects or other pressure effects. Indeed, the presence of these effects associated with a modest PRL excess indicates dopamine deficiency due to a non-PRL-secreting tumour in the pituitary stalk or above (e.g. a craniopharyngioma). Investigation Diagnosis depends upon demonstration, in several serum samples, of hyperprolactinaemia in the absence of other causes of PRL excess. The effect of stress can be eliminated by sampling 1 hour after the insertion of a cannula. A CT or (preferably) MR scan is also required; however, not all microadenomas visible on such scans are necessarily the source of PRL excess, and some microprolactinomas may be too small to visualize (see Fig. 17.15). The main purpose of scanning is to rule out stalk compression from a nonPRL-secreting tumour. Management Less than 5% of microprolactinomas enlarge over a 5-year period and repeated annual imaging is all that is required to assess tumour growth. If there has been no progression over 1-2 years, monitoring PRL levels will suffice thereafter, as growth will be indicated by rising PRL levels. Any change in size warrants treatment. Other indications for treatment are to restore fertility, to induce regular menses (and thus prevent the consequences of low oestrogen levels) and to treat decreased libido or dyspareunia (other symptoms of oestrogen deficiency). Medical treatment is with dopaminergic agents. Bromocriptine has been the most widely used but may initially cause nausea and postural hypotension. It should be started at a low dose (1.25 mg at night) with food, and increased gradually over 1-2 weeks to 2.5mg three times daily with food. Cabergoline has fewer side-effects and is now the drug of choice; the usual starting dose is 0.25 mg at night twice a week. In most cases this is highly effective

both in suppressing PRL and in resolving the amenorrhoea and galactorrhoea. If pregnancy is desired it may be sensible to advise contraception for 6 months to allow a reduction in adenoma size. In contrast to the situation with acromegaly, PRL-secreting tumours commonly shrink in size with dopaminergic agents. Although it may be safely continued, bromocriptine is usually stopped once the pregnancy test is positive, and at present cabergoline should be discontinued prior to conception once regular menses are resumed; PRL remains low for several months after treatment has ceased. With a microprolactinoma the risk of tumour expansion during pregnancy, sufficient to cause visual field defects, is probably negligible. It is as yet uncertain for how long dopaminergic therapy should be given in such cases. A reasonable policy, if pregnancy is not desired, is to treat for 1-2 years and then to repeat PRL levels several weeks after stopping the drug. Sustained normal levels would suggest that the tumour has regressed and that treatment can be safely stopped and the patient observed. If contraception is desired by a patient with microprolactinoma, bromocriptine or cabergoline may be combined safely with the contraceptive pill. Surgical removal (p. 901) of microprolactinomas gives a long-term cure rate of 60-70% in the best series. It has been used for patients intolerant of dopaminergic agonists or who do not wish to take a prolonged course of drugs. 2

Macroprolactinoma The definition of macroprolactinoma by size is arbitrary, and any non-pregnant patient with circulating PRL levels in excess of 10 times the upper limit of normal (over 5000 mU/L, 200ng/mL) probably has a more aggressive prolactinoma which is potentially or actually large and expanding. Virtually all detected prolactinomas in men and about one-fifth of those in women fall into this category. Clinical features All features are likely to be more extreme than with a microprolactinoma. These include the endocrine consequences of PRL excess: galactorrhoea, amenorrhoea and, in men, impotence. The latter is due principally to gonadotrophin (and hence testosterone) deficiency, suggested also by lethargy, depression and loss of secondary sexual hair. Rarely, presentation may be with infertility and oligo- or azoospermia. Local pressure effects - headache, visual field defects and other cranial nerve lesions - are often present at the time of diagnosis. As with other pituitary tumours, the occurrence of panhypopituitarism in the untreated patient indicates the presence of a large and destructive tumour. In males, galactorrhoea may be present even in the absence of gynaecomastia. Investigation PRL levels are 10-200 times normal. CT or MRI will show the full extent of the tumour. Formal plotting of the visual fields is required if scans reveal that the optic chiasm is being approached by the tumour.

Management The urgency of treatment depends upon the severity of local pressure effects. A therapeutic trial of bromocriptine (2.5-5 mg three times daily) or cabergoline (0.25-0.5 mg twice weekly), with regular measurement of visual fields and acuity, is the initial treatment of choice, followed by transsphenoidal decompression if visual failure persists and there is no tumour shrinkage on repeat scans. It is impossible to eradicate macroprolactinomas surgically. Lifelong dopamine agonist treatment is needed unless the tumour shows spontaneous remission (owing to infarction). Radiotherapy is only used if medical treatment fails to suppress prolactin or to induce tumour shrinkage over the long term. The response to treatment can be monitored by gradually tailing off the drugs and measuring PRL levels. 0

17

GONADOTROPHIN DISORDERS Gonadotrophin disorders are considered in more detail under the section on gonads (pp. 941-945). Gonadotrophin-secreting tumours are rarely diagnosed clinically. Most published cases have been FSH-secreting tumours. 'Functionless' pituitary tumours often stain for LH and FSH or their subunits, and these non-secreting gonadotrophinomas present with hypopituitarism or pressure effects. Treatment is usually transsphenoidal removal, with radiotherapy for residual tumour. Ectopic secretion of gonadotrophins appears to be confined to hCG, which is a normal product of the placenta and a tumour marker for hydatidiform mole and its malignant counterpart the choriocarcinoma (a tumour which can now be cured by intensive chemotherapy). Germ cell tumours of the testis, ovary and other sites (e.g. central nervous system) often secrete hCG, as may some carcinomas (e.g. adenocarcinoma of the lung). This may lead to excess testicular oestrogen secretion and gynaecomastia. In children, hepatoblastomas may produce pseudoprecocious puberty by hCG secretion. 4

TSH DISORDERS TSH disorders are discussed mainly under panhypopituitarism (p. 897) and thyroid disorders (pp. 914-918). Iso-

SUMMARY 6 Management of hyperprolactinaemia • Microprolactinomas are usually treated with dopaminergic agents, such as cabergoline 0.25-0.5mg twice weekly. • Surgical removal of microadenomas is an alternative in patients intolerant of these drugs or who prefer surgery. • Macroprolactinomas are best treated with dopaminergic agents, even when associated with compressive symptoms.

909

lated TSH deficiency is a very rare cause of secondary hypothyroidism. Primary TSH excess due to a thyrotrophinoma is a rare cause of hyperthyroidism. Surprisingly, TSH levels by immunoassay may be within normal limits in both conditions, which are recognized respectively by the low or high free T4 levels. However, the biological activity of the TSH is abnormal, accounting for the clinical picture. Patients with long-standing severe primary hypothyroidism (myxoedema) often develop pituitary enlargement owing to thyrotroph hyperplasia.

Osmotic and related stimuli Osmotic pressure Atrial natriuretic peptide Angiotensin II Osmoreceptors

Non-osmotic stimuli Arterial/venous pressure 'Stress' Hypoglycaemia ±

Thirst centre

Supraoptic nucleus

+ Volume receptors

Drinking behaviour Paraventricular nucleus

FURTHER READING ON THE ANTERIOR

PITUITARY GLAND Carroll P V, Christ E R and the members of Growth Hormone Research Society Scientific Committee 1998 Growth hormone deficiency in adulthood and the effects of growth hormone replacement: a review. J Clin Endocrinol Metab 83: 382-395. Colao A, Lombardi G 1998 Growth-hormone and prolactin excess. Lancet 352:1455-1461. Consensus guidelines for the diagnosis and treatment of adults with growth hormone deficiency: summary statement of the Growth Hormone Research Society Workshop on adult growth hormone deficiency. 1998 J Clin Endocrinol Metab 83: 379-381. Duncan E, Wass J A H 1999 Investigation protocol: Acromegaly and its investigation. Clin Endocrinol 50: 285-293. Lamberts S W J, de Herder W W, van der Lely A J 1998 Pituitary insufficiency. Lancet 352:127-134. Melmed S, Jackson I, Kleinberg D, Klibanski A 1998 Current treatment guidelines for acromegaly. J Clin Endocrinol Metab 83: 2646-2652. Orme S M, McNally J Q, Cartwright R A, Belchetz P E for the United Kingdom Acromegaly Study Group 1998 Mortality and cancer incidence in acromegaly: a retrospective cohort study. J Clin Endocrinol Metab 83: 2730-2734. Vance M L, Mauras N 1999 Growth hormone therapy in adults and children. N Engl J Med 341:1206-1216.

Magnocellular neurons ADH release (Ca2+dependent) Renal free water reabsorption FIG. 17.19 Factors stimulating ADH secretion by osmotic and non-osmotic mechanisms Osmoreceptors also activate the thirst centre to stimulate drinking.

nuclei as part of a larger precursor, which in each case also includes the sequence of another protein (a neurophysin). Axonal flow carries the normal precursors to the specialized nerve terminals in the posterior pituitary gland, where they are stored in cytoplasmic granules. Neuronal activation leads to the release of the hormone and its neurophysin into the hypophyseal capillaries and hence into the general circulation.

Control mechanisms THE POSTERIOR PITUITARY GLAND The posterior lobe of the pituitary gland consists principally of the secretory terminal extensions of neurons that arise in the preoptic nucleus of the hypothalamus. Its blood supply is derived principally from the hypophyseal arteries, rather than from the hypothalamopituitary portal circulation.

SYNTHESIS AND SECRETION OF THE MAIN HORMONES

910

The posterior pitutary gland secretes two principal octapeptide hormones, vasopressin and oxytocin. In humans the vasopressin produced is arginine vasopressin (AVP), which is also called antidiuretic hormone (ADH). Both hormones are synthesized in specialized (magnocellular) neurons in the supraoptic and paraventricular

ADH secretion is stimulated by an increase in osmolality, and by 'stress' stimuli, such as volume depletion (Fig. 17.19). Glucocorticoids exert an inhibitory effect on its release and also interact with ADH at the renal tubule, so that in the presence of glucocorticoid insufficiency diabetes insipidus may be masked. ADH acts on two different kinds of receptors, those on the renal tubules (type I) and those on blood vessels (type II). The action on the former is mediated by cyclic AMP; ADH opens up pores in the basolateral membrane for water and urea. Oxytocin acts on the smooth muscle of the uterus and mammary ducts (to cause milk ejection). It also causes contraction of myoepithelial cells of the seminiferous tubules.

ADH DEFICIENCY Deficiency of ADH causes the syndrome of diabetes insipidus (see also Ch. 21, pp. 1101-1103).

Aetiology ADH deficiency may be caused by trauma (head injury or neurosurgery); primary or secondary neoplasms of the pituitary, pituitary stalk or hypothalamus; inflammatory disorders such as sarcoidosis; eosinophilic granuloma; and bacterial meningitis and viral encephalitis. It may be part of a familial syndrome of diabetes insipidus, diabetes mellitus, optic atrophy and nerve deafness (DIDMOAD), or occur as an isolated autosomal dominant disorder. ADH deficiency is idiopathic in around a third of cases; autoimmunity may account for some of these. In addition, the condition may be simulated by disorders that lead to renal resistance to ADH. These include X-linked nephrogenic diabetes insipidus (confined to males), and hypercalcaemia and hypokalaemia, both of which lead to a water diuresis from resistance to ADH.

Clinical features The principal symptoms of ADH deficiency are thirst and incidental polyuria, as the patient is forced by the osmotic stimulus to drink large volumes of water or other fluids. It is not uncommon for patients to pass in excess of 10 L of urine a day, of very low specific gravity (1.003 or less, osmolality less than l00mmol/kg). The serum sodium concentration is generally moderately raised, but seldom over 150mmol/L, provided the patient has free access to water. The major danger is when such access is denied, or when the patient is unconscious, e.g. due to an anaesthetic or head injury. Under these circumstances the osmolality and sodium concentration rise rapidly. A serum sodium concentration over 160-170 mmol/L may lead to severe and irreversible brain damage. As with hyponatraemia, correction should be gradual.

Investigation The major differential diagnosis is from psychogenic polydipsia and from other causes of thirst and polyuria (see Table 20.10, p. 1045). The mainstay of diagnosis is measurement of serum and urine osmolality, and the diagnosis is suggested by a urine osmolality of less than 200mmol/kg or specific gravity of 1.005 or less. Plasma osmolality is usually above 287mmol/kg. Confirmation of the diagnosis usually depends on the water deprivation test. Free access to water is allowed up to the start of the test at 8 am, when the patient is weighted and blood and urine samples are taken for osmolality. Timed hourly urine collections, serum osmolality measurements and body weight recordings are made. For safety, the test is discontinued if 3% of body weight is lost or 3 L of urine are passed. At the end of 8 hours, if urine concentration has not occurred 2ug of the analogue DDAVP is given i.m. and further samples are taken; in true diabetes insipidus this leads to prompt urine concentration. Further details are given in Chapter 21, page 1101. In equivocal cases the failure of plasma ADH to rise after

infusion of hypertonic saline may be useful, but assays for this hormone are not widely available.

17

Management of diabetes insipidus The long-acting vasopressin analogue desamino-D-arginine vasopressin (DDAVP, desmopressin) acts almost exclusively on the V2 receptors of the renal tubule, and so does not cause hypertension and constriction of the splanchnic circulation (mediated by smooth muscle V1 receptors). It is also resistant to enzyme degradation in the circulation or peripheral tissues, and has a greatly prolonged half-life. DDAVP is usually given once or twice a day intranasally (10-20 ug) or, for the postoperative patient, intravenously (1-2 ug). Recently an oral formulation of DDAVP has been introduced and many patients prefer this to intranasal DDAVP; the maintenance dose is 100-200 ug three times a day. With the introduction of desmopressin diabetes insipidus is no longer a problem of management, provided the patient has an intact thirst centre and does not drink excessive volumes of water. Chlorpropamide enhances the renal response to ADH, but is only useful in partial forms of diabetes insipidus.

'INAPPROPRIATE' SECRETION OF ADH Aetiology The syndrome of inappropriate secretion of ADH is frequently encountered in a variety of different conditions (Ch. 21, p. 1103). These include acute and chronic pulmonary disease, congestive cardiac failure, small cell carcinoma of bronchus, cerebral disease, liver cirrhosis, cortisol deficiency and hypothyroidism. ADH secretion is a transient accompaniment of surgery for 24-48 hours. Of the above conditions, only small cell carcinoma of bronchus is ever associated with true ectopic tumour synthesis and secretion of vasopressin. Even in this condition, however, hyponatraemia is often caused by excess hypothalamopituitary ADH secretion, rather than an ectopic source.

Clinical features, investigation and management The hallmark is a low serum sodium concentration (often below 125 mmol/L) and serum osmolality (below 270mmol/kg), associated with an inappropriately high urine osmolality (usually greater than the plasma osmolality), with persistent urinary sodium excretion (>20 mmol/L), in a patient who is not clinically volume depleted. Volume depletion from any cause is a stimulus to ADH secretion, so these biochemical abnormalities would be appropriate in, for example, a patient overtreated with diuretics, a common cause of hyponatraemia in the elderly. Similarly, in states of hypervolaemia (e.g. cardiac failure, cirrhosis, nephrotic syndrome, inappropriate i.v. therapy) there is hyponatraemia simply due to the excess total body water, and this does not constitute the syndrome of inap-

911

propriate ADH secretion. In these states urine sodium loss is low (<10mmol/L). The major clinical features are confusion, coma and fits (water intoxication) if the serum sodium falls much below 120mmol/L (osmolality <250mmol/kg). Treatment is with fluid restriction (l000mL/day) and correction of the underlying cause. Cautious treatment with small volumes of hypertonic (1.8%) sodium chloride is indicated in patients with CNS manifestations to restore the serum sodium to 120-125 mmol/L: rapid increases above this risk central pontine myelinolysis and other CNS damage. Mild cases may respond to lithium or demeclocycline, which diminish the renal response to ADH. For further details, see Chapter 21, page 1107. 1

FURTHER READING ON THE POSTERIOR PITUITARY GLAND Baylis P H 1995 Investigation of suspected hypothalamic diabetes insipidus. Clin Endocrinol 43: 507-510. Hirshberg B, Ben-Yehuda A 1997 The syndrome of inappropriate antidiuretic hormone secretion in the elderly. Am J Med 103: 270-273. Kumar S, Berl T 1998 Sodium. Lancet 352: 220-228. McKenna K, Thompson C 1998 Osmoregulation in clinical disorders of thirst appreciation. Clin Endocrinol 49:139-152.

THE THYROID GLAND EMBRYOLOGY, ANATOMY AND PHYSIOLOGY The thyroid gland is derived in the first trimester from an outpouching of the floor of the pharynx which becomes displaced caudally and fuses with the fourth pharyngeal pouch. During its caudal displacement it leaves the thyroglossal duct, which usually becomes fragmented and resorbed, but may persist to form thyroglossal cysts. If migration is incomplete ectopic thyroid tissue may lie at the base of the tongue. In adults the thyroid gland weighs about 20 g and lies in front of the thyroid cartilage, its two lobes connected by a narrow isthmus. It moves upwards with the thyroid cartilage on swallowing. Histologically, the thyroid gland is composed of follicles of varying diameter lined by a single-layered epithelium and arranged into lobules of 20-40 follicles, each served by a common blood supply. The gland is highly vascular, being supplied by two pairs of thyroid arteries which arise from external carotid (superior) and subclavian (inferior) arteries. There is a rich lymphatic drainage and adrenergic and cholinergic innervation. The gland also contains parafol1

912

MCQ 17.12

2

licular or C cells, which lie next to the follicle but do not abut the colloid. These cells, which arise from the last pair of pharyngeal pouches, secrete the calcium-lowering hormone calcitonin. The glycoprotein thyroglobulin (TG), which is rich in thyroxine residues, is the major constituent of colloid. The thyroid epithelial cells synthesize and secrete TG into the colloid. Later, they resorb it, cleave the thyroid hormones from the glycoprotein backbone and secrete them into the circulation. TG is both an integral part of the process of thyroid hormone synthesis and a major storage form of iodine and thyroid hormones within the thyroid.

Synthesis and secretion of thyroid hormones The thyroid gland contains about 90% of the body's total iodine, mainly in organic form. The thyroid cells actively transport the iodide into the cells by a process which is competitively inhibited by other anions of similar size, such as perchlorate. Iodide is then oxidized to iodine and incorporated into mono- and diiodotyrosine (MIT and DIT) residues on TG by the enzyme thyroid peroxidase (TPO). Favoured residues at particular sites on the TG molecule are then converted to thyroxine (T4) and triiodothyronine (T3) residues (principally the former), either by interaction with other DIT and MIT residues or by interaction with an oxidation product of DIT and MIT themselves. This process of 'organification' of iodine (which requires the action of TPO) takes place principally at the apical membrane of the thyroid cell, as TG is being formed and secreted into the colloid (Fig. 17.20). lodination is most active when iodide levels are low. TSH is the principal active regulator and exerts its action on a cell-surface receptor, mainly via adenylate cyclase. TSH accelerates iodoprotein synthesis and the resorption of colloid by a phagocytic process, followed by fusion with lysosomes. TG is then hydrolysed, facilitated by reduction of disulphide bonds in the molecule. lodotyrosine deiodinase removes iodine from liberated MIT and DIT, and this iodine returns to the iodide pool for iodination of more thyronine residues.

MCQ 17.13

FIG. 17.20 Thyroid hormone synthesis and release (see text for details).

17

FIG. 17.21 Structure of T4, T3 and reverse T3 R is the alanine residue (-CH2-CHNH2-COOH).

Circulation, action and metabolism of thyroid hormones T4 is the major form of thyroid hormone secreted by the thyroid; it is converted enzymatically to either T3 or reverse T3 (rT3) (Fig. 17.21), of which only the former is biologically active. Regulation of the activity of the relevant deiodinases, in the liver and in other tissues, is important both in health and disease. Generally, the production of T3 and rT3 is reciprocally controlled. T4 is a prohormone which becomes active by virtue of its conversion to T3. T4 is, however, the principal circulating form of thyroid hormone and is more than 99% bound to three plasma proteins thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA; also called transthyretin) and albumin. TBG has the highest affinity but the lowest capacity, followed by TBPA. T3 binds with lower affinity to TBG, also binds to albumin, but not at all to TBPA. In their bound states T3 and T4 are not biologically active. It is the concentration of unbound (or free) hormone that determines the level to which the target cells are exposed. The liver is the major site of degradation. Although much of the iodine is recycled some is inevitably wasted, being excreted principally in the urine as iodinated degradation products and inorganic iodide. Under normal circumstances this is matched by a daily intake of iodide of about 150-300 ug in non-iodine deficient areas. The normal circulating level of T4 (50-150 nmol/L) exceeds that of T3 (1-3 nmol/L) by 50-fold; the difference in their unbound concentrations is about 10 times less than this, because of both the lower binding of T3 to TBG and its failure to bind to TBPA.

Physiological changes in thyroid hormones Physiological changes in thyroid hormones are shown in Figure 17.22. The fetus derives a small yet potentially important amount of T4 but no TSH from the mother. During the second trimester the fetal pituitary-thyroid axis becomes active. Up to the time of birth fetal hypothy-

FIG. 17.22 Relative changes of serum total T4, T3, reverse T3 and thyroxine-binding globulin (TBG) in different physiological states and in illness.

roidism does not greatly impair fetal development unless the mother is also hypothyroid, in which case severe neurological damage results. This typically occurs in areas of iodine deficiency, causing endemic cretinism. Although T4 is secreted in the fetus, very little T3 is produced before birth, rT3 being the major product. After birth there is an immediate switch of hepatic metabolism of T4 from rT3 to T3, so that levels of T3 rise briskly during the first week of life. This change may well be important in adaptation to postfetal life. TBG levels in the fetus are low, and rise after birth. T3 levels throughout infancy and childhood tend to be higher than those of the adult. In pregnancy total T4 and T3 levels rise passively in response to an oestrogen-induced rise in TBG. A similar change is produced by oestrogen therapy. In a wide variety of conditions of stress and ill-health, hepatic production of T3 declines and that of rT3 increases. Exposure to extreme cold is associated with reduced production of rT3 and increased production of T3. 2

PATHOLOGY OF THYROID DISEASE The thyroid gland may be the subject of defective development, inborn biosynthetic errors, toxic or nutritional damage, autoimmune disease, and benign and malignant tumours. Many of these abnormalities give rise to enlargement of the gland and to the appearance of a goitre (thyroid enlargement). This may be focal (as in adenoma, cyst or carcinoma) or generalized, in which case it may be either multinodular or diffuse and smooth. Clinical assessment alone will often allow an accurate assessment of the cause of the goitre.

Autoimmune disease and the thyroid (see p. 889) The thyroid is the endocrine gland most commonly affected by autoimmune disease. Immune mechanisms are involved

913

in the pathogenesis of Graves' disease, 1 Hashimoto's thyroiditis and primary myxoedema. For reasons that are as yet unclear, these disorders are about five times more common in women than in men. Similar mechanisms may underlie these conditions, which frequently occur together in some families. Patients occasionally progress from Graves' disease to autoimmune hypothyroidism or vice versa. A combination of genetic, environmental and hormonal factors is involved in pathogenesis, some of which may also account for the frequent associations with other autoimmune disorders. In Graves' disease the TSH receptor is the critical antigen to which antibodies are produced. These antibodies can bind to the receptor, causing stimulation. Antibodies may also be produced to TG and TPO. The factors which determine what antibodies are produced in an individual case are uncertain. Measurement of circulating levels of relevant antibodies may be of diagnostic value. In general, however, the presence of antibody is rather non-specific. The most commonly measured antibodies (which are of the IgG class) are those against TG and TPO, which are present in about 10% of apparently healthy individuals, usually women. Antibody-positive subjects have a higher than normal chance of future thyroid autoimmune disease. TPO antibodies are present in 85% or more of patients with autoimmune thyroid disease. Very high litres indicate extensive lymphocytic infiltration and Hashimoto's thyroiditis. Antibodies to the TSH receptor Antibodies to the TSH receptor are of importance in the pathogenesis of Graves' disease and hypothyroidism. Thyrotoxicosis in Graves' disease is due to the presence of antibodies which bind to and activate the TSH receptor, thereby simulating the action of TSH. These are now best detected in assays using cells transfected with recombinant TSH receptor and determining adenylate cyclase activation. The assay is generally used only for research purposes but has clinical value in pregnant patients with Graves' disease. These antibodies can cross the placenta and cause thyrotoxicosis in the newborn infant. Measurement of TSH-receptor-stimulating antibodies at the beginning of the third trimester in the mother allows the detection of babies at risk. Other antibodies bind to the TSH receptor and block it, resulting in hypothyroidism. In most cases of myxoedema, however, the thyroid dysfunction is due to the destructive effect of cell-mediated immunity and cytotoxic antibodies.

Nutrition and thyroid disease There is a wide geographical variation in the incidence of goitre, which is only partly understood. Goitre is said to be

1

914

Fig. 17.11

2

MCQ 17.14

endemic when more than 10% of children in a population are affected: approximately 200 million people have endemic goitre worldwide. The major factors in endemic goitre are dietary iodine deficiency and the ingestion of goitrogenic substances that interfere with either the uptake or the organification of iodine. For example, cassava, a root crop eaten extensively in Africa, is rich in goitrogens. Women are particularly susceptible to goitre because of the demands of the fetus for iodine. Endemic cretinism is a neurological disease that afflicts the offspring of goitrous mothers in parts of the world where iodine is deficient, especially in the mountainous regions of New Guinea. It is completely prevented by providing the mother with iodized salt.

INVESTIGATION OF THYROID DISEASE Examination of the thyroid gland The thyroid should be carefully examined by observation from the front, and by palpation from behind while the patient swallows. The consistency of the gland should be assessed. In Graves' disease, the gland is typically diffusely enlarged. The swelling may be firmer with a carcinoma and associated with enlargement of local lymph nodes. Loss of mobility on swallowing is another sign suggesting malignancy. A midline swelling that moves up with protrusion of the tongue is likely to be a thyroglossal cyst or ectopic thyroid. A bruit over a goitre indicates a vascular gland and usually points to Graves' disease.

Laboratory assessment of hypo- ana hyperthyroidism Rodioimmunoassay The laboratory assessment of hypo- and hyperthyroidism is now extremely simple, thanks to specific radioimmunoassays for T3 and T4, to a specific and sensitive immunoradiometric assay for TSH, and (where relevant) to methods of assessing thyroid hormone binding. In most cases clinical assessment combined with a single measurement of serum T4 and TSH levels is sufficient. Serum TSH is a useful screening test, as a normal level rules out primary thyroid disease, but an abnormal level does not necessarily indicate clinical thyroid disease (Table 17.8). Estimation of the T4 and, sometimes, T3 level is therefore required to confirm the presence of thyrotoxicosis or hypothyroidism. In primary hypothyroidism T4 levels are low and TSH rises markedly. T3 remains normal for a long time in some patients owing to peripheral conversion of T4, and need not be measured. In the early stages, or in patients who have had a subtotal thyroidectomy, T4 and T3 levels are normal and TSH modestly raised. It is a matter of clinical judgement whether or not to treat such patients; at the least, regular follow-up is required. In most cases of symptomatic hypothyroidism TSH will be more than four times the upper limit of normal.

TABLE 17.9 Features of the sick euthyroid syndrome

TABLE 17.8 Causes of an abnormal TSH level Cause Elevated TSH

Suppressed TSH

Free thyroid hormone level

Clinical hypothyroidism Subclinical hypothyroidism (risk of future hypothyroidism) Transient: non-thyroidal illness (recovery phase) Pituitary tumour secreting TSH Thyroid hormone resistance syndrome

Low

Clinical thyrotoxicosis Recently treated thyrotoxicosis Multinodular goitre (risk of future thyrotoxicosis) Thyroid-associated ophthalmopathy (risk of future thyrotoxicosis) Pituitary failure Severe non-thyroidal illness First trimester of pregnancy Excessive thyroid hormone replacement

Elevated Normal

Normal Normal Elevated Elevated

Normal Normal Low Normal or low Normal Normal or raised

In secondary (pituitary) hypothyroidism one would expect TSH to be undetectable, but this is frequently not the case; T4 levels are low. In thyrotoxicosis serum TSH is low and T3 and T4 levels are elevated. In mild cases serum T3 may be raised before T4 (T3 toxicosis), and so is a more reliable test for early detection of thyrotoxicosis. Protein-binding tests Tests of protein binding have been widely used until recently. Oestrogens promote the hepatic synthesis of TBG along with other binding proteins; thus, the situation most commonly encountered, where the T4 is raised and protein binding has to be taken into account, is in a woman during pregnancy or taking the contraceptive pill. The test long used to elucidate this problem is an in vitro thyroid hormone uptake test, in which TBG in dilute serum and sephadex compete to bind radiolabelled T3. In most centres, however, this has been superseded by direct assay of the free T4 and free T3 levels. Although this is generally reliable, anomalies can rarely occur. Any thyroid function test may be misleading in the 'sick euthyroid' syndrome (Table 17.9). 2 Radioactive uptake tests The main isotope to be used diagnostically is 99mTc (as radiolabelled pertechnetate), a short-lived gamma-emitter with a half-life of 6 hours. Scans are of value in assessing the distribution of uptake within the gland, particularly when palpation is difficult. Uptake may be confined to one area in a functioning autonomous adenoma, as uptake by

17

• Occurs in many non-thyroidal illnesses, including trauma, infection, myocardial infarction, malignancy, inflammation, starvation, psychiatric illness. • The severity of the thyroid hormone changes correlate with mortality. • Patients are believed to be euthyroid, despite abnormal hormone levels, which are due mainly to the effects of cytokines. • The most common form of the sick euthyroid syndrome is a fall in serum T3; T4 levels fall with more severe illness. • TSH levels are low or undetectable in some patients with the most severe illness; TSH levels may rise in others, or during recovery. • Treatment with thyroid hormones has no proven benefit in the sick euthyroid syndrome, • Routine thyroid function testing in all sick patients is far more likely to uncover the sick euthyroid syndrome than unsuspected thyroid disease; thyroid function testing should be reserved for those in whom thyroid disease is suspected clinically. • Repeated thyroid testing after recovery demonstrates normal thyroid function and is useful if there is doubt about the diagnosis.

the rest of the gland is suppressed, or may reveal multiple areas of high uptake in toxic multinodular goitre. Uptake is usually absent in non-functioning benign or malignant nodules, and failure of uptake cannot reliably distinguish between these. Ultrasound Ultrasound is useful for demonstrating the size and nodularity of a goitre. Although it can also reveal cysts, ultrasound cannot exclude malignancy in the solid tissue around a cyst. Fine needle aspiration Fine needle aspiration of the thyroid is a simple and increasingly used first-line test in the diagnosis of thyroid masses, particularly to exclude malignancy. Interpretation requires expertise on the part of the histopathologist. However, once the technique is mastered it greatly reduces the need for thyroid scans or ultrasound, and for surgery on benign nodules.

PRIMARY HYPOTHYROIDISM: CONGENITAL AND JUVENILE Hypothyroidism may be present before birth or may develop at any time thereafter.

Congenital hypothyroidism The causes of congenital hypothyroidism are listed in Table 17.10. Endemic cretinism is a severe developmental disorder occurring in areas of endemic goitre in children born to goitrous and iodine-deficient mothers. Severe neurological defects (deaf-mutism, spasticity and motor impairment) are associated with variable hypothyroidism and

915

TABLE 17.10 Causes of congenital hypothyroidism Non-goitrous Complete failure of thyroid development Ectopic thyroid Endemic cretinism

Selected recommendations for hypothyroidism

Pituitary or hypothalamic insufficiency Transplacental transfer of TSH receptor blocking antibodies (transient) Goitrous Maternal antithyroid drugs Endemic cretinism Iodine treatment of mother Defects in thyroid hormone biosynthesis Iodide transport, organification defects lodotyrosine coupling defect lodotyrosine dehalogenase (iodine recycling) defect Abnormal iodoprotein secretion Thyroid hormone resistance syndrome

goitre. In non-goitrous areas congenital hypothyroidism occurs with a frequency of around 1 in 5000 births, and is due mainly to failure of normal development of the thyroid. It is usually not clinically apparent at birth, but may be diagnosed reliably within 1-2 weeks by TSH assay on a blood spot dried on filter paper; routine screening programmes are now widely established. Suggestive clinical features include postmaturity, hypothermia, enlargement of the posterior fontanelle, neonatal jaundice and delayed passage of meconium. Failure to diagnose and treat early leads to permanent retardation of physical growth and mental development, which by late infancy becomes gross. The baby may have feeding difficulty, failure to thrive, a protuberant abdomen, dry skin and hair, and delayed eruption of teeth, and is slow to reach the usual milestones. Screening and early treatment have virtually eliminated these features.

Juvenile hypothyroidism Hypothyroidism starting in childhood results in mental slowness but not permanent mental retardation. Features seen are less obvious than in the myxoedematous adult, but growth and sexual development are retarded, often markedly. Delay in body development principally affects the long bones and the bones of the face, which therefore appears immature. Epiphyseal dysgenesis with 'stippling' of the epiphyses on X-ray is common, and epiphyseal closure is delayed. Puberty is usually delayed, although, 1

916

Fig. 17.12

2

SUMMARY 7 Summary of the Royal College of Physicians of London Working Party guidelines for management of hypothyroidism and hyperthyroidism

MCQ 17.15

• Patients with hypothyroidism only require specialist referral if aged less than 16 years, pregnant or postpartum, hypopituitary, or presenting a management problem. • The correct dose of thyroxine is that which achieves euthyroidism and restores symptoms; this is usually achieved with normalization of the TSH level. • Patients with subclinical hypothyroidism and positive thyroid antibodies should receive thyroxine; those without antibodies require follow-up. • If there is any doubt about the need for thyroxine therapy, this should be stopped and serum TSH and T4 measured 6 weeks later. • Once thyroxine dosage is established, TSH and T4 levels should be measured annually. Selected recommendations for hyperthyroidism • All patients require specialist referral. • Prolonged medical treatment with antithyroid drugs is generally only indicated in Graves' disease. • Radioiodine is indicated in most types of hyperthyroidism, but caution is needed in the presence of active Graves' ophthalmopathy. • Thyroid surgery, performed by an experienced surgeon, is an alternative method of treatment, especially in patients with a large goitre or because of a patient preference for this treatment. • All patients require an annual check of thyroid function after treatment.

paradoxically, precocious puberty may also occur. Replacement therapy results in some catch-up growth and in spontaneous puberty (if this was delayed).

PRIMARY HYPOTHYROIDISM DEVELOPING IN ADULT LIFE Hypothyroidism with onset in adult life is almost always due to autoimmunity or previous treatment of thyrotoxicosis. It occurs in 1-2% of women, with a 5-10-fold lower prevalence in men.

Clinical features The onset is usually gradual and the symptoms are often attributed incorrectly to increasing age. Increasing lethargy, slowness, memory loss and depression are often coupled with increasing weight (without eating more) and cold intolerance. The skin becomes dry and the hair 'lifeless'. Hair loss is a major concern in some women. Puffiness below the eyes, especially in the morning, is frequently noted. 1 Other early signs include slowness in answering questions, a malar flush and delayed relaxation of the tendon reflexes (e.g. ankle jerks, if present, or biceps jerks). The voice may be husky or 'gruff. There is usually a relative or absolute bradycardia. Symptoms are referred to

131

SUMMARY 8 Clinical features of myxoedema • Symptoms include lethargy, increased weight, cold intolerance, mental slowing. • Signs include dry skin, puffy face, gruff voice. • Complications include serous effusion, psychosis, coma.

TABLE 17.11 Autoimmune polyglandular syndromes (APS)

Type 1 APS

Type 2 APS

I therapy) and a family history of thyroid disease should be sought. Although the complete picture is easy to recognize, the aim should be to make the diagnosis before overt thyroid failure develops, and serum T4 and TSH estimation allows this to be done. The commonest conditions with which hypothyroidism is confused are obesity and depression. With good clinical practice, gross myxoedema should be a thing of the past. In doubtful cases, thyroid function tests (TSH will suffice for screening) should be measured on a serum sample. 2

Main features*

Less frequent features

Autosomal recessive; rare

Alopecia and vitiligo

Investigation

Chronic mucocutaneous candidiasis

Ovarian failure

Hypoparathyroidism

Hypothyroidism

Addison's disease

Enamel hypoplasia Nail dystrophy

Autosomal dominant with incomplete penetrance; common

Alopecia and vitiligo

Autoimmune hypothyrodism

Coeliac disease

Graves' disease

Myasthenia gravis

TSH is raised and total and free T4 are low. T3 may remain normal for a long time. Investigations to establish the aetiology depend on the clinical setting. In a child, a thyroid scan may demonstrate ectopic tissue and, if a goitre is present, a perchlorate discharge test may rarely uncover an organification defect (Pendred's syndrome, associated with sensory nerve deafness). This test depends on the failure of iodide to be used in thyroxine synthesis; preadministered radioiodine can therefore be discharged from the gland when perchlorate is given. TG and TPO antibodies point to an autoimmune aetiology. It is important to carry out investigations to determine the extent of damage that has resulted from the hypothyroidism in a child, such as X-rays of bones and endocrine tests to assess pubertal stage. Juvenile hypothyroidism is sometimes confused with panhypopituitarism, but TSH will be low in the latter and high in the former. An ECG is important in the elderly patient with possible ischaemic heart disease; T4 replacement should be started cautiously, possibly under B-adrenergic blockade. Measurement of serum electrolyte levels may reveal hyponatraemia due to inappropriate ADH secretion.

Type 1 diabetes mellitus

Chronic active hepatitis

Addison's disease

Sjogren's syndrome Dermatitis herpetiformis Autoimmune pituitary disease

* Patients have two or more of these conditions.

many systems; constipation is common and may be associated with abdominal distension; in the nervous system, symptoms of carpal tunnel syndrome and a complaint of dizziness are common. Deafness is a frequent symptom owing to fluid in the middle ear. Rarely, the patient develops cerebellar ataxia or myotonia. There may be a firm, often irregular goitre (Hashimoto's thyroiditis) or the thyroid may be atrophic and impalpable (primary myxoedema). Hypercholesterolaemia predisposes to vascular atheroma, and angina in the untreated patient is particularly important, as treatment may precipitate myocardial infarction. Effusions may occur into any serous cavity - pericardial, pleural, peritoneal or joint spaces. Mild anaemia of macrocytic type is quite common; megaloblastic anaemia suggests coincidental pernicious anaemia. Other autoimmune disorders are often associated (Table 17.11). Menorrhagia and galactorrhoea (with elevated PRL) are often seen, with amenorrhoea in severe cases. In severe myxoedema patients are grossly retarded and may become psychotic when treated; rarely, however, they can also paradoxically appear mentally hyperactive (myxoedema madness). Hypothyroidism predisposes to hypothermia; it may also cause hyponatraemia. If hypothyroidism is suspected, a past history of thyrotoxicosis (with surgery or

17

Management In treating marked hypothyroidism it is important to be certain before commencing thyroid hormone that the patient is not hypopituitary or hypoadrenal, as decompensation of the adrenal failure may occur. If in doubt, hydrocortisone replacement should also be given until ACTH and/or cortisol deficiency has been excluded. In mild cases the patient can be commenced forthwith on 50-100 ug T4 a day, the higher dose being used for patients with high TSH levels (4-5 times or more above normal). Doses should be increased or decreased by 25ug every 2-3 months based on TSH levels, until these are within normal limits. More frequent sampling of TSH can be misleading. Once the TSH level is normal, the need for lifelong treatment should be stressed and an annual estimate of TSH levels should be performed to ensure the correct level of T4 is maintained. A computerized recall scheme is usually used for this. In severe cases, especially if there is ischaemic heart disease, replacement should be more cautious, starting with 25 ug of T4 daily or on alternate days.

917

TABLE 17.12 Features of myxoedema coma • Myxoedema coma is caused by decompensation of undiagnosed or poorly treated hypothyroidism, almost always in the elderly. • Mortality is around 50% even with treatment. • The three key features are hypothermia (as low as 24°C), altered mental state (confusion, psychosis or coma) and a precipitating cause - infection, trauma, congestive heart failure, myocardial infarction, stroke, or drugs that depress respiration. • Prompt treatment is essential and should not await biochemical confirmation. • Non-specific laboratory test abnormalities occur: hyponatraemia, hypoglycaemia, hypoxia, hypercapnia, elevated creatinine phosphokinase. • Ventilatory support is often needed. • Other supportive measures include i.v. fluids (avoid hypotonic fluids with low serum Na+), glucose for hypoglycaemia and gradual warming with space blankets (external warming may produce cardiovascular collapse). • Treat any underlying cause; empirical broad-spectrum antibiotics and hydrocortisone are usually given at the outset. • Replace thyroxine either as a single 500ug dose by nasogastric tube or as an intravenous bolus if a suitable preparation is available. An alternative is triiodothyronine, 10ug every 4-6 hours, given intravenously or orally.

Myxoedema coma (Table 17.12) with hypothermia carries a poor prognosis. There is no clearly established optimum form of thyroid hormone replacement: a large oral dose of T4 may be given by nasogastric tube, or parenteral T3 or T4 can be administered.

Prevention Thyroid failure cannot be prevented, but much can be done to ensure its early detection and treatment. Thyroid hormone replacement is the simplest form of therapy so, for practical purposes, prevention is by early detection. Patients previously treated for thyrotoxicosis should be offered annual follow-up testing of thyroid function to detect early hypothyroidism. This also applies to euthyroid subjects found to have thyroglobulin or thyroid peroxidase antibodies. Borderline thyroid function tests may present a problem; in such cases the tests can be repeated after a 3-month month interval and, if thyroid failure is developing, TSH will rise progressively. 1

THYROTOXICOSIS Thyrotoxicosis is common, with a prevalence of 1-2% in women in non-iodine deficient countries; men have a 10-fold lower prevalence. Most patients have autoimmune thyroid disease (Graves' disease). Thyrotoxicosis due to multinodular goitre, or to a toxic adenoma, is less common.

1

918

MCQ 17.16

Figs 17.13-17.17

There is a wide clinical spectrum of severity of thyroid hormone excess, of the systemic manifestations of the disease, the size and vascularity of the thyroid gland, and the extent to which other systems, notably the extraocular muscles and the skin, are involved in associated autoimmune disorders. Toxic multinodular goitre usually develops after the age of 50 against a background of many years of non-toxic goitre. It is therefore more common in areas of past or present iodine deficiency. For reasons that are not clear, focal autonomous nodule formation develops in the enlarged thyroid (detected as areas of increased radioiodine uptake), with associated thyrotoxicosis which is generally relatively mild in degree and associated with suppressed TSH. In toxic adenoma, an autonomous nodule (follicular adenoma) develops and progressively enlarges. It secretes an increasing amount of thyroid hormone until TSH is completely suppressed and (generally mild) thyrotoxicosis develops. This usually happens only when the nodule reaches 2.5 cm in diameter or more. Neither this disorder nor toxic multinodular goitre is associated with ophthalmopathy. In Graves' disease, antibodies to the TSH receptor stimulate the thyroid gland in ways analogous to the normal action of TSH. The disease presents most commonly in the third and fourth decades of life. Hyperthyroidism may be induced in incipient cases of Graves' disease or toxic multinodular goitre by high doses of iodine or iodinecontaining drugs (the Jod-Basedow phenomenon). Hashimoto's disease, which is also autoimmune in aetiology, may rarely be associated with mild thyrotoxicosis in the early stages, as may subacute (viral) thyroiditis. Occasionally, thyrotoxicosis is due to exogenous hormone consumption.

Clinical features of thyrotoxicosis History Typically, the patient develops weight loss, increased appetite, heat intolerance and sweating, and becomes anxious, nervous, restless, depressed, irritable and difficult to live with. A fine tremor is common, and proximal myopathy may cause muscle weakness, especially in the elderly. In women, menstrual disturbances, especially oligomenorrhoea, are common. Increased gut motility may lead to diarrhoea. Palpitations are common and symptoms of heart failure are especially likely in the elderly, often precipitated by atrial fibrillation. A goitre may be noted and complained of, especially if the gland is large and vascular. It rarely obstructs swallowing or breathing unless it is retrosternal. To assess the patient quickly when thyrotoxicosis is suspected, a clinical checklist, such as that given in Table 17.13, is useful. Examination Most of the features of thyroid hormone excess are due to increased sensitivity to circulating catecholamines. Part of

TABLE 17.13 Symptoms and signs of thyrotoxicosis Mechanisms Primary autoimmune process (specific for Graves' disease)

Thyroid hormone excess (found in all forms of thyrotoxicosis)

Symptoms

Signs

Exophthalmos, discomfort Diplopia, blurred vision Lesions on legs

Exophthalmos, congestion Ocular palsies, papilloedema, Pretibial myxoedema (rare)

Neck swelling, dysphagia Palpitations* Breathlessness

Goitre, bruit

Heat intolerance* Sweating* Increased appetite Weight loss Diarrhoea* Weakness Nervousness and irritability* 'Staring' eyes*

Resting tachycardia* atrial fibrillation, other arrhythmias* Heart failure Warm and sweaty* Increased bowel sounds Malabsorption Proximal myopathy Inability to sit still Emotional lability* Tremor* Lid retraction and lag (also due to autoimmune process)

* Signs and associated symptoms (partially) blocked by B-blockers.

the levator palpebrae superioris is sympathetically innervated, and overactivity causes a staring appearance. This may be associated with signs of anxiety, nervousness, tremor, sweating, tachycardia and supraventricular arrhythmias (notably atrial fibrillation). Other common features include increased reflexes and a proximal myopathy. The signs of thyroid-associated ophthalmopathy and pretibial myxoedema only occur in thyrotoxicosis caused by Graves' disease, and are described later. Thyroid hormones also stimulate the metabolic rate, probably both directly by inducing a number of metabolic enzymes, and indirectly through catecholamine sensitivity. Heat intolerance and weight loss (in spite of increased appetite) result. Features that may occur less frequently include myopathy, cardiac failure, hypercalcaemia, raised liver enzymes and ferritin, gynaecomastia and infertility. Gynaecomastia and infertility probably result from metabolic alterations of androgen and oestrogen metabolism, and increased sexhormone-binding globulin (SHBG) levels, which lead to an increased ratio of free oestradiol to testosterone. Thyrotoxicosis in the elderly may have few clinical features and can even masquerade as depression (apathetic thyrotoxicosis). For reasons at present unclear, a common presentation of thyrotoxicosis (often otherwise mild) in oriental men is with acute hypokalaemic flaccid paralysis.

Natural history of thyrotoxicosis Graves' disease Although it is difficult to be certain, it seems likely that, before treatment became available, up to a quarter of patients with Graves' disease had a spontaneous remission of their thyrotoxicosis. One reason for remission is that about 15% of patients will spontaneously become hypothyroid if followed long enough. The reverse pattern - hypothyroidism progressing to hyperthyroidism - is a rare but recognized presentation of Graves' disease.

17

Toxic adenoma and multinodular goitre Usually, these conditions gradually progress until the patient becomes overtly toxic. Remission does not occur.

Thyroid-associated ophthalmopathy (Fig. 17.23) This condition has been given various names (dysthyroid eye disease, infiltrative or Graves' ophthalmopathy) and remains one of the most puzzling clinical features of endocrinology.

Aetiology Ophthalmopathy occurs in Graves' disease but not in other causes of thyrotoxicosis, and is also infrequently found with autoimmune hypothyroidism. Some patients present with eye signs months or years before thyroid disease is apparent. An autoimmune process involves the extraocular muscles and appears to be indirectly linked with that causing the thyroid disease. The eye muscles become infiltrated with lymphocytes, swollen and ultimately fibrosed. Later, there is involvement of the retro-bulbar fat in the inflammatory process. Patients with Graves' disease who smoke are most likely to develop eye signs, for unknown reasons. Clinical features 2 The symptoms of dysthyroid eye disease include discomfort, grittiness, swelling, redness and pain in the eyes which is often most marked on wakening (because of orbital congestion on recumbency and exposure of the cornea during sleep). The patient may have noticed the development of 'bulging eyes' or diplopia. Occasionally presentation may be with visual failure owing to optic nerve compression by the enlarged extraocular muscles. The signs of a dangerous rise in ocular and orbital pressure are obvious conjunctival or periorbital oedema, painful eyes, exposure keratitis, retinal venous congestion and papilloedema. These should lead to urgent specialist referral. Management In most cases the symptoms and signs are mild and settle spontaneously. Local use of artificial tears is helpful to relieve grittiness, together with simple eye ointment at night, when the eyelids may need to be taped shut if there is corneal exposure. Periorbital and conjunctival oedema

919

FIG. 17.23 Eye signs in thyrotoxicosis and thyroid-associated ophthalmopathy A Eye signs in thyrotoxicosis: (1) lid retraction; (2) lid lag; (3) exophthalmos with conjunctival oedema; (4) strabismus with diplopia due to paralysis/tethering. Arrows indicate direction of gaze. B CT scan through orbits in a case of exophthalmos. Note oedematous and enlarged extraocular muscles (*). C Patient with typical features of ophthalmopathy, including periorbital oedema, lid retraction and exophthalmos. As is sometimes the case, signs are asymmetrical.

are helped by sleeping propped up and by diuretics. Severe congestive ophthalmopathy, particularly associated with visual impairment, is uncommon but requires urgent treatment, usually with systemic steroids in high dosage (e.g. prednisolone, 60-80mg daily). Radiotherapy to the orbits is used as an alternative in some centres. In severe cases, if improvement does not occur, or if deterioration follows gradual reduction in steroid dosage, orbital decompression may save vision. This usually involves removal of the medial wall of the orbit. Later (but only after the condition has been stable for 6 months or more), surgery may be indicated for diplopia that cannot be managed by refractive means (e.g. use of prismatic spectacles) or to improve appearance. Treatment-induced hypothyroidism can lead to deterioration in the eyes because of myxoedematous congestion. There is some evidence that radio-iodine therapy (see below) may also worsen ophthalmopathy. Careful follow-up or even prophylactic steroids (prednisolone in reducing doses for 3 months) 1

920

Fig. 17.18

2 2MCQ17.17 MCQ 17.17

should be offered to patients with eye signs receiving radio-iodine.

Pretibial myxoedema and thyroid acropachy Pretibial myxoedema occurs in 1-5% of patients with Graves' disease, 1 almost always in association with eye signs. There is purplish infiltration of the dermis of the skin over the anterolateral aspect of the lower legs and sometimes elsewhere (Fig. 17.24), and the surface resembles the skin of an orange. Pathology shows deposition of mucin between collagen bundles. Pretibial myxoedema may present incidentally, for cosmetic reasons, or because the lesion is itchy. Thyroid acropachy is even rarer, occurring in around 10% of patients with pretibial myxoedema. There is finger clubbing and periosteal reaction in the bones of the forearm. 2

Management of thyrotoxicosis Only Graves' disease is cured by antithyroid drugs, and even then only 40-50% of patients have a permanent

TABLE 17.14 Features of thyrotoxic crisis

17

A rare complication of poorly treated or untreated thyrotoxicosis. Mortality is 100% when untreated and 20% with treatment. A precipitating cause of the acceleration in thyrotoxicosis can usually be identified - thyroid damage due to surgery or radio-iodine, or severe illness such as trauma, non-thyroid surgery, infection, stroke, pulmonary embolus, diabetic ketoacidosis or parturition. Features include severe hyperthermia, marked tachycardia, congestive heart failure, nausea and vomiting, and progression from agitation to coma. Initial treatment is propylthiouracil 300 mg every 4 hours by nasogastric tube or per rectum. One hour after the first dose of propylthiouracil, stable inorganic iodine is given, which acutely retards thyroid hormone release, e.g. Lugol's iodine 8 drops every 6 hours, or ipodate 0.5 g every 12 hours. Dexamethasone 2 mg every 6 hours inhibits thyroid hormone release and T4-T3 conversion. Propranolol 40-80 mg every 6 hours is used to control the tachycardia, but should be used with caution in patients with heart failure. Supportive measures include external cooling, intravenous fluids, and treatment of the precipitating cause.

FIG. 17.24 Marked pretibial myxoedema extending over the feet.

remission. Remission occurs because the drugs not only reduce thyroid hormone synthesis (by inhibiting TPO) but also have an immunomodulatory effect. Traditionally, younger patients with Graves' disease have been treated with antithyroid drugs (carbimazole or propylthiouracil). If the condition relapses they have been offered subtotal thyroidectomy, whereas patients over about 40 years of age have been given radioactive iodine therapy. Different strategies are used in different centres, many physicians now prescribing 131I as definitive treatment for young patients, and others giving carbimazole long term. As a general principle, surgery should not be undertaken, nor 131 I given, while the patient is grossly thyrotoxic. The patient should first be made euthyroid with antithyroid drugs because there is a risk of precipitating a thyrotoxic crisis or 'storm' with 131I or surgery when the patient is still thyrotoxic (Table 17.14). Drug therapy The major antithyroid drugs used are thiourea compounds, of which carbimazole is usually used in the UK and methimazole and propylthiouracil in the USA. They are generally well tolerated, with reversible skin rashes developing in only about 1 % of cases, usually during the first 6 weeks of therapy. Arthralgia and hepatitis are less common. A rare but serious complication is agranulocytosis, which cannot be predicted. Patients should be warned in writing to stop the drug if they develop a sore throat, mouth ulcers or a fever, and to have a white cell count urgently, treatment being resumed if the neutrophil count is normal. Carbimazole is given at first in a dose of 40-60 mg daily, in three or four divided doses because of its short half-life.

This is tapered off after 3-4 weeks to a maintenance dose of 5-30mg daily (the titration regimen). An alternative policy is to continue carbimazole at 40 mg daily and maintain euthyroidism by adding in T4, 100-150 ug daily (the block-replace regimen). The latter achieves maximum remission rates after 6 months, whereas 18-24 months are usually needed for equivalent rates with the titration regimen. Graves' disease most commonly relapses within a year of stopping treatment but can recur up to 15 years later, and so annual follow-up should be arranged. Relapse is almost inevitable with a large goitre or if a second course of antithyroid drugs is given for a recurrence, and in some centres such patients are offered long-term antithyroid drugs. B-Adrenergic blocking drugs are useful for symptomatic treatment during the first 4-8 weeks until euthyroidism is achieved. Usually, small doses (e.g. 10-40 mg of propranolol three times daily) are sufficient. In mild cases, Bblockers alone may be used while the effect of 131I therapy is awaited. Potassium perchlorate is now no longer used because of a high incidence of toxic reactions. Thyroid surgery The indications for thyroid surgery are not clear-cut and depend largely on patient preference. Patients should be rendered euthyroid medically for 3 months before surgery is undertaken (see above). Surgery is particularly useful in thyrotoxic patients with large goitres, retrosternal goitres or toxic adenomas (although the latter also do well with radio-iodine). It is the treatment of choice for toxic multinodular goitre where there are obstructive symptoms (p. 924).

921

SUMMARY 9 Management of hyperthyroidism • Carbimazole is usually the first treatment for patients of all ages. • B-Blockers are useful symptomatically for the first 1-2 months. • Surgery is considered for failed medical treatment, especially in children and adolescents and large goitres. • 131I is considered for older patients and for toxic adenomas. • All patients should have regular follow-up.

Pre- and postoperative management Potassium iodide is generally administered by mouth in a dose of at least 5mg daily (many surgeons use much more) for 7-10 days before operation. This blocks the release of thyroid hormones but also, more importantly, leads to a marked accumulation of colloid in the thyroid follicles and, partly as a consequence of this, reduces the vascularity of the gland. Laryngoscopic examination of the cords is often undertaken routinely before surgery. Most surgeons remove about seven-eighths of the gland, taking care to identify and preserve the parathyroid glands and, of course, the recurrent laryngeal nerves. Serum calcium levels should be checked 12 and 24 hours after surgery. Hypoparathyroidism is uncommon, often transient, and can be treated with alfacalcidol (initially lug daily). Other early complications include bleeding and laryngeal oedema; later, hypothyroidism or a recurrence of thyrotoxicosis can occur. Radio-iodine treatment This is the treatment of choice for toxic multinodular goitres and is being used increasingly for Graves' disease and toxic adenoma. There are many dosage regimens, based on the size of the gland, the age and health of the patient and, in some cases, on preliminary isotope uptake studies. None has proved superior. One practical, simple scheme is to give 200 MBq radio-iodine with a small goitre, 400-600MBq with a moderate-large goitre and 800 MBq in severe thyrotoxicosis, in elderly patients with heart problems or atrial fibrillation and with a nodular goitre. Antithyroid drugs should be stopped for a few days beforehand and can then be restarted 7-10 days afterwards, but are not required routinely. There is an acute effect in the first few weeks or months and a more prolonged effect thereafter. Around 10% of patients become hypothyroid within a year and 3-5% do so each year thereafter. Patients should be told of this complication and reassured that it is easily treated. There does not appear to be any increased risk of cancer after 131I therapy. The treatment is obviously contraindicated in pregnancy and breast-feeding, and pregnancy should be avoided for 4-6 months after treatment.

1

922

Figs 17.19,17.25

Radio-iodine may worsen existing thyroid-associated ophthalmopathy. As with other treatments, all patients should be offered regular follow-up, usually by means of a computerized recall scheme. Management of thyrotoxicosis in the elderly In the elderly the same principles of management of thyrotoxicosis apply, except that surgery is rarely indicated. When atrial fibrillation is present it is advisable to anticoagulate the patient or give aspirin (if there is no contraindication). Cardioversion may be undertaken if the patient is off digoxin and does not revert to sinus rhythm spontaneously. Treatment of toxic adenoma is either surgical excision or, particularly in the elderly or frail, 131I. Thyrotoxicosis and pregnancy A number of autoimmune conditions commonly improve during pregnancy, probably due in part to hormonal changes. Graves' disease often enters remission during pregnancy and relapses in the puerperium. It is important to avoid overtreatment with antithyroid drugs during pregnancy. In the fetus these can cause hypothyroidism, increased TSH secretion and thyroid enlargement (which may cause respiratory obstruction in the newborn). It is therefore the rule to avoid the block-replacement regimen and keep the mother on the minimum dose needed to maintain euthyroidism, and usually to discontinue the drug in the last trimester. If the level of thyroid-stimulating antibodies (which can cross the placenta) is high this may lead to significant thyroid stimulation in the baby and neonatal thyrotoxicosis. As the level of antibodies declines, so does the thyrotoxicosis. The infant is treated with B-blockers and carbimazole until the condition subsides spontaneously. Neonatal thyrotoxicosis can be predicted by measuring maternal levels of thyroid-stimulating antibodies in the last trimester and by fetal tachycardia and failure to thrive. All babies born to mothers with Graves' disease should have urgent thyroid function tests at birth (and 4-7 days later if the mother is on antithyroid drugs, as these may have crossed the placenta and masked neonatal thyrotoxicosis).

OTHER THYROID DISORDERS Simple diffuse goitre Simple diffuse goitre 1 with euthyroidism is common, especially in women, and declines with age. The aetiology is poorly understood. Most such goitres are TSH dependent and generally diminish on T4 in replacement doses, but treatment is not generally needed. Pseudogoitre is also common. Here, a normal gland is readily visible because it is high-lying, usually in a girl with a long neck.

17

CASE STUDY 17.2 WEIGHT LOSS AND TREMOR A 33-year-old nurse developed tremor and heat intolerance over 2 months. At the same time she noticed a 3 kg weight loss, but was attempting to diet anyway. Although she was continuing to work, she felt more tired than usual and her partner had commented on her irritability. She had recently returned to work, having had a baby 6 months previously. Her periods were regular and she had not experienced palpitations, but was occasionally aware of her heart 'racing'. There was no significant past medical history. Her aunt had been treated for hypothyroidism. She smoked 10 cigarettes a day, drank no alcohol and was taking no medication. On examination, she was slim and rather anxious. There was a fine tremor of her outstretched hands, the palms were warm and sweaty and the pulse was 92 in sinus rhythm. Examination of the neck revealed a small, firm, diffuse goitre which was mobile, non-tender and not associated with lymphadenopathy. There were no eye signs. The reflexes were symmetrically brisk and the remainder of the examination was normal.

Discussion The symptoms and signs are very suggestive of thyrotoxicosis. The main differential diagnosis is anxiety, but the heat intolerance, warm extremities and goitre all make this less likely. Phaeochromocytoma and other causes of weight loss are much less likely without other symptoms and signs. Once a diagnosis of thyrotoxicosis is suspected, the next step is to confirm the diagnosis of excess thyroid hormone production. This is achieved by measuring the serum TSH and free T4; measurement of free T3 is indicated if the TSH is suppressed and the free T4 is normal, to rule out T3 toxicosis. If thyrotoxicosis is confirmed, the cause must be established. The commonest cause is Graves' disease in a woman of this age, and she has a family history of thyroid autoimmunity, which would be compatible with Graves' disease, as would the character of the goitre. There is no thyroid-associated ophthalmopathy, which would clinch the diagnosis, but these signs are absent in 50% of cases. She has recently had a baby, and this suggests the alternative possibility of

postpartum thyroiditis. Against this diagnosis is the duration of symptoms: thyrotoxic symptoms rarely last more than 4 weeks and are not severe in postpartum thyroiditis. However, the postpartum period is also a time of increased risk for the development of Graves' disease, and there is therefore a need to distinguish between these two conditions. A 99mTc scan will reveal increased isotope uptake and confirm the diffuse goitre in Graves' disease; in postpartum thyroiditis the isotope is not taken up by the damaged gland. Thyroid peroxidase antibodies are found in both conditions and will not help to distinguish them, but the presence of these antibodies tends to rule out other causes of thyrotoxicosis. In this patient the TSH was <0.03 mU/L, FT4 35nmol/L and FT310.9 pmol/L. Thyroid peroxidase antibodies were positive and there was a diffuse goitre with elevated 99m Tc uptake after radionuclide administration. This confirmed the diagnosis of Graves' disease and treatment with carbimazole was started.

Questions 1, What are the most likely causes of this woman's symptoms? 2, What investigations are indicated?

Diffuse multinodular goitre

Management of multinodular goitre

Diffuse multinodular goitre is common, but poorly understood. In western countries, where dietary iodine is sufficient, new cases are now seldom due to iodine deficiency. The high prevalence in many underdeveloped parts of the world is due in part to the ingestion of goitrogens, e.g. cassava. Eventually in multinodular goitre, the nodules (which are initially TSH dependent) may become autonomous and thyrotoxicosis develops.

In the early stages, non-toxic goitre will often respond either to suppression of TSH with exogenous thyroid hormones, or to removal of the cause (goitrogens or iodine deficiency). Once autonomous nodules have developed, TSH suppression with T4 is much less effective, and iodine administration carries the risk of precipitating hyperthyroidism. The chances of a successful response are highest if TSH levels are not suppressed before giving T4.

923

RECENT ADVANCES SIMPLE GOITRE

THE TREATMENT OF

Diffuse non-toxic goitre is common and affects 5-10% of the population. Those affected are euthyroid. Women are three to four times more likely to develop a goitre, with a peak incidence between the ages of 20 and 30. In up to half of these subjects the goitre may disappear spontaneously, but in the remainder it may progress and cause cosmetic problems or even compressive symptoms. The aetiology is unknown, but a proportion of such goitres become multinodular, which may in turn cause hyperthyroidism. The traditional method of treatment is surgery or thyroxine treatment. Recurrence occurs in around 20% of goitres treated surgically. Thyroxine, in doses sufficient to suppress TSH levels, decreases goitre size modestly in two-thirds of patients but there is a risk of atrial fibrillation developing. Thyroxine is ineffective in patients whose TSH is already low, but is the treatment of choice in a goitre associated with a high TSH: in such patients the diagnosis is autoimmune hypothyroidism rather than simple goitre. Radio-iodine has recently been used to treat simple goitre. The mean reduction in goitre size is around 50% and hypothyroidism, in the short term, occurs in 50%. This treatment seems equally effective in non-toxic nodular goitre. Best results are obtained when the goitre is small. It therefore appears that radio-iodine is an effective treatment for simple goitre, in the absence of hyperthyroidism. Such treatment spares the patient the risks of surgery or suppressive thyroxine treatment, at the expense of hypothyroidism requiring replacement doses of thyroxine. Toxic multinodular goitre is usually treated with 131I therapy, though it is often relatively resistant and repeated doses may be needed. Patients should generally be rendered euthyroid with carbimazole first. Where the goitre is large or causing severe obstructive symptoms (especially pressure on the trachea), surgery is the treatment of choice, especially as 131I therapy may temporarily cause further thyroid enlargement. Tracheal compression is best confirmed by analysing flow-volume loops and by CT scanning. 1 Familial goitre There are a number of rare conditions where defects in thyroid hormone synthesis lead to goitre. Most are autosomal recessive. The commonest is Pendred's syndrome, caused by an iodine organification defect (as a result of mutation in the pendrin gene) and nerve deafness.

1

924

Fig. 17.20

2

Case 17.2

3

MCQ 17.18

Riedel's thyroiditis Riedel's thyroiditis is a rare condition of unknown aetiology associated with woody hard fibrous infiltration of the thyroid gland and surrounding tissues. Some patients have more widespread disease, including mediastinal and retroperitoneal fibrosis and sclerosing cholangitis.

Subacute (de Quervain's) thyroiditis 2 This commonly presents with acute painful generalized swelling of the thyroid gland, fever, and mild thyrotoxicosis followed by transient hypothyroidism. The ESR is raised and radionuclide uptake by the thyroid is low, in contrast to non-destructive types of thyrotoxicosis. Destruction by one of many different viruses leads to the release of stored hormone and later impaired thyroid function, accounting for this clinical picture. Treatment is with aspirin or, for moderate or severe disease, a short course of prednisolone, beginning at 40 mg daily and tapering over 6-8 weeks.

Localized thyroid swellings Apparently solitary thyroid nodules are common, affecting around 5% of the population, but only 1-2% of these are malignant. Over two-thirds of carcinomas are papillary (more in areas of high iodine intake), which have a very good prognosis, metastasizing via lymph nodes. Follicular carcinomas account for 10-15% of cases and also have a good prognosis, particularly in younger patients; bloodborne metastases occur especially in lung, liver and bone. Anaplastic carcinomas account for 5-10% of tumours and are commonest in the elderly. They are highly malignant and have a poor prognosis. All these tumours are derived from the thyroid epithelial cell. About 5% of thyroid carcinomas are of different origin, being derived from the calcitonin-secreting parafollicular C cells. These are the medullary carcinomas, associated with high circulating levels of calcitonin. They are sometimes familial and may be associated with multiple endocrine adenomatosis type 2 (see p. 939). Lymphoma of the thyroid is a rare but important complication of Hashimoto's thyroiditis. Clinical features are unhelpful in most patients, but malignancy should be suspected more strongly with a hard, fixed mass; rapid enlargement; lymphadenopathy; or a change in voice. Both a cystic lesion and a dominant nodule in a multinodular goitre (Fig. 17.25) have a reduced but still appreciable risk of malignancy compared to a solid lesion. Most centres now use fine needle aspiration biopsy in the initial investigation of isolated thyroid swellings, sometimes supplemented by thyroid scans or ultrasound. A toxic adenoma should be excluded by measuring TSH and free T4. If doubt remains, the nodule is removed surgically.

Management of thyroid cancer Where possible, thyroid carcinomas are treated surgically. 131 I therapy is of value if the carcinoma takes up the

RECENT ADVANCES IN POSTPARTUM THYROIDITIS (PPT)

17

PPT is defined as the appearance of thyroid dysfunction, usually based on biochemical evidence, within the year after delivery. It is due to transient autoimmune destruction. PPT is common, affecting 5% of women postpartum, and may be predicted by the presence of thyroid peroxidase (TPO) antibodies in the first trimester. At present it is unclear whether such screening is worthwhile, as the condition is usually mild and self-limiting and does not require treatment. However, recent evidence suggests that 10-20% of such women will develop permanent autoimmune hypothyroidism within 10 years, and that postpartum depression is more severe in women with TPO antibodies. Future studies will determine the value of screening all pregnant women. At present, patients with type 1 diabetes are known to have a threefold increased risk of PPT and should be screened: a high index of suspicion should be maintained for the emergence of thyroid dysfunction in other women during the postpartum period. FIG. 17.25 Dominant left-sided nodule in a multinodular goitre

Bodenner D L, Lash R W 1998 Thyroid disease mediated by molecular defects in cell surface and nuclear receptors. Am J Med 105: 524-538. Hermus A R, Huysmans D A 1998 Treatment of benign nodular thyroid disease. N Engl J Med 338:1438-1447. Le Moli R, Wesche M F T, Tiel-van Buul M M C, Wiersinga W M 1999 Determinants of longterm outcome of radioiodine therapy of sporadic non-toxic goitre. Clin Endocrinol 50: 783-789. Lindsay R S,Toft A D 1997 Hypothyroidism. Lancet 349: 413-417. Schlumberger M J 1998 Papillary and follicular thyroid carcinoma. N Engl J Med 338: 297-306. Vanderpump M P J, Ahlquist J A O, Franklyn J A, Clayton R N 1996 Development of guidelines for good practice and audit measures in the management of hypothyroidism and hyperthyroidism. Br Med J 313: 539-543. Weetman A P 1997 Hypothyroidism: screening and subclinical disease. Br Med J 314:1175-1178. Weetman A P 2000 Graves' disease New Engl J Med 343:1236-1248. The use of radioiodine in the management of hyperthyroidism 1995. Royal College of Physicians, London.

isotope, and is required for patients with residual and metastatic disease. Uptake only occurs in papillary and follicular tumours. If the patient has had a subtotal or near total thyroidectomy, the remaining normal thyroid is ablated with a high dose of 131I. Thyroid hormone replacement therapy is then started and continued for 6 weeks. It is then withdrawn to allow TSH levels to rise, following which an ablative dose of 131I is given to treat metastatic or persistent local disease. T3 is often used initially instead of T4, as less time is needed off treatment to achieve high TSH levels, but patients may none the less experience hypothyroidism. This can now be avoided by giving recombinant TSH to achieve the necessary levels for 131I uptake, but recombinant TSH is expensive. Treatment with 131I can be repeated as long as isotope scans show persistent metastatic or local disease. Measurement of circulating TG levels is useful in monitoring for relapse of differentiated carcinoma. Anaplastic cancers, and those that do not take up 131 I, are treated with radiotherapy to the local tumour. Results of treatment of metastatic disease with chemotherapy are disappointing. Lymphoma is treated with radiotherapy or chemotherapy. 3

ANATOMY AND PHYSIOLOGY

FURTHER READING ON THE THYROID GLAND

The gross anatomy of the adrenal glands is shown in Figure 17.26. The adult adrenal glands weigh 4-5 g each and are situated at the upper poles of the kidneys.

Amino N,Tada H, Hidaka Y, Crapo L M, Stagnaro-Green A 1999 Screening for postpartum thyroiditis. J Clin Endocrinol Metab 84:1813-1821. Bartalena L, Pinchera A, Marcocci C 2000 Management of Graves' ophthalmopathy: reality and perspectives. Endocrine Revs 21:168-199.

THE ADRENAL GLANDS

The adrenal cortex The cortex, whose role is to secrete steroid hormones, consists of a capsule, a subcapsular layer (the zona glomerulosa), the middle zone (zona fasciculata) and a zona

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FIG. 17.27 Two-dimensional structures of three adrenal steroids aldosterone, cortisol and dehydroepiandrosterone sulphate

ences between the three zones are due to the presence or absence of a few critical enzymes.

Physiological control of the adrenal cortex

FIG. 17.26 Coronal section through the adrenal gland

926

reticularis. The latter envelops the adrenal medulla. The blood supply runs from the cortex to the medulla. All the steroid-secreting cells appear to be of common origin. Cell division occurs between the zona glomerulosa and zona fasciculata, and cell cords loop up through the zona glomerulosa and then down through the zona fasciculata to the zona reticularis, cells changing function as they go. In utero the glands are much larger and the cortex is dominated by a large innermost (fetal) zone, which degenerates shortly after birth. The zona glomerulosa synthesizes and secretes mineralocorticoids, of which the most important is aldosterone. The zona fasciculata synthesizes cortisol, and the reticularis and fetal zone the weak adrenal androgens, notably dehydroepiandrosterone (DHEA) and its sulphate. The fetal zone appears to develop as a consequence of the high levels of ACTH and oestrogen in utero. Oestrogens impair cortisol synthesis by inhibiting the action of the enzyme 3B-hydroxysteroid dehydrogenase. The two-dimensional structures of aldosterone, cortisol and dehydroepiandrosterone sulphate are shown in Figure 17.27. The basic pathways of steroidogenesis in the adrenal cortex are set out in Figure 17.28. The functional differ-

M ineralocorticoids Aldosterone is the most potent adrenal steroid; about 100 ug are secreted per day, compared to 10 mg for cortisol. Aldosterone acts on intranuclear mineralocorticoid receptors in the distal renal tubule to promote sodium uptake and potassium secretion. The receptor does not distinguish between mineralocorticoids and glucocorticoids. Specificity is conferred by rapid local conversion of cortisol to cortisone (by the enzyme llB-hydroxysteroid dehydrogenase), which ensures that aldosterone alone is available to the receptor. Normally, cortisone produced in the kidney is then 'shuttled' back to cortisol by the reciprocal enzyme in the liver. Liquorice can inhibit the renal enzyme and hence lead to excess mineralocorticoid action. Rare genetic defects in llB-hydroxysteroid dehydrogenase also produce hypertension and hypokalaemia. The synthesis and secretion of aldosterone are relatively independent of ACTH secretion. The major control factors are angiotensin II and the extracellular sodium and potassium concentration (see Fig. 20.25, p. 1073). Angiotensin II acts through cell surface receptors by activation of phospholipase C (p. 885), and principally stimulates enzymes late in the biosynthetic pathway. Renin is an enzyme secreted by the juxtaglomerular apparatus, which acts on angiotensinogen (of hepatic origin) to release the decapeptide angiotensin I. This is then converted to the active octapeptide angiotensin II in peripheral tissues, including lung, by angiotensin-converting enzyme (ACE). Glucocorticoids Glucocorticoids, of which the main one in humans is cortisol (hydrocortisone), have a wide range of actions on many

17

FIG. 17.28 The major steroid pathways in adrenal zona glomerulosa, fasciculata and reticularis, plus ovary or testis The balance of steroids secreted is determined by the enzymes present (represented by arrows).

different cells and tissues. They have a major influence on glucose homeostasis, with catabolic actions on muscle and enhanced hepatic gluconeogenesis. In their absence, the response to stress of any kind is greatly impaired. Glucocorticoids inhibit the immune system, repair processes and collagen synthesis in bone and soft tissues. They also modify the effect of many other hormones on a range of cell types. Glucocorticoids are secreted episodically, with a pronounced diurnal variation. It is probable that they facilitate the immediate requirements of daytime activity while inhibiting other processes, such as tissue repair, which then occur at night. Adrenal androgens Apart from their role as oestrogen precursors in utero, adrenal androgens appear to be of relatively minor importance. Increased synthesis before puberty (the adrenarche) contributes to the development of secondary sexual hair.

The adrenal medulla The adrenal medulla receives a sympathetic nerve supply, which is responsible for initiating adrenaline (epinephrine) secretion in response to stress. Its blood supply comes largely from the adrenal cortex and is therefore very rich in cortisol. The pathway of adrenaline synthesis from tyrosine, derived from the diet or synthesized by the liver from phenylalanine, is indicated in Figure 17.29. The last stage is cortisol dependent; cortisol appears to control the synthesis of the enzyme phenylalanine N-methyl transferase.

FIG. 17.29 Pathway for the biosynthesis of adrenal catecholamines

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Adrenal glands and the response to changes in trophic hormones Chronic ACTH excess leads to hypertrophy of the adrenal cortex, particularly the zona fasciculata-reticularis, and to alterations in the blood vessels. In some individuals the chronic consequence appears to be multinodular hyperplasia, in which the nodules of hyperplastic tissue tend to become semi-autonomous; rarely, malignant tumours may develop in these nodules. Chronic ACTH insufficiency leads to adrenal atrophy. The zona glomerulosa continues to function under the trophic stimulation of angiotensin II, so that the picture is predominantly one of glucocorticoid (and adrenal androgen) deficiency, rather than of mineralocorticoid lack.

INVESTIGATION OF ADRENAL DISORDERS Methods once considered essential have been supplanted by direct, simple, cheap and reliable techniques. For example, chemical methods for the analysis of steroid metabolites have now been largely replaced by radioimmunoassay of the levels of the steroids themselves. The clinical investigator should only use such tests as are necessary to answer a question beyond reasonable doubt. Electrolyte disturbances may provide an important clue to the presence of an adrenal disorder.

Mineralocorticoid assays Aldosterone can be measured by radioimmunoassay in serum or urine; plasma renin measurements are also reasonably reliable. Provided the patient is not on diuretics and the electrolyte levels are known, renin and aldosterone measurements in lying and standing positions are helpful in the investigation of suspected mineralocorticoid disorders, notably in the diagnosis of primary hyperaldosteronism.

Adrenal androgen assays A virilizing tumour of the adrenal in women can be excluded by measuring serum testosterone levels (p. 951). Plasma androstenedione and DHEAS assays are available but contribute little extra to the practical management of hirsutism or adrenal disorders.

Use of dynamic function tests Adrenal function is intrinsically dynamic, and much can be learnt from examining spontaneous changes in activity, e.g. diurnal changes in serum cortisol. Repeated 9 a.m. and midnight samples will be helpful in diagnosing Cushing's syndrome, where there is loss of the diurnal rhythm and levels remain high in the evening. In contrast, there is little point in taking late evening samples in a patient with suspected cortisol deficiency, as cortisol levels are normally low at that time.

Cortisol assay

928

The urinary free cortisol excretion in 24 hours correlates well with both the cortisol secretion rate (a tedious radioisotopic measurement) and the mean 24-hour free plasma cortisol level. It is more widely used to diagnose hyper- than hypocortisolism. Random serum cortisol assays have the disadvantage that the hormone is normally secreted episodically, so that repeated measurements are usually needed for reliable interpretation. However, any morning cortisol value below l00nmol/L supports a diagnosis of hypoadrenalism, and one above 400 nmol/L virtually excludes this diagnosis. The midnight cortisol assay, taken while the patient is asleep (often used in the investigation of Cushing's syndrome), has the disadvantage that stress can cause its elevation, even in normal individuals. Also, the patient has to be admitted to hospital, which makes it expensive. Assays for precursors of cortisol are of use in diagnosing enzyme deficiencies or assessing drug-induced enzyme blocks; they include 17-hydroxyprogesterone (or its urinary metabolite pregnanetriol) and 11-desoxycortisol. The two-site immunoradiometric assay has made the plasma ACTH assay more sensitive and reliable. An elevated ACTH level is found in Addison's disease and ACTH-dependent forms of Cushing's syndrome, but ACTH is undetectable when Cushing's syndrome is due to an adrenal tumour.

Suppression tests (Fig. 17.30) The most useful suppression test involves the administration of dexamethasone (which does not cross-react in the cortisol assay), with subsequent measurement of serum cortisol. The overnight dexamethasone suppression test involves the patient taking 1 mg of dexamethasone orally at midnight, with a serum sample being taken for cortisol assay 8 hours later. In a normal individual dexamethasone suppresses the morning secretion of ACTH, so that the morning serum cortisol value is low. This can be done without admitting the patient and is a useful screening test for Cushing's syndrome. Failure to suppress indicates Cushing's syndrome or excess metabolism of dexamethasone due to enzyme induction by alcohol, or drugs such as phenytoin and carbamazepine. Depression, obesity and pregnancy may also cause false positive tests. Confirmation of Cushing's syndrome involves the use of low-dose (0.5 mg 6-hourly for 48 hours) suppression with dexamethasone; serum and sometimes urine cortisol levels are assayed. The high-dose dexamethasone suppression test is used to distinguish between the causes of Cushing's syndrome. After 2mg dexamethasone 6-hourly for 48 hours there is at least 50% suppression of serum cortisol in pituitary-dependent (but not other forms of) Cushing's syndrome. Unfortunately, false positive and false negative results occur with this test.

and has been used to differentiate between pituitarydependent Cushing's syndrome, in which ACTH and cortisol precursors rise, and ectopic ACTH syndrome, in which there is no response. It is no longer widely used. Petrosal sinus sampling plus CRH testing is now the most reliable way to distinguish between these two types of Cushing's syndrome. Catheters are inserted via the femoral veins into the inferior petrosal sinuses, where ACTH levels can be measured directly after release from the pituitary. A gradient between petrosal and peripheral vein ACTH levels indicates Cushing's syndrome due to a pituitary adenoma, whereas with an ectopic source of ACTH the two levels will be similar. Administration of CRH and demonstration of a rise in petrosal sinus ACTH levels further strengthens the diagnosis of a pituitary corticotroph adenoma. The CRH test with peripheral blood sampling alone can be used prior to petrosal sinus sampling, as a 50% or greater rise in ACTH or cortisol is strongly suggestive of a pituitary rather than an ectopic source of ACTH in Cushing's syndrome.

17

Investigation of the adrenal medulla

FIG. 17.30 Dexamethasone suppression test A Normal feedback mechanism for cortisol production. B Normally, dexamethasone suppresses ACTH and hence cortisol production, [c] In Cushing's syndrome due to pituitary or ectopic ACTH excess, or adrenal adenoma, dexamethasone has no effect, and cortisol is not suppressed.

Stimulation tests The short synacthen test is generally used to identify adrenal insufficiency. Synacthen is synthetic ACTH; i.m. injection of 250 ug should produce a rise in cortisol to 550 nmol/L 30-60 minutes later. This does not occur in primary or secondary adrenal failure, but the test is unreliable if secondary failure is recent (e.g. after pituitary surgery). In this situation the insulin tolerance test (Fig. 17.13, p. 899) should be used. In some centres a low-dose (lug) synacthen test is used, as this is believed to be more physiological and sensitive. Primary and secondary adrenal failure are usually distinguished by measuring serum ACTH levels, which are high in the former and low in the latter. An alternative is to give synacthen repeatedly for 4-5 days (the long synacthen test). A cortisol response will be found only in secondary adrenal failure. Corticotrophin-releasing hormone (CRH) can be of value in distinguishing pituitary-dependent ACTH secretion (where ACTH responds to CRH) from ectopic ACTH secretion (where there is no response). Metyrapone blocks the last stage in cortisol biosynthesis

The diagnosis of phaeochromocytoma is confirmed by one or more of a number of methods for measuring catecholamines or their metabolites. The simplest is the urinary excretion of vanillylmandelic acid (VMA), but urinary metanephrines are more reliable. Serum assays for noradrenaline (norepinephrine) and adrenaline (epinephrine) taken lying and standing and their metabolites, normetanephrine and metanephrine, are also of considerable diagnostic value. The clonidine suppression test is useful in difficult cases: prompt suppression of plasma catecholamines normally occurs after giving 0.3mg of this a2-agonist.

Radiological methods CT scanning is particularly valuable in localizing adrenal tumours of the cortex and medulla (Fig. 17.31). Radioisotope scans using a labelled catecholamine precursor (131I-MIBG) are useful to localize phaeochromocytomas.

DISEASES OF THE ADRENAL CORTEX ADRENOCORTICAL INSUFFICIENCY Aetiology The major causes of adrenal insufficiency are shown in Table 17.15. Acute adrenal destruction occurs in septicaemia, particularly that due to meningococcus (the so-called Waterhouse-Friedrichsen syndrome). Meningococcal septicaemia is associated with purpura and haem-

929

TABLE 17.15 Causes of adrenocortical insufficiency Primary (High ACTH) Congenital/familial Adrenal enzyme defects (usually 21-hydroxylase deficiency) Congenital adrenal hypoplasia Adrenal leukodystrophy Acquired Infections - tuberculosis1 - histoplasmosis - HIV infection Autoimmune1 Vascular - meningococcal septicaemia and haemorrhagic destruction - thrombosis (adrenal vein catheterisation) Neoplastic - secondary carcinoma Degenerative - amyloid Drugs - ketoconazole, etomidate, metyrapone Secondary (Low ACTH) Hypopituitarism Isolated ACTH deficiency Glucocorticoid therapy Enhanced glucocorticoid metabolism Drug-induced, e.g. rifampicin*, carbamazepine 1 These commonly present as Addison's disease (chronic adrenal insufficiency with pigmentation). * Important - may precipitate adrenal failure if already compromised, e.g. in tuberculosis. Accelerated hepatic steroid metabolism enhances steroid requirements.

FIG. 17.31 CT scan of the adrenal glands In A the scan shows an adrenal adenoma (arrowed) in a patient with Cushing's syndrome; in B there is bilateral adrenal enlargement (arrowed) due to ectopic ACTH secretion in a patient with pancreatic carcinoma and Cushing's syndrome.

orrhage, including massive haemorrhagic destruction of the adrenals. Untreated, it leads rapidly to circulatory collapse and death. Chronic destruction of the adrenal glands is most commonly due to tuberculosis or autoimmune disease, leading to the clinical features of Addison's disease (see below). Adrenal insufficiency should always be considered in any patient with circulatory collapse; the picture will vary somewhat depending on whether it is primary or secondary (p. 897). However, the presentation of adrenal 1

930

Fig. 17.21

0 Fig. 17.22

insufficiency tends to be much more insidious. Tuberculosis leads to enlargement of the adrenals and, eventually, total destruction of the normal tissue and caseation. Possibly the high cortisol levels within the adrenal make it difficult to mount the necessary cellular immune response to eradicate the bacteria. In western countries the decline in tuberculosis makes autoimmune destruction of the adrenals the commonest cause of chronic adrenal insufficiency, with a prevalence of 30-60 per million. Autoimmune adrenal insufficiency is often associated with a high incidence of other organ-specific autoimmune disease, especially thyroid failure (Table 17.11, p. 917). There is an association with HLA-DR3. Secondary adrenal insufficiency due to hypopituitarism and isolated ACTH deficiency is discussed on page 897.

ADDISON'S DISEASE Clinical features This was first described by Thomas Addison in 1855. The speed of onset varies from insidious to sudden. When the

SUMMARY 10 Clinical features of Addison's disease • Increased pigmentation in mouth, skin creases, pressure areas. • Crises of hypotension, salt and water loss, hyperkalaemia, hypercalcaemia, hypoglycaemia. • Associated vitiligo, thyroid disease or pernicious anaemia.

onset is insidious the early symptoms are lassitude, somnolence and depression. Dizziness due to postural hypotension, or fasting hypoglycaemia and nocturia owing to failure to excrete a water load in the daytime, may occur. Frequently, the patient notices an increased pigmentation or simply retention of the summer suntan; as a result they may appear 'healthy' to relatives. In its most dramatic form the disease presents with Addisonian crisis, which in the absence of effective treatment is also the terminal picture. The patient is ill and anorexic, with vomiting and abdominal pain, often with rigidity simulating an abdominal emergency. There is usually a fever, tachycardia, hypotension (with a marked postural drop in blood pressure), cramps and postural dizziness, and signs of sodium and water depletion. There is marked loss of skin turgor, with loose skin .like damp leather and sunken eyes. The blood urea rises because of poor renal perfusion, the serum potassium concentration is raised and serum sodium is low. Hypercalcaemia sometimes occurs. Hypoglycaemia may be present, particularly in children. The features of the associated ACTH excess are variable, and consist of increased pigmentation 1 of the skin (especially exposed areas, pressure points, creases and recent scars), buccal mucous membrane and sometimes sclerae, and streaked pigmentation of the nail beds. These changes are due to stimulation of melanocytes by ACTH and related peptides, and are absent in secondary hypoadrenalism. The clinical features due to mineralocorticoid deficiency - principally sodium and water depletion, hyperkalaemia and hypercalcaemia - are unique to primary adrenal failure, and are absent or much less marked in secondary adrenal failure. The serum sodium concentration is usually low in both conditions, in part owing to excessive secretion of ADH. Features due to glucocorticoid deficiency include hypoglycaemia (more marked in pituitary insufficiency, as GH is also usually lacking), inability to respond to stress and infection, and also, in part at least, hypotension and pyrexia. Anaemia is common, with a lymphocytosis and an elevated eosinophil count. Other suggestive clinical features are the presence of other forms of organ-specific autoimmune disease such as vitiligo 2 (Table 17.11, p. 917) or a history, or signs of, tuberculosis.

Investigation A high index of suspicion is important in the diagnosis of Addison's disease. Once suspected in a collapsed or ill

patient, the appropriate blood samples should be taken for electrolyte and cortisol assay, and treatment instituted forthwith. Hyperkalaemia (with or without a low serum sodium concentration) in a patient with Addisonian-type pigmentation, hypotension and fluid depletion is very suggestive of primary adrenal insufficiency. A low or undetectable cortisol in a stressed, sick patient confirms adrenal failure. Once the patient is well, further investigation can be conducted to establish the aetiology. Ideally the diagnosis should be made before severe insufficiency presents as an emergency. The short synacthen test (p. 929) is the investigation of choice to confirm adrenal insufficiency. ACTH levels or the long synacthen test are used to show that this is primary adrenal failure. The aetiology can be identified by tests for adrenal (and other) autoantibodies, plain X-ray of the abdomen (to show adrenal calcification due to tuberculosis) and CT scanning of the adrenals (to exclude tuberculosis and adrenal infiltration).

17

Management Immediate treatment of the acutely ill patient is with fluids, electrolytes and hydrocortisone (Table 17.16). Mineralocorticoid therapy is only required when the dose of hydrocortisone is being reduced to two to three times normal replacement doses (i.e. about 60mg/day), and then only in primary adrenal insufficiency. Long-term management of adrenal failure is generally simple if the patient adheres to medication. It is not possible to simulate precisely the normal episodic pattern of hormone secretion. Cortisol itself can be conveniently given as hydrocortisone in a split dose, which for an adult is often given as 20 mg on rising and 10 mg at about 5 pm, although patients often feel better if the morning dose is split to 10 mg on rising and 5-10 mg at lunchtime, and then 5-10 mg at teatime. Some tailoring of the dose is possible by repeated cortisol measurements through a day. Mineralocorticoid replacement is with the synthetic mineralocorticoid fludrocortisone (0.05-0.2mg daily). The dose is adjusted according to blood pressure, serum potassium levels and, more precisely, by maintaining renin levels TABLE 17.16 Treatment of acute adrenal insufficiency (Addisonian crisis) • Treat as soon as the diagnosis is suspected: do not await biochemical confirmation. • Take a blood sample for retrospective cortisol and ACTH analysis prior to the administration of steroids. • Establish i.v. access and administer 1L of normal saline over 2-4 hours; monitor for signs of overload using CVP if possible; continue normal saline thereafter at a slower rate. • Monitor glucose levels; give 5% dextrose in normal saline as appropriate. • Hydrocortisone is given as a 100mg bolus intravenously immediately and then every 6 hours; alternatively, give as an intravenous infusion of 4mg/h. • Treat any underlying precipitant, such as infection.

931

within normal limits. Elevated renin levels indicate the need to increase fludrocortisone. A minority of Addisonian patients do not need mineralocorticoid therapy, because zona glomerulosa function may be spared and replacement glucocorticoids have a weak mineralocorticoid effect. Recent work indicates that dehydroepiandrosterone improves libido and general wellbeing in women with Addison's disease. Patients on long-term steroid replacement should be given a special card clearly stating the steroids that they are on, and should keep it with them at all times. It is important that additional glucocorticoid is given in emergencies and for incidental infections. If the patient has a gastrointestinal upset he or she should be given an increased dose parenterally. Some drugs increase steroid requirements because they accelerate steroid metabolism; this occurs particularly with anticonvulsants and the antituberculous drug rifampicin, which is given as part of triple chemotherapy if tuberculosis is the cause of Addison's disease. 1

with azoospermia. Ultimate height is reduced and, if treatment with replacement glucocorticoids is delayed until the epiphyseal bone age has advanced to 11 years or more, affected males often undergo true precocious puberty. There is a high prevalence (up to 1 in 100) of a mild enzyme deficiency resulting in the non-classic form of the disorder, which is the commonest autosomal recessive condition in humans. There is no obvious abnormality at birth, but girls may present with premature pubic hair development, short stature and, later, menstrual irregularities and hirsutism. Most such individuals, however, do not come to medical attention. Once suspected, the diagnosis is easily made by demonstrating elevated levels of plasma, salivary or urinary levels of 17-hydroxyprogesterone or its urinary metabolite pregnanetriol, with or without ACTH stimulation. The importance of early diagnosis in female infants is obvious, and corrective genital surgery is generally required in infancy and again later with the onset of sexual activity. Replacement therapy is with glucocorticoids and mineralocorticoids.

ADRENAL ENZYME DEFECTS

11 B-hydroxylase deficiency

The pathways of steroidogenesis are discussed on pages 925-928. The principal defects in these pathways involve the cytochrome P450 enzymes 21-hydroxylase and 11Bhydroxylase deficiency (Fig. 17.32), although other defects occur rarely.

21 -hydroxylase deficiency 21-hydroxylase deficiency is inherited as a recessive condition. It is due to a mutation or loss of the gene for 21hydroxylase, which is located on chromosome 6, between the HLA-B and HLA-D loci. The incidence, based on neonatal 17-hydroxyprogesterone screening, is around 1 in 15 000 births, but this misses many with a milder defect. The severe 'classic' form can be recognized in newborn girls by ambiguous external genitalia caused by high levels of adrenal androgens. Around 75% of affected newborn babies develop severe mineralocorticoid deficiency and salt loss. Male infants appear normally virilized. Salt-losing males present with acute adrenal insufficiency and sodium and water depletion, usually within the first few weeks of life. The mortality is therefore much higher with male infants and the cause of death may not be recognized unless previous affected siblings have drawn attention to its likelihood. Non-salt-losing males will present with accelerated growth and sexual development but small testes (sexual precocity and pseudopuberty) and, later,

1MCQ17.19

932

3

2

Fig. 17.23

Figs 17.24, 17.25

Deficiency of llB-hydroxylase (Fig. 17.32) is 20 times less common than 21-hydroxylase deficiency. It also causes virilization, but the androgen excess is generally less marked and the picture is dominated instead by the presence of hypertension. This is due to ACTH-induced excessive secretion of 11-desoxycorticosterone (DOC). The treatment is similar to that of 21-hydroxylase deficiency, although transient salt wasting may occur when treatment is started.

CUSHING'S SYNDROME Harvey Cushing first identified this syndrome in 1912 and later suggested that pituitary dysfunction was a cause. The diagnosis and the treatment of the disorders that lead to adrenal glucocorticoid excess (Cushing's syndrome) are often difficult. latrogenic Cushing's syndrome is common but readily identified. The annual incidence of the other types combined is around 25 per million.

Aetiology Cushing's syndrome is either ACTH dependent or independent (Table 17.17). Around 80% of non-iatrogenic cases are due to pituitary adenomas, although ectopic secretion of ACTH is actually more common owing to the prevalence of lung carcinoma. Most such cases are not recognized because of the high mortality rate. ACTHindependent Cushing's syndrome is caused by a steroidsecreting tumour (carcinoma or adenoma) of the adrenal cortex. Adrenal tumours generally predominate in children and young adults; adenoma is the easiest form of the syndrome to treat.

Glomerulosa

Reticularis

Fasciculata

17

Cholesterol (20Q-OH Cholesterol)

DHEA Sulphate

Pregnenolone

17a-OH preonenolone

DHEA

Progesterone

17a-OH progesterone

Androstenedione

11-Desoxycorticosterone

11-Desoxycortisol

Corticosterone

Cortisol

A 5 Androstenediol

21-Hydroxylase

11B-Hydroxylase

18-OH Corticosterone

Aldosterone FIG. 17.32 Normal adrenal steroid pathways with sites of action of 21-hydroxylase and 11p-hydroxylase, the two enzymes most commonly defective in congenital adrenal hyperplasia

ACTH-dependent causes are pituitary or non-pituitary in origin. Pituitary Cushing's syndrome is almost always due to a pituitary adenoma (Cushing's disease) and is three times more common in women. Some rare cases are due to secretion of CRH by a hypothalamic or extrahypothalamic tumour. Ectopic ACTH syndrome is caused by ACTH secretion from a tumour outside the pituitary gland. The commonest types are carcinoid tumours of the bronchus, thymus and pancreas, small cell lung cancer and thymoma. Pancreatic carcinoma, medullary thyroid carcinoma and phaeochromocytoma are other rare causes (see Table 6.4, p. 154). Alcohol can sometimes induce clinical features of Cushing's syndrome, but these and abnormal cortisol levels become normal with abstinence. Depression and obesity can cause diagnostic problems, as abnormalities in cortisol levels can mimic Cushing's syndrome (p. 928).

TABLE 17.17 Causes of Cushing's syndrome Cause ACTH driven Pituitary dependent

Ectopic ACTH secretion

Pituitary adenoma* Pituitary carcinoma** CRH-secreting tumour** Hypothalamic Ectopic Tumours Small cell carcinoma Branchial carcinoid Medullary thyroid carcinoma Pancreatic carcinoma Phaeochromocytoma

Non-ACTH driven

Adrenal adenoma Adrenal carcinoma Micronodular or macronodular hyperplasia Glucocorticoid therapy

Mixed aetiology

Multinodular hyperplasia Alcohol-induced 'pseudo' Cushing's Cyclical Cushing's syndrome

Clinical features Common features Features common to all forms of Cushing's syndrome are those due to glucocorticoid excess. They include centripetal obesity, proximal muscle weakness and wasting, thin skin, striae, 0 poor wound healing, osteoporosis often presenting as vertebral fractures, hypertension, venous thrombosis, diabetes mellitus, depression and psychosis (Fig. 17.33). Mild hirsutism and acne are common, 3

Example

* 'Cushing's disease' ** Very rare

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TABLE 17.18 Investigation of suspected Cushing's syndrome 1. Clinical assessment 2. Confirmation:

24-hour urine free cortisol Overnight dexamethasone suppression

3. If one or both abnormal:

Plasma electrolytes Further 24-hour urine free cortisol Circadian blood cortisol 9 am and midnight ACTH levels Low-dose dexamethasone suppression test (2 mg/day)

4. If abnormal, find cause:

Alcohol? Ectopic ACTH? Adrenal tumour? Pituitary dependent?

- Withdraw and reassess - CXR and mediastinal CT - Adrenal CT ACTH levels - High-dose dexamethasone suppression test Pituitary CT or MRI scan CRH test with petrosal sinus sampling

5. Treat

SUMMARY 11 Clinical features of Cushing's syndrome

FIG. 17.33 Classic features of severe Cushing's syndrome

owing to adrenal androgen as well as glucocorticoid excess. In men, LH and testosterone secretion may be inhibited and libido consequently reduced. Oligomenorrhoea or amenorrhoea are frequent in women.

• • • • • • •

Central obesity, moon face, buffalo hump Proximal myopathy Osteoporosis Striae and poor wound healing Depression and psychosis Hypertension Diabetes mellitus

may well be absent, and a rapid onset also suggests a malignant ectopic source.

Investigation

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Features unique to specific forms Cushing's syndrome that disappears or diminishes under hospital scrutiny is commonly alcohol induced. Some other forms may be cyclical. Addisonian-type pigmentation suggests marked ACTH excess, which is found most often with the ectopic ACTH syndrome (unless the adrenals have been removed, when it suggests Nelson's syndrome; see below and p. 906). The presence of profound hypokalaemia and oedema suggests the ectopic ACTH syndrome. The ectopic ACTH syndrome due to a small cell carcinoma of lung may not be attended by centripetal obesity, because of cachexia. Other typical clinical features

The investigation of suspected Cushing's syndrome is summarised in Table 17.18. The difficulties have been discussed under dynamic testing (see p. 928). The 24-hour urinary free cortisol excretion and overnight low-dose dexamethasone test (p. 928) are the mainstays of initial diagnosis. ACTH-independent causes can be diagnosed by adrenal CT scan (Fig. 17.31, p. 930) and the suppressed plasma ACTH level. Pituitary CT or MR scanning is often surprisingly unhelpful (and occasionally misleading) in the investigation of ACTH-dependent causes of Cushing's syndrome. Pituitary tumours are usually small, and rarely cause any distortion of the pituitary fossa. CT scan of the

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CASE STUDY 17.3 DEPRESSION AND WEIGHT GAIN A 43-year-old woman complained of weight gain of approximately 2kg over several months, associated with swelling of the ankles. She noticed that, in particular, her abdomen had become distended. At the same time she had noticed increasing tiredness, which had become progressive, and her skin had become dark. Friends had commented that she appeared to have a suntan, although there was no recent exposure to the sun. In the previous month her skin had started to bruise easily. Her periods were less regular than previously, occurring every 40 days or so. Her sleep was disturbed and she was waking up to 2 hours earlier than normal. She was also short of breath. She smoked 20 cigarettes a day but drank no alcohol. She had had a laminectomy for a prolapsed intervertebral disc, and took ibuprofen and dihydrocodeine to relieve back pain. She was also taking furosemide (frusemide), recently prescribed by her GP for ankle oedema. On examination she was tearful and acknowledged that she had been feeling depressed over the preceding 2-3 weeks. Her skin thickness was slightly reduced and the abdomen was distended, with striae. There was filling-in of the supraclavicular fossae with fat, a moon-shaped face and a small pad of fat over the nape of the neck. Several bruises were noted over the shins in particular. Her blood pressure was normal at 130/80, and the remainder of the examination was normal except for mild weakness of the proximal muscles. Questions 1. What is the most likely cause of this woman's symptoms? 2. What investigations are indicated? Discussion The symptoms and signs point to a diagnosis of Cushing's syndrome. The features are very typical, although

missing from the presentation in this case are other fairly frequent findings, such as hypertension (85% of cases), hirsutism (around 70% of women) and acne (around 50% of women). Other less frequent features are polydipsia (30%) and poor wound healing (around 35%). Back pain and bone pain occur in around 50% of patients with Cushing's syndrome, but in this woman's case the problems were ascribed to pre-existing musculoskeletal problems which had been treated surgically. Indeed, her back problem had not deteriorated during recent months. It was noted that the patient was depressed, and biochemical changes of Cushing's syndrome can occur with severe depression. On the other hand, mental changes occur in 50% of patients with true Cushing's syndrome, and therefore her depression would fit with this diagnosis. Another common problem that can cause confusion is alcoholism, which can produce a clinical and biochemical picture of Cushing's syndrome (so-called pseudo-Cushing's syndrome) but this patient denied alcohol ingestion and a random blood alcohol level test was negative. She was taking no drugs that would affect cortisol metabolism and interfere with tests for Cushing's syndrome (in particular, anticonvulsants can interfere with diagnosis). Investigation consists of a twostage process. First, the diagnosis of Cushing's syndrome must be confirmed biochemically, and once this is done the exact cause needs to be determined. The first of these goals can be accomplished as an outpatient procedure using urine free cortisol measurement or administering 1 mg of dexamethasone at midnight, followed by estimation of the cortisol level at 8.00-9.00 am, values of plasma cortisol greater than 50nmol/L being highly suggestive of Cushing's syndrome. There are problems with ensuring a complete

collection of urine as an outpatient, and therefore if there is doubt about the diagnosis arrangements should be made for admission to hospital, where the diurnal rhythm of cortisol can be assessed. This is best done by taking the cortisol at midnight when the patient is asleep, a value above 50 nmol/L being very suggestive of Cushing's syndrome. This woman's cortisol at midnight was 254 nmol/L and the diagnosis of Cushing's syndrome was further confirmed by performing a long, low-dose dexamethasone suppression test (dexamethasone 0.5 mg, four times a day for 2 days). The cortisol value at the end of this was 210 nmol/L, indicating Cushing's syndrome (normal <50 nmol/L). The second stage is to confirm the cause of the syndrome. A number of different tests can be used, but essentially the first distinction to make is whether the ACTH level is detectable or not: a detectable ACTH implies Cushing's disease (i.e. pituitary-driven Cushing's syndrome) or an ectopic ACTH syndrome, whereas an undetectable ACTH is compatible with an adrenal adenoma or carcinoma. Rare patients have bilateral micronodular adrenal hyperplasia, again with an undetectable ACTH. When an adrenal problem is suggested by low ACTH levels, an adrenal CT or MRI scan will reveal the source of the Cushing's syndrome. ACTH levels tend to be very high with the ectopic ACTH syndrome and the source is often obvious, most typically small cell carcinoma of the lung, visible on a chest X-ray. In pituitary-dependent Cushing's disease there is often suppression of the cortisol after highdose dexamethasone (2mg dexamethasone four times a day for 2 days, with suppression being judged as a 50% or more decrease in the basal cortisol level taken at 9.00 am). It can be difficult to distinguish between an occult, ectopic source of ACTH and a pituitary tumour.

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CASE STUDY 17.3 CONTINUED Unfortunately, the mere presence of a pituitary tumour on MRI or CT does not confirm that this is the source of ACTH, as pituitary tumours are found in up to 5% of the healthy population. Moreover, not all pituitary tumours secreting ACTH are visible by current scanning methods. The use of a corticotrophinreleasing hormone (CRH) test, often combined with petrosal sinus sampling, is currently the best way to differentiate between these two possibilities. Patients with Cushing's disease have a rise in plasma cortisol

and plasma ACTH levels 15 minutes after administration of CRH, but this does not occur in ectopic ACTH syndrome. This test is also useful in differentiating pseudo-Cushing states from Cushing's syndrome, as there is no response to CRH with pseudoCushing's syndrome due to alcoholism, depression, obesity or drugs. This test can be performed using peripheral blood samples, but if the diagnosis remains unclear the test can be extended by carrying out cannulation and sampling of the petrosal sinuses draining the pituitary,

thorax may reveal a small bronchial or thymic carcinoid, which is the source of ectopic ACTH. 1

Management Drug therapy Drugs have a place in the preoperative, and occasionally also the long-term, management of Cushing's syndrome. Steroid production can readily be inhibited in patients with adrenal tumours by the llp-hydroxylase inhibitor metyrapone. Indeed, there is real risk of inducing adrenal insufficiency. The dose (250-750 mg every 4 hours, omitting 4am dosage) should be titrated against the serum and urinary cortisol response. Ketoconazole (200-400 mg twice a day) is an alternative that does not exacerbate hirsutism in women, unlike metyrapone. It causes nausea and regular checks of liver function are required. Before surgery, it is wise for the patient to be treated with either drug for several weeks to improve wound healing. Palliative drug therapy in ectopic ACTH syndrome generally requires the simultaneous use of metyrapone and ketoconazole to block biosynthesis of cortisol; replacement doses of steroids can be given once endogenous production is blocked. Aminoglutethimide (0.25-1 g daily in divided doses) can also be used. The DDT analogue mitotane (10-20 g daily) also has an established place in the palliation of adrenal carcinoma; it induces adrenal cell necrosis but causes major gastrointestinal and neurological side-effects; lower doses may be preferable. Cytotoxic chemotherapy is the treatment of choice for small cell lung cancer, but the prognosis of the disease is especially poor when accompanied by ectopic ACTH secretion.

1

936

MCQ 17.20

2

Figs 17.26-17.28

and showing a direct release of ACTH in response to CRH, which confirms a pituitary-dependent cause. In this case the ACTH level was 50ng/L (reference range <20) and the cortisol was suppressed to >50% after a high-dose dexamethasone suppression test. The plasma cortisol level rose by more than 100% in response to CRH, and a pituitary MRI scan revealed a 3 mm microadenoma on the left side of the pituitary. Removal of the adenoma by the transsphenoidal route led to cure of the Cushing's disease.

Adrenal surgery Surgery is clearly indicated for an adrenal adenoma or carcinoma, where operable. Surgery is also the treatment of choice for carcinoid tumours causing ectopic ACTH secretion. Bilateral adrenalectomy was formerly the preferred treatment for Cushing's disease. This has the advantage of eliminating the possibility of cortisol excess (provided no remnant is left behind). The disadvantages are that it involves major surgery, with a significant mortality, and also a significant (10-20%) risk of developing Nelson's syndrome (the condition of hyperpigmentation, increasing ACTH excess and an expanding pituitary tumour). The syndrome probably only develops where there is already a semi-autonomous ACTH-secreting pituitary tumour, previously kept under partial restraint by the high circulating cortisol levels. If bilateral adrenalectomy is performed in Cushing's disease, for instance when pituitary surgery fails, external pituitary irradiation minimizes the risk of this unpleasant complication. 2 Bilateral adrenalectomy is the treatment of choice in multinodular adrenal hyperplasia. Pituitary surgery The treatment of choice for Cushing's disease is surgery by the transsphenoidal route (p. 901). If a tumour is present it is removed; if not, then as much as possible of the pituitary gland is resected. Hypopituitarism (with replacement therapy) is generally preferable to continuing active Cushing's syndrome. Pituitary radiotherapy Pituitary radiotherapy can be an effective treatment for Cushing's disease. Radiotherapy may be particularly useful in the elderly or frail patient with moderately active disease who has shown some hormonal response to drug therapy.

CLINICALLY SILENT ADRENAL TUMOURS Adrenal tumours are increasingly being detected in the absence of symptoms owing to the widespread use of CT and MRI carried out to diagnose non-adrenal disease. Between 0.4 and 4.0% of patients scanned have a previously unsuspected adrenal mass. Adrenal carcinoma is very rarely silent, whereas metastases from other cancers are common, although in most such patients there will be evidence of metastases elsewhere or of the primary tumour. The majority of adrenal masses are benign adenomas, of which only around 15% exhibit hormonal hypersecretion. There is currently no consensus on the best way of eliciting the nature of these clinically silent tumours. At present, a careful history and examination remain the key to determining further investigations, but all patients should probably also have screening for phaeochromocytoma (usually urinary catecholamine metabolites), Conn's syndrome (serum potassium) and Cushing's syndrome (urine or serum cortisol). Dehydroepiandrosterone sulphate may be elevated in adrenal carcinoma. Any mass greater than 5 cm has an increased risk of malignancy and should be removed; repeat scans at 3-6 months are indicated to verify that smaller lesions have not increased in size. CTguided fine needle biopsy may improve future diagnostic accuracy.

DISORDERS OF ALDOSTERONE SECRETION The basic components (renin, angiotensin and aldosterone) of the mineralocorticoid system are discussed on page 926. In addition, the heart is also involved in salt and water homeostasis, through atrial natriuretic peptide (ANP). This peptide is produced by endocrine cells in the right atrium, and acts on the renal tubule to cause a sodium diuresis (Ch. 20, p. 1035).

Hypoaldosteronism Hypoaldosteronism may be a result of general adrenal insufficiency owing to destruction of the adrenal glands (p. 929), or it may occur in the presence of normal secretion of other adrenal steroids. The disorder may rarely be primary, owing to a selective adrenal enzyme deficiency late in the aldosterone pathway. Hypoaldosteronism secondary to renin deficiency occurs quite commonly in long-standing diabetes mellitus, and may be a consequence of autonomic neuropathy. Aldosterone deficiency is manifested by a tendency to sodium depletion, hypotension and hyperkalaemia. Treatment is with fludrocortisone. Pseudohypoaldosteronism is rare and mimics aldosterone deficiency, but is due to mutations in the epithelial sodium channel or in the mineralocorticoid receptor. In both types there is resistance to aldosterone, which rises to high levels.

Hyperaldosteronism Primary hyperaldosteronism (Conn's syndrome) is a rare cause of a generally mild hypertension and hypokalaemia, occurring in around 1% of the hypertensive population. Not all patients have hypokalaemia, and in some patients the diagnosis is suggested by the provocation of significant hypokalaemia with diuretics. In the Chinese especially primary hypoaldosteronism may present with hypokalaemic paralysis. It is caused by an adrenal adenoma. Idiopathic zona glomerulosa hyperplasia results in a similar clinical picture, but there is recent evidence that this is not a primary adrenal disorder; it may be due to enhanced sensitivity of the zona glomerulosa to angiotensin II. The diagnosis of primary hyperaldosteronism is confirmed by the finding of elevated serum aldosterone and low renin levels, and by demonstrating an adenoma on CT or MRI scan. Treatment is with spironolactone or (in the case of definite adenoma) adrenal surgery. Hypokalaemia and hypertension may rarely occur with llp-hydroxysteroid dehydrogenase deficiency (p. 926) and this responds to suppression of endogenous cortisol levels by dexamethasone. Secondary hyperaldosteronism is a common physiological adaptation seen in such disorders as congestive cardiac failure, accelerated hypertension, cirrhosis of the liver and nephrotic syndrome. Reduced renal perfusion is the major stimulus to increased renin secretion, angiotensin II production and aldosterone secretion, and thus to sodium retention and potassium excretion. Rarely, hyperaldosteronism is caused by a renin-secreting tumour of the kidney. Liddle's syndrome is rare and mimics hyperaldosteronism, with hypertension and hypokalaemia, but is due to mutations in the epithelial sodium channel in the collecting tubule, leading to sodium retention and potassium wasting. Aldosterone and renin levels are low. In Bartter's syndrome there is hypokalaemia but no hypertension, despite high aldosterone and renin levels. Several gene mutations lead to this syndrome, all producing defective sodium chloride transport in the kidney. Gitelman's syndrome is a further variant associated with hypomagnesaemia and hypocalciuria. Salt wasting in these syndromes leads to hyperaldosteronism.

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FURTHER READING ON DISEASES OF THE ADRENAL CORTEX Fraser R, Murray G D, Connell J M C 1998 Conn's syndrome: no longer a needle in a haystack? Clin Endocrinol 49: 709-710. Hughes I A 1998 Congenital adrenal hyperplasia - a continuum of disorders. Lancet 352: 752-754. Latronico A C, Chrousos G P 1997 Adrenocortical tumors. J Clin Endocrinol Metab 82: 1317-1324. Mantero F, Arnaldi G 1999 Investigation protocol: adrenal enlargement. Clin Endocrinol 50:141-146. Newell-Price J, Grossman A 1999 Diagnosis and management of Cushing's syndrome. Lancet 353: 2087-2088. Oelkers W 1996 Adrenal insufficiency. N Engl J Med 335:1206-1212.

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Peppercorn P D, Grossman A B, Reznek R H 1998 Imaging of incidentally discovered adrenal masses. Clin Endocrinol 48: 379-388. Ross R J M, Trainer P J 1998 Endocrine investigation: Cushing's syndrome. Clin Endocrinol 49:153-155. Scheinman S J, Guay-Woodford L M, Thakker R V, Warnock D G 1999 Genetic disorders of renal electrolyte transport. N Engl J Med 340:1177-1187. Speiser P W, White P C 1998 Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency. Clin Endocrinol 49: 411417.

DISEASES OF THE ADRENAL MEDULLA Adrenaline (epinephrine) is the major product of the normal adrenal medulla and adrenaline in the circulation arises from this gland. Under basal conditions, plasma noradrenaline (norepinephrine) is derived mainly from the sympathetic nervous system, but large amounts can be released rapidly with adrenaline by the adrenal medulla on stimulation. These hormones are of particular importance in the acute response to stress, causing increased alertness, tachycardia, nervousness, glucose and fat mobilization, and inhibition of insulin secretion.

ADRENAL MEDULLARY INSUFFICIENCY There are no demonstrable effects of adrenal medullary insufficiency, e.g. after bilateral adrenalectomy. The sympathetic nervous system alone suffices to maintain normal catecholamine-dependent functions.

ADRENAL MEDULLARY EXCESS Phaeochromocytoma Phaeochromocytomas are tumours of the adrenal medulla and are, fortunately, rare. The usual figure quoted is 1 per 1000 cases of hypertension; however, in a large autopsy series from the Mayo Clinic, three-quarters of the patients found to have had phaeochromocytoma were undiagnosed during life, so the true incidence may be considerably higher. Death in cases previously undiagnosed is commonly from cardiovascular disease or cerebral haemorrhage. The tumours are usually located in the adrenal medulla, 10% being bilateral; 10% are located in extraadrenal chromaffin tissue, usually in the sympathetic chain in the abdomen. Most predominantly secrete

1

938

MCQ 17.21

noradrenaline. Ten per cent of all phaeochromocytomas are malignant. They can occur at any age but present most commonly between 40 and 60 years, and are slightly more common in women. Phaeochromocytomas are associated with neurofibromatosis, von Hippel-Lindau syndrome (p. 1341) and multiple endocrine neoplasia type 2 (see below). Clinical features Presentation may be with sustained, difficult-to-treat hypertension, hypertensive crisis or 'attacks' of headache, sweating, palpitations, flushing and nervousness. The blood pressure is generally moderately raised and becomes grossly so during 'attacks', which may be precipitated by exercise or abdominal palpation. Because the hypertension is accompanied by secondary volume depletion, there is commonly a significant drop in blood pressure on standing; this is unusual in untreated hypertension from other causes. Investigation The diagnosis of phaeochromocytoma is made by measurement of plasma levels of adrenaline and noradrenaline, or their urinary precursors or metabolites - vanillylmandelic acid, metanephrines and normetanephrines. The paroxysmal nature of the secretion may lead to normal levels being obtained at times, and repeated blood and urine measurements may therefore be necessary. The tumour can be localized by adrenal CT scan, but MRI is superior as the T2-weighted image is unusually intense. Radioisotope scanning with 131I-MIBG is helpful to demonstrate an ectopic site. Management The principles of treatment are to start with pharmacological measures, namely adrenergic blockade (initially with the cc-adrenoreceptor blocking agent phenoxybenzamine 10-20mg twice daily or doxazosin 1-2mg twice daily), followed a few days later by B-blockade (e.g. with propranolol 10 mg three times daily, and titrated to control the pulse rate). At least 2 weeks should be allowed for volume repletion before surgery. During surgery, blood pressure is closely monitored and any elevation treated with an intravenous infusion of phentolamine (an oc-adrenoreceptor antagonist). 1

Multiple endocrine neoplasia (MEN) There are at least three different syndromes associated with multiple neoplasia of endocrine glands (Table 17.19); in each case inheritance is autosomal dominant. The involved glands may be the subject of hyperplasia, adenoma or carcinoma development, and different glands may be involved in different individuals in the same family. In MEN type 1, hyperparathyroidism due to parathyroid hyperplasia is present in 95 % of cases at the time of diagnosis. Major morbidity and mortality result from the de-

TABU 17.19 Multiple endocrine neoplasia (MEN)

FURTHER READING ADRENAL MEDULLA

DISEASES OF THE

Major glands/areas involved

Clinical features

Type

1 (Autosomal dominant)

Parathyroid Pancreas

Hypercalcaemia Insulinoma Gastrinoma Glucagonoma

Anterior pituitary

Prolactinoma Acromegaly Cushing's syndrome

Bronchus, bowel

Carcinoid tumours Lipomas

2a (Autosomat dominant)

Thyroid (C cell) Adrenal medulla Parathyroid

Medullary carcinoma Phaeochromocytorna Hypercalcaemia

2b (Autosomal dominant)

Thyroid (C cell) Adrenal medulla

Medullary carcinoma Phaeochromocytorna

ANATOMY AND PHYSIOLOGY

Tongue etc.

Mucosal neuroma Martanoid habitus

The testes have a crucial early role in the male fetus in determining that primary sex differentiation is male. After puberty they serve the dual function of spermatogenesis and androgen (testosterone) production. The initial gonadotrophin stimulation in utero comes principally from the placental hormone human chorionic gonadotrophin (hCG). However, during and after puberty the stimulation comes from the pituitary via its two gonadotrophins, FSH and LH.

velopment of pancreatic tumours, notably insulin-secreting islet cell tumours causing hypoglycaemia, and gastrinomas causing intractable peptic ulceration (Zollinger-Ellison syndrome). Pituitary tumours (prolactinomas, GH or ACTH secreting) are also common, and carcinoid tumours too are recognized as part of the syndrome. The gene responsible is located on chromosome 11 and has been given the name menin, but its function is unknown. Its identification will greatly help family screening. In type 2 MEN the components include medullary cell thyroid carcinoma (calcitonin secreting) and phaeochromocytoma. Hyperparathyroidism is found in 20% of patients with MEN 2a but not MEN 2b. The latter patients uniquely have mucosal neuromas. MEN 2a and 2b are caused by separate point mutations in the RET protooncogene on chromosome 10. Similar mutations to MEN 2a occur in some patients with familial medullary thyroid carcinoma and no other features of MEN 2a, so presumably other genes are involved in MEN. Once MEN 1 or MEN 2 has been identified, first-degree relatives should be offered screening. This is biochemical at present in MEN 1 and is based on annual measurements of calcium, prolactin and gut hormones, but DNA screening may be possible if the menin gene mutation is known. Unfortunately, mutations are diverse, which makes such screening difficult. Genetic screening is now possible in MEN 2a and 2b, allowing thyroidectomy before the emergence of medullary carcinoma of the thyroid. DNA testing for MEN 2 should be done in infancy, as medullary carcinoma can be fatal once established (preceded by years of C-cell hyperplasia).

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Brandi M L, Gagel R F, Agneli A, Bilezikian V P, Beck-Peccoz P, Bordi C et al 2001 Consensus Guidelines for diagnosis and management of MEN type 1. J Clin Endocrinol Metab 86:5658-5671 Bravo E L 1994 Evolving concepts in the pathophysiology, diagnosis, and treatment of pheochromocytoma. Endocrine Reviews 15: 356-368 Eisenhofer G, Lenders J W M, Linehan W M, Walther M M, Goldstein D S, Keiser H R 1999 Plasma normetanephrine and metanephrine for detecting pheochromocytoma in von Hippel-Lindau disease and MEN2. N Engl J Med 340:1872-1879. Thakkar R V 1998 Multiple endocrine neoplasia - syndromes of the twentieth century. J Clin Endocrinol Metab 83: 2617-2620.

THE TESTES

The testes in utero: sex differentiation After the primitive germ cells have been joined by steroidproducing cells, the primitive 'indifferent' gonads develop in fetuses of both sexes. Much of the current knowledge on the role of the testes was obtained more than 50 years ago, in pioneering experiments by the French biologist Alfred lost on rabbit fetuses. The Y chromosome contains a testisdetermining gene (SRY) that controls differentiation at 6 weeks into a testis. Shortly thereafter, two pairs of duct systems, the Miillerian and the Wolffian, extend from the region of the gonads to the genital groove. The basic pattern of sex differentiation, which requires no hormonal function for its persistence, is female. In the absence of testes the Miillerian ducts persist and become the uterus and fallopian tubes, and the Wolffian ducts disappear. The Sertoli cells of the developing testes produce a peptide hormone, the anti-Miillerian hormone, which causes the Miillerian ducts to disappear permanently. The major pathway of steroidogenesis that leads to testosterone production occurs in the Leydig cells and is shown in Figure 17.28 (p. 927). At around 12 weeks testosterone is secreted, under stimulation from hCG, and acts on the Wolffian ducts to ensure they persist to form the male internal genital ducts. If testosterone is absent at this time, the duct cells die.

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The development of the external genitalia is also dictated by androgen secretion from the Leydig cells between weeks 10 and 20. Full virilization involves fusion of the labioscrotal folds to form a scrotum, enlargement of the genital tubercle to become a penis, and incorporation into the latter of a penile urethra. Both these effects and the development of the prostate require conversion of testosterone to dihydrotestosterone; this occurs by local action of the enzyme 5a-reductase in target tissues. Later in utero, at around 20 weeks, pituitary secretion of LH and FSH commences. hCG secretion reaches a peak at around 12 weeks and subsequently declines.

The testes in infancy and childhood Late in utero or shortly after birth the testes descend to the scrotum. During the first 6 months of extrauterine life, there is a transient rise in plasma levels of LH and secretion of testosterone. Because levels of the plasma-binding protein sex-hormone-binding globulin (SHBG) also rise during the first week of life, plasma testosterone levels in early infancy are in the low adult male range (although free testosterone levels are lower). Gradually, the activity of the hypothalamopituitary-testis axis subsides and remains low throughout childhood.

form tight junctions which ensure that the germ cells and contents of the tubule are kept secluded by a very effective 'blood-testis barrier'. During puberty the systemic secretion of testosterone initially occurs only at night, but later, as LH levels rise during the day, throughout the 24 hours. Testosterone and, in some tissues, dihydrotestosterone lead to the progressive development of secondary sexual characteristics. In humans these include the enlargement and development of external and internal genitalia; male pattern hair growth; muscular development; growth of long bones followed by closure of the epiphyses; and male sex drive and sexual behaviour, including nocturnal emissions and masturbation. There is no evidence that homosexuality is in any way related to abnormal sex hormone levels. Oestradiol is also produced by conversion from testosterone, in amounts otherwise sufficient to cause breast development,

The testes in puberty The first endocrine event of puberty is the onset of pulsatile secretion of LH during sleep; this initiates pulsatile nocturnal secretion of testosterone (Table 17.20). FSH levels also rise, which, together with testosterone from the Leydig cells, stimulates spermatogenesis. During the course of puberty the volume of the testes increases some 20-fold, from about 1mL to 15-25mL each; 95% of the volume consists of the tubules and their contents. The intersitital (Leydig) cells are the sole source of de novo steroidogenesis, which occurs under stimulation of LH (Fig. 17.34). The action of LH is via specific cell surface receptors, mediated principally by cyclic AMP. FSH also acts via surface receptors and cyclic AMP, but on the Sertoli cells. The Sertoli cells are now known to be crucial in the control of spermatogenesis. Beyond the stage of type A spermatogonia, the germ cells are enclosed in the cytoplasm of Sertoli cells (Fig. 17.35). Adjacent Sertoli cells

FIG. 17.34 Regulation of testicular function

TABLE 17.20 Actions of LH and FSH Effect on ovary

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Hormone

Effect on testis

Follicular phase

Midcycle

Luteal

LH

Stimulates Leydig cells to produce testosterone, which has local and general effects

Thecal cell androgen secretion

Midcycle surge induces ovulation and luteinization

Sustains corpus iuteum until hCG from blastocyst takes over

FSH

Stimulates Sertoli cells. With local testosterone, regulates spermatogenesis

Stimulates next cohort of follicles, and growth of dominant follicle

Small midcycle surge possibly helps ovum maturation

FSH prepares next crop of follicles if no pregnancy

TABLE 17.21 Features of precocious puberty

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• Pubertal development before the age of 8 years in girls and 9 years in boys. • The commonest cause is idiopathic central precocious puberty, which affects girls and is due to abnormal sensitivity to GnRH. • Central precocious puberty may also be secondary to cerebral tumours, hydrocephalus, trauma and radiotherapy. • Other causes include hypothyroidism, congenital adrenal hyperplasia, adrenal and gonadal tumours and the McCune-Albright syndrome (due to mutation of the Gsa protein, causing pigmented skin patches, polyostotic fibrous dysplasia and hormone hypersecretion). • Premature thelarche is isolated premature breast development in girls without other signs of puberty; the cause is unknown. • Precocious puberty causes major social and psychological disturbance and retards final adult height. • Treatment is with steroid antagonists (cyproterone acetate, ketoconazole, testoiactone) or GnRH analogues, which prevent pulsatile endogenous GnRH release. FIG. 17.35 Relationship between testicular tubules (cut in crosssection) and interstitial (Leydig) cells Only type A spermatogonia lie outside the Sertoli cells (blue) and so outside the blood-testis barrier.

but testosterone normally inhibits this. Plasma SHBG levels decline by about 50% during male puberty.

The testes in adult life In men there is no evidence of an abrupt decline in gonadal function in old age equivalent to that of the female menopause. This is because there is a constant supply of new germ cells from mitotic division of type A spermatogonia; in women the supply of oocytes declines progressively even from before birth, and eventually none remain.

CLINICAL ASSESSMENT OF TESTICULAR FUNCTION The clinical assessment of testicular function depends upon the age of the subject. A detailed history of sexual activity is important. For example, if a patient has normal nocturnal erections and ejaculation (wet dreams or masturbation), a complaint of lack of potency (erection or ejaculation) during intercourse is unlikely to be due to androgen deficiency. Assessment of testicular size can best be made by reference to an orchidometer - a series of ovoids of known volume. Small testes are usually a sign of damage to the seminiferous tubules. Examination of external genitalia will also determine if there has been any failure of intrauterine virilization. Failure of normal pubertal development may be associated with a degree of growth failure or, conversely, with excessive growth of the long bones before the epiphyses close, so that span exceeds height. Female fat distribution, gynaecomastia and failure

of development of secondary sexual hair are also features of failure of pubertal development, but the latter is most difficult to interpret in view of the great inherited variability in potential for body hair. Precocious puberty is commoner in girls than boys; clinical features are summarized in Table 17.21. Where the patient is normally virilized and the clinical problem is subfertility, examination for proper intrascrotal descent or previous damage (leading to a small testis or testes), phimosis and varicocele (which may depress the sperm count) is important.

DEFECTIVE TESTICULAR FUNCTION IN UTERO Pseudohermaphroditism is the appearance of ambiguous genital ducts and/or external genitalia in the presence of a gonad that is exclusively ovary or testis. True hermaphroditism is much rarer and is due to sex chromosome abnormalities that give rise to both ovarian and testicular tissue in the gonads. Defective testicular function in utero leads to male pseudohermaphroditism. The major causes are listed in Table 17.22. The defects in testosterone and dihydrotestosterone biosynthesis are inherited as autosomal recessive disorders and are extremely rare. They are discussed below, under disorders of sex differentiation (p. 949).

DEFECTIVE TESTICULAR FUNCTION IN ADULT LIFE Male infertility without androgen deficiency In at least one-third of couples presenting with infertility the condition is attributable largely or entirely to abnor-

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TABLE 17.22 Causes of male pseudohermaphroditism

TABLE 17.23 Causes of male Infertility

XY gonadal dysgenesis

Level of dysfunction

Cause

Testicular enzyme deficiencies With adrenal enzyme deficiency Side-chain cleavage enzyme 3p-hydroxysteroid dehydrogenase 17a-hydroxylase Without adrenal deficiency 17, 20-lyase 17B-hydroxysteroid oxidoreductase

Pituitary/ hypothalamic

Gonadotrophin deficiency Primary*1 Secondary, e.g. tumour**, radiation etc. Gonadotrophin suppression Exogenous androgens e.g. body builders* Endogenous, e.g. 21-hydroxylase deficiency*

Testicular

Chromosomal defect, e.g. Klinefelter's syndrome1 Germ cell damage, e.g. Sertoli cell only syndrome Undescended testes Radiotherapy1 Drugs: cytotoxic, sulphasalazine* Temperature-induced damage: varicocele*, pyrexia* Castration1 Anorchia1

Post-testicular

Absent or obstructed vasa Vasectomy* Epididymal damage Prostatitis, orchitis*

Ejaculatory failure

Erectile failure: psychogenic, vascular, neurogenic Retrograde ejaculation Spinal cord or cauda equina damage

Spermatozoal dysfunction

Infection* Antisperm antibodies Failure to penetrate mucus/poor viability Miscellaneous, e.g. defects in sperm structure

Target organ abnormalities 5a-reductase deficiency Androgen receptor defect - testicular feminization, complete or partial

malities in the male, leading either to azoospermia, oligospermia or abnormal sperm. A general classification of causes is given in Table 17.23. Management is in most cases unsatisfactory and is beyond the scope of this book. In general, if the serum level of FSH is elevated in a patient with azoospermia or severe oligospermia, severe irreversible testicular damage will be present and no treatment will be effective. With subnormal semen, in vitro fertilization may be useful in increasing the chances of conception, possibly because problems of poor sperm motility are overcome.

Androgen deficiency (male hypogonadism) The presentation of testicular dysfunction with androgen deficiency may be at the time of puberty, or much later. A few men presenting with infertility have a mild degree of androgen deficiency and associated oligo- or azoospermia; most such men, and all who are severely androgen deficient, are sexually inactive. The causes of androgen deficiency, classified according to whether the gonadotrophin levels are low (hypogonadotrophic) or high (hypergonadotrophic), are given in Table 17.24. In both groups the severity of the androgen deficiency can vary considerably. It is usually least severe in Klinefelter's syndrome 1 (which in most cases is associated with an XXY chromosomal constitution), where the Leydig cells continue to function (although subnormally) despite severely damaged tubules. The incidence is about 1 per 1000 men. The testes are usually firm and pea-sized. Gynaecomastia may occur, as in any form of hypogonadism, owing in part to increased oestrogen but mainly to reduced testosterone

1

942

Fig 17.29

* Partially or totally treatable or reversible Associated with androgen deficiency and therefore also with infrequent or absent intercourse.

action on the breasts. Typically the limbs continue to grow, so that the final height is increased, with long extremities ('eunuchoidal proportions', Fig. 17.36). Isolated gonadotrophin deficiency (owing usually to GnRH defficiency) may be sporadic or familial (usually X-linked). When associated with anosmia, it is termed Kallmann's syndrome. The anosmia is due to hypoplasia of the olfactory lobes. When hypogonadism develops after puberty it is highly likely that a pituitary tumour or craniopharyngioma is responsible, a suspicion that can be confirmed by appropriate radiology and hormone assays. A common clinical problem is the teenage boy with delayed puberty. The differential diagnosis between simple delayed puberty and permanent isolated gonadotrophin deficiency may be impossible until age 18, when failure of gonadotrophins and testosterone to rise confirms the latter. For psychological wellbeing boys over 14 with delayed puberty often benefit from 6-month courses of testosterone (e.g. Sustanon 50-100 mg i.m. every 4 weeks,

TABLE 17.24 Causes of androgen deficiency in phenotypically normal men

These tests are generally no more informative than basal hormone measurements.

Gonadotrophin levels

Cause of androgen deficiency

Management

Low LH and FSH

Simple delayed puberty Illness and malnutrition Anorexia nervosa Isolated gonadotrophin/GnRH deficiency Normal sense of smell Anosmia (Kallmann's syndrome) Panhypopituitarism Drugs - cyproterone acetate*

High LH and FSH

Developmental Klinefelter's syndrome (XXY and its variants)

Male infertility Semen analysis should be the first investigation in an infertile couple when the woman has regular periods. The principal treatable causes of male infertility (Table 17.23) are oligospermia due to varicocele, or exposure of the testes to high temperature (the scrotum keeps the normal testes at about 32°C and prolonged high temperature impairs spermatogenesis). Sulphasalazine-induced infertility in ulcerative colitis can be treated by transfer to 5-aminosalicylic acid. Gonadotrophin deficiency from any cause may lead to some permanent testicular damage. In most such cases adequate spermatogenesis can be stimulated by administering hCG, with the later addition of FSH (as human menopausal gonadotrophins). An adequate trial of therapy is 3-6 months, the response being followed by semen analysis (count and motility). An alternative is to administer GnRH by subcutaneous pump in a pulsatile manner (15 ug every 90 minutes) but this is not clearly better than hCG plus FSH. Where gonadotrophin deficiency is caused by extratesticular androgens (as in congenital adrenal hyperplasia) the appropriate treatment is with replacement glucocorticoid therapy.

Acquired Trauma Anorchia (testicular degeneration) Viral orchitis (mumps) Radiation Drugs, e.g. cyclophosphamide Dystrophia myotonica Variable LH and FSH

Prader-Willi syndrome Hyperprolactinaemia Noonan's syndrome Cirrhosis of liver Drugs, e.g. spironolactone, alcohol Cushing's syndrome

* Gonadotrophin suppression combined with androgen resistance.

or oral testosterone undecanoate 40mg 2-4 times daily). Evidence of spontaneous puberty can be assessed during a 4-6-month period off treatment. Usually only one or two courses are required, and final height is not significantly affected.

Investigation of endocrine function of the testes A great deal can be learned about the endocrine function of the testes from a single measurment of the serum testosterone (especially when combined with measurement of sex-hormone-binding globulin, to allow determination of the free androgen index) plus the gonadotrophins LH and FSH. A grossly raised prolactin points to a prolactinoma, which, although rare in men, is important to diagnose as early as possible as such tumours are often rapidly growing. If gynaecomastia is present, serum oestradiol should be included in the assessment. Stimulation tests can be carried out at the level of the pituitary (with GnRH 100 ug i.v.) or the testes (with hCG 1500-5000IU i.m.), or oestrogen negative feedback can be assessed (with clomiphene citrate).

17

Androgen deficiency Testosterone esters (e.g. Sustanon 250 mg i.m. every 2-4 weeks) are the most practical form of replacement, although testosterone patches are now available and provide more physiological levels. To induce puberty, smaller doses (e.g. 50 mg) should be used and gradually increased. An alternative is to implant testosterone pellets, under local anaesthetic, subcutaneously in the lower abdominal wall, but this is now little used. Oral testosterone undecanoate is less effective than i.m. testosterone esters.

Impotence Around 2-5% of men aged 40 are impotent; this increases to around 15% by age 60 and continues to rise thereafter. Changing attitudes to sexuality have enhanced both general awareness of this problem and the patient's expectations for successful treatment, now fortunately matched by advances in therapy. The main causes of impotence are . detailed in Table 17.25; psychogenic impotence is considered in Chapter 8. A detailed sexual history and examination generally reveal a likely cause and initial investigation should be limited to full blood count, plasma glucose, serum creatinine and electrolytes, liver function tests and testosterone, unless the history and examination point to a rare cause of impotence such as thyrotoxicosis. In specialized centres, direct measuring of penile erection, particularly sleep-related circumference increase, is employed to differentiate between psychogenic impotence (in which

943

FIG. 17.36 Testicular dysfunction with androgen deficiency Grossly eunuchoidal 31-year-old man with Kallmann's syndrome [A] before and [£] after 2 years of androgen replacement. C A 21-year-old man with Klinefelter's syndrome. Note partial virilizaton and minimal gynaecomastia.

TABLE 17.25 Main causes of impotence Psychogenic

Depression, stress

Vascular Neurological Genitourinary

Aortic or iliac arteriosclerosis, hypertension Autonomic neuropathy, spinal cord damage Micropenis or hypospadias, Peyronie's disease, phimosis, prostatic, retroperitoneal or rectal surgery, pelvic fracture

Drugs

Antihypertensive agents, antidepressants, sedatives, alcohol, antiandrogens, cocaine, amphetamines, liquorice Hypogonadism (primary or secondary), hyperprolactinaemia, oestrogen-secreting tumours, thyrotoxicosis, hypothyroidism, Cushing's syndrome Cardiac, hepatic, renal, lung Due usually to a combination of the above factors

Endocrine

Organ failure Age

spontaneous erections occur during sleep) and organic causes (in which all erections are lost). Unfortunately, in around a quarter of patients it is difficult to differentiate between these two broad categories. Apart from diabetes mellitus, endocrine causes of im1

944

MCQ 17.22

potence are rare and can usually be excluded by finding a normal testosterone level. Low testosterone warrants further investigation to determine the cause, as detailed in Table 17.24. A prolactin-secreting tumour in particular must be excluded. When testosterone deficiency is the cause of impotence, replacement usually restores normal function. There is no place for testosterone treatment of impotent men with normal levels of testosterone, although some patients may have a placebo response, and testosterone is contraindicated if a patient has prostatic or breast cancer. When impotence is psychogenic, or related to vascular or neurological disorders, intracavernosal injections of prostaglandin E1, alone or with papaverine and phentolamine, are effective in around two-thirds of patients. Age does not seem to alter efficacy. The main side-effects are pain, plaque formation and priapism. A refinement of this is to administer the prostaglandin as a gel inserted into the urethra. However, the most important development is the oral drug sildenafil, which relaxes the smooth muscle of the corpus cavernosum by enhancing nitric oxide levels. Caution is required in patients with cardiovascular disease. In selected cases psychotherapy, external vacuum devices or implanted inflatable penile prostheses have been successful. With all of these therapies, specialist counselling (often undertaken by urologists) is important to achieve optimum results. 1

FURTHER READING ON THE TESTES

17

Albanese A, Stanhope R 1995 Investigation of delayed puberty. Clin Endocrinol 43:105-110. de Kretser D M 1997 Male infertility. Lancet 349: 787-790. Hawton K 1998 Integration of treatments for male sexual dysfunction. Lancet 351: 7-8. Elders M J, Scott C R, Frindik J P, Kemp S F 1997 Workup for precocious puberty. Lancet 350: 457-458. Fabbri A, Aversa A, Isidori A 1999 Sildenafil and erectile dysfunction. J Endocrinol Invest 22: 486-492. National Institute on Aging Advisory Panel 2001 Special report. Report of National Institute on Aging Advisory Panel on testosterone replacement in men. J Chin Endocrinol Metab 86:4611-4614.

THE OVARIES

ANATOMY AND PHYSIOLOGY The ovaries consist of germ cells surrounded by granulosa cells (the homologue of the Sertoli cell); these are surrounded in turn by stromal cells of the theca interna. The ovaries have no role in female genital development, which simply requires the absence of testes. They secrete little steroid before birth, and so FSH and LH are higher in female fetuses. After birth and a transient surge in LH levels, the hypothalamopituitary-ovarian axis becomes quiescent until puberty.

Changes during puberty On average, puberty starts about 2 years earlier in girls than in boys. The full complement of ovarian follicles (about half a million) is complete at birth, and their number declines progressively thereafter, until exhaustion at the time of the menopause. Crops of immature follicles advance to a certain stage and become atretic even before puberty. With the rise in FSH levels, these crops of follicles produce increasing amounts of oestrogen; at about 7 days before ovulation, one follicle becomes sensitive to FSH and LH (via increased numbers of receptors) and makes more oestradiol (Fig. 17.37). This suppresses FSH and leads to atresia of the less advanced follicles in that cohort. There is good evidence that the first cycles in girls are anovulatory, and they may be associated with erratic 'breakthrough' menstrual bleeding, owing to oestrogenic stimulation of the endometrium. Eventually, however, conditions are right for the first ovulatory cycle.

Ovulation and the normal menstrual cycle The biological purpose of ovulation is pregnancy. Menstruation may be thought of as biological failure and the starting point of the next cycle, whose purpose is once again to achieve the release of a single fertilizable ovum

FIG. 17.37 The normal menstrual cycle [A] The sequence of events of the normal menstrual cycle. (1) FSH leads to follicle maturation and secretion of oestradiol, which leads to proliferative endometrium and, with other factors, (2) feedback on pituitary and hypothalamus. The midcycle positive feedback triggers LH surge (3), leading to follicle rupture and luteinization. Corpus luteum (4) secretes progesterone and oestradiol, leading to a secretory endometrium. If conception occurs, the implanted blastocyst secretes hCG, which maintains the corpus luteum and its secretions. B Overall pattern of circulating hormone levels during a normal menstrual cycle.

and to prepare the reproductive tract for pregnancy. The menstrual cycle depends on inherent cyclicity within the ovary, the hypothalamus and the pituitary gland. Defects in this complex system are common. Figure 17.37 shows the stylized profile of hormone levels obtained if blood samples are taken at daily intervals throughout a normal cycle. Oestradiol exerts predominantly negative and intermittently positive feedback. When follicular oestradiol secretion rises, this appears to

945

switch the pituitary gonadotrophs from an FSH- to a mainly LH-secreting mode, and to reduce the pulse amplitude of GnRH secretion. Meanwhile, the gonadotrophs become more sensitive to GnRH. The signal for the preovulatory surge in LH secretion is a decline in oestradiol levels, together with the onset of progesterone secretion with an attendant rise in GnRH pulse amplitude. The midcycle LH surge, characterized by 24-48 hours of high peaks of LH secretion, is one of the turning points of the cycle. It arrives at the ovary when one follicle has reached a diameter of 2cm, and its granulosa cells have proliferated and developed LH receptors sufficient to be induced to ovulate. The LH surge completes ovulation, and induces the granulosa cells to become the corpus luteum. Postovulatory steroid secretion, which is still dependent on low concentrations of LH, comes principally from the corpus luteum, whose cells have developed the capacity for de novo steroid synthesis and secrete both progesterone and oestradiol. It should be noted that plasma oestradiol levels fluctuate 10-fold and progesterone more than 20fold during the normal menstrual cycle. In the uterus the changes are first, proliferative-phase development, due to the preovulatory oestradiol surge; and second, postovulatory progesterone and oestradiol conversion of this to the receptive secretory-phase endometrium. Mucus secretion from the cervix is only conducive to sperm penetration during the late proliferative phase and midcycle; thereafter, progesterone rapidly inhibits it. If fertilization occurs, the blastocyst penetrates the endometrium and secretes its own LH-like hormone, hCG, which is absorbed into the circulation and maintains the corpus luteum. In the absence of hCG the corpus luteum atrophies, progesterone secretion declines, the spiral arteries of the endometrium collapse and the surface layers of endometrium die and are shed as menstrual blood.

Secondary sexual changes during and after female puberty Breast development commences at around 9-11 years. Primary changes are caused by the action of oestradiol on the duct epithelium; this in turn probably stimulates stromal fat development (most of the bulk of the breast). Progesterone also acts on the oestrogen-primed breast epithelium, which is important in pregnancy to prepare for lactation. Progesterone is responsible for the increase in breast volume (about 20%) during the luteal phase. Oestradiol, and ovarian and adrenal androgens are responsible for the stimulation of female pubic and axillary hair growth. Changes in uterine size (myometrial and endometrial) are caused by the joint effects of oestrogen and progesterone.

Oestradiol is principally responsible for the pubertal growth spurt by a direct effect on epiphyseal cartilage, and an indirect effect on GH and gonadotrophin secretion. The earlier time of puberty and the potent effect of oestrogens on epiphyseal plates leads to the shorter final stature of women compared to men. Oestradiol has a major effect in increasing endosteal new bone formation and skeletal mass, but is less potent in this respect than testosterone. The increased muscle mass in males in probably also a factor in increasing the bone density (cortical and trabecular) in men (see also p. 954).

Age-related changes in ovarian function and the menopause The menopause is preceded by hormone changes over 10 years or more, which stem from the progressive depletion of follicles, causing deeper troughs in oestradiol levels and higher peaks of FSH. The role of the ovarian peptide hormone inhibin is still not entirely clear. High FSH levels stimulate premature development of the next crop of follicles. Luteinization without ovulation is commonplace; bleeding becomes erratic and women are subfertile long before the last menstrual period, which usually occurs at about 50 years of age. The menopause is commonly attended by frequent disabling and embarrassing hot flushes, owing to central sympathetic nervous discharge. The flushes coincide with discharge of LH and FSH, but are not caused by them. Vaginal dryness, lack of libido, breast atrophy, urethritis and bone loss are all common features of postmenopausal oestrogen deficiency.

OVARIAN DYSFUNCTION: AMENORRHOEA AND OLIGOMENORRHOEA Ovarian dysfunction is usually associated with erratic and infrequent cycles (oligomenorrhoea) or absent periods (amenorrhoea). The presenting complaint may be of the menstrual disorder, infertility, or accompanying problems such as breast discomfort, galactorrhoea or hirsutism. Amenorrhoea or oligomenorrhoea may occur from the time of puberty (primary) or develop later (secondary). It is obviously always important to exclude pregnancy by a pregnancy test or ultrasound scan, even in women who ovulate only occasionally. It is especially important in patients with primary amenorrhoea to try to determine whether the external and internal genitalia are those of a normal female. Pituitary/hypothalamic causes

1 946

MCQ 17.23

Gonadotrophin deficiency Deficiency of GnRH is most commonly secondary to weight loss. Many teenage girls diet excessively and, as a

consequence, develop amenorrhoea at a weight or lean body mass that varies between different individuals. In anorexia nervosa (Ch. 8, p. 239) circulating LH and FSH levels are low, as are those of oestradiol and progesterone. As a consequence, in addition to amenorrhoea there is a degree of regression of secondary sexual characteristics towards a prepubertal state, with a reduction in oestrogenization of the breasts and genital tract. A variable degree of osteoporosis will occur in the long term. A similar state can result from weight loss or starvation, or in athletes (especially long-distance runners) and ballet dancers: the periods usually, but not always, return if and when weight is regained. Isolated gonadotrophin deficiency without weight loss (due almost certainly to GnRH deficiency) may occur as a selective hypothalamic defect in the female, as in the male. If associated with anosmia, it is called Kallmann's syndrome (p. 942). It may also be seen in patients with craniopharyngioma, or after pituitary irradiation, in which case it is likely to be associated with other pituitary hormone deficiencies. Proloctin excess PRL excess from any cause is frequently associated with disordered ovarian function, with amenorrhoea occurring when the PRL level rises to more than two or three times above normal. PRL excess is believed to exert a 'short loop feedback' effect at hypothalamic level, reducing the pulse frequency of GnRH secretion. A classification of the causes is given in Table 17.7 and the condition discussed on pages 907-909.

Ovarian causes The ovarian causes of amenorrhoea and oligomenorrhoea are summarized in Table 17.26. In such cases the circulating levels of LH and FSH are elevated. Premature menopause Menopause is considered premature below the age of 40, and this occurs in 1 % of women. Occasionally the immune system may be implicated, with the production of ovarian antibodies (p. 889). An identical syndrome often results from irradiation of the ovaries or the administration of chemotherapeutic agents, usually directed against Hodgkin's lymphoma or other malignancies (p. 161). Gonadal dysgenesis An important group comes under the general heading of gonadal dysgenesis. Here, the ovaries may either fail to develop or degenerate before puberty, often because of an abnormal X chromosome complement, which leads to follicular death. Turner's syndrome Turner's syndrome (see Fig. 3.15, p. 68) is the commonest form, with a prevalence of around 1 in 5000 female births. Primary amenorrhoea is associated with short stature and a variable number of skeletal and somatic abnormalities

TABLE 17.26 Ovarian causes of amenorrhoea or oligomenorrhoea

17

Failure of normal ovarian development Pure XX gonadal dysgenesis Familial Sporadic Turner's syndrome (XO) Ovarian enzyme deficiencies (e.g. 17, 20 lyase) Premature ovarian failure (follicular degeneration) Idiopathic (low initial follicle number) Autoimmune (antiovarian antibodies) Infection (e.g. mumps oophoritis) Radiotherapy Cytotoxic drugs (e.g. for Hodgkin's disease, leukaemia) Surgical/traumatic Galactosaemia Ovarian dysfunction Polycystic ovary syndrome (possibly ovarian in origin) Resistant ovary syndrome Mutations in gonadotrophin receptors

(Table 17.27; see also Ch. 3, p. 69), but patients vary considerably in their expression of these. The condition is most commonly caused by a 45,X (termed XO) chromosome constitution, which results from the loss of an X or Y chromosome before the first mitotic division of the fertilized ovum. The features of this syndrome result in part from the existence of only one X chromosome (without a Y), and in part from the resulting sex hormone deficiency from the time of puberty onwards. Other forms of gonadal dysgenesis Some patients with a classic Turner's phenotype (Fig. 3.14) have a normal chromosome complement but have part of an X chromosome missing. With XO/XY mosaicism a range of clinical features, from Turner's syndrome to male genitalia, may be present. These patients frequently develop gonadal tumours, and prophylactic removal of dysgenetic gonads is indicated. Rare individuals have an apparently normal male genotype (46, XY) but normal female or ambiguous genitalia (pure XY gonadal dysgenesis; see p. 949). These patients also have an increased risk of gonadal tumours. 1

SUMMARY 12 Polycystic ovary syndrome • • • • • • •

Erratic cycles or amenorrhoea Subfertility Variable obesity and hirsutism Polycystic ovaries on ultrasound Inappropriately high LH Modest increase in androgens Mild hyperprolactinaemia

947

TABLE 17.27 Clinical features of 45, XO Turner's syndrome Type

Features

Sexual

Streak ovaries Sexual infantilism Primary amenorrhoea High gonadotrophins Normal female genitalia

Skeletal

Short stature (<150 cm) Characteristic facies - micrognathia, epicanthic folds, low-set ears, fish-like mouth, high arched palate Shield-like chest Wide carrying angle Short neck, low hairline Short fourth metacarpals Scoliosis Localised areas of rarefaction Osteoporosis

Soft tissues

Lymphoedema Webbing of neck

Cardiovascular

Coarctation of aorta Bicuspid aortic valve Aortic stenosis

Renal

Abnormal position of kidney or horseshoe shape Duplex ureters Hydronephrosis

Cutaneous

Small nipples Pigmented naevi Keloid formation

The polycystic ovary syndrome This was originally described by Stein and Leventhal in 1935 as hirsutism, obesity and oligomenorrhoea associated with enlarged ovaries with a thickened and whitish-looking 'capsule' and multiple follicular cysts. There is persistent elevation of serum LH. Hirsutism occurs in around 70% of affected women, amenorrhoea in 50% and obesity in 40%. It is likely that the cause varies, from hypothalamic, pituitary, ovarian and possibly even adrenal defects. About 20% of normal women have polycystic ovaries on ultrasound, although many of these have no specific signs or symptoms. The high LH levels are generally associated with increased ovarian secretion of androstenedione, which is converted in peripheral tissues to testosterone.

1 948

MCQ 17.24

Plasma oestradiol is relatively constant at levels seen in the midfollicular phase of the cycle; levels of SHBG are reduced, and so the unbound testosterone level is modestly raised. The extent of development of hirsutism and more marked virilization in this syndrome is very variable, and depends both on the hormone abnormality (which can be measured) and on the capacity of target tissues to respond. Likewise, the ovulatory disturbance varies from slightly erratic cycles through to long-standing amenorrhoea (primary or secondary).

Management of amenorrhoea The treatment of patients with erratic cycles depends on the underlying cause, the age of the patient and their requirements (e.g. for contraception, treatment of hirsutism or infertility). With PRL excess, restoring the PRL level to normal is usually sufficient to restore normal ovulation and fertility. If the latter is not desired, then the oral contraceptive pill can be given safely with bromocriptine or cabergoline. With gonadal dysgenesis or ovarian failure, attempts to restore ovarian function and fertility are generally unsuccessful. These women are suitable candidates for ovarian hormone replacement and embryo implantation (donor eggs fertilized by husband's sperm). Sex hormone replacement is indicated in most cases, at least until the time of the menopause. This can be provided by low-dose oral contraceptive pills, most of which provide 20-30 ug daily of ethinyl oestradiol, and a progestogen (21 days out of 28). When oral oestrogens are contraindicated (e.g. a history of venous thrombosis) percutaneous oestrogen can be given. Adhesive plastic patches containing oestradiol dissolved in ethanol (Estraderm), which are applied to the skin, or a gel preparation (Oestrogel) applied to a wide surface area are alternatives. A progestogen (oral or, in the case of patches, percutaneous) is needed in addition for 10-14 days every 1-2 months to prevent endometrial hyperplasia and induce periods. After the menopause, for most women, opinion increasingly favours hormone replacement therapy (HRT). There is little doubt that it protects the bones against osteoporosis and the genital tract against atrophy, and that many women feel much better on it. Cyclical progestogens prevent an increased risk of endometrial cancer. It is not clear by how much HRT increases the risk of breast cancer but the benefits usually outweigh any risk, at least up to 5 years of treatment, and probably longer. 1

Management of female infertility With hyperprolactinaemia, returning the PRL to normal usually restores both periods and fertility. Gonadotrophin deficiency may be treated either by gonadotrophin administration, or by pulsatile administration of GnRH. Both require careful monitoring. Gonadotrophin therapy consists usually of 3-7 days of

injections of a preparation of human FSH. The dose is titrated by measuring blood or urine oestrogens and by ovarian ultrasound scanning. When the right amount of follicular development has occurred, ovulation is induced by an injection of hCG. This treatment is only given in specialized units where there is also an egg retrieval and fertilization programme. Polycystic ovaries. Treatment of the infertility is difficult and often unsatisfactory. If the patient is obese, weight reduction may restore fertility. Clomiphene citrate (an antioestrogen) is often given, 50 mg daily for 5 days, commencing on the fifth day after a period starts, and induces ovulation in about half the cases. Side-effects include multiple pregnancy. Wedge resection of the ovaries, and more recently laser surgery, may be effective in cases resistant to clomiphene. Gonadotrophin therapy can also be used.

ate sex of rearing. Parents are under great pressure to declare the sex of the infant and to stick to it. They require very sensitive handling. Most cases of abnormal sex differentiation are cases of pseudo- (rather than true) hermaphroditism.

17

MALE PSEUDOHERMAPHRODITISM The male pseudohermaphrodite is a genetically male infant who does not have completely normal male sexual characteristics. In its mildest form the infant has failure of development of the penile urethra (hypospadias); in its most severe form the external genitalia appear to be those of a completely normal female. The causes are listed in Table 17.22 (p. 942).

Pure XY gonadal dysgenesis PREMENSTRUAL TENSION Premenstrual tension is a common but rather poorly defined condition in which a wide range of physical and emotional symptoms and signs are worst during the week or two preceding a menstrual period, and generally improve with its onset. It is not primarily an endocrine disorder, but is probably best thought of as a cyclical disorder 'locked in' on the normal fluctuation in hormone levels that accompanies the menstrual cycle. In many women, however, it can be extremely disabling. Treatment may be directed at smoothing out or eliminating the normal hormone changes, by using an oral contraceptive preparation, or at treating the symptoms.

FURTHER READING ON THE OVARIES Adashi E Y, Hennebold J D 1999 Single gene mutations resulting in reproductive dysfunction in women. N Engl J Med 340:709-718. Con way G S 1996 Polycystic ovary syndrome: clinical aspects. Bailliere's Clin Endocrinol Metab 10: 263-279. Greendale G A, Lee N P, Arriola E R 1999 The menopause. Lancet 353:571-580. Kyei-Mensah A A, Jacobs H S 1995 The investigation of female infertility. Clin Endocrinol 43: 251-255. Saenger P, Albertsson Wikland K, Conway G S, Davenport M, Gravholt C H, Hintz P et al 2001 Recommendations for the diagnosis and management of Turner syndrome. J Clin Endocrinol Metab 86: 3061-3069.

DISORDERS OF SEX DIFFERENTIATION The underlying mechanisms of primary sex differentiation are described on page 939. Where sex differentiation is evidently abnormal at birth, the problem is made particularly difficult by the urgency of determining the appropri-

Here, the individual is XY in sex chromosome constitution but testes never imposed maleness on the 'background' female phenotype. Apart from the absence of gonads, the patient is a completely normal female. The gonadal remnants (streak gonads) are at risk of developing tumours (dysgerminomas) at or after the age of puberty, and should therefore be removed. From puberty onwards, female sex hormone replacement should be given.

Testicular feminization Testicular feminization occurs with a frequency of about 1 in 20000 male births and is caused by a heterogeneous group of molecular defects in the androgen receptor, inherited in an X-linked fashion. XY individuals develop testes as normal but are unable to respond to the androgen they produce. The heterogeneity of genetic defects is responsible for the complete and partial forms of the syndrome. In the complete form the external genitalia are those of a normal female, but with a very short blind vagina. Miillerian structures are absent. There is no development either at or after puberty of even the normal female amount of pubic and axillary hair. The testes are in the inguinal canal. Presentation is often with inguinal herniae. The correct sex of rearing for individuals with either the partial or the complete form of the syndrome is undoubtedly female. It is generally felt to be advisable to leave the testes in situ until breast development has taken place at the normal age of puberty. Feminization of the breasts is usually excellent, under the influence of normal levels of testicular oestradiol (unopposed by androgen action). Circulating levels of LH and FSH are usually somewhat elevated, and testosterone levels in the high adult male range (after puberty). Oestradiol levels are also elevated owing to increased testicular production and peripheral conversion from testosterone. The gonads should be removed in early adult life, as there is considerable risk of development of tumours (dysgerminomas) within them.

949

5a-reductqse deficiency 5a-reductase deficiency is an autosomal recessive disorder, and is therefore most common where there has been intermarriage. The primary defect lies in the enzyme 5areductase, which is absent or reduced in activity. The production of dihydrotestosterone (DHT) in androgen target tissues is reduced (Fig. 17.28, p. 927) and those effects that depend on DHT are therefore compromised. Females with the condition appear normal, but males have impairment of virilization of the external genitalia. 1The phallus is small, and there is complete perineoscrotal hypospadias and incomplete fusion of the scrotum, with a blind vaginal opening. The testes, epididymes, vasa and seminal vesicles are normal, but the prostate gland is, and remains, atrophic. Regardless of the sex of rearing, affected individuals generally insist that they are male, both at the time of puberty and beyond, and generally demonstrate male patterns of behaviour. After puberty, the voice deepens and normal male muscular development occurs, but facial hair is absent or scanty.

FEMALE PSEUDOHERMAPHRODITISM In female pseudohermaphroditism a genetic female is partially or completely virilized. The most likely cause is excess androgen secretion in utero, generally as a result of the action of increased ACTH on the (abnormal) adrenal glands. The commonest cause is 21-hydroxylase deficiency (p. 932).

RARE DISORDERS OF STEROID BIOSYNTHESIS Rare deficiencies of almost all the enzymes have been described, and the clinical picture can usually be understood by reference to these pathways and the normal physiology of the glands (Fig. 17.28, p. ••). Conditions that affect the testosterone pathway lead to male pseudohermaphroditism; if they lie early on the pathway (which is shared with the adrenals) then adrenal insufficiency also occurs. In addition to 21-hydroxylase deficiency (which is about nine times more common than the others put together), there are a number of other disorders of steroid biosynthesis that also lead to pseudohermaphroditism in affected females. These include 3B-hydroxysteroid dehydrogenase deficiency, in which the weak A5-androgens from the adrenals cause some virilization in females (but males are inadequately virilized). Likewise, llB-hydroxylase defi-

1

950

Fig. 17.30

2

MCQ 17.25

TABLE 17.28 Causes of gynaecomastia Physiological Neonatal Pubertal Old age 'Refeeding' (after starvation) Pharmacological Spironolactone Digitalis glycosides Cannabis Cyproterone acetate Oestrogen ingestion Alcohol

Pathological Hypogonadism Steroid disorders 17B-hydroxysteroid oxidoreductase deficiency Testicular feminization Cirrhosis Thyrotoxicosis Tumours hCG-secreting Leydig cell Adrenal

ciency is associated with a build-up of adrenal androgens, leading to virilization (p. 932).

DISORDERS OF MALE SECONDARY SEX DIFFERENTIATION The physiological mechanisms that lead to male secondary sex differentiation are discussed on page 939.

Gynaecomastia Gynaecomastia (breast development in the male) is so common in puberty and old age as to be regarded as physiological. It also features in a wide range of disorders (Table 17.28). These are generally associated with an increase in oestrogen production and/or a decline in testosterone production. Some drugs cause gynaecomastia, the most notable being the aldosterone antagonist Spironolactone. This compound also binds to androgen receptors and is an antiandrogen. It also inhibits the secretion of androgen. Digitoxin and the main metabolite of cannabis cause gynaecomastia because of intrinsic oestrogenic activity. Treatment may be directed at the underlying cause, but that is often not apparent. Hypogonadism should be treated with testosterone replacement. Drugs such as danazol and tamoxifen may help if used early, but the best treatment for severe gynaecomastia is surgery. 2

Prostatic hyperplasia Prostatic hyperplasia begins in the fifth decade and results from increased androgen effect (via dihydrotestosterone and its hydroxylated metabolites). It commonly causes urethral obstruction and is usually treated by transurethral resection, although the 5a-reductase inhibitor finasteride (5mg daily) may be helpful in mild to moderate cases, sometimes combined with a-adrenergic blockade.

Prostatic cancer Prostatic cancer is the most common cancer in elderly males and is generally androgen dependent. The management of early-stage disease is with surgery or radiotherapy, depending on stage. For more advanced cases and in metastatic disease, a mainstay of treatment is suppression of androgen secretion and/or action. GnRH analogues such as buserelin, goserelin or leuprorelin are as effective. These agents can cause a transient worsening of disease owing to initial LH stimulation before LH becomes downregulated. Such 'flares' may be prevented by the antiandrogens cyproterone acetate (100 mg two or three times daily) or flutamide (250mg three times daily). These agents may also be used in palliation.

DISORDERS OF FEMALE SECONDARY SEX DIFFERENTIATION Hirsutism in women is the obverse of gynaecomastia in men and is almost equally common. The term virilization is reserved for the much less common androgenization associated with very high levels of testosterone, in or approaching the adult male range. This may be due to ovarian or adrenal tumours, or to the so-called late-onset form of congenital adrenal hyperplasia. Virilization usually declares itself by a rapid development of hirsutism, with other signs such as male pattern muscle development, frontal balding, clitoral enlargement and deepening of the voice. Measurement of serum testosterone is sufficient to exclude a virilizing tumour of the adrenal or ovary. The cut-off point for further investigations is about 5 nmol/L.

Hirsutism Most cases are due to the polycystic ovary syndrome or are idiopathic. In the latter there is probably heightened sensitivity of hair follicles to normal androgen levels. It is evident from the wide variation in the extent of facial and body hair in men that the same genetic variability must also exist in women. Thus, some women with chronic anovulation, erratic cycles, polycystic ovaries and

high levels of testosterone and androstenedione coming from the ovaries under the stimulation of LH show little or no hirsutism, whereas others, with a lesser endocrine defect, are severely hirsute. Another problem is to determine how much of the androgen excess is arising from the ovaries and how much from the adrenals. With the exception of 21-hydroxylase deficiency, the ovaries are usually the major source.

17

Management of hirsutism There is no ideal treatment and a careful explanation of the likely outcome is important. Psychological support is of great importance and must include reassurance that the woman is not losing her femininity, or 'turning into a man'. Sometimes minimal hirsutism is a focus for an anxiety state; conversely, some women react by refusing to accept that there is a problem, and avoid even elementary cosmetic measures. Cosmetic treatment involves the use of creams, waxes (which root out the hairs), shaving or electrolysis. The latter is usually reserved for strong terminal hairs on the face and breasts, or other psychologically important areas, and should only be carried out by a trained electrologist. Contrary to popular belief, shaving does not make unwanted hair grow faster or thicker. Hormonal treatment involves the use of adrenal and/or ovarian suppression and antiandrogens. Adrenal androgens can generally be suppressed with doses of glucocorticoid that are less than those required to suppress cortisol, but this tends to be unhelpful in practice. Ovarian suppression is achieved by using a low-dose oral contraceptive. The antiandrogens include cyproterone acetate, which in low dosage is a component of a contraceptive pill (Dianette); much higher doses (50-100 mg daily) are needed for maximum antiandrogen effect. Spironolactone (50-200 mg daily) is sometimes remarkably effective, but can lead in some cases to menstrual disturbance. Finasteride has recently been reported to be of benefit. Drug treatment does not cure the problem and can take 6-9 months to have an effect. Pregnancy must be avoided while taking these drugs, as male fetal development would be affected. An oestrogen is usually therefore given as a contraceptive and to ensure regular periods. The duration of drug therapy for hirsutism can be openended and determined by the severity of the problem and the response; the patient will simply have the same problem (no worse) when treatment is stopped.

SUMMARY 13 Management of hirsutism • Exclude a virilizing tumour by history and serum testosterone level • Psychological support has considerable importance • Cosmetic treatments are often effective and do not increase hair growth • Antiandrogens such as spironolactone, cyproterone and finasteride are effective in severe cases but require careful monitoring for side-effects

SEX HORMONES AND BEHAVIOUR Androgens, oestrogens and progestogens all affect the individual's behaviour, either directly or indirectly. However, homosexuality, transsexualism and sexual deviation are not directly linked to androgen or oestrogen levels. It has been suggested that XYY men are more violent than normal men, in view of the finding of an increased number

951

in penal institutions; however, the significance of this is uncertain. Androgen-deficient men may develop protective mechanisms and become aggressive to compensate for the lack of physical development. If they are then abruptly put on to androgens at high doses, the aggression may become more overt. The transition through an endocrine adolescence very late requires medical guidance. Generally, hypogonadal men adapt very well to their new endocrine status and many go on to develop satisfactory heterosexual relationships.

952

FURTHER READING ON DISORDERS OF SEX DIFFERENTIATION Azziz R, Dewailly D, Owerbach D 1994 Non-classic adrenal hyperplasia: current concepts. J Clin Endocrinol Metab 78: 810-815. Azziz R, Carmina E, Sawaya M E 2000 Idiophic hirsutism. Endocrine Revs 21: 347-362. Braunstein G D 1993 Gynecomastia. N Engl J Med 328: 490-495. Rey R, Picard J-Y 1998 Embryology and endocrinology of genital development. Bailliere's Clin Endocrinol Metab 12:17-33. Rittmaster R S 1997 Hirsutism. Lancet 349:191-195.

18 Metabolic Bone

Disease

and

Mineral

Metabolism John Cunningham and John P Monson

lar fluid, the free intracellular calcium ion concentration is approximately 10-7-10-6 molar, which is one thousandth of the free calcium ion concentration in the ECF (10-4 molar, or ImM). Most of the intracellular calcium is sequestered in, or on, specific cell organelles. Calcium in blood plasma at 2.4 mM is present in three main forms: free ionized, protein bound and anion bound (Table 18.1). The biological functions of ECF calcium are thought to be effected by the ionized fraction only. Inorganic phosphate in plasma is only slightly protein bound (approximately 12%), the rest being present as HPO2/H2PO4 (in the ratio 4:1 at physiological pH), as well as in the form of sodium, calcium and magnesium phosphates. Most of the intracellular phosphate is covalently bound to organic compounds or in the form of phospholipids. The free inorganic phosphate concentration in cells is probably less than 1 mM.

Bone composition Anatomy and physiology 953

Rickets and osteomalacia 962

Hormonal control of bone, calcium and phosphorus metabolism 954

Hypercalcaemia 965

Magnesium homeostasis 956 Investigation of bone disease 957

Hypocalcaemia 972 Paget's disease of bone 974 Miscellaneous rare bone diseases 978

Osteoporosis 959

ANATOMY AND PHYSIOLOGY The skeleton: • Supports the soft tissues • Encases and protects certain organs such as the central nervous system (CNS) • Acts as an enormous reservoir for minerals, in particular calcium, phosphorus, magnesium and sodium. Although in health these functions are not in conflict, there are circumstances - for example calcium deprivation when the skeleton's contribution to chemical homeostasis may lead to progressive demineralization and compromise its mechanical functions.

Distribution of mineral The adult skeleton contains some 99% of total body calcium (Table 18.1), ranging from 1 to 2kg (25-50mol) depending on size, 88% of total body phosphorus, 80% of body carbonate, 50% of body magnesium and 35% of body sodium. Although calcium is distributed approximately equally between extracellular fluid (ECF) and intracellu-

Bone consists of a calcified (mineralized) organic matrix. The organic matrix, osteoid, makes up about 30% of the total skeletal mass, and consists mainly of type I collagen and the vitamin K-dependent protein osteocalcin, with small amounts of other proteins. The mineral component, which is deposited throughout the organic matrix, makes up the remaining 70% of skeletal mass and consists mainly of a complex crystalline salt of calcium and phosphate called hydroxyapatite. There are also smaller amounts of amorphous acid phosphate, carbonate, sodium and magnesium. Bone undergoes continual modelling and remodelling by bone cells, which allows the skeleton to grow and adapt itself to prevailing mechanical needs. The result is an organ that, for its weight, is extremely rigid and strong without being brittle. The skeletal adaptation provides for appropriate strength only where it is needed, thereby avoiding excess weight. At least three distinct cell types contribute to these processes (Fig. 18.1). The osteoblast The osteoblast is derived from mesenchymal precursor cells and is the main bone-forming cell. It synthesizes organic matrix (osteoid) and probably also controls the subsequent mineralization of the matrix. It has plentiful mitochondria and an extensive Golgi apparatus associated with rapid protein synthesis. It is rich in alkaline phosphatase. Cells of the osteoblast line possess specific receptors for parathyroid hormone (PTH) and 1,25dihydroxyvitamin D (1,25(OH)2D, calcitriol). The osteocyte Osteocytes are derived from osteoblasts that no longer have a major biosynthetic role and have become encased in bone, communicating with each other by extensions running through canaliculae in the bone. They are likely to be involved in the movement of mineral in the vicinity of the osteocyte lacunae and in detecting stresses in bone.

953

FIG. 18.2 Relationship between bone mass and age

FIG. 18.1 Diagram of normal trabecular bone undergoing osteoclastic resorption followed by new bone formation by osteoblasts

citonin, thyroxine, glucocorticoids and the sex steroids. The functions of osteoclasts and osteoblasts are closely linked, osteoclastic bone resorption being followed by an increase in osteoblastic bone formation. This coupling is effected by locally produced regulators.

Bone qrowth, modelling and remodelling TAlLE 18.1 Distribution of body calcium Compartment

Quantity/concentration

Whole body Skeleton Rapidly exchangeable/bone surface Extracellular fluid (ECF) Intracellular fluid (ICF)

1kg(25mol) 8g(200mmol) 1g(25mmol) 1g(25mmol)

In plasma Free ionised Ca2+ Protein-bound Albumin Globulin Ultrafiltrable bound (by bicarbonate citrate and phosphate) Total in plasma

954

1.1mmol/L 0.75mmol/L 0.25mmol/L 0.3mmol/L 2.4mmol/L

The osteoclast Osteoclasts are multinucleated cells derived from cells related to macrophages. Their function is bone resorption. When actively resorbing they have a deeply folded plasma membrane, creating a 'ruffled border' in close proximity to the bone surface. Although they are influenced by the calcium-regulating hormones, PTH and 1,25(OH)2D, they do not apparently possess specific receptors for these hormones; it is therefore likely that hormonal control is exerted by way of communication with osteoblasts, or by effects of hormones on osteoclast precursors. Osteoclasts may also be influenced by other hormones, including cal-

Longitudinal bone growth in childhood depends on the proliferation of cartilage at the hypertrophic zone, which becomes mineralized and then formed into bone. This process is mediated by growth hormone, through the action of locally produced insulin-like growth factor 1 (IGF-1), and thyroid hormone. Diameter is increased by periosteal bone formation. Once growth has ceased the coupled activity of osteoblasts and osteoclasts continues, although at a much slower rate, a process which allows alteration of bone architecture (without growth) in response to factors such as mechanical loading. As shown in Figure 18.2, skeletal mass peaks at about the age of 25, decreasing thereafter at a constant rate in males, and with a transient acceleration after the menopause in females. This progressive decrease indicates that, throughout most of adult life, net bone resorption just exceeds net formation. In some individuals, especially postmenopausal women, bone mass may decrease to the point where clinically important mechanical weakening arises (osteoporosis), leading to fractures that may be spontaneous or follow minimal trauma.

HORMONAL CONTROL OF BONE, CALCIUM AND PHOSPHORUS METABOLISM The interrelationships between calcium and inorganic phosphorus in the ECF, the skeletal reservoirs of these ions, and their main sites of entry and exit in the body (the intestine and the kidney, respectively), are controlled by a hormonal system that is dominated by PTH and 1,25(OH)2D (Fig. 18.3). The role of the third potential calcium-regulating hormone, calcitonin, is more enigmatic.

• To decrease the renal tubular reabsorption of inorganic phosphate, thereby promoting phosphaturia; • To stimulate the production of 1,25(OH)2D, thereby promoting intestinal calcium absorption.

18

1,25-dihydroxyvitamin D (1,25(OH)2D, calcitriol)

FIG. 18.3 Vitamin D metabolism and the hormonal regulation of calcium metabolism Processes raising blood calcium are shown in blue and calcium-lowering ones in black.

Parathyroid hormone PTH is an 84 amino acid peptide hormone that is manufactured, stored and released by the chief cells of the parathyroid glands. Two intracellular precursors have been identified, prepro-PTH being cleaved successively to yield pro-PTH and, finally, PTH 1-84 itself. Its synthesis is regulated by the concentrations of extracellular calcium, extracellular phosphate and 1,25(OH)2D3, each forming a negative feedback loop with the parathyroid gland (Fig. 18.3). Calcium and phosphate regulate PTH production at the post-transcriptional level, whereas 1,25(OH)2D, a steroid hormone, acts via a vitamin D receptor and a vitamin D response element on the PTH gene. Both PTH synthesis and release are highly responsive to the prevailing ionized calcium concentration in the ECF, particularly in and near the range of physiological calcaemia, and are mediated by a calcium sensor located in the membrane of the parathyroid cells. Thus, modest hypocalcaemia triggers a substantial PTH response and modest hypercalcaemia almost completely suppresses the secretion of biologically active PTH. As shown in Figure 18.3, PTH forms part of a feedback loop that is well suited to maintaining calcium homeostasis. The actions of PTH itself are directed towards the elevation of blood and ECF calcium concentration. These actions are: • To promote recruitment and activation of osteoclasts and so accelerate bone resorption (indirectly through osteoblasts); • To increase the renal tubular resorption of calcium;

The potent steroid hormone 1,25-dihydroxyvitamin D is produced almost entirely in the kidney, although small amounts are found in other tissues, such as alveolar macrophages and the placenta. It is the product of a series of chemical transformations that starts with the production of cholecalciferol (vitamin D3) in the skin under the influence of ultraviolet light, or with the ingestion of ergocalciferol (vitamin D2) added to the diet. Normally, the latter is quantitatively less important. 25-Hydroxylation of vitamin D in the liver, and subsequent 1-hydroxylation of 25hydroxyvitamin D in the kidney, result in production of the active hormonal form of vitamin D, 1,25(OH)2D3 (Fig. 18.3). The 1-hydroxylation in the kidney is stimulated by PTH and hypocalcaemia. Other hydroxylated metabolites of vitamin D are also produced by the kidney, but 1,25(OH)2D is the only one with clearly defined biological actions. Like PTH, 1,25(OH)2D is a calcaemic hormone; its known actions complement those of PTH. 1,25(OH)2D has three major target organs, the intestine, bone and the parathyroid glands. In the intestine, 1,25(OH)2D increases the absorption of calcium and, to a lesser extent, phosphate by: • Increasing the permeability of the brush border to calcium; • Promoting the synthesis of a high-affinity calciumbinding protein in the cell; • Accelerating active extrusion of calcium across the basolateral membrane. In bone, the main action of 1,25(OH)2D is to increase resorption. This is probably by stimulating proliferation and differentiation of osteoclast precursors. In addition, osteoblasts (which possess receptors for 1,25(OH)2D, can probably modulate the function of nearby osteoclasts (Fig. 18.1). In the parathyroids, 1,25(OH)2D suppresses PTH gene transcription, thereby completing a negative feedback loop that limits excessive PTH response to hypocalcaemia. These actions of 1,25(OH)2D favour elevation of the concentration of ionized calcium and inorganic phosphorus in blood. The extent to which bone formation and resorption are under the direct control of vitamin D metabolites is unclear, although indirectly the vitamin D system certainly influences bone formation by controlling calcium and phosphate concentrations in the ECF. Renal production of 1,25(OH)2D is under tight control by PTH, hypocalcaemia and hypophosphataemia, all of which stimulate production of la-hydroxylase. The phosphaturic effect of PTH prevents the calcium phosphate product rising when PTH rises and bone resorption increases.

955

Other hormones Although many other hormones have demonstrable effects on bone metabolism under appropriate circumstances, their physiological role is uncertain. Calcitonin Calcitonin is a 32 amino acid peptide hormone secreted by the C cells of the thyroid gland. Its best-defined actions are on bone, where it binds to specific receptors in osteoclasts, leading to decreased resorptive activity. This effect is most striking where bone turnover is high, such as in growing bone or in Paget's disease (p. 974). Even when given in pharmacological doses, the influence of calcitonin on calcium and bone metabolism in the normal adult is minimal. Sex steroids Oestrogens The acceleration of bone loss after the menopause and its amelioration by oestrogen therapy, together with the high prevalance of osteoporosis in women with untreated primary or secondary hypogonadism, has long suggested that oestrogens exert an important influence on bone metabolism. Recent evidence suggests a direct effect, mediated by oestrogen receptors on osteoblasts. Androgens These are responsible for the attainment of higher peak bone mass in males (Fig. 18.2), either directly, or indirectly by increasing muscle bulk and strength. Androgens and oestrogens also act on growth cartilage, in concert with growth hormone, promoting growth and, later, epiphyseal closure. Glucocorticoids In physiological amounts, glucocorticoids are important regulators of bone growth, probably by actions on both bone-forming and bone-resorbing cells. Pharmacological doses of these steroids reduce bone mass, leading to osteoporosis. Thyroxine About one-third of patients with thyrotoxicosis have mild hypercalcaemia, hypercalciuria or both, and neglected thyrotoxicosis may lead to osteoporosis. Conversely, hypothyroidism is associated with low bone turnover, which may be restored to normal by physiological doses of thyroxine. Growth hormone Even after cessation of statural growth, growth hormone (GH), acting through IGF-1, remains an important regulator of bone remodelling. Acquired GH deficiency in adult life is associated with a reduced bone density.

1

956

MCQ18.1

Local modulation of bone, calcium and phosphorus metabolism A variety of local factors contribute to the delicate balance that exists between the actions of the different types of bone cell, although many of these have not yet been fully characterized. Prostaglandins Local production of prostaglandins, such as PGE2, may influence bone metabolism directly, or by promoting the synthesis of other locally acting factors, such as epidermal growth factor and platelet-derived growth factor. Inhibitors of prostaglandin synthesis have little if any effect on bone. Cytokines There are many cytokines with proven or possible paracrine function in bone. Interleukin-1 (IL-1) is a potent bone-resorbing agent derived from activated macrophages. It has many interactions with other cytokines, such as yinterferon, consistent with local regulatory functions in bone. Tumour necrosis factors and transforming growth factor p also have effects, and some or all may be involved in bone cell coupling. IL-4 and IL-11 exert inhibitory effects on osteoblasts. Osteoclast development and/or function is influenced by IL-3, IL-6 and IL-8, as well as by macrophage colony-stimulating factor (MC-CSF) and by granulocyte macrophage CSF. Cytokine-induced bone resorption is an important mechanism in bone metastasis and hypercalcaemia of malignancy (see Fig. 18.8, p. 970). O

MAGNESIUM HOMEOSTASIS Magnesium ions have a similar cellular/extracellular distribution to potassium, and parallel alterations in concentration of these cations are observed in a number of situations. The high content of magnesium in bone results in important associations with calcium metabolism; for example, magnesium is an effector of PTH secretion. Hypomagnesaemia may occur with: • Severe malnutrition - lack of magnesium intake; • Long-term intravenous feeding in the absence of magnesium supplements; • Some long-term renal tubular disorders; • Chronic diuretic therapy causing renal loss; • Uncontrolled diabetes mellitus - renal loss; • Alcoholism - malnutrition; • Following surgical correction of hyperparathyroidism owing to calcium and magnesium deposition in bone; • Cytotoxic treatment with cisplatin (as a result of failure of magnesium reabsorption owing to renal tubular damage). Hypomagnesaemia is rarely severe, but may occasionally give rise to symptoms and signs similar to those of hypocalcaemia, with tetany progressing to convulsions and cardiac

arrhythmias, with or without associated hypocalcaemia. This may necessitate magnesium supplementation by oral magnesium salts (of which magnesium glycerophosphate is least likely to cause diarrhoea) or parenteral magnesium sulphate. Coexisting hypocalcaemia is refractory until the hypomagnesaemia has been corrected; this is owing to impaired secretion of PTH, and also to target organ resistance to circulating PTH during hypomagnesaemia. Hypermagnesaemia may complicate renal impairment. It results in gastrointestinal disturbance and may, if severe, cause neuromuscular dysfunction and CNS depression. Cardiac toxicity, including complete heart block, may occur with plasma magnesium concentrations in excess of 7.5mmol/L (normal is 0.7-0.8mmol/L). However, hypermagnesaemia is rarely of clinical significance.

INVESTIGATION OF BONE DISEASE Investigations of bone disease fall into five groups: • • • • •

Biochemical: blood and urine Radiographic Radionuclide studies Measurement of bone mass Histology.

TABLE 18.2 Biochemical investigation of bone disease Measurements Blood plasma Urea creatinine Na+, K+, CI-, HC03Calcium

Phosphate

Alkaline phosphatase (total or bone-specific) and osteocalcin Parathyroid hormone (PTH) 25-hydroxyvitamin D Urine Calcium Phosphate

Biochemistry (Table 18.2) Blood calcium Total calcium in plasma or serum is the usual measurement taken in clinical practice, although in some instances direct measurement of the physiologically important ionized fraction is undertaken. The latter is likely to be used increasingly as it avoids the difficulties that may arise when abnormalities of plasma protein concentration or acid-base status alter the normal relationship between total and ionic calcium in blood. A reduced plasma protein concentration leads to a reduction in plasma total calcium concentration, even though free ionic calcium is normal. The error may be reduced by 'adjustment' of the observed calcium concentration, using the formula: l

Ca (adjusted) = Ca + 0.02(46 - alb) 1

where Ca is the observed concentration of total calcium in mmol/L and alb is the albumin concentration in g/L. Some laboratories have a reference range for serum calcium based on correction to a serum albumin of 40 g/L. As pH falls, so does calcium binding to plasma proteins. Thus, during severe acidosis, plasma total calcium may be low but with a normal free ionic calcium concentration. Increases in blood calcium usually reflect accelerated entry into the ECF. This occurs as a result of either rapid bone resorption (primary hyperparathyroidism, vitamin D intoxication, osteolytic metastases or PTH-rp in humoral hypercalcaemia of malignancy), or increased intestinal

Hydroxyproline, pyridinoline and deoxypyridinoline

18

Associated disease Renal disease Acid-base disturbance Increased in primary hyperparathyroidism, malignant disease, granulomatous disease, vitamin D intoxication Decreased in renal disease, osteomalacia, hypoparathyroidism Increased in renal disease, hypoparathyroidism and pseudohypoparathyroidism Decreased in primary hyperparathyroidism, vitamin D deficiency, renal tubular disorders Increased in childhood, hyperparathyroidism, vitamin D deficiency, fracture, malignancy, Paget's disease Decreased in hypophosphatasia Increased in hyperparathyroidism and pseudohypoparathyroidism Vitamin D deficiency or intoxication Hypercalciuria Familial hypocalciuric hypercalcaemia Decreased tubular reabsorption in hyperparathyroidism Reflect increased bone resorption, e.g. in hyperparathyroidism, thyrotoxicosis and immobilization

absorption (high dietary calcium intake, primary hyperparathyroidism, vitamin D intoxication or milk alkali syndrome), or both processes acting together. Decreases in blood calcium are due to diminished bone resorption and/or diminished intestinal absorption of calcium. Important causes are hypoparathyroidism, vitamin D deficiency with calcium malabsorption, and severe renal disease. Urine calcium Urine calcium ranges from 2.5 to 7.5mmol/24h in adults and is increased in situations where calcium entry to the ECF is enhanced (leading to potential or actual hypercalcaemia), or where the renal tubular reabsorption of calcium is decreased ('renal leak' type of hypercalciuria), or both. Plasma inorganic phosphate Plasma phosphate is normally determined by the level of renal tubular reabsorption of phosphate, a process that is itself modulated by the dietary intake of phosphate and by PTH. Tubular reabsorption of phosphate is decreased by PTH and increased by low dietary intake of phosphate. A low plasma phosphate is found in association with primary

957

FIG. 18.4 X-ray showing subperiosteal erosions in the hands in a case of hyperparathyroidism

hyperparathyroidism, vitamin D deficiency, certain renal tubular disorders (p. 964) and prolonged dietary phosphate deprivation. Serum phosphate is elevated in patients with substantial impairment of renal function with reduction of glomerular filtration rate (GFR), in hypoparathyroidism, and occasionally in patients with greatly accelerated tissue catabolism (e.g. rhabdomyolysis, tumour necrosis).

vitamin D status. 25(OH)D in plasma shows a seasonal variation, being high in summer and lower in winter because cutaneous production of vitamin D depends on ultraviolet light. Plasma levels are low in vitamin D deficiency, because of lack of sunlight exposure and poor diet normal in patients with renal disease, elevated in patients with vitamin D intoxication.

Alkaline phosphatase The bone-specific isoenzyme of alkaline phosphatase is produced by osteoblasts, and its release into the circulation increases as osteoblast numbers and/or activity increase. This is seen in normal children during the phase of active bone growth, and also in generalized disorders characterized by high bone turnover (e.g. hyperparathyroidism) and in focal lesions (e.g. healing fractures, Paget's disease or bone metastases). Many other tissues also contain alkaline phosphatases, which differ slightly from one another (isoenzymes). To avoid diagnostic confusion, elevation of blood alkaline phosphatase must be interpreted in the clinical context and not in isolation. Specific isoenzymes can be measured to identify the tissue of origin, but even the best assays suffer from cross-reactivity between two or more of the isoenzymes. Serum concentration of osteocalcin provides an additional marker of osteoblastic activity but has little clinical application at present.

Urinary deoxypyridinoline Deoxypyridinoline and pyridinoline are cross-linking compounds in mature collagen. Bone collagen contains both compounds, and their release from bone undergoing resorption constitutes the main source of these compounds excreted in the urine. Urinary collagen cross-links are more sensitive and more specific markers of bone resorption than hydroxyproline and have the advantage of not being susceptible to dietary influences. Deoxypyridinoline has greater specificity for breakdown of collagen from bone than other tissues.

Parathyroid hormone Measurement of PTH by radioimmunoassay is an important adjunct to the diagnosis of some metabolic bone disorders. PTH in plasma is present as intact PTH (84 amino acids) and also as several different peptide fragments. Current assays use antibodies to two sites on the molecule and detect only intact PTH. Elevated PTH is found in primary or secondary hyperparathyroidism, and in all patients with target organ resistance to the action of PTH (pseudohypoparathyroidism, p. 974). PTH is undetectable in patients with hypoparathyroidism. 25-hydroxyvitamin D Although 25-hydroxyvitamin D (25(OH)D) is only the precursor of the active hormonal form of vitamin D (Fig. 18.3), measurements of 25(OH)D are the best guide to

Radiography Plain radiographs are of great value in the diagnosis of localized.disorders of bone, e.g. developmental abnormalities, fractures, tumours and infections. Some diseases affecting the entire skeleton may also be diagnosed in this way. For example, severe osteoporosis may lead to radiologically evident fractures, and hyperparathyroidism may be associated with visible subperiosteal erosions in the hands and elsewhere (Fig. 18.4). In these instances, local abnormalities are acting as markers for generalized disease.

Radionuclide studies Bone-seeking radionuclides such as 99mTc methylene bisphosphonate may be given by intravenous injection and the pattern of uptake assessed by external counting using a gamma camera. Uptake is largely determined by blood flow to bone and by the rate of bone turnover; the technique is therefore extremely good at detecting focal lesions, such as metastases, infections, Paget's disease or subtle fractures, that may not be visible on conventional radiographs.

Measurement of bone mass 1

958

Figs 18.1-18.2

2

Figs 18.3-18.6

The increasing proportion of elderly people in populations worldwide had led to an increase in the incidence of agerelated diseases such as osteoporosis. Accurate measure-

ment of bone mass, simply and safely, is essential for the identification, assessment and monitoring of patients with osteoporosis. Conventional radiography is imprecise and has little to offer apart from the identification of fractures. Dual X-ray absorptiometry (DXA or DEXA) gives an accurate measurement of bone and the mineral content of the spine and femoral neck. 1 In contrast to quantitative computerized tomography (CT), it involves very low radiation exposure. DXA measurements are good predictors of fracture risk. Peripheral sites such as the calcaneum are also used as surrogates for the wider skeleton - X-ray absorptiometry and heel ultrasound (speed of sound transmission) both show promise as screening tests.

Histology The technique of transiliac bone biopsy, whereby a cortexto-cortex core of bone 5-8 mm in diameter is taken from the ilium under local anaesthetic, is sometimes used in the diagnosis and assessment of generalized metabolic bone disease. The specimens may yield useful information on the number and activity of osteoblasts and osteoclasts, and indicate whether organic matrix production is normal and being appropriately mineralized. 0 A useful adjunct is the technique of tetracycline labelling. Here, tetracycline (600-900 mg of demeclocycline) is given twice, with a 10day interval between; the biopsy is performed 4 or more days after the second label is taken. The drug is taken up at the mineralization front in bone, and can be detected in the biopsy specimen by fluorescence under ultraviolet light. Uptake is poor or absent in osteomalacia (pp. 962-965) and enhanced in states of high bone turnover (e.g. hyperparathyroidism and thyrotoxicosis).

OSTEOPOROSIS The term osteoporosis denotes loss of bone mass per unit volume; bone composition is normal, although microscopic trabecular bone architecture is not. The WHO definition of osteoporosis is based on a T-score (standard deviation score compared to the young adult reference range) of less than -2.5 and osteopenia as less than -1.0 at the lumbar spine and/or femoral neck. It is estimated that T-scores of -1.0 to -2.5 are associated with a doubling of fracture risk. Osteoporosis becomes clinically important when bone is so weak that pathological fractures result. Most examples of osteoporosis arise as a result of the progressive decrease in bone mass with age (see Fig. 18.2); as this occurs to a greater or lesser extent in all individuals, the distinction between pathology and the normal ageing process is blurred.

Pathological changes in bone mass Bone mass is governed by the balance between bone for-

mation and resorption. Positive, neutral and negative bone balances are found at different ages. In infancy and adolescence, bone formation clearly exceeds resorption; in early adult life the processes are approximately equal, and later a disparity in favour of resorption results in a slow decline in total bone mass (Fig. 18.2). Whether or not this gives rise to clinical problems (fractures) depends to a large extent on the maximum bone mass achieved as an adult. This is greater in men than women, and is also greater in Afro-Carribeans than in whites. Women are further disadvantaged by a more rapid decrease in bone mass in later adult life, and the net result is a much higher incidence of osteoporotic complications. On average, women also live for about 5 years longer than men. The reasons for the sex differences in rate of bone loss are probably multiple, but postmenopausal oestrogen deficiency is most strongly implicated. This condition may sensitize the skeleton to the bone-resorbing effects of PTH, and possibly also impairs renal synthesis of 1,25(OH)2D. These metabolic changes may lead to mild, but chronic, calcium malabsorption and consequent secondary hyperparathyroidism (pp. 962 and 972). In extreme old age, bone loss in men catches up with that in women. Idiopathic osteoporosis may occasionally occur in young people, especially during the adolescent growth spurt. It is usually self-limiting, but may be complicated by fractures. A particularly severe form of juvenile-onset osteoporosis is associated with decreased sex steroid receptor expression in bone, which is probably genetic in origin.

18

Clinical features and investigation Osteoporosis remains asymptomatic unless structural collapse or fracture of bone occurs. Damage is particularly likely to occur in the dorsal vertebrae, femoral neck and distal radius. The precipitating trauma may be trivial, but fracture frequently follows a fall. There are usually no abnormalities on routine plasma biochemistry, except in cases secondary to specific endocrine disorders (see below). In some patients urinary calcium excretion may be increased, consistent with net bone resorption, and plasma calcium may be marginally elevated. This is particularly common when immobility is a contributory factor. Plain radiographs demonstrate decreased bone density due to loss of trabeculae, and reduced cortical thickness of long bones in severe cases. The dorsal vertebrae may show the classic 'wedge collapse' of osteoporotic crush fracture and herniation of the disc into the centre of the vertebra to give a 'codfish' vertebra, and exaggeration of the normal curvature of the thoracic spine (Fig. 18.5). Detection and assessment of osteoporosis is best achieved by measurements of bone mass by dual X-ray absorptiometry or CT scanning of the spine. Normality of plasma calcium, phosphate and alkaline phosphatase helps to exclude osteomalacia, but in doubtful cases further investigation may be necessary, including

959

TABLE 18.3 Causes of generalized osteoporosis and their mechanisms* Cause

Bone resorption

Common causes Corticosteroid excess Early menopause Immobility Multiple myeloma1 Rare causes Hypogonadism (primary or secondary) Thyrotoxicosisf Type 1 diabetes mellitus Pregnancy Primary hyperparathyroidism* Adult GH deficiency

Bone formation

Normal

Normal

Normal

4

Normal

* Primary liver disease is omitted as this is associated with a combination of osteoporosis and osteomalacia. Conditions in which the plasma calcium may be increased. FIG. 18.5 X-ray of lateral thoracic spine of a 60-year-old woman with severe postmenopausal osteoporosis Note gross loss of density, collapsed and 'codfish' vertebrae and kyphosis.

Management measurement of plasma 25-hydroxyvitamin D and transiliac bone biopsy. In most instances no specific underlying cause for osteoporosis will be found. However, careful consideration should be given to the causes outlined below, and further investigation initiated if the overall clinical picture so warrants.

Specific causes of osteoporosis

960

Osteoporosis is common in the elderly and it may be difficult to decide whether a vertebral collapse is due to osteoporosis or to another, coincidental, underlying disease, such as secondary carcinoma. Cancers of the breast, lung, kidney and thyroid typically cause lytic lesions in bone. Prostatic cancer may also do so, though sclerosis is more common. Breast cancer in particular has a predilection for secondary spread to the axial skeleton. Myeloma (Ch. 24, p. 1435) may be accompanied by generalized thinning of bones and/or focal lytic areas. Breast cancer will often be detected by physical examination, but further investigation may be needed to exclude other forms of cancer and myeloma. Chronic liver disease (especially primary biliary cirrhosis) may give rise to a mixed picture of osteoporosis and osteomalacia (see below). Hereditary abnormalities in bone formation are discussed on page 978. Conditions that may be complicated by significant generalized osteoporosis are listed in Table 18.3.

Prevention Prevention of the development of osteoporosis in individuals at risk is of the utmost importance. This is most obviously the case in females with primary or premature ovarian failure, who should be treated with either oral oestrogen, e.g. oestradiol valerate l-2mg/day, or transdermal oestradiol 50-100 ug patches twice weekly. Progesterone supplements should also be given cyclically, or at low dose continuously (p. 948), to avoid unopposed endometrial stimulation with its risk of neoplastic change. However, the use of prophylactic oestrogen supplements after the physiological menopause is more controversial. Oestrogen alone undoubtedly reduces the rate of bone loss after the menopause (and even increases bone mass in many patients). This is probably not associated with an increased risk of atheroma development, at least at low dosage but is associated with an increased relative risk of breast cancer. Appropriate exercise, e.g. regular swimming, should be encouraged in patients with relative immobility, and regular non-strenuous exercise in the elderly. Treatment Osteoporosis is a heterogeneous condition that arises most commonly in postmenopausal women, but also as a consequence of specific conditions, including thyroid disease, parathyroid disease, renal disease, chronic liver disease, hypogonadism and corticosteroid excess (both endogenous and iatrogenic). The role of growth hormone (GH) deficiency in the development of osteoporosis in the hypopituitary patient, and possibly also in the elderly,

18

CASE STUDY 18.1 ACUTE BACK PAIN A 68-year-old woman presented with a history of sudden onset of localized dorsal spinal pain. She experienced severe pain on attempted movement and examination demonstrated localized tenderness over the sixth dorsal vertebra. There were no breast masses and no neurological signs. Previous medical history was unremarkable, apart from a relatively early menopause at the age of 44. She had not received postmenopausal oestrogen replacement therapy, was a non-smoker, and consumed occasional alcohol only. Initial investigations indicated haemoglobin 12.9 g/dL, ESR 13mm/h, normal serum electrolytes, urea 5.2mmol/L, serum creatinine 86 umol/L, serum calcium 2.22 mmol/L, serum phosphate 0.98 mmol/L and alkaline phosphatase 78IU/L. Questions 1. What is the most likely cause for her pain? 2. How might this be confirmed? 3. What treatment options are available for long-term management?

Discussion The presentation with acute dorsal spinal pain in a patient of this age is strongly suggestive of a vertebral crush fracture. Pre-exisiting osteoporosis is the most likely precipitant, and the early onset of post menopausal oestrogen deficiency would be considered a significant predisposing risk factor for this. However, vertebral metastasis is a common manifestation of malignancy, with cancer of the breast, kidney and lung and myeloma being common underlying causes. The high risk of spinal cord compression makes this an important differential diagnosis. The normal breast examination is an important negative finding in this respect, as is the normal blood count. Osteomalacia, or rarer causes of metabolic bone disease, are improbable given the normal serum concentrations of calcium, phosphate and alkaline phosphatase. Plain radiological imaging confirmed a wedge-shaped fracture of the body of the sixth dorsal vertebra against a background appearance of reduced bone mineral density. Formal assessment of bone mineral density by dual-energy X-ray absorptiometry demonstrated T-scores (standard

in whom GH secretion declines with age, is increasingly recognized. The treatment of established osteoporosis includes: • Avoiding immobility and encouraging exercise; • Adequate dietary calcium; • Treating sex steroid deficiency (particularly when this has occurred pathologically or physiologically at an early age); • Treatment of underlying disorders; • Bisphosphonate therapy. Patients should be encouraged to take regular, but not over-strenuous exercise: walking and activities such as golf are convenient for many. Dietary calcium should be generous (at least 20mmol/day); if this is not achieved, the diet may be supplemented with calcium carbonate tablets. The evidence that calcium supplements are of benefit is con-

deviation scores compared to the young adult reference range) of -2.6 and -2.1 at the lumbar spine and femoral neck, respectively, indicating osteoporosis. An isotope bone scan showed no evidence of metastases at other sites. Long-term management of this patient's condition should include dietary assessment, with calcium and vitamin D supplements (400IU/day) if her diet is deemed to be inadequate. Specific treatment in the form of bisphosphonate therapy (e.g. cyclical etidronate with calcium supplementation or alendronate) should be commenced. It is uncertain whether the addition of oestrogen replacement, in addition to bisphosphonate therapy, would have any substantial effect in a patient of this age. However, there is emerging evidence of an additive effect of these two modalities of treatment, so that in the absence of any specific contraindication, oestrogen and progesterone replacement in the form of a continuous 'no bleed' preparation (either oral or transdermal) might be given. Followup bone densitometry measurements at biannual intervals will be indicated.

flicting, but the therapy is easy and does no harm. There is now strong evidence that in the very old, calcium (1.5g) and vitamin D (400 units daily) supplementation reduces hip fracture incidence. Preparations of 'hydroxyapatite compound' are of no proven benefit above that of simple calcium salts, and anabolic steroids are of doubtful value. Other measures currently under investigation include the use of calcitonin, PTH and sodium fluoride. Oestrogen replacement therapy should be considered as for prevention. Accumulating experience of the use of selective oestrogen receptor-modulating agents (SERMS, e.g. raloxifene) in the management of osteoporosis is promising. Oral bisphosphonate therapy given as an interval therapy in conjunction with calcium supplements (Didronel PMO) has been shown to reduce the rate of bone loss in postmenopausal osteoporosis. Recent large trials of the bisphosphonate alendronate have confirmed substantial increments in bone mineral density and a reduction in fracture rates. Calcitonin, by s.c. injection or intranasal

961

SUMMARY 1 Risk factors and prevention of osteoporosis Risk factors • • • • • • •

>65 years Premature menopause (<45 years) Personal/family history of low-trauma fractures History of amenorrhoea >6 months, excluding pregnancy Body mass index <19kg/m2 Immobility Predisposing conditions, e.g. thyrotoxicosis, glucocorticoid excess and primary hyperparathyroidism

Prevention • • • • • •

Lifestyle measures Avoid excessive alcohol Stop smoking Regular weight-bearing exercise Avoid excessive dieting and exercise resulting in amenorrhoea Maintain adequate calcium and vitamin D intake: Calcium: 1500mg daily in postmenopausal women, teenagers and pregnant women; 1000mg in other patient groups Vitamin D: 400 units daily • Minimize risk of falls by consideration of problems with gait, eyesight, medication etc.

administration, has a significant effect but is relatively inconvenient and expensive. Oestrogen, calcitonin and bisphosphonate therapy all exert their major benefit by inhibiting bone resorption; the only agent that has a predominant effect on bone formation in simple osteoporosis is fluoride. Endemic fluorosis, in which excessive fluoride is ingested in certain parts of South Africa and China, is associated with bone of increased mineral density and, paradoxically, increased fragility. However, early concerns that fluoride therapy might produce bone of poor quality have not been borne out by recent studies using lower doses. GH replacement in hypopituitary adults has been shown to produce a sustained increment in bone mineral density after 18 months of therapy. The long-term effects of GH therapy on bone density in the elderly are under investigation. The prevention and management of corticosteroidinduced osteoporosis is shown in Figure 18.6. In all studies of the effectiveness of treatment for osteoporosis it is important to monitor the effect of treatment on fracture risk rather than simply on bone mineral density, because these two endpoints may not always be concordant. Furthermore, we should be cautious about extrapolating data obtained from studies in women to the population as a whole. None the less, the emergence of effective therapies which modify the bone remodelling

1 962

MCQ18.2

cycle has gradually extended the treatment of established osteoporosis to the prevention of bone loss, particularly in situations in which it may be predicted (e.g. long-term corticosteroid therapy). Therapeutic nihilism in the management of reduced or threatened bone density is clearly no longer justified. 1

RICKETS AND OSTEOMALACIA Rickets and osteomalacia are conditions characterized by pathological defects in bone matrix mineralization. Rickets refers specifically to osteomalacia, where the defect occurs in growing bone. The aetiological factors are diverse, but the end result is an increased quantity of unmineralized bone matrix (osteoid). Histologically this is characterized by widened osteoid seams, morphologically flat 'inactive' osteoblasts, and an absence of tetracycline uptake, indicating impairment of mineralization. The increase in osteoid must be distinguished from that seen in thyrotoxic bone disease, Paget's disease or hyperparathyroidism. In all these conditions there is high bone turnover with increased formation of osteoid, but mineralization of matrix is normal or increased.

Aetiology The aetiology of osteomalacia (or rickets) is shown in Table 18.4. The conditions may arise in three distinct situations: • Deficiency or abnormal metabolism of vitamin D • Phosphate depletion • Chronic metabolic acidosis. Vitamin D deficiency is numerically by far the most important cause of osteomalacia (or rickets): it leads to a combined deficiency of calcium and phosphorus. There is intestinal malabsorption of calcium and, to a lesser extent, phosphorus. Secondary hyperparathyroidism results from the fall in plasma calcium, and the ensuing phosphaturia accelerates the phosphate deficiency. Lack of vitamin D is often due to a combination of poor exposure to sunlight and dietary deficiency. The elderly are particularly at risk. In the UK there is a high incidence of osteomalacia in the Asian immigrant population (p. 122). The reason for this is multifactorial and incompletely understood, but dietary deficiency of vitamin D and calcium, together with binding of calcium by the phytate contained in chapati flour, may contribute. In addition, deeply pigmented skin generates less vitamin D3 in response to a given amount of ultraviolet exposure, and this may be disadvantageous in temperate climates. Vitamin D deficiency may complicate fat malabsorption from any cause. Finally, calcium deficiency enhances the rate of degradation of 25(OH)D in the liver, further exacerbating the shortage of vitamin D and its metabolites.

TABLE 18.4 Causes of osteomalacia/rickets Cause

Mechanism

Vitamin D deficiency

Defective intake/formation Lack of solar exposure (D3) and lack of dietary intake or fat malabsorption (D2) Severe chronic liver disease Increased/wasteful metabolism Liver-enzyme-inducing drugs, e.g. phenytoin, phenobarbitone, carbamazepine, rifampicin Failure of activation, 25(OH)D->1,25(OH)2D Chronic renal failure Hereditary vitamin D-dependent rickets type I Target organ defect Hereditary vitamin D-dependent rickets type II

Phosphate deficiency

Poor intake Aluminium hydroxide - excess binding of dietary phosphate Increased loss X-linked hypophosphataemia (vitamin D-resistant rickets) Fanconi's syndrome Renal tubular acidosis Ureterocolic anastamosis Tumour-associated

Chronic metabolic acidosis

Renal tubular acidosis (may be phosphate depletion also) Ureterocolic anastamosis

Osteoblast/ mineralization defect

Hypophosphatasia Etidronate therapy Aluminium intoxication (in renal disease, seep. 1055)

Failure of 25-hydroxylation of vitamin D (p. 955, Fig. 18.3) This may be a feature of severe hepatocellular dysfunction. It may also result from hepatic enzyme induction consequent upon long-term anticonvulsant medication (leading to enhanced degradation). Reduced 1-hydroxylation of25-hydroxyvitamin D by the kidney occurs in chronic renal failure, and also as a rare recessively inherited condition in which levels of the 1hydroxylase enzyme are low (vitamin D-dependent rickets type I). Failure to hydroxylate 25-hydroxyvitamin D also occurs in hypoparathyroidism and pseudohypoparathyroidism. Another rare form of rickets is associated with an

1MCQ18.3

964

abnormality of the 1,25(OH)2D receptor in target tissues (vitamin D-dependent rickets type II). Phosphate depletion is a less common cause of rickets than deficiency or altered metabolism of vitamin D. It arises as a result of a reduced maximal capacity for renal tubular phosphate reabsorption. This may either be inherited as an X-linked recessive characteristic (vitamin Dresistant rickets, X-linked hypophosphataemia) or occur as part of Fanconi's syndrome - a more generalized hereditary or acquired renal tubular defect typified by aminoaciduria and glycosuria (p. 1057). Rarely, excessive ingestion of antacids may restrict intestinal phosphate absorption to the point where clinically important phosphate depletion, and even osteomalacia or rickets, may appear. Chronic metabolic acidosis, usually resulting from renal tubular disorders, may lead to rickets or osteomalacia. The bone lesions usually heal satisfactorily following treatment to correct the acidosis. Oncogenic osteomalacia Severe osteomalacia may rarely be a non-metastatic manifestation of tumours. The tumours are almost always sarcomas or connective tissue tumours of borderline malignancy (neurofibromatosis, haemangioendothelioma), and all produce a humoral factor that mediates phosphate. The osteomalacia is cured by removal of the tumour. The humoral factor responsible has been termed phosphatonin.

Clinical features In children, failure of bone mineralization gives rise to classic bone deformities, which include widening of the metaphyses, prominence of costochondral junctions (socalled 'rickety rosary'), and varus or valgus abnormalities of the knee joints. The bones are painful and statural growth is reduced. In adults, bone pain and tenderness are the most prominent features. A characteristic proximal myopathy may develop, and is more common in cases due to vitamin D deficiency.

Investigation Biochemical In osteomalacia due to deficiency or abnormal metabolism of vitamin D, investigations typically demonstrate a low normal plasma calcium (leading to secondary hyperparathyroidism), a low plasma phosphate due to phosphaturia as a result of increased PTH secretion, and a raised alkaline phosphatase indicating increased numbers of osteoblasts (Table 18.5). Vitamin D deficiency may be confirmed by measurement of 25-hydroxyvitamin D in plasma. X-linked hypophosphataemia (vitamin D-resistant rickets), on the other hand, is characterized by normocalcaemia, hypophosphataemia, and little or no alteration in plasma alkaline phosphatase level. Radiological Features of rickets include widening and irregularity of the metaphyses with an increased width of the growth plate. In

18

TABLE 18.5 Plasma measurements in various causes of osteomalacia/rickets Plasma measurements Cause

Calcium

Vitamin D deficiency Familial hypophosphataemia Chronic renal failure Renal tubular acidosis

Nor

Phosphate

N

N or N or

Nor

Alk. phos.

Nor Nor Nor

Urea

Creatinine

PH

N N

N

N

N

N

N

N

14

N = normal.

FIG. 18.7 Radiological features of osteomalacia Arrow indicates Looser's zone.

osteomalacia the bones appear less dense than normal, and the long bones may show localized areas of decalcification on the concave surface, referred to as pseudofractures or Looser's zones (Fig. 18.7). Decreased bone strength may result in biconcave deformity of the vertebrae. In hypophosphataemic rickets there may be a paradoxical apparent increase in bone density.

(500-1000 units/day). This can conveniently be given as combined calcium with vitamin D tablets. Alternatively, a single i.m. does of 150 000IU of D2 in oil is effective prophylaxis and treatment for at least 6 months. The possibility of intestinal malabsorption should be borne in mind, and appropriate investigation initiated if necessary. Osteomalacia associated with anticonvulsant therapy requires higher doses of vitamin D (3000-6000 units/day) unless a change in anticonvulsant is clinically feasible. Treatment of X-linked hypophosphataemia is generally unsatisfactory. The logical treatment is with oral phosphate supplements, but the doses needed are large and they may be poorly tolerated because of gastrointestinal side-effects. Oral phosphate works better when combined with pharmacological doses of vitamin D, or (and probably best) in combination with 1,25(OH)2D3. When 1,25(OH)2D3 or laOHD3 is given, great care must be taken to adjust the dose against the serum calcium, as hypercalcaemia may easily be induced. The management of renal tubular acidosis and renal osteodystrophy is dealt with in Chapter 20, pages 1065-1068. 1

HYPERCALCAEMIA Elevation of total plasma calcium is usually associated with a concomitant increase in ionized calcium concentration.

Causes

Histological Occasionally a bone biopsy may be needed (following double tetracycline labelling) to confirm a diagnosis of osteomalacia when biochemical investigations are equivocal. This is particularly the case when seeking possible treatable factors in elderly patients with decreased bone density.

Table 18.6 gives the proximate cause of the elevated blood calcium concentration (increased ingress from bone or intestine, or decreased egress via the kidneys), together with the key hormonal changes associated with the major causes of hypercalcaemia. Note that the appropriate response of PTH and of 1,25(OH)2D during hypercalcaemia is to be low - elevation of either or both of these hormones may therefore be presumed to be causally related to the hypercalcaemia.

Management

Clinical features

Dietary vitamin D deficiency is treated by oral replacement of vitamins D2 or D3 in physiological quantities

Mild hypercalcaemia is generally asymptomatic. Severe hypercalcaemia, however, leads to a life-threatening

965

CASE STUDY 18.2 PROXIMAL MUSCLE WEAKNESS A 64-year-old Bangladeshi woman presented to her GP with a 4-month history of generalized aching discomfort. Through an interpreter she described muscular discomfort, particularly in her shoulders, present at rest. The symptoms were not worse in the morning and there were no specific relieving factors. Her weight was stable. She had a previous history of gestational diabetes in two consecutive pregnancies, and 2 years previously had been diagnosed as having diabetes mellitus. This had been controlled with dietary measures alone. On examination she exhibited mild proximal weakness in both arms and legs, but no muscle tenderness and the reflexes were preserved. There was no temporal artery or scalp tenderness, and the remainder of the examination was unremarkable. Subsequent investigation demonstrated haemoglobin 10.9 g/dL, ESR 16mm/h, plasma glucose (postprandial) 7.6mmol/L, glycated haemoglobin 5.6%, plasma urea and electrolytes within normal limits, plasma calcium 2.04mmol/L, phosphate 0.78 mmol/L and plasma alkaline phosphatase 198IU/L (normal <110IU/L).

Questions 1: What is the most likely explanation for her symptoms and what other causes should be considered? 2. How might this problem arise? 3. What is the mechanism underlying the abnormalities in serum calcium, phosphate and alkaline phosphatase?

Discussion This patient's presentation with myalgia associated with a combination of mild hypocalcaemia, hypophosphataemia and elevation of alkaline phosphatase is strongly suggestive of vitamin D deficiency. This would be confirmed by measurement of serum 25-hydroxyvitamin D. This condition is very much more common in Asian patients than in whites. Important precipitants include dietary deficiency, limited exposure to sunlight and a calcium chelating effect of phytates present in chapati flour. A finding of proximal muscle weakness with preservation of reflexes raises the possibility of either glucocorticoid or thyroid hormone excess, which will usually (but not invariably) have other clinical features evident. Malignant ectopic ACTH syndrome may present, with muscle wasting and weakness as the sole clinical features of glucocorticoid excess (see Ch. 17, p. 933). Hypokalaemia is very frequent in this situation and pigmentation may occur. These were not evident in this case. Thyrotoxicosis may present with an indolent clinical picture dominated by proximal myopathy. However, brisk reflexes are usually found and weight loss is the rule. Furthermore, the proximal myopathies of glucocorticoid excess and thyrotoxicosis are not painful. Diabetic femoral radiculopathy (amyotrophy) is a relatively uncommon but characteristic complication of poorly controlled diabetes which presents with proximal muscular pain and profound weakness; reflexes are reduced or absent, and therefore this patient's

acute illness, treatment of which constitutes a medical emergency. The principal symptoms and signs are renal, gastrointestinal and neurological.

966

Renal Thirst and polyuria are early symptoms of nephrogenic

signs are atypical for this diagnosis. Polymyalgia rheumatica should always be considered in any older patient presenting with proximal muscle pain and discomfort. However, the absence of a diurnal variation in symptoms and the normal ESR effectively exclude this diagnosis in the present case. Although dietary deficiency of vitamin D is the most likely explanation for this condition, conditions causing malabsorption of fat-soluble vitamins (A, D, E, K) should be considered and serum tested for antiendomysial antibodies as an initial screen for gluten enteropathy. In dietary vitamin D deficiency, supplementation in the form of calcium and ergocalciferol tablets (two daily, supplying 800IU calciferol) provides satisfactory therapy. Deficiency of vitamin D results in reduced intestinal calcium absorption and a secondary stimulation of parathormone secretion, the latter promoting phosphaturia and hypophosphataemia. Increased production of alkaline phosphatase reflects increased osteoblast activity, stimulated in response to bone resorption.

diabetes insipidus. The increased ionized calcium level impairs the ADH-mediated augmentation of water reabsorption in the distal nephron. Sodium and potassium excretion is increased, leading to volume contraction, prerenal reduction of GFR (Ch. 20, p. 1035) and a further decrease in renal calcium excretion. The situation is com-

18

CASE STUDY 18.3 HYPERCALCAEMIA A 64-year-old man presented with nocturia and hesitancy of micturition. Initial clinical assessment demonstrated prostatic enlargement, and investigation showed elevation of serum prostate-specific antigen (PSA, 12ng/mL; reference range <4.1ng/ mL). In his previous medical history he described a single episode of acute left loin pain radiating to the left groin 6 months previously, which had been treated with intramuscular pethidine; these symptoms had not recurred. Prostatic biopsies confirmed adenocarcinoma of the prostate (T3, NO, MO Gleason grade 3-4). He was treated with radical radiotherapy and commenced on GnRH agonist therapy in the form of goserelin subcutaneously every 4 weeks. During follow-up 1 year later he complained of fatigue and generalized aches and pains. Investigations demonstrated serum calcium 2.83 mmol/L, phosphate 1.12mmol/L, alkaline phosphatase 96IU/L, sodium 140 mmol/L, potassium 4.5 mmol/L, chloride 109 mmol/L, bicarbonate 25 mmol/L, urea 8.5 mmol/L, creatinine 130(imol/L and serum PSA 2.5 ng/mL. Plain radiology demonstrated multiple calculi in both kidneys. Examination at that stage indicated a well-nourished man with clinically normal thyroid function. He was normotensive, there was no corneal calcification, and the remainder of the examination was unremarkable. Investigation confirmed hypercalcaemia (corrected serum calcium 2.73 mmol/L) and serum parathormone 172pg/mL (reference range 10-50 pg/mL). Urine calcium excretion was 8.7mmol/24h. Full blood count was unremarkable and ESR was normal at 17mm/lst

hour; serum albumin was 42 g/L and total globulin 26 g/L.

Questions

1. Wliat is the most likely diagnosis? 2. What features in the clinical presentation and investigations,point towards a benign cause of hypercalcaemia? 3. How might the increased fatiguability and musculoskeletal symptpms be explained?

Discussion The hypercalcaemia is most likely to be due to primary hyperparathyroidism. This is supported by the unequivocally raised serum parathormone level, and the pattern of serum electrolytes, with a high normal serum chloride, and low normal serum bicarbonate, is consistent with this diagnosis. The serum phosphate concentration was in the mid-normal range and was therefore atypical for primary hyperparathyroidism. However, the modest elevation of serum creatinine, suggesting some reduction in glomerular filtration rate, might explain this. Importantly, urine calcium excretion was not decreased, thereby excluding a diagnosis of hypocalciuric hypercalcaemia, an improbable diagnosis given the previous history suggesting renal colic and the radiological evidence of renal calcification. Benign hypercalcaemia due to hyperparathyroidism is more likely

than a malignant aetiology in the context of non-specific symptoms and only modest serum calcium elevation. Furthermore, the normal haemoglobin and serum albumin provide some circumstantial evidence against disseminated malignancy. The finding of renal calculi also suggests hypercalcaemia of longer duration than is usually the case with malignant hypercalcaemia, whether due to bone metastases or to parathormone-related peptide (PTHrp) secretion. The normal ESR and serum total globulin concentration provide good evidence against multiple myeloma, but a serum protein electrophoresis would be required to definitely exclude this, especially in view of the musculoskeletal symptoms. Although humoral hypercalcaemia of malignancy (PTH-rp secretion) may produce some biochemical features in common with hyperparathyroidism, PTH-rp is not detectable in PTH assays in current use, and this diagnosis is effectively excluded by the documented elevation of serum PTH, which would be suppressed in hypercalcaemia from causes other than hyperparathyroidism. Although frequently absent, nonspecific symptoms of increased fatigue and musculoskeletal discomfort are well recognized in primary hyperparathyroidism and do not necessarily indicate parathyroid bone disease. The normal serum alkaline phosphatase argues against a substantial degree of bone resorption in this case, although this is a common finding in more advanced disease. Myeloma and bone metastasis should be considered as a cause of skeletal symptoms, but are effectively excluded in this instance.

pounded if the patient is ill and confined to bed, because immobilization accelerates bone resorption and the mobilization of skeletal calcium.

Later, particularly when prerenal uraemia develops, the patient develops nausea and vomiting.

Gastrointestinal

Symptoms commonly include lassitude, anxiety and depression, or any psychosis to which that person may

Common early symptoms are anorexia and constipation.

Neurological

967

CASE STUDY 18.4 ACCELERATING HYPERCALCAEMIA A 54-year-old man presented to his GP with a 48-hour history of nausea and vomiting. He described weight loss over the preceding 6 weeks and had experienced several episodes of haemoptysis. He had no significant previous medical history but had smoked heavily throughout his adult life. Examination demonstrated obvious weight loss, pallor of the mucous membranes, and dullness to percussion and reduced breath sounds at the right lung base; abdominal examination was unremarkable. Further investigation revealed haemoglobin 9.8g/dL, MCV 88, serum urea 11.7mmol/L, creatinine 138umol/L, sodium 133mmol/L, potassium 3.4 mmol/L, calcium 4.1 mmol/L, phosphate 0.82 mmol/L and alkaline phosphatase 163IU/L (NR < 120). He was referred urgently to the local hospital for further management. On admission, chest X-ray demonstrated collapse of the right lower lobe, hypercalcaemia was confirmed, and serum sent for parathormone measurement.

Questions 1. What clinical features point towards a malignant cause for the hypercalcaemia? 2; What is the most likely mechanism for the hypercateaemia? 3. What is the immediate management?

Discussion The patient's acute symptoms at presentation are attributable to accelerating hypercalcaemia. The severity of the hypercalcaemia, the associated normochromic anaemia and the preceding history of weight loss are all suggestive of a malignant cause. Furthermore, haemoptysis and the presence of focal chest signs in a patient with a long smoking history points towards bronchial carcinoma as the underlying aetiology. Hypercalcaemia as a complication of bronchial carcinoma is most commonly due to the production of parathormone-related peptide (PTHrP) by squamous carcinoma cells. PTH-rP promotes calcium absorption in the intestine and renal tubules and also increases net calcium loss from bone. In contrast to primary hyperparathyroidism, the production of this humoral factor is not subject to negative feedback control. Continued PHT-rP release, the progressive salt and water depletion which occur as a combined result of reduced renal concentrating capacity, and vomiting induced by hypercalcaemia, result in accelerating and eventually life-threatening hypercalcaemia and salt and water depletion. The emergency management of this condition depends primarily on the restoration of extracellular fluid volume by means of isotonic (0.9%) saline infusion, which should be

be otherwise predisposed. In severe hypercalcaemia (calcium levels above 4mmol/L), confusion and drowsiness may be followed by coma. Regardless of cause, hypercalcaemia is liable to be complicated by ectopic calcification. This is particularly likely

1

968

Fig. 18.7

administered at an initial rate of 1.0 L every 1-2 hours. Restoration of ECF volume allows the further promotion of calciuresis by means of the addition of a loop diuretic, e.g. furosemide (frusemide), with continued saline infusion. It is obviously important that frusemide should not be given until the patient has been adequately rehydrated. In parallel with these emergency measures, an infusion of a bisphosphonate (e.g. pamidronate) should be commenced. The effects of this will not be evident for 24 hours or more, but it is essential in limiting subsequent relapse of the condition and can be repeated as required. The availability of parenteral bisphosphonate therapy has eliminated the use of other measures, such as intravenous phosphate and mithramycin. Ultimately the successful treatment of malignant hypercalcaemia will depend on management of the primary lesion, but this is frequently not possible, so continuing oral or interval intravenous bisphosphonate therapy is an important component of palliative care.

if the hypercalcaemia is of long standing, as in primary hyperparathyroidism or sarcoidosis. The renal tract is particularly susceptible, and renal stones or nephrocalcinosis (Fig. 18.8) commonly occur. Frequently there is calcification of blood vessels, especially the media of arteries. Calcification bands on the medial or lateral edge of the cornea may be visible (band keratopathy), 1 and conjunctival inflammation may develop if hypercalcaemia is severe. Acute pancreatitis is an important complication, particularly if other predisposing factors, such as high alcohol intake, are also present.

18

TABLE 18.6 Causes of hypercalcaemia Intestinal absorption

Bone resorption

Urine calcium

PTH

1,25(OH)D

Malignancy - osteolytic metastases (carcinoma of breast, lung, thyroid. Myeloma) - humoral - PTH-rp (squamous carcinomas, renal cell carcinoma) - 1,25(OH)D produced by tumour (lymphoma) Primary Hyperparathyroidism - adenoma - hyperplasia - carcinoma Renal hyperparathyroidism (severe) Extrarenal1,25(OH)D synthesis ' - sarcoidosis - tuberculosis - glucocorticoid deficiency (Addison's) Vitamin D intoxication Milk alkali syndrome Familial hypocalciuric hypercalcaemia Drugs - thiazide diuretics - lithium *only when hypercalcaemia overwhelms the renal tubular reabsorptive capacity. ** suppressed by hypercalcaemia. Specific assay for PTH-rp shows elevated PTH-rp in plasma. ***high if 1a-hydroxylated compound ingested (e.g. calcitriol). Low or normal if native vitamin D ingested.

Finally, the cardiovascular system is also susceptible through the increased incidence of hypertension associated with chronic hypercalcaemia. The ECG shows shortening of the QT interval.

Management

Investigation

General measures Symptomatic hypercalcaemia requires measures directed towards rehydration and appropriate sodium and potassium repletion. A forced saline diuresis (normal saline given i.v. at 4-6L/day) substantially and immediately augments the urinary excretion of calcium. A further increase

Potentially useful investigations in hypercalcaemia are listed in Table 18.7. The steroid suppression test aims to identify those cases in which pharmacological doses of glucocorticoids significantly reduce the elevated plasma calcium. Hypercalcaemia due to extrarenal 1,25(OH)2D synthesis usually suppresses fully, and this is likely to be the case with underlying granulomatous disease (e.g. sarcoidosis, tuberculosis), some malignancies (e.g. leukaemia, lymphoma) and glucocorticoid deficiency (Addison's disease). Prednisolone is given at 30mg/day for 10 days, with measurement of plasma calcium before, after 5 days and after 10 days of treatment.

Asymptomatic hypercalcaemia requires no therapy except appropriate management of the underlying condition.

SUMMARY 2 Treatment of severe hypercalcaemia • • • •

Correct salt and water deficit with normal saline Begin forced saline diuresis + frusemide Give bisphosphonate, e.g. pamidronate, clodronate Treat underlying cause if possible

969

TABLE 18.7 Diagnostic yield in hypercalcaemia Investigation

Potential information

Full blood count

Anaemia suggests non-parathyroid aetiology if renal function normal Usually over 80 in myeloma Upper normal in hyperparathyroidism Low normal in hyperparathyroidism Significantly raised in the tertiary autonomous hyperparathyroidism of renal failure. Moderately raised in renal impairment secondary to hypercalcaemia Monoclonal band suggests myeloma Presence of light chains suggests myeloma

ESR Plasma chloride Plasma bicarbonate Creatinine

Plasma protein electrophoresis Bradshaw's test and urinary immunoelectrophoresis Plasma phosphate Plasma PTH

Steroid suppression test FIG. 18.8 Nephrocalcinosis in a patient with severe primary hyperparathyroidism 24 h urine calcium Chest X-ray

in calciuria may be induced by the addition of frusemide (20 mg/h), provided that the saline infusion is fast enough to keep the patient volume expanded. With such treatment alone, the plasma calcium will usually come down to safe levels (3.5mmol/L or less). Specific measures Specific treatment depends on the cause. Glucocorticoids are only effective for the hypercalcaemia of sarcoidosis, vitamin D intoxication, lymphomas and Addison's disease. For the first two, a high dose rapidly tapering down is used. The treatment of choice in hypercalcaemia of malignancy and hyperparathyroidism is usually the bisphosphonate pamidronate, which reliably restores calcium levels to normal within 5 days when infused as a single dose of 60 mg over 4 hours. Clodronate is equally effective, and can be given orally as maintenance treatment. The drugs act by inhibiting osteoclastic bone resorption, but because of a delayed action (24-72 hours) saline diuresis remains an important part of early management. Calcitonin given at the same time accelerates the fall in calcium by up to 24 hours. Sodium phosphate infusion (l0mmol/h for a maximum of 10 hours) is very effective in the short term, but is dangerous as it lowers calcium principally by causing microscopic precipitation of calcium phosphate in soft

1MCQ18.4

970

2

Fig. 18.8

Isotope bone scan X-ray hands

Low normal in primary hyperparathyroidism unless renal function impaired Upper normal or raised in hyperparathyroidism Suppressed with other causes of hypercalcaemia Sarcoid hypercalcaemia always suppresses; hyperparathyroid never; malignant causes occasionally Decreased in familial hypocalciuric hypercalcaemia Look for primary neoplasm; metastases; hilar lymphadenopathy suggesting sarcoid 'Hot spots' suggest metastatic malignant disease Subperiosteal erosions suggest hyperparathyroidism

tissues; this is particularly marked if initial plasma phosphate is high. 1

SPECIFIC CAUSES OF HYPERCALCAEMIA Primary hyperparathyroidism Primary overactivity of one or more parathyroid glands is common, especially in elderly women. In the UK, routine measurement of serum calcium in the hospital population reveals an incidence of 1 in 100. In the general population the incidence is 1 in 500 to 1 in 1000. Of these, approximately three-quarters are associated with a single adenoma. In the others there is either more than one adenoma, or four-gland hyperplasia. In about 1 % of cases a parathyroid carcinoma is the cause. Adenoma or hyperplasia may be associated with one of the syndromes (I or II) of multiple endocrine neoplasia (MEN) (p. 938). In MEN I, inactivation of a tumour suppressor gene (meniri) on 11ql3 is the underlying mechanism. In primary hyperparathyroidism PTH is elevated, usually as a result of a parathyroid adenoma, and stimulates osteoclastic bone resorption, tubular reabsorption of

calcium and the activity of 1-hydroxylase in the proximal renal tubular cells. This in turn promotes conversion of 25(OH)D to 1,25(OH)2D, which acts on the upper small intestine to increase active calcium transport. Because PTH also enhances renal phosphate excretion, the serum phosphate level falls. Clinical features The clinical features of primary hyperparathyroidism are variable. Patients commonly remain asymptomatic for long periods, and the finding of a mild elevation of serum calcium in an elderly asymptomatic patient requires no active intervention. In more severe cases the symptoms may be those of hypercalcaemia (p. 965). Immobilization is a potent precipitating factor and may lead to a rapid rise in serum calcium. Renal complications include renal calculi, which may present with renal colic and nephrocalcinosis (Fig. 18.7). This is particularly likely in warm climates, where insensible fluid and sodium loss are excessive and urine flow rate is low. Hypertension is common, even in the absence of overt renal damage. It may respond to surgical treatment of hyperparathyroidism. The bone disease of hyperparathyroidism is characterized by high turnover and remodelling rates. Bone is lost progressively, mainly from cortical sites - osteoporosis and increased fracture risk may ensue. Very infrequently, osteitis fibrosa cystica occurs, with the development of socalled 'brown tumours' of the mandible or long bones. Again, the finding of such a lesion is an indication to check the serum biochemistry. The typical radiological lesion is subperiosteal erosion in the phalanges of the hands (see Fig. 18.4). Management Management depends on the severity of the hypercalcaemia and the presence of complications. In cases with severe clinical hypercalcaemia, emergency treatment should be initiated along the lines outlined on page 970. The only curative therapy is parathyroid surgery. Modern diagnostic techniques which may help to localize a tumour include 99mTc sestamibi 2 and ultrasound scanning of the neck, and (rarely) catheterization of the veins draining from the neck for measurement of PTH in blood from different sites. High-resolution CT or MRI scanning may also be of value. In recent years there has been a shift away from the conservative approach to asymptomatic primary hyperparathyroidism. This has been based on the recognition of osteopenia as a long-term risk, especially in females, and the fact that subtle deficits in wellbeing may be present. For these reasons, we believe that surgical therapy should be the general rule, unless there are obvious contraindications. Surgery Surgical expertise in identifying all four parathyroids will determine the success of the operation. Adenomas of the lower parathyroids (derived from the upper pair of branchial arches) are sometimes retrosternal. Adenoma-

tous tissue should be removed and a least one other gland biopsied. With four-gland hyperplasia the safe course is probably to remove all four, and then to maintain the hypoparathyroid patient on 1,25(OH)2D3 or 1(OH)D3 (alfacalcidol), a synthetic precursor of 1,25(OH)2D3. Preand postoperative treatment with 1,25-(OH)2D3 or 1(OH)D3 may be helpful in preventing postoperative hypocalcaemia, which is especially likely to occur when there are bone lesions.

18

Other measures In some patients surgical cure is not achieved. Failure to remove enough parathyroid tissue may leave the patient with 'incurable' hyperparathyroidism. Some patients refuse surgery, and because primary hyperparathyroidism is principally a disease of the elderly, some will be deemed unfit for surgery. Conservative management of these patients may entail observation only, with monitoring of plasma calcium concentration and checking for complications. More active measures include the use of oral phosphate supplements, oestrogens, or the oral bisphosphonates such as clodronate (p. 970). These measures aim to protect the skeleton from the excess PTH. However, although these measures will alleviate hypercalciuria and hypercalcaemia in the short and medium term, surgery remains the preferred treatment in most younger and symptomatic older patients. In the future it is likely that calcimimetic drugs will provide the best non-surgical option. These agents bind to the extracellular calcium receptor on the parathyroid cells and increase the sensitivity of the receptor to extracellular calcium. Thus the parathyroid cells respond as if the plasma calcium is higher than it really is - both PTH and calcium fall as a result.

HYPERCALCAEMIA OF MALIGNANCY Malignancy is an important cause of hypercalcaemia. There are several mechanisms (Fig. 18.9): • Direct invasion of bone and the production of local factors, which either destroy bone directly or stimulate local osteoclasts to do so, lead to accelerated bone resorption. Breast cancer usually causes hypercalcaemia by this mechanism. If the serum calcium is elevated in a patient with breast cancer, it almost always indicates that bony metastases are present. • Haematological malignancies may produce cytokines which act as osteoclast-activating factors. Hypercalcaemia in the presence of multiple myeloma is often by this mechanism. • Some solid tumours (such as renal carcinomas and squamous carcinomas of the lung and oesophagus may cause hypercalcaemia by secreting PTH-related peptide (PTH-rp), a factor which binds to the PTH receptor and activates bone resorption and/or enhances renal tubular calcium reabsorption and the renal production of

971

FIG. 18.9 Mechanism of malignancy in hypercalcaemia

1,25(OH)2D. This peptide has partial sequence homology with PTH (accounting for the hypercalcaemia) but is not detected by PTH immunoassays.

Clinical features These are of hypercalcaemia normally associated with those of the underlying cancer. The hypercalcaemia is usually rapidly progressive and severe, with salt and water depletion and disturbance of renal and CNS function.

in the form of calcium carbonate, to relieve dyspepsia. The hypercalcaemia is accompanied by metabolic alkalosis and is due to a combination of increased intestinal calcium absorption and decreased renal calcium excretion. Addison's disease may present with hypercalcaemia through extrarenal production of 1,25(OH)2D. Glucocorticoid replacement leads to a prompt response. Thyrotoxicosis. Thyroid hormones increase bone turnover and, in excess, cause net efflux of calcium from bone. Some 30% of patients display hypercalciuria and/or hypercalcaemia, although the latter is not severe. These abnormalities are corrected by treatment of the underlying thyrotoxicosis. Familial benign hypocalciuric hypercalcaemia is a syndrome that may be detected at any age. It is usually asymptomatic and is not associated with renal damage (although it may cause pancreatitis). It is inherited as an autosomal dominant condition, and so can usually be excluded if both parents are available for blood sampling. It is due to a defect in the parathyroid gland calcium sensor - an inactivating mutation reduces the sensitivity of the receptor to calcium, and the parathyroid gland therefore sets the serum calcium at a supranormal level. The same mutation affects the calcium receptor in the renal tubular cells, and there mediates the hypocalciuria. 1 Thiazide diuretics. These drugs are anticalciuric. The hypercalcaemia, when present, is mild unless other factors coexist favouring the elevation of calcium, for example Paget's disease, mild hyperparathyroidism or immobilization.

Management This is as for hypercalcaemia generally (p. 971). Saline rehydration and diuresis and bisphosphonates are the main methods. The cancer is treated when possible.

HYPOCALCAEMIA

Causes and pathophysiology MISCELLANEOUS HYPERCALCAEMIC SYNDROMES In sarcoidosis, and some other granulomatous diseases, macrophages in the diseased tissue produce 1,25(OH)2D outside the kidneys in amounts that are sufficient to produce hypercalcaemia. Calcium is absorbed by the intestine in increasing amounts, PTH is suppressed, and the normal feedback of the vitamin D-endocrine system is effectively sabotaged. The same mechanism occurs in some lymphomas and sarcomas. Treatment is with small doses of glucocorticoids - the extrarenal synthesis of 1,25(OH)2D is exquisitely sensitive to steroids. Milk alkali syndrome, now rarely seen, is associated with excessive ingestion of milk and alkali, particularly if taken 1

972

Case 18.1

The principal causes of hypocalcaemia are listed in Table 18.8. As the major calcium-binding protein in plasma is albumin, hypoalbuminaemia is associated with a proportionate fall in plasma total calcium (see correction formula on p. 957), though not in ionized calcium. The ionized calcium concentration is affected by the blood pH, as the avidity of albumin for calcium falls at acid pH and rises with alkalosis. Hence, respiratory alkalosis due to overbreathing can lead to depression of ionic calcium and tetany. Rarely, infusion of citrate (e.g. in repeated blood transfusions) leads to a serious fall in ionized calcium by complexing the ion. In hypoparathyroidism (p. 973) the major abnormalities result from failure of PTH-dependent renal synthesis of 1,25(OH)2D, leading to a reduction of intestinal calcium absorption (see Fig. 18.3). This is compounded by failure of osteoclastic bone resorption, by enhanced (inappropriate) urine calcium excretion and by hyperphosphataemia. These are all due to loss of the effects of PTH on bone and kidney. Secondary hyperparathyroidism is a consequence of hypocalcaemia (Table 18.9). In chronic renal failure

TABLE 18.8 Causes of hypocalcaemia

TABLE 18.9 Causes of secondary hyperparathyroidism

Cause

Comments

Cause

Example

With low levels of PTH Hypoparathyroidism Postsurgical Congenital Idiopathic (autoimmune)

Vitamin D deficiency Phosphate high Alkaline phosphatase and renal function normal

Lack of solar exposure Dietary deficiency Increased catabolism - drug-induced (e.g. anticonvulsants, rifampicin)

Dietary calcium deficiency

Low calcium intake High phytic acid intake (chapatis, wholemeal bread)

Gastrointestinal causes of low calcium or vitamin D intake

Gastric surgery Partial gastrectomy Gastroenterostomy Vagotomy and pyloroplasty Jejunal diverticulosis Crohn's disease Small bowel resection Gluten enteropathy

Renal

Chronic renal failure Phosphate retention Reduced 1a-hydroxylation of 25(OH)D

With normal or high levels of PTH Rickets/osteomalacia Sunlight/dietary deficiency Malabsorption Increased D metabolism Tumour-induced Chronic renal failure Pseudohypoparathyroidism

Phosphate low Alkaline phosphatase high Calcium deficiency Drug-induced Urea, creatinine, phosphate high Phosphate high, somatic manifestations (type I only)

(CRF), hypocalcaemia results from phosphate retention and loss of renal substance, with failure to produce normal amounts of 1,25(OH)2D. The rise in serum phosphate depresses the serum calcium, partly by leading to microprecipitation of calcium phosphate in soft tissue. The associated bone disease is discussed on page 1055. In CRF, metabolic acidosis is commonly present and this diminishes the fall in ionized calcium. Tetany in CRF is rare in adults (but more common in children), at least until the acidosis is corrected. Hypocalcaemia in vitamin D deficiency is usually not severe, because secondary hyperparathyroidism enhances bone resorption and maintains the serum calcium level. The typical biochemical changes are borderline low serum calcium, a low phosphate, and elevated alkaline phosphatase levels. If the parathyroid glands do not respond, or calcium intake is very low, hypocalcaemia may be more profound. In CRF and vitamin D deficiency, and in other conditions (see Table 18.9), the parathyroid hypersecretion (secondary hyperparathyroidism) is an appropriate response to threatened or actual hypocalcaemia. In some patients, however, long-standing appropriate hypersecretion (secondary hyperparathyroidism) transforms to inappropriate autonomy and consequent hypercalcaemia. This is called tertiary hyperparathyroidism, and histologically the glands show nodular hyperplasia. The nodules consists of clonally proliferating cells and are therefore resistant to the normal suppressive influence of 1,25(OH)2D.

Specific causes of hypocalcaemia Hypoparathyroidism There are three principal types of hypoparathyroidism, all of which are associated with hypocalcaemia and hyperphosphataemia despite normal renal function.

18

Postsurgical hypoparathyroidism Postsurgical hypoparathyroidism is the commonest cause of hypocalcaemia and follows thyroid or parathyroid surgery. Estimates of its frequency vary from 0.2% to 22%, depending on diagnostic criteria and the length of followup after surgery. Vascular or mechanical trauma to the parathyroid glands may contribute to the subsequent parathyroid insufficiency. Idiopathic hypoparathyroidism This is usually acquired in adolescence or early adult life, and may be associated with autoantibodies to parathyroid tissue, and with other organ-specific autoimmune diseases such as Addison's disease and immune thyroiditis. Some cases are familial. An autoimmune aetiology has been postulated but not proven. Patients may suffer from widespread Candida infections and dystrophic nails, alopecia, calcification in the basal ganglia and cataracts, in addition to other symptoms and signs of hypocalcaemia. PTH is undetectable despite hypocalcaemia, and the lack of its effect on the kidney is reflected by renal phosphate retention leading to hyperphosphataemia and low conversion of 25(OH)D to 1,25(OH)2D. Administration of PTH corrects all the biochemical abnormalities, indicating that target organ responsiveness to PTH remains normal in this condition. However, long-term treatment with PTH is impractical and management is with 1,25(OH)2D3 or 1(OH)D3. Most cases respond well to 1-3 ug daily of either. There is, however, little margin for error, and the dose should be titrated carefully against the serum calcium

973

levels. Oral calcium supplements enhance the effect of any given dose. 1 Pseudohypoparathyroidism Pseudohypoparathyroidism is a rare disorder thought to be due to a defect in the PTH receptor or its coupling to adenylate cyclase. The clinical and biochemical features of hypoparathyroidism are associated with characteristic somatic manifestations; these include short stature, mental deficiency, and unusually short fourth and fifth metacarpals and metatarsals. There is a partial or complete failure of response (urinary cAMP or phosphaturia) to PTH, and high serum PTH levels. As with true hypoparathyroidism, 1,25(OH)2D levels are low. Some patients have the somatic manifestations without the hypocalcaemia (pseudopseudohypoparathyroidism). In some cases the biochemical changes are associated, paradoxically, with hyperparathyroid bone disease, possibly reflecting isolated renal resistance with normal skeletal responsiveness to PTH. 2 Hypomognesaemia Hypomagnesaemia is a rare but important cause of hypocalcaemia. It is refractory to calcium, but responds to magnesium therapy (p. 956).

Clinical features The clinical manifestations of hypocalcaemia are principally in the nervous system. Tetany, painful cramps and tingling in the extremities may occur, and muscle spasm may lead to a characteristic position of the hand, the socalled 'main d'accouncheur. These symptoms may be precipitated by exercise. Laryngeal spasm may lead to stridor and obstructed respiration. Increased neuromuscular excitability in the presence of hypocalcaemia may be demonstrated by gentle percussion over the facial nerve at its point of exit from the parotid gland. This produces ipsilateral twitching contraction at the angle of the mouth (Chvostek's sign). Hypocalcaemia lowers the epileptic seizure threshold, and fits may be the presenting symptom. Hypocalcaemia, particularly when chronic, may present with psychiatric manifestations varying from general malaise to overt psychosis. Clinically, the differential diagnosis is principally of tetany due to anxiety, leading to hyperventilation and respiratory alkalosis, or hypokalaemic metabolic alkalosis.

Differential diagnosis of hypocalcaemia Correction for a low serum albumin concentration will allow the distinction between true (ionized) hypocal-

caemia and the spurious fall due to hypoalbuminaemia. As with other calcium disorders, the combination of clinical context and routine biochemistry will usually establish the cause. Uraemia and elevated serum creatinine concentration point to CRF. Hypoparathyroidism and pseudohypoparathyroidism are associated with normal renal function and an elevated serum phosphate level. There may also be clinical pointers, e.g. recent thyroid or parathyroid surgery for the former, skeletal abnormalities for the latter.

Management Hypocalcaemic tetany responds rapidly to the intravenous infusion of 10mL of 10% calcium gluconate. The response, however, is short-lived. The underlying cause should be treated, and in the case of hypoparathyroidism this has been greatly helped by the availability of 1,25(OH)2D3 (calcitriol) or 1-hydroxyvitamin D3 (alfacalcidol). The latter is then 25-hydroxylated in the liver to yield 1,25(OH)2D3. By virtue of their high potency, rapid onset and short duration of action, these compounds have converted a very difficult therapeutic problem into an easy one. Maintenance treatment of hypoparathyroidism should aim to keep the serum calcium in the lower part of the reference range, in order to avoid the increased risk of renal calculi consequent upon the increased urine calcium for a given filtered load of calcium. Hypocalcaemia in osteomalacia due to vitamin D deficiency is seldom marked; here, correct treatment is with vitamin D itself, rather than the active metabolite (p. 955).

PAGET'S DISEASE OF BONE In 1879, Sir James Paget described a bone disease which he named 'osteitis deformans'. Paget's disease is common and its frequency increases with age. In the UK as many as 4% of the population over the age of 40 may have evidence of the disease, although most have no associated symptoms. It is a chronic focal disease which may affect virtually any bone in the body. It varies widely in extent, with individual patients having anything from one to 20 or 30 bones affected. Even in a patient with extensive disease, the structure of unaffected bones appears to be quite normal. In general, the axial bones and large long bones are more commonly affected than the small bones of the hands or feet, or the ribs. Within an individual, the distribution appears to be random. In most patients the majority of affected bones are asymptomatic. This does not mean that they will always remain so.

Aetiology and pathophysiology 974

1

MCQ 18.5

2

3

Figs 18.9-18.11

Case 18.2

The primary disease process in Paget's disease appears to be in the osteoclasts of affected bone, and there is much circumstantial evidence pointing to a viral aetiology. These

18

CASE STUDY 18.5 HYPOCALCAEMIA A 67-year-old woman was admitted for an elective thyroidectomy for a large multinodular goitre. There was no significant previous medical history, she was euthyroid and was not on any medication. At surgery, a near total thyroidectomy was performed. Two parathyroid glands were identified and preserved. Twenty-four hours postoperatively she complained of tingling in her hands and feet. Examination demonstrated positive Chvostek and Trousseau signs and serum calcium was measured at 1.73mmol/L, with serum phosphate 1.49mmol/L. She was treated with a slow infusion of intravenous calcium gluconate and her symptoms resolved. Maintenance treatment with oral calcium was commenced, and the following day serum calcium was 1.83mmol/L. At that stage she was commenced on Icchydroxycholecalciferol 2 ug daily, with subsequent normalization of serum calcium (2.23mmol/L), and thyroxine replacement therapy. Histology of the

resection specimen confirmed multinodular goitre and two normal parathyroid glands. Her surgical recovery was otherwise uncomplicated and she was discharged from hospital. On outpatient review some 4 weeks later her serum calcium was 2.73 mmol/L; the dose of loc-hydroxycholecalciferol was reduced to 1 ug daily. Repeat serum calcium 1 week later was 2.56 mmol/L; lochydroxycholecalciferol was discontinued. Subsequent serum calcium measurements were within normal limits.

Questions 1, What was the mechanism for the hypocalcaemia in the immediate postoperative period? 2. What features suggested a likelihood of reversal of this phenomenon?

osteoclasts are abnormal in both structure and function, being larger than normal with more nuclei, and resorbing bone apparently without regard to normal anatomical restraints. Affected osteoclasts contain numerous cytoplasmic and nuclear particles thought to be viral nucleocapsids. Immunological and other evidence from molecular biology techniques suggests that a virus similar to the measles virus may be responsible. There is also evidence that at least some examples of Paget's disease may have a primarily genetic basis, with autosomal dominant inheritance linked to mutations of the gene for receptor activator of NFKB (RANK) on chromosome 18q21-22. Clearly the viral and genetic hypotheses are not mutually exclusive. Even if there is a genetic predisposition, other factors must determine which bones are affected. The apparent decline in the incidence of the condition in recent years points towards a role for an infective agent. Residual osteoclasts in bone behind the leading edge of advancing disease remain abnormal in size and shape, and continue to resorb bone chaotically. Wherever it occurs, bone resorption is followed by bone formation which, after an initial lag, catches up and keeps pace with resorption. However, the new bone laid down follows the chaotic

Discussion The occurrence of acute symptomatic hypocalcaemia after thyroid surgery is strongly suggestive of hypoparathyroidism. The severity of this phenomenon may be increased by pre-existing thyrotoxicosis, which was not evident in this case, by dietary vitamin D deficiency, or by rarer causes of metabolic bone disease. The fact that two parathyroid glands were identified and preserved at surgery suggests trauma/ischaemia as the underlying mechanism, and would suggest (but not confirm) subsequent improvement. This case highlights the importance of frequent monitoring of serum calcium after initiation of lahydroxycholecalciferol therapy in order to avoid overtreatment, which might delay the recovery of residual parathyroid function because of the inhibitory effect of modest hypercalcaemia.

pattern of bone resorption, and the gross structure of the whole bone therefore becomes progressively distorted. Affected bones are greatly weakened and become expanded and bent - this is particularly the case for the major long weight-bearing bones, such as the tibia and femur, as well as the humerus and radius, which may develop partial fractures. The latter are unusual in extending from the inner cortex outwards, and being concentrated on the convexity of the bowing bone (Fig. 18.10). Vertebrae and the pelvis become distorted. The skull thickens and its front and back sink, as the vertebral column selectively supports its centre. 3 Secondary bone changes include osteoarthritis, e.g. of the hips and knees. Within an individual the disease usually appears to be at. the same stage of development at different sites, and unaffected bones remain so throughout the disease. This possibly reflects a single episode of widespread viral infection of bloodborne osteoclast precursors, which were then carried into affected bones. Continuing viral replication within affected cells, combined with transfection by cell fusion (cell fusion being a normal property of the osteoclast), appears to explain why the disease is rampant in affected bones while initially unaffected bones generally seem to remain normal.

975

• A sharp pain, worse on movement or pressure, at the site of a partial or complete fracture; • The pain of secondary osteoarthritis; • Pain due to pressure on nerve roots. The patient may complain of deformity of an affected bone or bones, or enlargement and irregularity of the skull. There may be pressure effects, including cranial nerve lesions - of which tinnitus and deafness (nerve, as well as conductive) are very common - if the disease involves the skull. Occasionally, Paget's disease of the spine leads to paraparesis. Platybasia of the skull may lead to obstruction of the aqueduct and internal hydrocephalus. Pagetic bone is highly vascular, and the patient is often aware of the warmth of an affected limb, especially of the tibia. The limb is obviously hot to touch. Increased vascularity of the skull leads to prominence of the superficial temporal arteries and, occasionally, to distended external jugular veins. Cardiac output is modestly increased in extensive Paget's disease, as a result of vascular shunting of blood through diseased bone. This may occasionally lead to high-output congestive cardiac failure. Patients with extensive Paget's disease commonly have generalized malaise and lethargy, which may improve with effective treatment. An uncommon but serious complication of the condition is the development of bone sarcoma (usually osteogenic sarcoma), which is marked by expansion of the affected bone and further elevation of serum alkaline phosphatase activity. This complication may arise simultaneously at more than one pagetic site, and probably develops in less than 1 % of cases. FIG. 18.10 Gross expansion and deformity of right tibia in longstanding Paget's disease

Clinical features Since the natural time course of Paget's disease is very long, and many patients have had it for 20-40 years or more before diagnosis, virtually nothing is known of its early clinical features or whether there is an acute illness at the onset of the putative initial viral infection. Many patients present fortuitously, either because a biochemical screen has revealed a high serum alkaline phosphatase level, or because an X-ray has revealed an affected bone. Typically the disease starts in one or more specific areas, e.g. the epiphysis of a long bone or the skull base, and spreads through it with a lytic advancing edge at a rate of about 1 cm per year. In the skull this gives rise to the picture of osteoporosis circumscripta, and in long bones to the 'blade of grass' appearance. This is the leading edge of 'vandal' osteoclasts, which resorb bone in an uncontrolled way. Bone pain is of at least four types:

976

• A deep, boring dull pain, probably due to increased vascularity, which is present at rest and not relieved by analgesics;

Investigation Bone resorption is reflected by increased excretion of collagen-derived hydroxyproline or deoxypyridinoline in urine (best measured as the fasting morning urine hydroxyproline (or deoxypyridinoline)/creatinine ratio). Deoxypyridinoline has greater specificity than hydroxyproline. Bone formation is reflected by the level of serum alkaline phosphatase. These two markers, which together provide a measure of bone turnover rate, are a function both of the extent of skeletal involvement and of the disease activity within affected bones. In addition to these measurements, a bone scan is performed using 99mTc-labelled bisphosphonate (Fig. 18.11), followed by radiology of 'hot' bones. It is important to document the baseline state of disease before instituting therapy.

Management Until the late 1960s there was no effective treatment for Paget's disease. Although most patients have a mild condition which is rarely fatal, in some the disease is extremely disabling. Traditional criteria for instituting treatment, hitherto only for symptomatic disease, will change once an effective and simple treatment can be shown to arrest the progress of advancing disease or cure the condition.

18

FIG. 18.11 Bone scan from a patient with extensive Paget's disease A In skull. B In several dorsal vertebrae, sternum and left humerus. C In the whole pelvis.

Most authorities currently recommend treatment for pain, progressive disease with actual or threatened deformity, neurological complications and evidence of widespread disease. The bisphosphonates (diphosphonates) The bisphosphonates are analogues of pyrophosphate that bind to hydroxyapatite, and are therefore taken up by newly laid-down bone collagen matrix. Pamidronate and clodronate are highly effective, especially parenterally. Figure 18.12 illustrates the dramatic response to a short course of intravenous infusions of pamidronate in severe Paget's disease. Remineralization of lytic Paget's disease may be evident radiologically as early as 4 months after the start of a 1-3-month course of therapy, and in many cases is followed by prolonged remission. In the early stages, pamidronate treatment is commonly followed by a transient increase in bone pain and mild fever. This is quickly followed by symptomatic improvement and a reduction in bone pain. Intravenous pamidronate (three 60 mg infusions 2 weeks apart) is now licensed for Paget's disease and is the preferred treatment. Treatment is continued for up to 3 months, but may be repeated at intervals thereafter for recurrence of symptoms. Mithmmycin, although also quite effective, is much more toxic than pamidronate and cannot now be generally recommended for the treatment of Paget's disease. Calcitonin Calcitonin given by repeated injection was the first treatment to have any beneficial effect on bone pain or the

FIG. 18.12 Response to pamidronate treatment in Paget's disease A Paget's disease in a 71-year-old woman before (left) and 9 months after a course of i.v. pamidronate (right). Note restoration of bone in areas of osteolysis. Bone distortion remains. B Decline in alkaline phosphatase level (normal less than 130IU/L) and hydroxyproline/creatinine (HOP/Cr) ratio (normal less than 20umol/mmol) during and after a single course of 12 weekly 30 mg infusions of i.v. pamidronate (APD). Note decline in activity. Upper limit of normal indicated by blue dotted line.

977

course of the disease. The hormone inhibits osteoclasts. There is an abrupt reduction in bone resorption, but bone formation continues. For this reason, the onset of treatment in a severely affected patient with extensive disease leads to a transient fall in serum calcium concentration. Synthetic salmon or human calcitonin is given in doses of 50-100IU by subcutaneous injection three times a week. The hydroxyproline and plasma alkaline phosphatase levels fall, but rarely dramatically, and an improvement in bone structure and recalcification of affected bone occurs. Unfortunately, 'escape' is commonly seen within a year of treatment, usually as a result of antibody production. Side-effects are frequent and include flushing, palpitations, headache and malaise shortly after each injection. 1

MISCELLANEOUS RARE BONE DISEASES HYPOPHOSPHATASIA Hypophosphatasia is characterized by failure of mineralization, possibly as a result of inhibition by increased concentrations of pyrophosphate. Its inheritance is autosomal recessive and it takes its name from the low levels of plasma alkaline phosphatase usually found. The fully expressed severe form of the disease may be lethal neonatally, but later a clinical picture similar to that of severe rickets is found, with abnormal dentition and premature fusion of the cranial sutures. Urinary phosphoethanolamine excretion is increased, but the mechanism is not known. There is no specific therapy.

OSTEOGENESIS IMPERFECTA Osteogenesis imperfecta, which is also termed fragilitas ossium or brittle bone syndrome, is a collection of rare inherited disorders in which there appear to be specific defects in the formation of type I collagen, the predominant collagen in mature bone. There are four main forms: • A dominantly inherited mild form in which structural abnormalities are unusual; • A dominant form with fragility and short stature; • A recessive form with early multiple fractures and skeletal deformity; • A severe, often lethal, form due to new mutations in collagen genes.

1MCQ18.6

978

Abnormal dentition may occur in all forms and in forms 1, 3 and 4 the sclerae are often blue. Treatment is directed towards the prevention of trauma and correction of posttraumatic deformity. Some patients with osteoporosis and a strong family history of the disease may in fact have mild forms of osteogenesis imperfecta.

OSTEOPETROSIS (MARBLE BONE DISEASE, ALBERS-SCHOENBERG DISEASE) The term osteopetrosis describes a number of very rare conditions characterized by increased bone mass throughout the skeleton. Of these, a dominantly inherited and relatively mild form, and a recessively inherited severe form, are numerically the most important. The increase in bone mass is thought to be due to a defect in osteoclast activity. Radiological appearances are characteristic, with patchily increased bone density throughout the skeleton. In severe disease, encroachment of bone on the marrow and neural canals may lead, respectively, to bone marrow failure with leukoerythroblastic anaemia (which may be fatal) and cranial nerve palsies. Hepatosplenomegaly may be evident, indicating extramedullary haemopoiesis. The dominantly inherited mild disease is usually symptomless, but classic radiological changes are found in adults, with increased bone density and alternating dense and lucent bands in the vertebral column. Severe osteopetrosis presents in childhood and is, predictably, associated with a markedly positive calcium balance. Some benefit has been claimed for the treatment of severe disease by calcium restriction. Treatment by marrow transplantation has been tried with some success: transplanted osteoclast precursors, formed in the bone marrow, are able to re-establish normal bone resorption.

FURTHER READING Altmann P, Cunningham J 1987 Postgrad Med I 63: 77. Anderson D C 1995 Paget's disease of bone. Collected reports on the rheumatic diseases. Arthritis and Rheumatism Council, pp. 126-131. Bikle D D, Negro-Vilar A (eds) 1995 Hormonal regulation of bone mineral metabolism. Endocrine Reviews Monographs, vol 4. Cohen R D, Lewis B, Alberti K G M M, Derman A M (eds) 1990 Metabolic and molecular basis of acquired disease. London: Bailliere Tindall. Favus M J (ed) 1993 Primer on the metabolic bone diseases and disorders of mineral metabolism, 2nd edn. American Society for Bone and Mineral Research. Kanis J A 1991 Pathophysiology and the treatment of Paget's disease of bone. London: Martin Dunitz. Mallette L E 1991 The parathyroid polyhormones - new concepts in the spectrum of peptide hormone action. Endocr Rev, 12: 110-117. Mundy G R 1990 Calcium homeostasis: hypercalcaemia and hypocalcaemia, 2nd edn. London: Martin Dunitz. Nordin EEC 1993 Metabolic bone and stone disease, 2nd edn. Edinburgh: Churchill Livingstone.

19

Diabet sMelitus andDisordes ofLipdand Intermediary Metabolism John Wilding and Gareth Williams

Regulation of metabolism 979

Porphyria 1026

Diabetes mellitus 984

Inherited disorders of carbohydrate metabolism 1028

Hypoglycaemia 1018 Plasma lipoproteins and their disorders 1021

Lysosomal storage disorders 1029

REGULATION OF METABOLISM An appreciation of metabolic processes is essential to understand the causes, effects and treatment of diabetes, which is a common, important and interesting disease. The following is therefore a brief account of the normal control of metabolism.

Insulin Synthesis and structure Insulin is synthesized and secreted by the [3 cells, which form the core of the islets of Langerhans. Translation of the insulin gene yields a precursor, preproinsulin, which is cleaved proteolytically to produce proinsulin. This is further split into equimolar amounts of insulin and C peptide, which are released from the B cell by exocytosis of secretory vesicles (Fig. 19.1). Insulin consists of A and B chains, linked by two disulphide bridges. Human insulin differs structurally from porcine insulin in a single amino acid residue, and both these species differ from bovine insulin in two additional residues (Fig. 19.2). Various point mutations in the molecule ('insulinopathies') have been identified, some of which cause glucose intolerance by interfering with the molecule's

biological activity. Insulin belongs to a large family of structurally similar proteins, conserved during evolution, including the epidermal and insulin-like growth factors. C peptide is biologically inert. It is cleared more slowly than insulin and its circulating levels are therefore a more stable indicator of B-cell secretion than insulin itself. Subnormal C-peptide levels ('C-peptide negative') after stimulation by either glucagon (a powerful insulin secretagogue) or a high-carbohydrate meal can be used to identify diabetic patients who are sufficiently insulin deficient as to need insulin replacement. Insulin secretion Some insulin is secreted all the time and is important in restraining glucose release from the liver and preventing triglyceride breakdown in fat. This 'basal' secretion occurs in regular 10-15-minute pulses, which may serve to maintain the sensitivity of insulin receptors on target tissues. Eating induces an additional, rapid surge of insulin secretion, roughly proportional to the size of the meal; levels rise severalfold after an average breakfast (Fig. 19.3).This is due mainly to the secretagogue actions of absorbed nutrients, and also to stimulation by humoral and autonomic nervous signals. Glucose is the main insulin secretagogue, and arginine and other amino acids are also active. Glucose is first metabolized in the B cell to glucose-6phosphate by the enzyme glucokinase. This is the ratelimiting step, and allows the pancreas to 'sense' the extracellular glucose concentration. The further metabolism of glucose via the glycolytic pathway generates ATP. This closes a potassium efflux channel, causing a rise in intracellular potassium, which depolarizes the (3-cell membrane. Depolarization opens calcium channels in the membrane, allowing calcium to enter the (3 cell, and this in turn activates the microtubules that propel insulin-containing vesicles to the cell surface (Fig. 19.4). After an acute secretagogue challenge (e.g. an intravenous glucose bolus), there is an immediate first phase surge of insulin secretion lasting a few minutes, followed by a slowly rising second phase, which declines when the stimulus ends. This pattern is less clear after meals owing to the relatively sluggish absorption from the gut. Prandial insulin release is also stimulated by the vagal innervation of the islet and by the 'incretins'. These are hormones secreted by the gut into the circulation after eating, such as gastric inhibitory peptide and glucagon-like peptide 1 (7-36) amide, a gut-derived product of the preproglucagon gene. Insulin is secreted into the islet capillaries, which drain into the pancreatic vein, a tributary of the portal vein. It is therefore delivered directly to the liver, where it exerts many of its metabolic effects. Insulin is cleared from the circulation within a few minutes, mostly being removed during its first pass through the liver. Metabolic actions of insulin Insulin is an exclusively anabolic hormone, promoting the storage of carbohydrate, fat and protein. It:

979

FIG. 19.1 Electron micrograph showing secretory granules containing insulin in B cells Higher magnification (inset) shows granules that are released from the cell surface by exocytosis.

FIG. 19.2 Structure of insulin Proinsulin is cleaved to produce insulin and the connecting C peptide. The amino acid residues that differ between human, porcine and bovine insulins are highlighted.

SUMMARY 1 Main metabolic effects of insulin Carbohydrate Promotes glycogen formation reduces hepatic glucose output* Inhibits gluconeogenesis Stimulates glucose uptake into muscle and fat Lowers blood glucose concentration Fat Promotes triglyceride formation Inhibits lipolysis and ketogenesis*

Protein Promotes protein synthesis *Action occurring at low (basal) insulin concentrations The counter-regulatory hormones (glucagon, catecholamines, growth hormone and cortisol) oppose these actions

• causes glucose to be converted into glycogen (glycogenesis) in the liver and muscle; • promotes the formation of triglyceride (lipogenesis) in fat; • stimulates protein synthesis in many tissues; • inhibits the opposing catabolic processes of glycogenolysis, lipolysis and proteolysis.

980

Basal insulin levels are enough to inhibit lipolysis and restrain glucose output by the liver, by inhibiting glycogenolysis and gluconeogenesis. The much higher levels that occur postprandially also stimulate the uptake of glucose into muscle and fat, by activating specific glucose transporter proteins in these tissues. Insulin acts through specific receptors on its target cells (Fig. 19.5). Rare cases of congenital insulin resistance have been attributed to mutations affecting the insulin-binding or phosphorylation domains of the receptor (Figs 19.5 and 19.6).

FIG. 19.3 Diurnal changes in plasma insulin and glucose concentrations in non-diabetic subjects Insulin levels vary severalfold, whereas plasma glucose is maintained between tight limits of 4 and 7mmol/L

Counter-regulatory hormones and somatostatin Counter-regulatory hormones oppose the anabolic effects of insulin, either by direct catabolic actions or by making the tissues insensitive to insulin. Glucagon, secreted by the a cells in the islet periphery, powerfully stimulates glycogenolysis and gluconeogenesis in the liver; together, these actions rapidly increase hepatic glucose output and cause hyperglycaemia. Glucagon also stimulates ketogenesis. All these actions are accentuated by insulin deficiency, when glucagon also enhances lipolysis. Catecholamines, either circulating or released locally in tissue by activation of the sympathetic nervous system, cause glycogenolysis and gluconeogenesis in the liver and lipolysis in fat.

19

FIG. 19.4 Insulin secretion Glucose enters the B cell via the GLUT-2 glucose transporter. Within the B cell, glucose is metabolized intially by glucokinase, generating ATP. This closes ATPsensitive potassium channels, causing membrane depolarization, which triggers calcium influx, resulting in exocytosis of insulin secretory granules. Sulphonylurea drugs promote insulin release by closing the potassium channel, mimicking the effect of glucose.

Cortisol renders tissues insensitive to insulin and stimulates proteolysis, lipolysis and gluconeogenesis. Growth hormone also reduces insulin sensitivity and stimulates lipolysis, but cooperates with insulin in promoting protein synthesis (see also p. 894). The counter-regulatory hormones are secreted during stress and assist glycaemic recovery from hypoglycaemia. Their secretion is also influenced by insulin and vice versa, e.g. glucagon potently stimulates insulin release. In contrast, insulin inhibits glucagon secretion; insulin deficiency therefore allows glucagon levels to rise, aggravating catabolism in diabetes. Somatostatin, secreted by the 5 cells of the islet, is not a counter-regulatory hormone but strongly suppresses the release of both insulin and glucagon. It also inhibits the secretion of growth hormone, gastrin and many other peptides. The islets produce a fourth hormone, pancreatic polypeptide, secreted by PP cells. Its function is unknown.

Carbohydrate, fat and protein metabolism The three branches of metabolism - carbohydrate, fat and protein (Figs 19.7-19.9) - are all interlinked at various levels. Each is finely balanced between anabolism, largely mediated by insulin, and catabolism due to the counterregulatory hormones and activation of the sympathetic nervous system.

FIG. 19.5 The insulin receptor The insulin receptor consists of paired a and (3 subunits. Insulin binds to the a subunit, causing a conformational change resulting in activation of tyrosine kinase enzymes which are part of the B-subunit sequence. These become phosphorylated, resulting in a cascade of intracellular events. Other parts of the receptor are responsible for internalization of the receptor, following which insulin is removed and the receptor is recycled.

FIG. 19.6 Intracellular actions of insulin After insulin binds to its receptor it triggers a complex cascade of phosphorylation of intracellular proteins, beginning with insulin receptor substrate 1 (IRS-1). This results in the movement of glucose transporters (GLUT-4 in muscle and fat) to the cell surface; activation of key enzymes involved in glucose metabolism; effects on gene transcription and cell proliferation, which occur in the nucleus.

Carbohydrate metabolism Glucose is the body's main metabolic substrate and is normally the sole fuel for the brain, which uses about 50% of the 200 g of glucose produced by the liver each day. Glucose is supplied steadily to the brain and other tissues by maintaining blood levels between tight limits (4-7mmol/L; see Fig. 19.3). Between meals, blood glucose is determined mainly by

981

FIG. 19.8 Principal pathways of fat metabolism TG, triglyceride; FFA, free fatty acids; Cort, cortisol; Ins, insulin; Cats, catecholamines; GH, growth hormone; Glcg, glucagon; +, -, reactions stimulated, inhibited (shown in one direction only). FIG. 19.7 Principal pathways of carbohydrate metabolism Ins, insulin; Cats, catecholamines; Cort, cortisol; Glcg, glucagon; FFA, free fatty acids; +, -, reactions stimulated, inhibited. Blue indicates actions stimulated by insulin.

how much glucose is released by the liver into the circulation. The liver contains most of the body's glycogen, the glucose polymer that is the main storage form of carbohydrate. Glycogenesis is promoted by glycogen synthase, an enzyme that is stimulated by insulin and inhibited by glucagon. Conversely, glycogenolysis (under the action of phosphorylase) is inhibited by insulin and stimulated rapidly and powerfully by glucagon and the catecholamines. Hepatic stores of glycogen are soon depleted. The liver also secretes glucose produced by gluconeogenesis from lactate, amino acids and glycerol, either formed within the liver or taken up from the circulation. Lactate is a product of glycolysis in muscle. Amino acids, especially alanine and glutamine, derive from proteolysis or amination of pyruvate. Glycerol results from lipolysis. Gluconeogenic enzymes are stimulated by glucagon, catecholamines and cortisol, and inhibited by insulin; glucagon also stimulates amino acid uptake into the liver (Fig. 19.7). After meals, glucose enters the circulation from the gut and its storage is favoured by the high prevailing insulin levels. Insulin stimulates glucose uptake into skeletal muscle and adipose tissue and its subsequent conversion into glycogen and triglyceride, respectively. 1

982

MCQ19.1

Fat metabolism (Fig. 19.8) Circulating triglyceride, either absorbed from the gut or secreted by the liver, is hydrolysed by lipoprotein lipase in the capillary endothelium of adipose tissue and skeletal muscle (Fig. 19.8). This lipolysis yields free (non-esterified) fatty acids (FFA, or NEFA) and glycerol, which are metabolized mainly in adipose tissue. Their recombination into triglyceride (lipogenesis) is stimulated by insulin. Subsequent lipolysis of triglyceride (mediated by triacylglyceride lipase) is inhibited by insulin at low concentrations and stimulated by catecholamines, growth hormone and, in severe insulin deficiency, by glucagon. Glycerol is exported and in the liver is a substrate for gluconeogenesis. FFA are also exported and are used as a fuel by skeletal muscle and many tissues. FFA taken up by the liver can either be used for lipogenesis or undergo oxidation to ketone bodies (ketogenesis}.

Ketogenesis (Fig. 19.9) This takes place within the mitochondria of the hepatocytes, using fatty acyl-coenzyme A (CoA) derivatives formed in the cytoplasm by the reaction of FFA with CoA. These are carried inwards across the mitochondrial membrane by a 'shuttle' enzyme (carnitine palmitoyl transferase) and then undergo B-oxidation to acetyl-CoA and further conversion to acetoacetate. This and its derivatives, 3-hydroxybutyrate and acetone, are the ketone bodies. Ketogenesis is stimulated by glucagon and suppressed by insulin, which respectively enhance and inhibit the activity of the carnitine shuttle, the rate-limiting step of the pathway. Ketogenesis is also regulated by the supply of

19

FIG. 19.10 Major pathways of protein metabolism Ins, insulin; Glcg, glucagon; Cort, cortisol; +, -, reactions stimulated, inhibited (shown in one direction only).

FIG. 19.9 Ketogenesis Ketone body production is inhibited by insulin (Ins), which reduces both the supply of FFA (from lipolysis) and, indirectly, the activity of the shuttle enzyme (carnitine palmitoyl transferase), which carries the precursor fatty acyl-CoA into the mitochondria. Glucagon (Glcg), catecholamines (Cats) and growth hormone (GH) stimulate ketogenesis by opposing these actions.

FFA, and is therefore greatly increased by the combination of insulin deficiency and glucagon excess - as in untreated type 1 diabetes mellitus - which releases the brake on lipolysis. Normally, ketone bodies are exported from the liver and can be used by many tissues as metabolic fuels; indeed, they are the main source of energy in prolonged starvation, when fat reserves are mobilized. In uncontrolled type 1 diabetes, however, their overproduction greatly exceeds their utilization; 3-hydroxybutyrate and acetoacetate, and their accompanying hydrogen ions, accumulate to cause diabetic ketoacidosis. 1 Protein metabolism (Fig. 19.10) Protein synthesis is promoted by insulin and growth hormone and normally balances proteolysis, which is stimulated especially by cortisol. Circulating amino acids, derived either from proteolysis, amination of pyruvate or absorption of digested proteins, are taken up by the tissues. Alanine and glutamine are important substrates for gluconeogenesis in the liver, where their uptake is stimulated by glucagon. Regulation of metabolism in health, starvation and stress Fasting is characterized by low basal insulin levels without rises in counter-regulatory hormones. This permits controlled glycogen breakdown, gluconeogenesis and glucose production by the liver and so maintains blood glucose

levels. Lipolysis is not increased; FFA and ketone body levels remain low. After eating, insulin release increases in step with the influx of glucose, triglycerides and amino acids from the gut, promoting the storage of nutrients not immediately needed. High insulin levels promptly suppress hepatic glucose secretion, and stimulate glucose uptake and storage in skeletal muscle (as glycogen) and adipose tissue (as triglyceride). This prevents postprandial hyperglycaemia, and lipogenesis and protein synthesis are encouraged. In prolonged starvation, insulin levels fall below the threshold necessary to suppress lipolysis, ketogenesis and hepatic glucose production. These processes are enhanced by increased glucagon levels (stimulated by depressed insulin secretion) and by the other counter-regulatory hormones (pp. 980-981), whose secretion is increased by the stress of starvation. The result is controlled catabolism. Blood glucose levels are maintained initially by hepatic glycogenolysis and then, when this is exhausted, by gluconeogenesis, again predominantly in the liver. The body's fat reserves, its major energy store, are then mobilized by lipolysis and ketogenesis. Blood ketone levels increase greatly (the ketosis of starvation) and are used as fuels by most tissues - even the brain - after several days of starvation. Protein metabolism is defended until relatively late, possibly because ketone bodies inhibit proteolysis. Muscle and other proteins are ultimately broken down under the influence of increased cortisol concentrations to support gluconeogenesis. Severe stress (e.g. sepsis, trauma or surgery) greatly increases counter-regulatory hormone secretion and leads to uncontrolled catabolism. Excess gluconeogenesis, lipolysis and proteolysis lead to rapid loss of body fat and muscle, the latter being exacerbated by impaired protein synthesis. The situation is even more precarious in diabetic patients who are insulin deficient, because they are

983

often either untreated or inadequately treated. Profound ketoacidosis and hyperglycaemia can develop with alarming speed. 1

FURTHER READING ON REGULATION OF METABOLISM Kruszynska Y T 1997 Physiology of fuel homeostasis. In: Pickup and Williams eds Textbook of diabetes. Blackwell Science, Oxford.

DIABETES MELLITUS The simple definition of diabetes mellitus as 'a state of chronic hyperglycaemia' belies the immense medical, scientific, social and economic implications of the disease. Because it is common and affects virtually every system in the body, every medical practitioner must be familiar with it. People with diabetes must learn to cope with a lifelong disease which is treatable but not curable, and which carries the threat of complications that may endanger the future quality of life and even life itself. Society as a whole has to shoulder a considerable burden from diabetes. In the UK, diabetes affects about 2% of the population (over 1 million people) and may absorb as much as 10% of healthcare expenditure. Worldwide, there are probably over 150 million people with diabetes, and this is set to rise to over 240 million by the year 2010. Research and advances in clinical care are steadily making the disease easier to live with, at least in richer countries. The problem of diabetes in the developing world is only now receiving the attention it deserves.

The diagnosis of diabetes Blood glucose concentrations are normally remarkably constant: fasting concentrations in whole blood are 3.5-6.7 mmol/L and peak values after meals rarely exceed 8 mmol/L. Glycosuria therefore never occurs unless the renal threshold for glucose reabsorption is below the normal value of 10 mmol/L. The diagnostic criteria for diabetes have recently been revised. The revision has been recommended because it has recently become evident that the fasting glucose concentration used in the 1985 WHO criteria missed many cases of diabetes that would only be diagnosed using the oral glucose tolerance test (Fig. 19.11). The new American Diabetes Association criteria are based on fasting plasma glucose concentration. A value above 7.0mmol/L indicates diabetes, whereas a concentration above 6.0 mmol/L defines a new category known as impaired fasting glucose (IFG).

1

984

MCQ19.2

2 2MCQ19.3 MCQ19.3

FIG. 19.11 Diagnostic criteria for diabetes A fasting plasma glucose concentration >6.0 mmol/L indicates impaired fasting glucose (IFG). After a 75 g glucose load a 2-hour value of >11.0 mmol/L identifies diabetes. A value >7.0mmol/L but <11.1 mmol/L indicates impaired glucose tolerance. The 1-hour intermediate readings on OGTT are not used for diagnosis.

A single very high value (>15 mmol/L) in a symptomatic patient is diagnostic, but otherwise two separate estimations should be made. The values relate to venous whole blood; as red cells contain less glucose, the corresponding plasma values are about 1.1 mmol/L higher. Because glucose is extracted by the tissues, arterial and capillary (e.g. fingerprick) blood levels are higher than those in venous blood. In borderline cases and for research applications, the oral glucose tolerance test (OGTT) is recommended. After an overnight fast, the subject drinks 75 g of glucose (dextrose) dissolved in water; plasma glucose is measured both before and 2 hours afterwards. The normal values and diagnostic criteria for diabetes and impaired glucose tolerance (IGT) are shown in Figure 19.11. A low renal threshold is diagnosed if glycaemia is normal but glycosuria occurs. Urine should be collected during the test if this is suspected. The diagnosis of diabetes carries considerable personal and social disadvantages and must be certain. Only laboratory measurements of blood glucose should be used for diagnostic purposes. Test-strip readings, urinary glucose levels or glycosylated haemoglobin or fructosamine concentrations must never be used. OGTT results vary considerably between and within normal individuals and the test should be repeated if a marginal abnormality is found. Glucose tolerance is particularly sensitive to changes in nutritional state and is worsened in normal subjects by dieting during the preceding days. An adequate diet must therefore be taken for 3 days before an OGTT. 2

Classification of diabetes As more is understood about the aetiology of diabetes it is likely that the classification will change to reflect this. The latest WHO classification (Table 19.1) reflects the two main types of diabetes that are recognized clinically: type 1 (previously known as insulin dependent) and type 2 (previously known as non-insulin dependent) diabetes mellitus, as well as a number of rarer, but specific, aetiological forms of diabetes. Some of the features distinguishing between

TABLE 19.1 New aetiological classification of disorders of hyperglycaemia (WHO 1998) Type 1 diabetes

Autoimmune Idiopathic

Type 2 diabetes

Predominantly due to insulin resistance Predominantly due to insulin secretory defect

Other specific types

Genetic defects of B-cell function Genetic defects of insulin action Diseases of the exocrine pancreas Endocrinopathies Drug- or chemically induced diabetes Infections Uncommon forms of immune-mediated diabetes Other genetic syndromes sometimes associated with diabetes

19

Glucokinase, hepatic nuclear factor-a mutations Insulin receptor mutations Chronic pancreatitis; fibrocalcific pancreatitis Cushing's syndrome, acromegaly, phaeochromocytoma, glucagonoma Steroid treatment, pentamadine Rubella, mumps, cocksackie B4 Insulin antibodies Haemochromatosis, mitochondrial mutations, myotonic dystrophy

Gestational diabetes

TABLE 19.2 Features distinguishing Type 1 from Type 2 diabetes

Metabolic features Insulin deficiency Spontaneous ketosis Need insulin to survive Insulin insensitivity Aetiology Genetic susceptibility HLA markers Autoimmune features Environmental factors

Type 1

Type 2

Severe (C-peptide-negative) Yes Yes Mild, variable

Moderate, variable (C-peptide-positive) No No Severe, variable

Moderate Yes (DRC3/4) Yes ? Viruses ? Cow's milk

Very strong None known No ? Overeating ? Physical inactivity

Clinical features at presentation Age (not very useful) Most <40 years (peak at 12 years) Body weight BMI* mostly <25; recent loss common Microvascular complications Rare

ketosis and will survive (albeit with hyperglycaemia) without insulin therapy. Many patients with type 2 diabetes are, however, treated with insulin, as this is the only available means to lower glycaemia effectively, but these insulin-treated patients can be distinguished from those who require insulin for survival because they have measurable C-peptide levels and do not become ketotic if insulin is withdrawn. It is also now beginning to be recognized that type 1 and type 2 diabetes do not necessarily define a specific pathology. Not all cases of type 1 diabetes have an autoimmune aetiology. Type 2 diabetes may be predominantly due to insulin resistance or to insulin deficiency, or indeed may progress from the former to the latter during the clinical course of the disease. Some examples of the other specific types are indicated in Table 19.1.

TYPE 1 DIABETES MELLITUS Most >40 years (peak at 70 years) BMI mostly <25; recent loss sometimes Sometimes present

*BMI, body mass index = weight (kg)/height (m)2.

the two are shown in Table 19.2. The critical difference is the degree of insulin deficiency, which is so profound in type 1 diabetes that even the low insulin concentrations that normally prevent lipolysis and ketogenesis cannot be sustained. Without insulin replacement, these patients become ketotic and die. By contrast, patients with type 2 diabetes have enough endogenous insulin to prevent

Epidemiology In Britain, type 1 diabetes accounts for about 10% of all diabetic patients and perhaps 30% of those treated with insulin. The frequency of type 1 diabetes shows striking geographical variation: in Finland it is some 35 times commoner than in Japan. Within the UK the highest frequency is found in Scotland, where, as in several other countries, the incidence appears to have doubled within a decade. Incidence shows a pronounced seasonal variation, with most cases presenting in the autumn and winter. These observations all suggest that environmental factors are important in causing or precipitating the disease. Also unexplained is the age predilection of type 1 diabetes. Any age can be affected, but most cases present before 20 years of age and the incidence peaks at 12 years (Fig. 19.12).

985

Environmental agent (? viruses)

Islet Bcell autoantigen exposed favourable configuration Islet Bcell FIG. 19.12 Incidences of type 1 diabetes and type 2 diabetes with age Note that the scale for type 2 is 10 times that for type 1.

DR3/4

Aetiology and pathogenesis

Genetic factors The genetic component of type 1 diabetes is less important than in type 2 diabetes, as is shown by studies of identical twins of whom one becomes diabetic. In the case of type 1 diabetes the chances of the unaffected twin developing the disease are less than 40%, whereas the overall risk for type 2 diabetes may be as high as 90%. Several markers for type 1 diabetes have now been identified, notably specific HLA class 2 antigens, glycoproteins which are encoded by genes that lie on the short arm of chromosome 6 (p. 73). Possession of either HLA-DR3 or DR4 antigens increases the risk of developing diabetes (60% of the population have one or both alleles, but 95% of patients with diabetes). Possession of HLA-DR2 is protective (less than 5% will develop diabetes). These antigens are encoded by the genes HLA-DR A and DRB1, which encode the a and B chains of the HLA-DR molecules, respectively. In the neighbouring region the HLA-DQA1 and HLADQB1 genes are also highly polymorphic, and recent evidence suggests they may also be important in determining disease susceptibility. Both HLA-DR and HLA-DQ molecules are involved in antigen presentation by T cells, and variations in the proteins expressed by these genes may determine the nature of the response if the B cell is damaged, with activation of lymphocytes and continuing B-

1

986

MCQ19.4

unfavourable configuration Islet Bcell

I-helper lymphocyte

Type 1 diabetes results from autoimmune destruction of the islet B cells, which is partly determined by heredity. The genetic markers for diabetes susceptibility are relatively common in Caucasian populations, whereas type 1 diabetes is relatively rare, again indicating that additional factors, presumably environmental, are superimposed.

aberrant expression of class II HLA antigens

Activation of T-lymphocyte

DR2

T-helper lymphocyte

No activation of T-lymphocyte

B-celI destruction FIG. 19.13 Hypothetical scheme of autoimmune B-cell destruction in type 1 diabetes Viruses or other agents could induce islet B cells to express class II HLA antigens and to 'expose' autoantigens (viral antigens could be expressed on B cells, or a normal B-cell antigen could mimic viral antigens). The autoantigen (indicated in blue), when coexpressed with HLA-DR3 and/or 4, has a 'favourable1 configuration, which activates T-helper lymphocytes and triggers autoimmune damage. In contrast, HLA-DR2 has an 'unfavourable' configuration, which prevents this from happening.

cell destruction only occurring if certain configurations of the protein molecules are present (Fig. 19.13). Other diabetes susceptibility genes include the region of the insulin gene on chromosome 11, and at least eight other genes. The ways in which these gene products interact with each other, and with possible environmental factors, to cause autoimmune destruction of the B cells is still not well understood. Autoimmune phenomena An association of type 1 diabetes with organ-specific autoimmune diseases has long been recognized, e.g. with Schmidt's syndrome (adrenal and thyroid failure) in type 2 polyglandular endocrinopathy syndrome (p. 930). Studies in human type 1 diabetes and in rodents that develop spontaneous type 1 diabetes-like syndromes have documented convincing evidence of autoimmune disease. Furthermore, B-cell damage in animals and man, if detected early enough, can be limited by immunosuppressive drugs. Like thyroid, adrenal and other tissues that are the target of autoimmune disease, the pancreatic islets of newly diagnosed patients with type 1 diabetes are infiltrated with immunologically active cells (mostly cytotoxic/suppressorT lymphocytes), an appearance termed 'insulitis'. With the

passage of time the intensity of the insulitis abates, but surviving islets are found to be specifically depleted of (3 cells, implying that these were the victims of the autoimmune attack. B cells may attract immune damage by their 'aberrant' expression of class II HLA antigens (which they do not normally express). The subsequent events thought to occur are shown in Figure 19.13. As well as insulitis, newly diagnosed type 1 diabetic patients show other evidence of ongoing autoimmune processes, with activated T cells and autoantibodies directed against islet cells and insulin, in the circulation. Although most islet-cell antibodies (ICA) react with all islet cell types, some complement-fixing ICA may recognize the B-cell membrane specifically. The crucial B-cell autoantigen is still unknown, although recent work has implicated the enzymes glutamate decarboxylase (GAD), protein tyrosine phosphatase B, and insulin itself. Viruses and environmental factors Environmental factors must account for a large part of the susceptibility to type 1 diabetes. Many viruses target the pancreas and some selectively attack the B cells, where they could persist and alter the cells' activity or antigenicity. Type 1 diabetes presents when seasonal viral infections are common, and some newly diagnosed patients have serological evidence of previous (sometimes recent) encounters with viruses such as mumps, coxsackie B, and retroviruses. Because type 1 diabetes has a long subclinical course, such infections may represent a final insult which tips the patient into critical insulin deficiency. Type 1 diabetes develops in up to 20% of children with congenital rubella, but there is little evidence that rubella is diabetogenic if acquired after birth. There is an apparent

protective effect of breastfeeding on the later development of type 1 diabetes. It has been hypothesized that early exposure to cow's milk may trigger an immune reaction which damages B cells because of 'molecular mimicry' between bovine serum albumin and certain B-cell surface proteins. Various chemical toxins destroy B cells and cause type 1 diabetes-like syndromes in animals (e.g. the cytotoxic agent streptozotocin in the rat) but no toxins have been convincingly implicated in human type 1 diabetes. 1

19

Natural history of type 1 diabetes Long-term prospective studies of subjects at high risk of developing type 1 diabetes (especially siblings of recently diagnosed children) indicate that type 1 diabetes is the culmination of many years of low-level autoimmune damage, which is manifest clinically when a critical mass (>95%) of (3 cells has been destroyed. This is in striking contrast to the acute presentation of type 1 diabetes: symptoms are present in most patients for less than 4 weeks. ICA and insulin autoantibodies appear during the prodromal phase, up to 10 years before type 1 diabetes presents (Fig. 19.14). This is asymptomatic, as is the subsequent prediabetic phase, in which subtle disturbances of insulin secretion (loss of first-phase release) can be identified. Later, the OGTT becomes abnormal and, finally, frank hyperglycaemia supervenes and symptoms appear. Interestingly, the process may abort without leading to type 1 diabetes in a proportion of susceptible subjects.

RECENT ADVANCES IN THE PREDICTION AND PREVENTION OF TYPE 1 DIABETES In families in whom one member has developed diabetes, it is possible to predict with reasonable accuracy whether other family members (e.g. siblings) are at risk of developing the disease. The risk for a sibling is about 1 in 20 and for a monozygotic twin 1 in 3. Accuracy can be improved to over 90% by a combination of HLA-DR phenotyping and measurement of islet-cell antibodies. This ability to predict with reasonable accuracy subjects at risk of developing type 1 diabetes now allows attempts to interfere with the disease processs to be tried in those at very high risk. Trials are under way with various agents, including immunosuppression with agents such as cyclosporine. Less toxic alternatives also under investigation include the vitamin B3 derivative nicotinamide, which may interfere with the immune-mediated (3-cell destruction, and low-dose insulin, which could modify the immune response. It is still too early to tell whether any of these interventions will be effective.

FIG. 19.14 Natural history of type 1 diabetes Islet-cell antibodies (ICA) may be present many years before the onset of clinical diabetes. Intercurrent illness may cause an acute decline in B-cell function and patients may present at this stage. Recovery from illness allows temporary improvement in function, accounting for the 'honeymoon period' before the inevitable development of true insulin dependence. Interventions interfering with immune destruction might therefore be possible before too many B cells have been lost (see Recent Advances box).

987

Biochemical disturbances of type 1 diabetes Insulin deficiency, with the glucagon excess it causes, results in hyperglycaemia due to unrestrained hepatic glucose output, lipolysis and proteolysis. These catabolic processes can be exacerbated by counter-regulatory responses to infection and other stresses. The insulindependent tissues, notably skeletal muscle and fat, 'starve in the midst of plenty', as lack of insulin decreases glucose entry despite its very high extracellular concentrations. An osmotic diuresis, polyuria and dehydration occur when blood glucose levels exceed the renal reabsorption threshold (usually l0mmol/L). Severe insulin deficiency greatly accelerates lipolysis, which fuels ketogenesis (p. 982). Proteolysis causes muscle breakdown and wasting.

Clinical features of type 1 diabetes Presentation Young patients typically have a short history (a few days or weeks) of the classic symptoms of polyuria, thirst, polydipsia, and weight loss. Polyuria is due to an osmotic diuresis caused by high glucose and ketone body concentrations in the urine, and may reach several litres per day. Sleep is disturbed by nocturia, and previously continent children may develop enuresis. Thirst is often intense. Weight is lost rapidly, often despite increased appetite, owing to both dehydration and catabolism of muscle and fat. General tiredness and malaise are common. Other features include blurred vision (due to osmotic disturbances in the lens), muscle cramps and infections, such as boils, urinary tract infections, or candidiasis causing balanitis or pruritis vulvae. Abdominal pain may occur, especially in children. Patients with impending ketoacidosis may have nausea, acidotic (Kussmaul) breathing and other features described on page 1003. Chronic diabetic complications (retinopathy, neuropathy) are exceedingly rare in newly diagnosed type 1 diabetes patients because significant hyperglycaemia is usually only a recent event. Very few cases are detected incidentally in asymptomatic subjects. A full examination should be performed, as it is important to document the presence of any complications and to identify precipitating illnesses. Examination may be unremarkable, and this makes it mandatory to check the blood glucose concentration in any patient who is severely unwell.

SUMMARY 2 Presentation of type 1 diabetes

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Polyuria, nocturia (enuresis) Thirst, polydipsia Weight loss Tiredness, lack of energy Blurred vision Infections (including candidiasis) Abdominal pain (in children) Features of ketoacidosis

triad of major symptoms

Investigations and diagnosis The diagnosis is confirmed by demonstrating hyperglycaemia (defined on p. 984). The urine must be tested for ketones. Routine blood biochemistry may show features of dehydration and ketoacidosis. Other tests should aim to identify any infection that could have precipitated diabetes (full blood count, urine and blood culture, chest X-ray) and, in older patients especially, any coexisting risk factors for diabetic complications, notably vascular disease (ECG, fasting lipid concentrations).

Management of type 1 diabetes Insulin replacement is mandatory, but other aspects diabetes education, blood glucose monitoring, diet and other lifestyle changes - are essential for the day-to-day and long-term management of type 1 diabetes Insulin treatment Insulin was originally extracted from porcine and bovine pancreases. Insulin of human sequence is now synthesized on an industrial scale by inserting a cloned synthetic gene into either bacteria or yeasts. Biosynthesis mimics the natural process, yielding proinsulin, which can be cleaved in vitro. Human insulins are unlikely to provoke antibody formation. In the UK, many preparations of bovine insulins have been phased out and porcine insulins are becoming less popular; over 90% of patients in the UK and Europe now use human insulin. Human insulin preparations are absorbed slightly more rapidly and have somewhat shorter action profiles than the porcine equivalents, but these differences are unimportant in clinical practice. Human insulins are less antigenic than porcine and especially bovine insulins, and allergic reactions (see below) are very rare. The suggestion that human insulin is associated with decreased awareness of hypoglycaemia is unsubstantiated, although porcine insulin should be prescribed if the patient requests it. Insulin preparations in the UK, North America and most European countries contain a standard concentration of l00U/mL. Insulin preparations Insulin replacement aims to reproduce the normal pattern of insulin secretion, with a background basal supply and additional peaks at mealtimes. Two basic types of insulin, short- and long-acting, are therefore required (see Table 19.3). Short-acting (soluble) insulins (e.g. Actrapid, Humulin S) are simple solutions of unmodified insulin, which appear clear. When injected subcutaneously they have a relatively short action profile, with a peak hypoglycaemic effect after 2-4 hours and a duration of 5-8 hours. Soluble insulins are therefore used to cover major meals, and are injected 30 minutes before eating so that their maximal effect coincides with the postprandial glycaemic peak. Soluble

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TABLE 19.3 Types of insulin preparation Approximate action profile (hours)* Type

Examples

Onset

Short-acting insulin analogues

Lispro Insulin Insulin Aspart

15-30min

1-2

4-6

Immediately before, with or after meals

Soluble

Actrapid, Humulin S

0.5-1

2-4

5-8

30-40 minutes before eating

Intermediate Isophane (NPH)

Duration

Insulatard Humulin I 6-10

12-24

Monotard, Humulin Zn

'Long-acting' Ultralente

Ultratard (human) 30:70 50:50

Mixtard 30 Humulin M5

Schedule

b.d. with soluble insulin before meals 2-4

Lente (IZS)

Biphasic Soluble: isophane

Peak

or

o.d. in the morning or evening

3-4

12-18

<24f

o.d. or b.d., as for intermediate

0.5-1

2-10

12-18

b.d. or o.d., 30-40 minutes before meals

* Action profiles vary widely between and within individuals. Intermediate and even 'long-acting' insulins based on human insulin often last less than 24 hours, and twice-daily injections are needed in many cases. NPH, neutral protamine Hagedorn; IZS, insulin-zinc suspension; o.d., b.d., once, twice daily.

f

insulins are also used for intravenous infusion (e.g. in treating ketoacidosis) and in insulin pumps. Short-acting insulin analogues (e.g. Lispro Insulin, Insulin Aspart) are a recent development. These insulins bind the insulin receptor and have identical action in vivo to soluble insulin, but their altered amino acid structure prevents them from forming hexameric complexes in solution. This means that they are absorbed much more rapidly after subcutaneous injection, with an onset of hypoglycaemic effect within 30 minutes, and a duration of action of about 4 hours. They can therefore be given immediately before, during or even after meals, which is preferred by some patients. In addition, late postprandial hypoglycaemia is less common in patients using these insulin preparations as part of a 'basal-bolus' regimen, and some studies suggest improved control as well. Prolonged-action insulins are chemically modified to delay absorption. These suspensions must be shaken gently before injection and appear cloudy. There are two main types: • Insulin-zinc suspensions are complexed with excess zinc to produce either large crystals which dissolve and are absorbed very slowly ('ultralente') or amorphous material with a shorter action profile ('semilente'). These are combined in a 70:30 ratio to produce the commonly used 'Lente' insulins (e.g. Humulin Zn and Monotard). • Isophane insulins (e.g. Humulin I, Insulatard) are combined with protamine, and are also known as NPH ('Neutral Protamine Hagedorn').

An ideal long-acting insulin would provide constant basal levels for 24 hours, so that a single daily injection would suffice. In practice, none of the available preparations - including the 'long-acting' human ultralente - reliably lasts a full day, and most severely insulin-deficient (C-peptide negative) type 1 diabetes patients therefore require two daily injections of prolonged-action insulin, Their sluggish onset of action means that these insulins can be injected at any time of day, but for convenience they are usually injected before meals, together with any short acting insulin. Lente insulins contain excess zinc, which combines with soluble insulin and retards its action. If the two are mixed in the same syringe, soluble insulin should be drawn up before lente to avoid contaminating the soluble bottle with zinc, and the mixture must be injected immediately. Insulin Glargine is a new, long-acting insulin preparation that has recently become available. It has an amino acid substitution resulting in slow absorption and has a 24-hour duration of action. Premixed (biphasic) insulins consist of isophane and soluble insulins mixed in 70:30 (e.g. Mixtard 30),50:50 (e.g. Humulin M5) or other proportions. Their action profiles reflect both components. Recent biphasic preparations include faster-acting analogues instead of standard soluble insulin, and so can be injected immediately before eating, Insulin injection regimens The normal pancreas produces about 40 U of insulin each day. A diabetic patient needs less than this if some endoge-

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nous B-cell function remains (e.g. during the 'honeymoon' period of type 1 diabetes, described below), and more if insulin sensitivity is impaired by increased counterregulatory hormone secretion during intercurrent illness, or by obesity in type 2 diabetes. If little endogenous insulin remains, insulin replacement must provide both the basal and the prandial components of normal insulin secretion. Most C-peptide-negative patients (i.e. those with little residual insulin secretion) ultimately require twice-daily injections of prolongedaction insulin, together with soluble insulin before breakfast and the evening meal. Midday meals (if not large) are usually covered by the morning dose of prolonged-action insulin. About two-thirds of the total daily dose is usually given before breakfast and one-third in the evening, each dose consisting roughly of two-thirds of prolonged-action and one-third soluble insulin. Some patients can be controlled by premixed insulins (two-thirds of the daily requirement before breakfast and one-third before the evening meal), whereas others prefer the flexibility of adjusting the soluble and prolonged-action components separately. 'Intensified' insulin regimens use more injections to try to achieve very tight glycaemic control. These are becoming more widely used in the light of the results of the Diabetes Control and Complications Trial (see below). Soluble insulin is injected 30 minutes before each meal, the dose being determined by the amount eaten and previous postprandial glucose measurements; for convenience, this is often given using a pen injection device (see below). The basal needs are covered by long-acting insulin injected once (before breakfast or at bedtime) or twice daily. Patients with enough residual insulin, for example during the 'honeymoon' period, will be able to fill in gaps in insulin replacement and can achieve good glycaemic control with fewer doses, such as one or two injections of prolonged-action insulin. Adjustment of insulin dosages on the basis of glycaemic monitoring is discussed on page 1000.

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Insulin injections, pen devices and pumps Insulin injections are almost painless. Disposable plastic syringes are now in general use and can be reused several times, if kept socially clean. Insulin should be injected at an angle into a skinfold raised between finger and thumb, to avoid intramuscular injection, which can hasten absorption unpredictably. The skin does not need to be cleaned. Suitable injection areas are the abdomen (where absorption is fastest and most reliable), upper arm and thigh. Sites should be used in rotation to avoid lipoatrophy or lipohypertrophy. 'Pen' injection devices contain a prefilled vial of soluble or isophane insulin, of which metered doses can be selected and injected by pressing a button. They are easily portable and popular with active and younger patients, especially for intensified injection regimens. Continuous subcutaneous insulin infusion (CSII) is delivered by a miniaturized battery-driven pump. Insulin

in a prefilled cartridge is infused continuously through a butterfly cannula implanted subcutaneously in the abdomen; the infusion site is changed daily. The basal rate can be varied and is often reduced at night, when insulin requirements fall. Prandial boluses, judged according to the size of the meal, are given about 30 minutes before eating, by pressing a button on the pump. Pump failure is rare, but interruption of insulin delivery, e.g. by blockage or disconnection of the cannula, can rapidly precipitate hyperglycaemia and ketoacidosis because the subcutaneous insulin depot is small. This has led to the development of pumps that sound an alarm if insulin delivery is interrupted. Other problems include infection at infusion sites and a transient deterioration in retinopathy, which can accompany any rapid tightening of glycaemic control (p. 1008). CSII is currently seldom used in the UK, but is more widely used in the USA and some European countries. These differences in prescribing practice do not appear to be based on pharmacological or clinical evidence. Carefully selected patients may be treated by insulin infused intraperitoneally, using a pump implanted subcutaneously. Intraperitoneal insulin is absorbed into the portal system and can achieve good control in patients with 'unstable' diabetes that cannot be controlled by less invasive approaches. Intensive insulin treatment can achieve essentially normal blood glucose levels in selected patients, including some who are poorly controlled by other regimens. However, the techniques require great commitment from the patient and the diabetes care team. Problems with insulin treatment Hypoglycaemia Most insulin-treated type 1 diabetes patients suffer occasional hypoglycaemia and, each year, about one in seven will have an episode severe enough to require help. Fear of hypoglycaemia probably prevents many patients from trying to achieve tight control. In the DCCT trial (see below) there was a threefold increase in the incidence of hypoglycaemia in the intensively treated group, compared with those on conventional treatment. Hypoglycaemia is a recorded cause of death in young type 1 diabetes patients, but the chances of a patient dying during a hypoglycaemic episode, even if profound, are very low. The threat of hypoglycaemia can be greatly reduced by education of the patient and his or her family. Causes of insulin-induced hypoglycaemia. Hypoglycaemia occurs when circulating insulin levels are too high and are insufficiently antagonized by counter-regulatory hormones. Contributory factors are: • Too much circulating insulin: wrong dose (errors in drawing up and injecting insulin are surprisingly common) or timing (e.g. injection given too long before next meal); • Not enough food: delayed, missed or inadequate meals; • Exercise: this hastens the absorption of insulin injected

SUMMARY 3 Symptoms and signs of hypoglycaemia Sweating Tremor Tachycardia Pallor Hunger Weakness Visual problems Hemiparesis Aggression, confusion Fitting Coma

sympathetic discharge

neuroglycopenia

into the limbs and increases glucose uptake into muscle; the latter effect continues for several hours after acute strenuous exercise in order to replenish muscle glycogen, and may cause hypoglycaemia the following day; • Alcohol: this is a potent cause of hypoglycaemia. Ethanol directly inhibits gluconeogenesis and glucose output by the liver; • Impaired awareness of hypoglycaemia; • Previous episodes of hypoglycaemia (see below). The widely variable absorption of insulin probably contributes to the many episodes that cannot be explained. Episodes recurring at the same time of day may be due to basic mismatching to the insulin, dietary and exercise regimens. Other possible causes of severe and repeated hypoglycaemia include loss of counter-regulatory hormones (especially in hypothyroidism and Addison's disease), alcohol abuse, the loss of awareness of hypoglycaemia that affects patients with long-standing type 1 diabetes, and factitious hypoglycaemia (see below). Patients with diabetic nephropathy clear insulin more slowly from the circulation and so are prone to hypoglycaemia. Clinical features of hypoglycaemia. Hypoglycaemia triggers sympathetic activity and counter-regulatory hormone secretion. This corrects hypoglycaemia by reducing insulin sensitivity in its target tissues; glucagon and adrenaline also stimulate gluconeogenesis, glycogen breakdown and hepatic glucose production. If this response fails to correct hypoglycaemia, neuroglycopenia may follow. The main symptoms of hypoglycaemia are attributed to either sympathetic stimulation (sweating, tremor, tachycardia and pallor) or neuroglycopenia, whose many features include hunger and weakness; irritability, confusion and aggression; clumsiness; blurred vision and diplopia; aphasia and hemiparesis (Summary 3). Profound neuroglycopenia can cause fitting, coma and finally death. Repeated, severe hypoglycaemia may cause intellectual impairment. Nocturnal hypoglycaemia may not wake the patient but may be suggested by sweating and restlessness (often apparent to the patient's partner), nightmares, and a 'hung-over' feeling with headache the following morning. Hypoglycaemia unawareness. Patients with longstanding type 1 diabetes (>10 years' duration) may lose

SUMMARY 4 Management of hypoglycaemia

19

• Check blood glucose to confirm hypoglycaemia and subsequent recovery • Mild episode (patient able to swallow): Oral carbohydrate (20g) • Severe episode (patient unconscious or uncooperative): Glucagon 1 mg i.m. or s.c. or Glucose 50 ml of 50% solution i.v. (use a large vein) Admit to hospital if recovery is not immediate

their perception of hypoglycaemic symptoms and suddenly develop neuroglycopenia (confusion, fitting, coma) without warning. Most long-standing patients also display blunted glucagon and noradrenaline responses to hypoglycaemia. Recent research has highlighted an important clinical message: a single episode of hypoglycaemia can itself delay the onset and blunt the severity of the autonomic warning symptoms; avoidance of hypoglycaemia can partly restore warning symptoms of hypoglycaemia. Diagnosis of hypoglycaemia. After a few episodes, most patients claim to be able to recognize hypoglycaemia. However, some tolerate very low glycaemia without symptoms. Insulin-treated patients must therefore be educated to check their blood glucose levels immediately if they feel unwell in any way, and their relatives should also be able to do this if the patient becomes confused or unconscious, or behaves atypically. Patients with possible nocturnal hypoglycaemia (see below) should test themselves during the night (especially at 1-\ am). Using test-strips, patients can diagnose hypoglycaemia quickly. Test-strip readings of <2.5 mmol/L on fingerprick samples require treatment. If severe features are present, treatment should be started immediately and levels checked as soon as possible afterwards, as they will remain low for some minutes. Management of hypoglycaemia. Because of the small but significant risks of cerebral damage and death, all episodes must be treated without delay. Most features, including fitting (which is often resistant to anticonvulsants) and coma, are rapidly reversible when glycaemia is normalized. Mild episodes, where the patient is conscious, cooperative and able to swallow safely, are treated with oral carbohydrate: 20-30 g should be taken initially (for example a glass of milk or 6 dextrose tablets), and again if the blood sugar has not started to rise after 10-15 minutes. Severe hypoglycaemia requires intravenous glucose (dextrose): 50mL of a 50% solution should be given over a minute into a large vein; small veins will be painfully thrombosed by the hypertonic solution. The patient may improve immediately, but the intravenous cannula should be left in place until glycaemic and clinical recovery are complete. An alternative is glucagon (Img; 0.5 mg in children), which mobilizes liver glycogen and acts within a few minutes after intravenous injection. Glucagon injected i.m. or s.c. produces recovery within 10-15 minutes. Prefilled syringes are available for emergency use outside hospital,

991

and the technique should be taught to the relatives of hypoglycaemia-prone patients. Patients should always carry easily swallowed carbohydrate, glucose test-strips and documentation that they are receiving insulin (e.g. a clinic or shared-care cooperation card, Medic Alert bracelet or necklace). All episodes should be recorded in the patient's self-monitoring diary and discussed with the diabetes care team. Injection-site problems Minor bleeding or bruising after injection sometimes worry the patient but are unimportant. Lipoatrophy (pitting of the skin due to loss of subcutaneous tissue) is apparently an allergic response to injected insulin and is uncommon with human insulin. Lipohypertrophy is local thickening of subcutaneous tissue, possibly due to the lipogenic and growth-promoting effects of high ambient insulin concentrations, which may form prominent lumps. Both conditions can be unsightly and may impair the absorption of insulin injected into lesions. They are more common at frequently used injection sites and can be avoided by using several sites in rotation. Insulin allergies Allergic reactions to insulin are now rare. Allergy can cause local inflammation, either acute or delayed. Anaphylaxis, mediated by IgE antibodies, is rare. Immune insulin resistance is due to absorbed insulin combining with IgG antibodies, forming large immune complexes which are cleared rapidly from the circulation by the reticuloendothelial system. Daily insulin requirements of several thousands of units have been recorded. Established insulin allergy may be circumvented by changing to an unrelated species of insulin (e.g. human, tunafish), and may respond to immunosuppressive drugs or desensitization with repeated small doses of the allergenic species. Specific problems with insulin treatment Starting insulin treatment If the patient is clinically well, insulin therapy can be started at home by the diabetes specialist nurse. The optimal regimen for an individual depends on the clinical

SUMMARY 5 Side-effects of insulin treatment • Hypoglycaemia • Injection-site lipoatrophy and lipohypertrophy • Allergies (rare with human insulin) local inflammation anaphylaxis immune insulin resistance

992

1

MCQ19.5

3

Figs 19.1-19.3

2

Case 19.1

situation, and discussion with the patient. Although some patients prefer to start with the flexibility of a basal-bolus regimen, good control can often be achieved with a simpler regimen of twice-daily injections, taken as approximately two-thirds of the daily dose in the morning before breakfast and the remaining one-third before the evening meal. Initial doses should be low (e.g. 8-12 U) to avoid severe hypoglycaemia, which can demoralize the newly presenting patient. Except for young children, the elderly and the partially sighted, patients should be encouraged to give their own injections as soon as possible. After starting insulin treatment, many patients with type 1 diabetes enjoy a period of high-quality glycaemic control, achieved relatively easily with low insulin requirements; dosages may fall to a few units per day, and very rare patients can manage without insulin. This 'honeymoon period' is due to the transient recovery of insulin secretion following correction of hyperglycaemia. This ultimately ends because remaining (5 cells are destroyed by continuing autoimmune processes. Both the 'honeymoon period' and its end have to be anticipated and explained to the patient, because failure to reduce insulin dosages can cause hypoglycaemia, and at the end, worsening control and increasing dosages can be dispiriting. Once residual insulin secretion is lost, the average daily insulin requirements for type 1 patients are usually about 0.7-0.8 U/kg/day, but this will vary according to the age, sex, weight and fitness of the patient. Poor glycaemic control overnight Many type 1 diabetes patients have fasting early-morning hyperglycaemia, sometimes preceded by nocturnal hypoglycaemia. The 'dawn phenomenon' is a rise in glycaemia during the 2-4 hours before waking. It is apparently due to delayed insulin insensitivity of the tissues, caused by surges of growth hormone secreted after falling asleep, which are accentuated in type 1 diabetes. Rebound hyperglycaemia may also occur after hypoglycaemia and is attributed to discharge of counter-regulatory hormones, but is probably unimportant in clinical management; a much commoner cause of 'rebound' hyperglycaemia is taking too much carbohydrate to treat a hypoglycaemic episode. Nocturnal hypoglycaemia followed by fasting hyperglycaemia is often due to the time-course of prolonged-action insulin. When injected in the early evening its hypoglycaemic action often peaks at 2-^ am, but fades thereafter. Simply increasing the evening dose of long-acting insulin may worsen nocturnal hypoglycaemia; the insulin does not last longer and so fasting hyperglycaemia may not improve. Both problems can be improved by delaying the evening injection of long-acting insulin until just before bedtime, so that its peak hypoglycaemic effect is postponed and helps to cancel out the hyperglycaemia of the dawn phenomenon. This regimen requires an extra injection, as shortacting insulin is still needed to cover the evening meal. Erratic control and 'brittle' diabetes Few patients enjoy continuously good glycaemic control. This is not surprising, as subcutaneous insulin absorption

is extremely variable, both between and within individuals, and because the short-acting preparations act too slowly and for too long, whereas long-acting insulins do not last long enough (Table 19.3). Patients whose metabolic control is so unstable as to prevent them from living a normal lifestyle (so-called 'brittle' diabetes) are, fortunately, rare. Unpredictable glycaemic swings are sometimes due to intercurrent infection, endocrine disease (e.g. hypopituitarism) and poor education or treatment regimens. When identifiable causes are excluded, most of the remaining patients are young women who are typically obese and apparently have high insulin requirements. They suffer recurrent ketoacidosis and/or hypoglycaemia. The causes of brittleness in these patients are unknown, but some deliberately manipulate their own treatment (e.g. by omitting insulin) to induce poor control. Management can be extremely difficult. They should be admitted to exclude known causes of unstable control and for intensive education and evaluation of control while following a strictly supervised intensive regimen. Continuous subcutaneous insulin infusion (CSII) may be useful in some patients with recurrent hypoglycaemia and/or recurrent ketoacidosis. Sympathetic counselling and psychotherapy Sympathetic psychotherapyofofthe thepatient patient

and her family may also help. 1 2

Insulin resistance

Most type 1 diabetes patients need less than 1 U/kg/day of insulin, but obese patients with type 2 diabetes are insulin insensitive and often need more. Clinical insulin resistance has been arbitrarily defined as a daily requirement of >200 U. Causes include excess counter-regulatory hormones (e.g. in septicaemia and glucocorticoid treatment), immune resistance due to insulin antibodies, and defects of the insulin receptor or postreceptor sites. The latter are either inherited (type A syndromes) or acquired (type B syndromes, due to autoantibodies to the receptor). Both syndromes are associated with acanthosis nigricans. 3 Intercurrent illness The stress of intercurrent illness stimulates the secretion of counter-regulatory hormones. Basal insulin requirements therefore increase and the total daily insulin dosage will tend to rise, even if the patient is unable or unwilling to eat. Failure to increase the insulin dosage therefore causes hyperglycaemia and ketoacidosis. Some patients reduce or even stop their insulin when they fall ill, mainly because they fear hypoglycaemia while not eating normally. This basic mistake, all too often endorsed by doctors, still causes avoidable deaths in the UK each year. Vomiting is particularly worrying, as it may herald ketoacidosis. Patients must be given clear rules stating what to do if they become ill (see Summary 6). Exercise Regular exercise should be part of the diabetic person's normal lifestyle. Exercise increases glucose uptake into muscle, so favouring hypoglycaemia. Insulin-treated patients can help to avoid hypoglycaemia by reducing

SUMMARY 6 'Sick-day rules'

19

• Increase monitoring and test for ketones. • NEVER stop insulin. • Call doctor if vomiting or ketonuria occurs.

TABLE 19.4 Current dietary recommendations for diabetic patients Carbohydrate: 50-55% of total calories

Choose complex carbohydrates (starchy foods) Avoid foods and drinks sweetened with sucrose or glucose Fat: 30-35% of total calories

Choose poly- or monounsaturated fats (vegetable oils) Avoid animal fats, dairy products and cholesterol-rich foods (eggs, fatty meats) Avoid fried foods Protein: 10-15% of total calories

Choose fish or vegetable protein (e.g. pulses)

Dietary fibre Increase intake of vegetables, bran, pulses, etc. Sweeteners Avoid 'diabetic' foods (which contain sorbitol or fructose) Aspartame is an acceptable calorie-free sweetener Salt: <6g/day (<3g/day if hypertensive) This is not a 'diabetic' diet, but a guide to healthy eating suitable for the general population.

insulin dosages before exercise, by checking blood glucose levels before and at intervals during exercise, and by taking carbohydrate (e.g. a small chocolate bar) if the blood glucose is <5 mmol/L. They must be told that delayed hypoglycaemia may occur up to a day after strenuous exertion. Dietary advice for patients with type 1 diabetes Food eaten by type 1 diabetes patients must balance insulin injections and exercise so as to limit both hyper- and hypoglycaemia. Total calorie requirements. These can be calculated from a person's sex, body weight and level of activity. Most patients with type 1 diabetes are not obese and calorie restriction is not needed, although it is in type 2 diabetes. Indeed, some type 1 diabetes patients with marked weight loss may need to increase their energy intake. Dietary composition. Advice for diabetic patients has changed radically in recent years. Current recommendations are essentially those for the general population (Table 19.4). Choosing foods from which the carbohydrate is absorbed more slowly ('low glycaemic index'), such as pulses, rye bread and pasta, may have beneficial effects

993

on postprandial glucose levels. The traditional 'diabetic diet', low in all types of carbohydrate and with a relatively high fat content, may have predisposed to macrovascular disease and is no longer recommended. Timing and size of meals. Meals must be coordinated with insulin injections and exercise. Twice-daily injection regimens fit best with a larger breakfast and evening meal, a small lunch, and snacks at mid-morning and bedtime. At present, judging insulin doses to cover meals is a matter of trial and error rather than a science. Hyperlipidaemic patients should reduce their fat intake, and hypertensive patients their salt. A low-protein diet may slow the progression of diabetic nephropathy. Diabetic education ana1 lifestyle changes The diabetic patient has to live with the disease every day and cope with treatment and self-monitoring procedures that many doctors and nurses do not fully understand. Careful education about diabetes, which generally is best provided by the diabetes specialist nurse, can greatly improve diabetic control and quality of life. Newly diagnosed patients need to learn a great deal, and every patient's understanding of diabetes should be checked and reinforced whenever possible. Some key points are: • Causes and effects of hyper- and hypoglycaemia; • Treatment: doses of insulin or tablets; injection technique; diet; • Monitoring: techniques; targets; how to respond to poor control; • 'Sick-day rules': when and how to call for help (Summary 6), General suggestions for healthy living apply particularly to diabetic patients. Stopping smoking reduces the risks of macrovascular disease and probably of nephropathy and retinopathy. Alcohol, which is both a source of 'invisible' calories and a cause of hypoglycaemia, should be limited to 21 units/week in men and 14 units/week in women, and less in hypertensive patients. Regular exercise should be advised. There are no employment restrictions on patients not receiving insulin and without complications, but because of the risk of hypoglycaemia, insulin treatment is a bar to joining the armed, police or fire-fighting forces and to driving public-service or medium-/heavy-goods vehicles. Insulintreated patients must inform the driving licence authorities and their insurance companies, and may need medical confirmation of fitness to drive. Special life insurance policies are available. Membership of a patient organization such as Diabetes UK (previously the British Diabetic Association (BDA)) may provide valuable support.

994

Pancreas and islet transplantation Segments of whole pancreas can be transplanted, with the exocrine ducts either occluded or drained into the bladder to prevent release of harmful enzymes into the peritoneal cavity. At present, however, pancreas transplants require

RECENT ADVANCES FUTURE TREATMENTS FOR TYPE 1 DIABETES Modified insulins. The use of monomeric short-acting insulin has rapidly gained acceptance in clinical practice, and the race is now on to develop a true 'basal' insulin, with a full 24-hour duration of action. The search is also continuing for alternative modes of insulin delivery, the latest idea being an 'inhaler' that delivers insulin via the lungs. Transplant of encapsulated islets. At present islet and pancreas transplantation require immunosuppression. However, it might be possible to encapsulate islets with a special semipermeable membrane; this would allow the entry of glucose and other insulin secretagogues and the exit of insulin, while preventing immunological attack. An alternative would be to genetically modify the patients' own fibroblasts to produce insulin in response to glucose. immunosuppression and so are generally performed in patients undergoing renal transplantation, who will receive long-term immunosuppressive therapy. The best results indicate that insulin dosage can be reduced, and in some cases withdrawn, for many months and even years. Successful islet transplantation has recently been reported in a few patients, with injection of isolated and purified islets into the liver via the portal vein, using a novel immunosuppressive regimen to prevent rejection, but it remains to be seen whether this approach will be widely adopted.

TYPE 2 DIABETES MELLITUS Ninety percent of British diabetic patients have type 2 diabetes. This is often incorrectly described as 'mild' diabetes, but these patients are nevertheless susceptible to chronic diabetic complications and most die prematurely, mainly from myocardial infarction. Type 2 diabetes is a common disease in well-fed societies, affecting perhaps 14% of Britons and North Americans over 70 years of age. There is a striking geographical and racial variation, which is totally different from that in type 1 diabetes. Type 2 diabetes is several times commoner in Asian immigrants to the UK than in the indigenous British population, and the highest recorded prevalence is in the Pima Indians of Arizona, of whom 50% are affected. Except for MODY (maturity onset diabetes of the young), most patients are over 40 years of age at presentation, and males predominate. There is, however, a worrying trend of type 2 diabetes occurring more commonly in younger patients, owing mainly to the rising prevalence of obesity.

Aetiology and pathogenesis Type 2 diabetes appears to be due to two separate defects - insensitivity of the tissues to insulin and defective insulin

Insulin resistance is associated with a constellation of metabolic abnormalities and conditions, including hypertension, obesity, dyslipidaemia, hyperuricaemia and diabetes (syndrome X). The mechanisms underlying these associations are poorly understood; possible mechanisms suggested by experimental data in animals and humans include increased activity of the sympathetic nervous system, induction of insulin resistance by the fat-derived cytokine tumour necrosis factor-a, and the fat-derived hormone leptin.

FIG. 19.15 Pathogenesis of type 2 diabetes mellitus Type 2 diabetes is associated with insulin resistance, obesity and defective insulin secretion. Various genetic and environmental factors may be involved. Hyperglycaemia may exacerbate the impaired insulin action and secretion (glucose toxicity). Eventually, impaired glucose tolerance (IGT) and, later, overt diabetes develop.

secretion - both of which may be partly inherited (Fig. 19.15). Genetic factors The concordance rate for type 2 diabetes in identical twins exceeds 90%. Inheritance appears to be polygenic, except in MODY (maturity onset diabetes of the young) and certain other families, where type 2 diabetes is transmitted as an autosomal dominant. About 20% of patients with MODY have a defect in the enzyme glucokinase, resulting in alteration of the 'set point' of insulin secretion in response to glucose. Two other genes for MODY have been identified, namely, those encoding transcription factors called hepatic nuclear factors (HNF) la and 4oc; this indicates that MODY is a heterogeneous condition. Despite intense research, no genetic markers have been found for the more common forms of type 2 diabetes. Insulin resistance This signifies the inability of insulin at physiological concentrations to exert its normal metabolic actions. Investigation shows that insulin's action is reduced by about 40% in type 2 diabetes. Liver, skeletal muscle and fat are all insensitive, so that increased hepatic glucose output and reduced peripheral uptake both contribute to hyperglycaemia (Fig. 19.15). The defect(s) causing insensitivity to insulin are unknown and apparently lie beyond its receptor. Possible contributory factors include obesity (which is strongly associated with type 2 diabetes), an inherited predisposition, and increased glucagon levels; hyperglycaemia itself also reduces insulin sensitivity ('glucose toxicity').

19

Defective insulin secretion Resting insulin levels, measured by conventional insulin radioimmunoassay, may be normal, high or low in patients with type 2 diabetes. Some of this 'insulin' immunoreactivity is now known to represent biologically inert cleavage products of proinsulin, which cross-react in the assay. True insulin levels (measured by a highly specific assay) are subnormal in many type 2 diabetes subjects. Furthermore, non-diabetic people exposed to hyperglycaemia would respond with far higher insulin levels than occur in type 2 diabetes, confirming that patients with type 2 diabetes are relatively insulin deficient. In addition, the spontaneous pulses and the first phase of insulin secretion are absent in type 2 diabetes. The cause is unknown. (3-cell numbers are reduced, but there are no signs of autoimmune damage. The islets become infiltrated with amyloid deposits containing a peptide named amylin, or islet amyloid polypeptide. Amylin is synthesized by the |3 cells, but its possible aetiological role in type 2 diabetes remains uncertain. Hyperglycaemia per se may also impair insulin secretion ('glucose toxicity'; Fig. 19.15). Recent epidemiological research has suggested a relationship between low birthweight and the prevalence of type 2 diabetes. It is possible that factors involved in intrauterine nutrition may either impair p-cell reserve or result in insulin resistance, but the precise mechanisms are not known. Biochemical abnormalities There is hyperglycaemia, but enough insulin secretion remains to prevent lipolysis. Spontaneous ketosis and ketoacidosis therefore do not occur, even in extreme hyperglycaemia (hyperosmolar, non-ketotic coma). Clinical features of type 2 diabetes Two-thirds of type 2 diabetes patients in the UK are obese. At diagnosis, hyperglycaemic symptoms (polyuria, thirst, polydipsia) have usually been present for months or even years. An acute presentation and sudden marked weight loss are unusual but may occur, especially with intercurrent illness, the introduction of diabetogenic drugs or carcinoma of the pancreas, which is associated with type 2 diabetes in older people. Women often have troublesome pruritus vulvae due to candidiasis. Type 2 diabetes often has a long subclinical course and many asymptomatic patients are diagnosed incidentally when screened routinely for glycosuria or hyperglycaemia.

995

RECENT ADVANCES THE UKPDS STUDY The UKPDS study was the largest study ever conducted into type 2 diabetes, including nearly 4000 patients studied for an average of 10 years. It showed that good control of blood glucose (HbAlc of 7%, compared with 7.9%) was effective at reducing the risk of microvascular complications of diabetes (25% risk reduction), and that using insulin or sulphonylureas as primary therapy did not affect outcome. A cohort of obese subjects were treated with metformin, and both microvascular and macrovascular disease were reduced in this group. The study also highlighted the progressive nature of type 2 diabetes, and the problems of weight gain and hypoglycaemia with sulphonylureas and insulin, but not with metformin. A blood pressure control study was later embedded into the UKPDS study design. This showed that tight control of blood pressure (mean 144/82 vs 154/87) with either captopril or atenolol significantly reduced both micro- and macrovascular complications of diabetes. The effects of blood glucose and blood pressure control are additive, and the benefits occur at all levels of HbAlc.

Others present with chronic diabetic complications, such as myocardial infarction, retinopathy (especially maculopathy), or foot ulceration. It has recently become clear that type 2 diabetes is a progressive disease, with early insulin resistance, often associated with obesity and physical inactivity, moving on to impaired glucose tolerance, through to predominantly insulin-resistant type 2 diabetes. There is a progressive failure of (3-cell function, and ultimately a requirement for insulin in many patients. It is important to remember that the condition is very heterogenous and progression can occur at different rates; some patients may never require insulin, whereas others (particularly lean patients) need insulin early in the course of the disease. There is evidence that some patients with apparently typical type 2 diabetes (either lean or obese) have islet-cell autoantibodies and other markers of autoimmune diabetes and may in fact have a late-onset, slowly evolving form of type 1 diabetes. Maturity onset diabetes of the young (MODY) By definition, MODY presents in patients under 25 years of age, who do not need insulin for at least 5 years. MODY is transmitted as an autosomal dominant trait. Hyperglycaemia may be mild, particularly in glucokinase-deficient MODY, and some affected families appear to be relatively protected from chronic diabetic complications; however, MODY should not be considered a benign disease, as severe complications may develop.

1

996

MCQ19.6

FIG. 19.16 Flow-chart for treating type 2 diabetes Glycaemic targets are shown in Table 19.5.

Type 2 diabetes is diagnosed and distinguished from type 1 diabetes as described on page 984 and in Table 19.2.

Management of type 2 diabetes Type 2 diabetes is often harder to treat effectively than type 1 diabetes. Diet is usually described as the 'cornerstone' of management, but unfortunately few patients are able to follow dietary advice in the long term, and the progressive nature of the disease often supervenes; in the recently reported United Kingdom Prospective Diabetes Study (UKPDS) only 5% of patients were able to maintain good control on diet alone for more than a few months. Oral hypoglycaemic agents, including metformin, sulphonylureas, acarbose, and perhaps thiazolidenediones, may be effective initially, but there is a progressive need to increase the dose and add-in a second or even a third agent. Eventually, insulin treatment is often needed, but this introduces its own problems. A flow-chart for treating type 2 diabetes is shown in Figure 19.16.

The importance of glycaemic control The UKPDS study has now demonstrated that there is a clear relationship between long-term metabolic control

and the microvascular complications of type 2 diabetes. Despite the limitations of many treatments, early and effective use of lifestyle measures, oral hypoglycaemic drugs and insulin is likely to improve long-term outcome. Careful attention should also be paid to other risk factors, particularly hypertension. Diet and general lifestyle changes All type 2 diabetes patients should eat a 'healthy' diet (Table 19.4) and obese patients will also need to reduce their total intake of calories, especially of fat. This often causes an acute fall in blood glucose levels, with symptomatic improvement; continued weight loss will produce a sustained reduction, and even normalization, of glycaemia. An acceptable rate of weight loss is about 0.5-1 kg per week, which corresponds to an energy deficit of at least 500 kcal/day. Weight loss, especially if combined with exercise, increases insulin sensitivity and also improves hyperlipidaemia and hypertension. Timing and distribution of meals are not critical in patients who are not taking insulin or sulphonylureas, as hypoglycaemia does not occur. A sympathetic dietitian, possibly reinforced by a slimming club, stands the best chance of success. Very lowcalorie diets (<700kcal/day), which are very expensive, and weight-reducing drugs such as orlistat or sibutramine may be helpful in some cases. Weight-reducing diets must be given an adequate trial of 1-3 months, but less than 20% of type 2 diabetes patients will achieve either their target weight or acceptable glycaemic control (Table 19.5). The rest, given the gloomy label of 'dietary failures', need oral hypoglycaemic agents or insulin. 1

It is essential to attempt to diminish the risk factors for cardiovascular disease, which is the main cause of pre-

TABLE 19.5 Targets for diabetic control Ideal Blood glucose (mmol/L) Fasting Postprandial

4.4-6.7 4.4-8.9

Glycosylated haemoglobin (%) **(HbA1c) (with normal range of 3.5-5.5%)

<7%

Other targets Few hypoglycaemic episodes Body mass index <25* Normal plasma lipid concentrations Normal growth (in children) No diabetic complications Normal lifespan

ultimate aims

* Body mass index = weight (kg)/height (m)2. ** Depends on local reference range.

Acceptable

<7.8 <10.0

7-8%

mature death in type 2 diabetes (see Fig. 19.29). General measures include stopping smoking, moderating alcohol intake, taking regular exercise and controlling hyperlipidaemia and hypertension. Monitoring of type 2 diabetes is generally assessed from HbA1c supplemented by the patient's own once- or twice-weekly fasting glucose levels, although insulin-treated patients will need to test more frequently (p. 1000).

19

Oral hypoglycaemic agents The major oral hypoglycaemic agents (Table 19.6) are the sulphonylureas, metformin and acarbose. Thiazolidenediones (e.g. rosiglitazone, pioglitazone) have recently been introduced have been found to be effective when combined with either sulphonylureas or metformin. Other drugs with minor hypoglycaemic effects include soluble vegetable fibres such as guar, which interfere with intestinal glucose absorption. Sulphonylureas These are derivatives of sulphonamides. 'First-generation' drugs include chlorpropamide and tolbutamide, and the newer 'second-generation' compounds include glibenclamide, gliclazide and glipizide (Table 19.6). Secondgeneration sulphonylureas are more potent, but seem to have few other specific advantages. Mechanism of action and pharmacology. Sulphonylureas act primarily as insulin secretagogues (see Fig. 19.4). They restore the missing first phase of insulin release and enhance basal and prandial insulin secretion. As sulphonylureas depend on releasing endogenous insulin they are ineffective in insulin-deficient type 1 diabetes patients. Sulphonylureas may exert an additional 'extrapancreatic' action by slightly enhancing insulin sensitivity. Overall, sulphonylureas reduce fasting and postprandial glycaemia by about 25% in moderately hyperglycaemic patients, but usually have little effect if fasting glycaemia exceeds 14 mmol/L. They are ineffective at the outset in 5% of type 2 diabetes patients, and subsequently fail in many of those who respond initially; poor compliance with treatment or progressive deterioration ('exhaustion') of (3 cells may be responsible. Most sulphonylureas are cleared through the kidneys, although glipizide is metabolized in the liver. Chlorpropamide has a very long plasma half-life (36 hours) and glibenclamide has prolonged biological effects which outlast its survival in the circulation. These long-acting drugs are taken once daily. Neither should be used in patients with renal impairment. The others, especially the very short-acting tolbutamide and glipizide, are usually taken before breakfast and the evening meal. Newer insulin secretagogues Two new drugs, glimepiride and repaglinide, have recently become available. These are chemically and pharmacologically distinct from the sulphonylureas, although their action in inducing insulin secretion through stimulation of the glucose-potassium ATPase on the (3 cell is similar, and they have comparable efficacy and side-effects, apart from

997

TABLE 19,6 Oral hypoglycaemic agents Drug

Dosage schedule

Comments

Chlorpropamide

250-500 mgo.d.

Tolbutamide

500 mgb.d.,t.d.s.

Hypoglycaemia +++ (long half-life) Avoid in elderly and in renal failure Alcohol-induced flushing Acceptable in mild renal impairment

Glibenclamide

2.5-1 5 mg o.d.

Gliclazide Glipizide

40-1 60 mgo.d., b.d. 2.5-15 mg o.d., b.d.

Biguanide

Metformin

500-850 mg b.d. , t.d.s.

Contraindicated in renal, hepatic, cardiac or respiratory failures Does not cause hypoglycaemia

a-Glucosidase inhibitor

Acarbose

50-100mg t.d.s.

Start at low dose (Gl side-effects) Does not cause hypoglycaemia Not absorbed systemically

Rosiglitazone

4-8 mg o.d.

Pioglitazone

15-30 mgo.d.

Can be used in combination with sulphonylureas or metformin Contraindicated with insulin; liver enzymes should be monitored Can be used in renal impairment

First-generation sulphonylureas

Second-generation sulphonylureas

Thiazolidinediones

a lower incidence of hypoglycaemia. Glimepiride is long-acting and can therefore be given as a single daily dose. In contrast, repaglinide is very short-acting, with a rapid onset of action, and may be particularly useful at controlling postprandial hyperglycaemia. Adverse effects of sulphonylureas • Hypoglycaemia is the main hazard, especially with the long-acting drugs in renal failure (when they accumulate) and in older people. Chlorpropamide and glibenclamide must therefore be avoided in patients over 60 years of age, and in renal failure. The short-acting agents are relatively safer in mild renal impairment but patients with nephropathy should be transferred to insulin when serum creatinine concentration rises above 250 |imol/L. • Weight gain further reduces insulin sensitivity and damages morale. It is probably due to the lipogenic effects of increased insulin levels, perhaps with relaxed dietary compliance in some cases. • Allergic skin rashes are unusual. Alcohol-induced facial flushing is an idiosyncratic reaction in patients taking Chlorpropamide. Rarer side-effects include water retention and hyponatraemia owing to potentiation of ADH action and blood dyscrasias. Their hypoglycaemic effects are potentiated by drugs such as the sulphonamides, cotrimoxazole, fibrates, salicylates and probenecid, which compete for binding to plasma proteins and reduce the clearance of sulphonylureas. 0MCQ19.7

998

2

Case 19.2

Hypoglycaemia +++ (long biological action) Avoid in elderly or in renal failure Acceptable in mild renal impairment Acceptable in mild renal impairment

Clinical use of sulphonylureas. They are indicated in type 2 diabetes if hyperglycaemia persists after a trial of dietary treatment (usually 3 months). They are used particularly in non-obese patients. Obese subjects may benefit more from metformin, which does not cause weight gain. In general, sulphonylureas will reduce HbAic by about 1 %. Sulphonylureas are Contraindicated in type 1 diabetes (C-peptide-negative) patients, or in type 2 diabetes patients during intercurrent illness or surgery, because insulin is required. Metformin Metformin (Table 19.6) reduces hyperglycaemia by stimulating glucose uptake into peripheral tissues and by inhibiting gluconeogenesis in the liver. It does not stimulate insulin secretion and so does not cause hypoglycaemia in normoglycaemic subjects. Metformin reduces glycaemia by a similar degree to the sulphonylureas, but is less likely to be effective if fasting glycaemia exceeds 14mmol/L. Adverse effects of metformin • Lactic acidosis. Blocking lactate utilzation through gluconeogenesis inevitably causes lactate accumulation. Lactic acidosis occurs rarely with metformin, except in the 'organ failures', which either increase lactate production or prevent its utilization (p. 1007). • Gastrointestinal symptoms - notably bloating, nausea, dyspepsia and diarrhoea - are common; anorexia may help to prevent weight gain during metformin treatment. Metformin impairs vitamin Eu absorption and occasionally causes a megaloblastic anaemia.

Clinical use of metformin. Metformin is indicated in patients who fail to respond to diet, either alone or together with a sulphonylurea, especially if obese. It is contraindicated in renal, hepatic, cardiac and respiratory failures because the risks of lactic acidosis are greatly increased. It is also contraindicated in insulin-deficient patients, although some recent studies have suggested that combination therapy with metformin may be useful in some obese type 2 diabetic patients who require insulin. This may be done conveniently by giving night-time NPH with metformin continued at conventional doses during the day. There is good evidence that lower insulin doses are needed with this regimen, which is associated with less weight gain. Acarbose Acarbose is an oc-glucosidase inhibitor and acts at the intestinal brush border by preventing breakdown of polysaccharides. Its main effect is therefore to reduce postprandial hyperglycaemia, and reductions of HbA1c have been reported in clinical trials. The main side-effects are gastrointestinal distubance with borborygmi and diarrhoea, caused by fermentation of unabsorbed sugars in the large intestine. These can be limited by gradual introduction of the drug over several weeks. It may be used in patients who have failed to respond to diet, but is usually reserved for those who are intolerant of, or have poor responses to, the other agents.

RECENT ADVANCES FUTURE TREATMENTS FOR TYPE 2 DIABETES Although the fundamental defects causing type 2 diabetes remain unknown, several agents that have beneficial effects on both insulin sensitivity and insulin secretion are under development. Insulin sensitizers. The thiazolidinediones have recently been introduced into clinical practice, but a range of compounds with similar actions are being investigated. These include agents that are agonists at the peroxisome proliferator-activated receptor (PPAR) a and y, combining the beneficial effects of fibrates (PPAR-a agonists) with the thiazolidenedione effects. Incretin hormones. Glucagon-like peptide 1 (7-36) amide (p. 979) is a powerful stimulus to insulin secretion and also delays gastric emptying. Preliminary studies suggest it may normalize fasting and mealrelated hyperglycaemia in type 2 diabetes, and the development of orally acting analogues is awaited. Anti-obesity drugs. Obesity is a major factor in the development of type 2 diabetes, and several agents that may be of benefit are being investigated. These include centrally acting appetite suppressants such as sibutramine, pVadrenergic agonists (which increase metabolic rate), and orlistat, which impairs digestion of fat by blocking the actions of intestinal lipases.

Thiazolidinediones This is a new class of drugs that are agonists at the peroxisome proliferator-activated receptor (PPAR)-y. They act as insulin sensitizers, and are effective at reducing HbAic by about 1 % when used as monotherapy, or in combination with sulphonylureas, metformin or insulin. Currently only combinations with sulphonylureas or metformin are licensed in Europe. Side-effects include weight gain and a small degree of fluid retention. Deranged liver function and, very rarely, fulminant hepatic failure have been reported with troglitazone, but not with other drugs in this class. Hypoglycemia does not occur, although the action of insulin or sulphonylureas may be potentiated. 1

19

Insulin treatment in type 2 diabetes Diet combined with one or both types of oral agent will only achieve satisfactory long-term control (Table 19.5) in 50% of patients with fasting glycaemia of <10mmol/L, and in few with higher glucose levels. Insulin is needed in patients with unacceptable hyperglycaemia or features of insulin deficiency (weight loss and spontaneous ketonuria). Many type 2 diabetes patients will be satisfactorily controlled by a single daily injection of ultralente or isophane insulin, as their remaining insulin secretion can cover mealtime requirements, but those with worsening insulin deficiency (low C-peptide levels) may ultimately need multiple injections, as for type 1 diabetes. Insulin treatment often causes weight gain, which further aggravates insulin insensitivity and increases insulin requirements, but the risks of hyperglycaemia probably outweigh those of obesity. Combination of insulin with metformin may be helpful in some cases. ©

IMPAIRED GLUCOSE TOLERANCE (IGT) This diagnostic category defines subjects whose blood glucose concentration lies between normality and diabetes, i.e. between 7.8 and 11 .Ommol/L 2 hours after a 75 g OGTT (p. 984 and Fig. 19.11). IGT is asymptomatic but must be distinguished from normal because long-term follow-up studies indicate that these subjects carry a considerably increased risk of cardiovascular disease (not microvascular disease, which only develops with truly diabetic glucose levels; see p. 1006). Many are obese and display the hyperinsulinaemia, insulin insensitivity, hypertension and hyperlipidaemia that strongly predict cardiovascular disease (see p. 1015). After 10 years most IGT subjects will remain in this category, but 25% will revert to normal and 25% progress to type 2 diabetes. IGT has no specific management, but diabetogenic drugs (e.g. thiazides) should be withdrawn if possible and the patient strongly encouraged to lose weight (which tends to normalize glucose tolerance), stop smoking and reduce other cardiovascular risk factors. Patients and their blood glucose levels should be reviewed annually, and the OGTT repeated if circumstances change.

999

SECONDARY DIABETES MELLITUS Malnutrition-related diabetes mellitus (MRDM). Malnutrition is associated with pancreatic damage (particularly stone formation) and diabetes, although it is not clear whether this represents a distinct disease entity. MRDM is reported from many developing countries, but even there seems to account for a minority of cases of diabetes. It has been subdivided into: • Fibrocalculous pancreatic diabetes with chronic pancreatitis, causing recurrent abdominal pain, large pancreatic calculi (easily visible on plain radiography or ultrasound scanning) and steatorrhoea; and the less clearly denned • Protein-deficient pancreatic diabetes (PDPD) Both affect young adults, who usually need insulin, sometimes in large doses in PDPD, but ketosis is rare. Pancreatic disease. Diabetes may be caused by chronic pancreatitis, usually due to ethanol abuse. Haemochromatosis causes diabetes, cirrhosis and, occasionally, bronzing of the skin owing to iron deposition in the islets, hepatocytes and dermis. Carcinoma of the pancreas is associated with type 2 diabetes in older people. Endocrine diseases causing diabetes are acromegaly (60% of patients have IGT or diabetes), Cushing's syndrome (including iatrogenic causes), phaeochromocytoma and the very rare glucagonoma. These conditions produce excessive counter-regulatory hormones, whereas Conn's syndrome may cause IGT and sometimes diabetes through potassium depletion, which impairs insulin secretion. Gestational diabetes is described on page 1003. Diabetogenic drugs include the glucocorticoids, pY adrenergic agents (e.g. salbutamol or ritodrine) given intravenously, thiazide diuretics (which cause potassium depletion) and diazoxide (which blocks insulin release directly). Other rare conditions associated with diabetes include the DIDMOAD syndrome (diabetes insipidus, diabetes mellitus, optic atrophy and deafness), myotonic dystrophy and haemochromatosis; see pp. 1404 and 868. Lipoatrophic diabetes (with partial or total loss of subcutaneous fat) and 'leprechaunism' are due to insulin receptor defects. Mitochondrial gene defects may result in diabetes with a maternal pattern of inheritance.

ASSESSING DIABETIC CONTROL Diabetic treatment aims to keep glycaemia close to normal, to avoid the acute and long-term complications. Various measures for immediate and medium-term glycaemic control are available (Table 19.5). 1 1000

MCQ19.8

Blood glucose monitoring The development of test-strips suitable for self-monitoring of blood glucose levels has revolutionized diabetes management. Most test-strips (e.g. BM sticks and Glucostix) contain glucose oxidase and a dye that reacts with the hydrogen peroxide generated by the oxidation of glucose in the blood sample. The colour developed can be read either visually against a colour chart, or electronically by a reflectance meter. Newer 'sticks' measure glucose oxidation electrically. Blood is usually obtained from the sides of the pulp of the finger and not the tip (which is a sensory organ), using various lancet devices. A generous drop is lowered carefully on to the reagent area, which must be covered completely, left in contact for exactly the reaction period stipulated, and then wiped off. The colour is allowed to develop for the correct time before reading. Inaccurate readings (sometimes dangerously misleading) are common in patients' own records and on ward charts. All doctors and nurses and all insulin-treated patients must be able to measure blood glucose with test-strips; the equipment, and the patient's technique and ability to interpret the results should be checked regularly. For type 1 diabetes patients taking twice-daily insulin or on intensified regimens the key time-points for testing are before breakfast (when levels are determined by the previous evening's long-acting dose), before lunch and before the evening meal (determined by the morning's dose), and before bed (influenced by the evening's dose). Generally, readings can be made at different time-points on different days, so that a pattern is built up. Patients should test whenever they feel unwell, and during the night if nocturnal hypoglycaemia is suspected (p. 992). Prandial doses of soluble insulin can be adjusted from the glucose level 90-120 minutes after eating. In type 2 diabetes patients treated with oral agents and diet, occasional fasting values are a useful index of control.

Urinalysis for glucose and ketones Urinalysis for glucose (using glucose oxidase test-strips) is inconvenient and usually unhelpful, as it reflects the average glycaemia above the renal threshold (which can lie anywhere between 7 and 13 mmol/L) since the bladder was last emptied. A crucial failing is that normo- and hypoglycaemia cannot be distinguished. Urinary glucose measurements are acceptable only in rare patients who cannot be persuaded to prick their fingers, and in type 2 diabetes patients with a normal renal threshold who are not receiving insulin and who are not subject to hypoglycaemia. Urinary ketone measurements provide useful warning of ketoacidosis and can be useful during intercurrent illness.

Glycosylated haemoglobin and fructosamine Valine residues on the (3 chain of the adult haemoglobin (HbA) molecule can react with glucose, and the result-

ing glycosylated haemoglobin (designated HbA t ) can be separated from native HbA and measured by electrophoresis. HbA! can be further resolved into subcomponents, of which HbAlc is the most stable and clinically useful. The proportion of HbA that is glycosylated depends on its total exposure to glucose and is proportional to the average glycaemia during the half-life of the red blood cell, i.e. the preceding 6-8 weeks. Non-diabetic HbA lc values are about 3.5-5.5% of total HbA; well and poorly controlled diabetic values are about 6-7% and >8%, respectively. HbAic measurements are a useful index of medium-term glycaemic control, but are invalidated if red-cell turnover is disturbed or if abnormally migrating Hb variants are present. One problem with HbAlc measurement is the wide variety of techniques available for measuring it, with the effect that results are rarely directly comparable between laboratories. Fortunately, the two major trials of diabetes control and complications, the DCCT and the UKPDS, used the same technique, and many laboratories are now moving over to report 'DCCT-aligned' HbAlc results. Serum albumin is also glycosylated and can be measured by the 'fructosamine' reaction. Albumin turns over faster than HbAlc and indicates mean glycaemia during the previous 1-2 weeks. Current assays are cheaper, but less reliable and reproducible, than those for HbAlc.1

ORGANIZATION AND DELIVERY OF DIABETES CARE The development of the diabetes care team, consisting primarily of doctors, specialist diabetes nurses, dietitian and chiropodist, has greatly improved efficiency by allowing effective division of labour. The diabetes specialist nurse is especially important, for educating patients about diabetes and for starting and adjusting treatment. Other specialists, e.g. ophthalmologist, vascular surgeon and obstetrician, should be readily available for referral, and combined clinics, such as for diabetic foot problems, are particularly useful. 'Shared-care' schemes, which involve both the general practice and the hospital team in looking after the patient, are becoming popular, as are community 'miniclinics'. However care is organized, all diabetic patients must be thoroughly reviewed annually, primarily to screen for complications (Table 19.7), and must have easy access to expert help.

INTERCURRENT EVENTS AND DIABETES Infection It is widely held that diabetic patients are generally more susceptible to infection than the non-diabetic population. Diabetic patients are more likely to suffer infections with certain atypical or unusual organisms. These include

TABLE 19.7 Annual review of the diabetic patient

19

Treatment and self-monitoring Check and adjust as necessary Coexistent risk factors and diseases Strongly discourage smoking Examination Body weight and BMI*: - determine target weight Cardiovascular: - blood pressure, lying and standing; signs of heart failure; peripheral pulses (presence, strength, bruits) Peripheral nerves: - examine limbs for neuropathy Feet: - examine carefully Eyes: - visual acuity (before mydriatics, ± glasses or pinhole), fundoscopy or retinal photography through dilated pupils; check for cataracts Investigations HbA1c

Plasma urea, creatinine and electrolytes Fasting plasma lipid concentrations Urinary albumin excretion ECG if >40 years of age *Body mass index; see Table 19.5.

tuberculosis, combined staphylococcal/streptococcal infections that result in a rapidly spreading cellulitis (progressive synergistic gangrene or necrotizing fasciitis), mucormycosis (p. 335), and gas-forming organisms that infect the soft tissues of the feet or urinary tract.

Surgery Surgery presents several potential hazards to diabetic patients. First, the trauma of surgery provokes a counterregulatory stress response, which causes catabolism and, especially in insulin-deficient patients, can rapidly lead to hyperglycaemia and ketoacidosis. Second, insulin and the sulphonylureas can cause severe hypoglycaemia in fasted or anorexic patients, and this is particularly dangerous during general anaesthesia. Finally, poorly controlled diabetes accelerates catabolism and delays postoperative wound healing. Diabetic control must therefore be meticulous. The risks of operating on diabetic subjects can be greatly reduced by agreeing a routine management policy between the diabetes care team, surgeons, anaesthetists and ward staff. Fitness for surgery should be carefully assessed in the light of cardiovascular or other complications. Patients should be admitted some days before surgery to stabilize their treatment if necessary, and blood glucose levels must be monitored regularly throughout the perioperative period. Basic treatment guidelines are as follows: • Patients with type 2 diabetes who are well controlled by diet or oral agents and undergoing minor surgery

1001

TABLE 19.8 Glucose-potassium-insulin ('GKI') regimen for surgery in diabetic patients Indication All diabetic patients except for those with type 2 treated with oral agents or diet alone and undergoing minor surgery only Infusion 15 U soluble insulin + "lOmmoL KCI in 500ml of 10% dextrose Delivery Infuse at 100 mL/hr Check blood glucose level hourly: - if <5mmol/L replace bag with one containing 10 U insulin + KCI - if >10mmol/L replace bag with one containing 20 U insulin + KCI

only. Change long-acting sulphonylureas (chlorpropamide, glibenclamide) to short-acting drugs (e.g. tolbutamide, gliclazide) some days before surgery to reduce the risk of hypoglycaemia; omit oral agents and breakfast on the morning of operation; monitor glycaemia carefully and treat persistent hyperglycaemia with the intravenous glucose-potassium-insulin regimen described below. • All other diabetic patients. Stop regular insulin on morning of surgery, give a continuous intravenous infusion of balanced amounts of glucose, potassium and insulin ('GKI'), which will both maintain satisfactory glycaemic control (5-10mmol/L) and prevent hypokalaemia (Table 19.8). This regimen should be started on the morning of surgery and continued until the patient is able to eat and drink normally, when the usual treatment can be resumed. Alternatively, insulin may be given as a variable rate infusion, which provides greater flexibility.

Pregnancy Pregnancy in diabetes poses problems for both mother and fetus. Two separate aspects need to be considered, namely pregnancy in women with established diabetes, and 'gestational' diabetes, which is precipitated by pregnancy in a previously non-diabetic woman. Pregnancy in established diabetes Diabetes can cause difficulties at all stages of pregnancy; fortunately, most can be avoided by careful diabetic management. Conception Menstrual disturbance, anovulatory cycles and subfertility are common in poorly controlled diabetic women.

1

1002

MCQ19.9

2

MCQ19.10

Risks to the mother during pregnancy Pregnancy worsens hyperglycaemia, especially during the second and third trimesters, apparently because the hormones of pregnancy (e.g. placental lactogen) are diabetogenic. Pregnant diabetic women are at increased risk of hypertension and pre-eclampsia, and both retinopathy and nephropathy may deteriorate rapidly, possibly secondary to improved glycaemic control (pp. 1008-1014). Delivery of overweight (macrosomic) babies also carries risks for the mother. Maternal mortality for diabetic women was previously high but is now comparable to that in the general population. Risks to the fetus Uncontrolled diabetes affects the fetus in several ways. Congenital malformations, especially cardiovascular and skeletal (e.g. agenesis of the sacrum), are three times commoner than in non-diabetic pregnancies and occur in up to 7% of cases. Diabetes is particularly teratogenic during the first 10 weeks of fetal life, when the major organs are being formed. The cause is not known. Macrosomia (increased body size and obesity) occurs because glucose crosses the placenta and high levels stimulate hyperplasia of the fetal P cells and insulin secretion; the resultant hyperinsulinaemia induces growth and lipogenesis in the fetus. Gross macrosomia can cause dystocia and so threaten both mother and fetus. Risks to the neonate Babies of diabetic mothers are liable to hypoglycaemia in the neonatal period (because their hyperplastic P cells continue to secrete excessive insulin) and the respiratory distress syndrome (hyperglycaemia decreases surfactant synthesis and lung maturation). Perinatal mortality has fallen but remains higher than in non-diabetic pregnancies. Diabetic women who intend to become pregnant require specific counselling, and strict diabetic control should be achieved before conception to ensure nearnormoglycaemia during the critical first few weeks of organogenesis. Patients must be encouraged to stop smoking and drinking alcohol, and other medical problems, such as hypertension or retinopathy, must be assessed and treated.

SUMMARY 7 Diabetes and pregnancy Effects on the mother Insulin resistance and increased requirements Microvascular complications may deteriorate Risk of dystocia with macrosomic babies

Effects on the fetus Congenital malformations Macrosomia

Effects on the neonate Birth trauma from macrosomia Hypoglycaemia Respiratory distress syndrome

Very tight glycaemic targets should be set (Table 19.5) and achieved if necessary by intensive insulin treatment with multiple daily injections or CSII. The few women taking oral agents should be transferred to insulin. Fetal growth must be carefully monitored. Ultrasound scanning can identify macrosomia, manifested as an excessive increase in abdominal girth, and major malformations. Fetal lung maturation can be difficult to assess, because diabetes spuriously increases the commonly used lecithin: sphingomyelin ratio in amniotic fluid. Macrosomia can be avoided by careful diabetic control, and full-term delivery (vaginal if possible) is preferred to reduce the hazards of prematurity, especially the respiratory distress syndrome. During labour, diabetes should be controlled by intravenous glucose-potassium-insulin infusion or a variable insulin infusion (see above and Table 19.8). Insulin requirements rise rapidly if dexamethasone is given to encourage fetal lung maturation or ritodrine to delay delivery, and dosages fall dramatically after the placenta is delivered. The neonate needs careful monitoring for hypoglycaemia (especially if macrosomic) and respiratory distress. The mother's usual diabetic treatment can be resumed soon after delivery, but oral agents must be avoided during breastfeeding as they enter the milk. 1 Gestational diabetes This occurs in 1-2% of pregnancies. Diabetes develops during pregnancy, most commonly during the second and third trimesters; it usually resolves after delivery, but is likely to recur in subsequent pregnancies. Up to 70% of women who have had gestational diabetes subsequently develop type 2 diabetes. The risk factors for developing gestational diabetes are similar to those for type 2 diabetes, namely family history, age, obesity and ethnicity. It seems likely that the increased demands on the pancreas during pregnancy (insulin requirements increase threefold) unmask latent type 2 diabetes. Although gestational diabetes is a type 2 diabetes-like syndrome, in that ketoacidosis does not develop, patients frequently require insulin to achieve adequate glycaemic control. The mother is usually asymptomatic, but there is a significant risk to the fetus because of macrosomia (causing dystocia) and neonatal hypoglycaemia if the condition is untreated. Screening policies based on age, family history, previous macrosomia, neonatal hypoglycaemia or unexplained fetal loss will miss many cases of gestational diabetes. All pregnant women should be screened for gestational diabetes between 24 and 28 weeks' gestation. Many screening tests have been advocated, but the most practical is probably the short OGTT. A 75 g glucose load is given, followed by a plasma glucose measurement 1 hour later. Fasting is not required. A plasma glucose >7.8mmol/L should be followed by a full glucose tolerance test. A fasting glucose >5.5mmol/L or a 2-hour glucose >9.0mmol/L probably warrants treatment. A team approach to treatment is essential, with the dia-

betes specialist nurse and dietitian working alongside the physician and obstetrician. Patients should be taught blood glucose monitoring (preferably using a meter) and asked to test blood both fasting and 1 hour after meals. Targets are <5.5mmol/L fasting and <7mmol/L postprandially. Unless hyperglycaemia is severe, diet should be tried initially, but insulin is often required. This is usually given as a short-acting preparation to control postprandial glucose levels, with intermediate-acting insulin at night if there is fasting hyperglycaemia. Insulin can be stopped after delivery, but all women who have had gestational diabetes should have a repeat glucose tolerance test postpartum to exclude persistent diabetes, and be advised about the increased risk of diabetes in the future. ©

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DIABETIC METABOLIC EMERGENCIES Coma in diabetic patients is commonly due to the disease's metabolic complications or its treatment, but other causes (Table 19.9) are very important and must be considered.

Diabetic ketoacidosis Diabetic ketoacidosis (DKA) is severe uncontrolled diabetes with hyperglycaemia and metabolic acidosis due to high circulating ketone-body levels; acetoacetate and 3-hydroxybutyrate are organic acids. Ketone-body overproduction is due to unrestrained lipolysis, which only occurs with severe insulin deficiency, or under conditions in which a massive counter-regulatory response of stress hormones (e.g. severe infection, or following trauma) overwhelms residual insulin secretion. DKA is therefore the classic hallmark of type 1 diabetes, in which it occurs spontaneously, but it occasionally develops following intercurrent illness in type 2 patients, some of whom can subsequently be treated without insulin. Before insulin, DKA killed most patients with type 1 diabetes. It remains an important problem and the commonest cause of death in such patients under 20 years of age. Overall mortality approaches 10%, and exceeds 20% in older patients with severe intercurrent illness. Many deaths are due to avoidable delays and mistakes in diag-

TABLE 19.9 Causes of coma in a diabetic person Diabetic ketoacidosis Hyperosmoiar, non-ketotic coma Hypoglycaemia Lactic acidosis Others: Strokes (commoner in diabetes) Postictal (hypoglycaemia can cause fitting) Drug overdose (including insulin) Alcohol (can cause hypoglycaemia)

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nosis or treatment. The blood glucose level must always be checked in anyone who is ill. Pathophysiology DKA is due to insulin deficiency, compounded by excesses of glucagon and other counter-regulatory hormones. Insulin deficiency occurs in newly presenting or untreated type 1 diabetes patients, and in established patients who omit or reduce their insulin, or fail to increase it during intercurrent illness (see p. 1001). Counter-regulatory hormones are increased by the stress of intercurrent illness, such as infection (sometimes apparently trivial), trauma, surgery, burns or myocardial infarction. About 40% of episodes are unexplained, but patients often fail to take enough insulin during illness. The result is runaway catabolism in all three branches of metabolism (see Figs 19.7-19.9). • Unsuppressed lipolysis in fat yields FFA, which fuel ketogenesis, and glycerol, which, together with alanine from proteolysis, feeds hepatic gluconeogenesis. • When hyperglycaemia exceeds the renal reabsorption threshold, glucose remains in the urine and, together with high ketone-body levels, causes an intense osmotic diuresis which carries sodium and potassium with it. This causes dehydration, hypovolaemia and renal underperfusion, which reduces the clearance of glucose through the kidneys (an important mechanism for limiting hyperglycaemia) and may lead to acute tubular necrosis (Fig. 19.17). • Electrolyte and water depletion are exacerbated by vomiting, a direct central action of hyperketonaemia. DKA typically causes the loss of several litres of water and several hundred millimoles each (perhaps a week's normal intake) of sodium, potassium and chloride. • Acidosis develops when acetoacetate and 3hydroxybutyrate levels exceed the body's buffering capacity. Intracellular acidosis interferes with vital enzymes; death usually results from cardiac arrest. Clinical features The features of DKA are usually superimposed on those of untreated type 1 diabetes. Hyperventilation, driven by acidosis, may be mistaken for cardiac or respiratory dyspnoea. Acetone may be smelled on the breath. Nausea and vomiting are ominous, as water and electrolyte loss can become rapidly worse. Hypothermia, due to peripheral vasodilatation, may mask pyrexia of infection. Drowsiness and coma occur late. Investigations and diagnosis Once suspected, the diagnosis can be confirmed instantly by measuring blood glucose and urinary ketone levels with test-strips. Once diagnosed, treatment must begin immediately. Initial investigations aim to: 1004

• Assess the severity of DKA. Venous blood is taken for glucose, urea and electrolytes; arterial blood for pH and

A

Intercurrent illness

Dehydration

Insulin deficiency

Counter-regulatory hormone excesses

Muscle Proteolysis

Liver

Fat Lipolysis

Ketogenesis

FFA

Alanine

Gluconeogenesis •

Glycerol

tGLUCOSE

Glycosuria

B

Osmotic diuresis Na,K,CI depletion 4. renal losses of glucose

Vomiting

Dehydration Hypovolaemia Renal underperfusion

FIG. 19.17 Diabetic ketoacidosis Biochemical basis A and pathophysiological disturbances

B

gases; and urine is tested for ketones. Typical values are shown in Table 19.10. Blood ketone levels are measured by some laboratories and will exceed 5 mmol/L (normal range <1 mmol/L). Plasma osmolality can be measured formally or calculated approximately (in mmol/kg) as twice the sum of plasma sodium + potassium, plus the sum of urea + glucose (all in mmol/L). The 'anion gap' (plasma [Na + K] - [Cl + HCO3]) will be increased above normal (> 17 mmol/L) by the presence of acetoacetate and 3-hydroxybutyrate. Identify the cause of DKA. Tests should include a full blood count (note that DKA can cause a neutrophil leukocytosis, without infection), chest X-ray, blood and urine cultures, and ECG and cardiac enzymes in older patients.

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TABLE 19.10 Investigations in diabetic ketoacidosis Test

Normal range

Findings in ketoacidosis

Plasma glucose Plasma Na Plasma K Plasma urea Venous HC03 Plasma osmolality

4-8mmol/L 137-1 43 mmol/L 3.5-5.0 mrnol/L 3.5-7.0 mmol/L 18-28 mmol/L 288-298 mmol/kg

>1 7 mmol/L (may be lower, especially in children) >155mmo!/L indicates hyperosmolality. May be depressed by very high glucose levels Normal, high or low (total body K is always depleted) High in dehydration and renal failure Reduced (arterial blood pH and base excess are more useful) >350 mmol/kg indicates severe hyperosmolality

Arterial blood pH Base deficit

7.35-7.45 -2 to +2 mmol/L

<7.0 indicates severe acidosis <-10 indicates severe acidosis

Urinary ketones

Negative

++ or +++ (+ or ++ may occur in starvation without ketoacidosis)

Management of DKA The first priority is to correct fluid and electrolyte depletion, as this is the immediate threat to life. Insulin replacement, to correct hyperglycaemia and restore glucose supply to the tissues, and treatment of any intercurrent illness are also essential. Fluid replacement A large peripheral or central venous cannula is needed for intravenous fluids. Most patients recover rapidly with 1-2 L of saline given in 2 hours, then 2 L in 4 hours, then 4 L in 24 hours. Fluid losses (in urine or vomit) should be added to these volumes. Replacement should be faster in shocked or oliguric patients (who may require plasma expanders), and slower in the elderly or those with cardiac disease or signs of fluid overload, cerebral oedema or respiratory distress. Fluid balance must be monitored continuously from urine output (catheterize if necessary), clinical signs, or measurement of central venous or pulmonary wedge pressures. As sodium, chloride and potassium are depleted, the logical replacement fluid is saline with potassium chloride. Isotonic (0.9%) saline should be used until plasma glucose has fallen to 10-44 mmol/L, when 5% dextrose can be substituted. This is given with insulin, so the glucose is transported into cells and replenishes their stores. In severe hyperosmolality, half-isotonic (0.45%) saline may be given instead, as in hyperosmolar, non-ketotic coma (p. ••). Small amounts of sodium bicarbonate may be used in profound acidosis (see below). Total body potassium is always depleted in DKA, but acidosis causes potassium to leak out of cells, so that plasma levels can be low, normal or high. Plasma potassium often falls rapidly during treatment, as insulin carries it into cells together with glucose. Although potassium replacement is always needed, it must not be given during the period of hyperkalaemia because it may precipitate cardiac arrhythmias. Potassium chloride should be added to each litre of intravenous fluid as follows:

• 20mmol if plasma potassium is normal (3.5-5.0mmol/L); • 40mmol in hypokalaemia (<3.5mmol/L); • none in hyperkalaemia (>5.0mmol/L). Profound hypokalaemia may require additional potassium, which is best given by infusion pump. Patients with severe potassium disturbances should be monitored electrocardiographically. Insulin replacement Soluble insulin given intravenously acts most rapidly and reliably in DKA; intramuscular and particularly subcutaneous absorption are too slow and erratic. Insulin is best given by an infusion pump (50 U soluble insulin diluted in 50mL saline, i.e. lU/mL), or as 50U in a 500mL bag of saline (O.lU/mL). It should be infused initially at 6U/h, i.e. 6mL/h for the pump and 60mL/h for the drip, which should be regulated by a drip-counter or paediatric giving-set burette. Blood glucose must be measured hourly, and when it starts to fall the infusion rate should be titrated to achieve a glucose level of 10-15 mmol/L after 6-8 hours. Faster rates of fall are unnecessary and may cause hypoglycaemia. Most patients need 1-3 U/h. Other measures and problems Frequent monitoring of glucose, electrolytes and clinical state is crucial. Any coexistent illness should be treated. Broad-spectrum antibiotics are usually given prospectively. Myocardial infarction with DKA has a very high mortality. Other problems include: • Shock, which may cause acute prerenal and renal failure. This usually responds to adequate saline replacement, but plasma expanders and inotropes may be needed for severe hypotension (systolic BP < 90mmHg). • Severe acidosis. The use of bicarbonate in DKA is controversial, as it causes hypokalaemia and, although raising blood pH, may paradoxically worsen intracellular acidosis. Small volumes (250-500 mL) of isotonic sodium bicarbonate (1.4%) may be given if arterial pH is 6.9 or less. • Cerebral oedema. Subclinical brain swelling is probably common in DKA and may be exacerbated by water, ion

1005

SUMMARY 8 Management of diabetic ketoacidosis Fluid replacement 2L in 2 hours, then 2L in 4 hours, then 4 L in 24 hours (plus losses) Isotonic saline initially 5% dextrose when blood glucose falls to 10-14mmol/L Potassium replacement Replace according to plasma levels Add 0, 20 or 40mmol to each litre of i.v. fluid if plasma potassium is >5.0, normal or <3.5mmol/L, respectively Insulin replacement Continuous i.v. infusion of soluble insulin at 6U/h until blood glucose falls, then 1-3 U/h according to blood glucose Monitoring Blood glucose (hourly) Fluid balance and plasma electrolytes Clinical condition Identify and treat intercurrent precipitating illness Broad-spectrum antibiotics Identify and treat complications of ketoacidosis Severe acidosis (pH < 6.9) - consider i.v. bicarbonate and ventilation Shock - consider i.v. plasma expanders and inotropes Cerebral oedema - i.v. dexamethasone, mannitol Adult respiratory distress syndrome - ventilate Afterwards Stabilize insulin treatment Education to prevent further episodes

or glucose shifts in the brain during rehydration. It particularly affects children, causing a decline in consciousness, sometimes with papilloedema. It carries a high mortality, but dexamethasone or mannitol given intravenously before brain herniation occurs sometimes helps. Fluid overload should be avoided; a major reduction in the incidence of cerebral oedema is one of the successes of using lower rates of fluid repletion than were traditional. Adult respiratory distress syndrome (ARDS). Alveolar fluid accumulation, perhaps due to ion and water shifts, clinically resembles pulmonary oedema, but with a normal heart size on chest X-ray and low pulmonary wedge pressure. It is usually fatal. Treatment includes ventilation with high-concentration oxygen and correction of fluid overload. Acute gastric dilatation, with vomiting, a succussion splash and a ground-glass appearance on abdominal Xray, requires nasogastric drainage to prevent aspiration, especially if consciousness is reduced.

1

1006

MCQ 19.11

2 MCQ 19.12

• Coma requires standard nursing care, ideally in an intensive care unit. • Hypothermia indicates a poor prognosis. It may respond to rewarming with a space blanket. After the emergency is over Intravenous fluids and insulin should be continued until the patient is able to eat and drink, and ketonuria has diminished. Standard subcutaneous insulin can then be resumed or started in newly diagnosed patients using prolonged-acting insulin. Most patients who have had DKA require insulin for life, as the vast majority suffer from type 1 diabetes; rare patients with type 2 diabetes who develop DKA during severe intercurrent illness may return to oral hypoglycaemic agents. The cause of the episode must be identified if possible and discussed with the patient to prevent it happening again. 1

Hyperosmolar, non-ketotic coma This is distinguished from DKA by the absence of gross hyperketonaemia and metabolic acidosis. Hyperglycaemia is generally greater than in DKA and, together with a rise in urea due to dehydration and prerenal failure, may elevate the plasma osmolality to >350 mmol/kg. Hyperketonaemia does not develop because these patients have enough insulin secretion to suppress lipolysis and ketogenesis, but not enough to prevent the liver from producing glucose. These patients are therefore C-peptide positive with type 2 diabetes, which is often previously undiagnosed. It is commoner in people of AfroCaribbean origin. Precipitating factors include myocardial infarction, stroke, infection, and diabetogenic drugs such as glucocorticoids and thiazide diuretics. Presentation is with severe hyperglycaemic symptoms (polyuria, intense thirst, weight loss, blurred vision), without the features of ketoacidosis. Confusion, drowsiness and coma are commoner than in DKA. Complications include stroke and thromboembolic disease (such as mesenteric artery thrombosis, deep venous thrombosis and pulmonary embolism) owing to increased blood viscosity. Mortality exceeds 30% because these patients are old and often have a serious precipitating illness. The biochemical features are: • Hyperglycaemia: often >50mmol/L, sometimes >100mmol/L; • Hypernatraemia: often >155 mmol/L (may be depressed by high glucose levels); • Uraemia: due to dehydration, with or without renal failure; • Hyperosmolality: >350 mmol/kg; • Blood and urine ketone levels: normal or slightly raised (in starvation); • Arterial pH, venous bicarbonate and anion gap: normal. Management is largely as for DKA. Saline replacement, using half-isotonic (0.45%) solution if plasma sodium exceeds 150 mmol/L or osmolality >350 mmol/kg, must be

CASE STUDY 19.1 DIABETIC KETOACIDOSIS A 23-year-old heavy-goods vehicle driver was taken to the accident and emergency department by his girlfriend. He had been becoming progressively unwell over the previous 2 weeks, with thirst, polyuria, blurred vision and weight loss of about 6kg. On the day of admission he had vomited on two occasions, and although he was intermittently confused she managed to persuade him to seek medical help. He had no relevant past medical history and was taking no medication. On examination he was drowsy, but rousable. He had deep, sighing respiration and smelt strongly of ketones; he was clinically dehydrated and had a pulse of 100 beats per min and blood pressure 100/60 mmHg. The only other abnormality was a gastric succussion splash.

Questions 1. What investigations should be carried out? 2. Describe the initial management.

Discussion Initial investigations confirmed the suspected diagnosis of diabetic ketoacidosis. The plasma glucose was 34 mmol/L and he had glycosuria and +++ketonuria. Serum sodium was 132 mmol/L, potassium 6.3 mmol/L, urea 13.4mmol/L, creatinine 140(imol/L, arterial pH 7.1, Po2 13.5 kPa, Pco2 2.3 kPa, base excess -16. He had a moderate leukocytosis; chest X-ray and ECG were normal. These abnormalities are typical of diabetic ketoacidosis; note that the potassium is raised, although the patient will have a potassium deficit of several hundred mmol. This will fall as acidosis is corrected, and potassium supplementation will be needed soon after treatment has begun. A leukocytosis is common in DKA and does not necessarily indicate infection but, if this is suspected, a careful screen, including urinalysis, CXR and blood cultures, is indicated. An ECG may show changes due to hyperkalaemia. In older subjects with known diabetes a myocardial infarction may present

cautious in older patients, in whom cardiac disease is common. Potassium levels must be carefully monitored and replaced as needed. Most patients respond rapidly to intravenous insulin infusion at low doses. Prophylactic low-dose heparin (5000 U s.c. 8-hourly) should be given, but full anticoagulation should be reserved for proven thromboembolism as the risks of fatal gastrointestinal bleeding are high. Despite often impressive hyperglycaemia at presentation, these patients have type 2 diabetes and many later do not need insulin. Drugs and other precipitating factors must be avoided subsequently if possible. 2 Lactic acidosis Lactate is generated by glycolysis in muscle (Fig. 19.7). Lactate levels rise rapidly during tissue anoxia (e.g. shock, cardiac failure, pneumonia) and when the liver and kidney are prevented from utilizing it (e.g. by hepatic impairment or biguanides). Lactic acidosis is rare with metformin (and even with phenformin, which carries an intrinsically higher risk) as long as other predisposing factors (major organ

with ketoacidosis, but without chest pain. The patient requires intravenous fluids and insulin. Initially he should be given 1L of 0.9% saline rapidly, and an insulin infusion started at 6 units per hour, and adjusted according to bedside measurement of capillary blood glucose. Frequent monitoring of glucose, electrolytes and acid-base status is essential. The fluid deficit (predicted to be 5-6 L) should be gradually replaced over 24 hours. He has been vomiting, has a reduced conscious level, and has a succussion splash indicating gastric paresis, and so requires insertion of a nasogastric tube to reduce the risk of aspiration. Once the plasma glucose falls to 12mmol/L or below, a 10% dextrose infusion (with potassium if necessary) should be substituted for saline. At this stage he will soon be able to eat and drink, and subcutaneous insulin can be started, followed by education in diabetes and its management.

failure) are avoided. It presents as coma with metabolic acidosis (reduced arterial pH and venous bicarbonate) and a wide anion gap (p. 1004) due to lactate. Blood glucose levels are usually within the diabetic range. Treatment often fails to prevent death. Intravenous sodium bicarbonate may paradoxically aggravate intracellular acidosis (see above), which may be limited by vigorous ventilation to blow off carbon dioxide. Haemodialysis may both clear lactate hydrogen ions and remove sodium overload due to bicarbonate administration.

CHRONIC COMPLICATIONS OF DIABETES The chronic tissue complications of diabetes are the single greatest anxiety for most diabetic people. However, over 40% of type 1 diabetes patients survive for over 40 years, half of them without developing significant complications, and there is already encouraging evidence - notably from the results of the Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study and

1007

the falling incidence of nephropathy during the last decade • that continuing advances in diabetic care will reduce the damage caused by diabetic complications. Chronic diabetic complications are usually classified as: • Microvascular (microangiopathic) disease. This is an essential component of retinopathy and nephropathy, and is characteristic of and specific to diabetes. The role in neuropathy is less certain. Common features are basement membrane thickening and abnormal leakiness of the microcirculation. The lesions affect particularly type 1 diabetes patients who developed the disease before puberty but can be devastating in patients with type 2 diabetes. Indeed, significant complications are often found in type 2 patients at diagnosis, reflecting the long unsuspected presence of the disease. • Macrovascular (large-vessel) disease. This is atherosclerosis, distinguished from that affecting non-diabetic people only by its rapid and extensive development.

Microvascular complications Pathogenesis Microvascular lesions in type 1 diabetes and type 2 diabetes are identical, suggesting that hyperglycaemia or some other metabolic disturbance of diabetes is responsible. Epidemiological evidence indicates that microvascular complications are commoner in poorly controlled and rarer in well-controlled diabetic patients. The long-term DCCT (Diabetic Control and Complications Trial) in the USA has now confirmed that tight glycaemic control can more than halve the long-term incidence of retinopathy, nephropathy and neuropathy (Fig. 19.18) in type 1 diabetes. Similar findings were found in the UKPDS study for patients with type 2 diabetes, and, importantly, control of blood pressure (with a target of <150/85) reduced the risk of both microvascular and macrovascular complications of diabetes. Suggested mechanisms of microvascular disease include: • Overactivity of the polyol pathway. This alternative pathway converts glucose and other sugars to their respective polyols or sugar alcohols (e.g. glucose to sorbitol, galactose to galactitol) through the action of aldose reductase. This enzyme is found in the retina, lens, glomerulus and Schwann cell of nerves, which are all damaged in long-standing diabetes. Glucose flux through the polyol pathway increases dramatically in hyperglycaemia, and this may cause accumulation of sorbitol in these tissues. How these changes might cause tissue damage is unknown. • Glycation of proteins. Hyperglycaemia increases nonenzymatic glycation of many proteins, which may impair their structural and metabolic functions.

1

1008

Figs 19.4-19.6

2

Fig. 19.7

FIG. 19.18 Diabetes Control and Complications Trial Diabetic retinopathy is reduced with intensive (mean HbA1c 7%) vs conventional treatment (mean HBA1c 9%) of type 1 diabetes in the DCCT trial. Similar reductions were seen in the development of microalbuminuria, albuminuria and clinical neuropathy, but not of macrovascular disease. These considerable benefits were offset by a threefold increase in the incidence of severe hypoglycaemia and by excessive weight gain.

• Haemodynamic and coagulation disorders. Resting blood flow is increased in the retinal, glomerular and other microcirculations and could cause microvascular damage. Smoking, hypertension and a tendency to enhanced coagulability of the blood may also contribute. • Other factors. As 60-70% of type 1 diabetes patients never develop nephropathy or proliferative retinopathy, an inherited susceptibility may be important.

Ocular complications Diabetic eye disease, especially retinopathy, is the commonest cause of blindness in the British population of working age, and for most patients is the most frightening complication of the disease. Fortunately, it is easily detected and now often treatable. Diabetic retinopathy Retinopathy is a readily visible sign of widespread microvascular damage. Background retinopathy (see below) affects 30% of patients with type 2 diabetes at diagnosis and virtually all patients after 20 years of either type 1 or type 2 diabetes; these changes therefore seem to result from hyperglycaemia or associated metabolic disturbances. In contrast, proliferative changes only ever develop in 30-50% of diabetic people, who may constitute a specific susceptible subset. Early abnormalities include capillary dilatation with increased retinal blood flow, thickening of the capillary basement membrane, loss of the surrounding pericytes and increased leakiness of the capillaries. Focal occlusion of capillaries and later arterioles, possibly due to microthrom-

bus formation, ultimately causes retinal ischaemia and infarction. The progression of retinopathy is apparently accelerated by poor glycaemic control, smoking and hypertension. Retinopathy may deteriorate acutely during pregnancy and after a sudden improvement in previously poor glycaemic control, probably because this reduces retinal blood flow and aggravates ischaemia in critically perfused areas of the retina. Stages and lesions of retinopathy The stages and lesions of retinopathy are detailed in Figure 19.19. Background retinopathy. Capillary dilatation and leakage can only be demonstrated by fluorescein angiography (Fig. 19.20). The first lesions visible on fundoscopy are red dots, which are either microaneurysms (localized dilatations of weakened capillaries) or haemorrhages from ruptured capillaries. Haemorrhages deep in the retina appear as small dots or larger 'blots', whereas superficial ones fan out along nerve fibre bundles into a 'flame' shape. 'Hard' exudates are lipid-rich precipitates of protein extravasated from leaky capillaries. These have a shiny, waxy appearance and are often clustered in arcs and rings around the macula. Background lesions alone do not impair vision, unless extensive exudates cause maculopathy, and in most cases do not progress to new vessel formation. 1 Preproliferative changes. These indicate worsening ischaemia, and 50% of cases develop new vessels 2 within 12 months. Multiple cotton-wool spots ('soft' exudates) are fluffy, greyish-white patches of axoplasm released from retinal infarcts; they also occur in accelerated hypertension. Venous abnormalities include beading and looping. Intraretinal microvascular abnormalities (IRMA) are clusters of dilated capillaries (not new vessels). Vision is not affected by preproliferative changes alone. Proliferative retinopathy. New vessels usually sprout from veins, especially where they bifurcate or enter the optic disc. They advance in leashes or arcades within the retina or into the vitreous, and may extend anteriorly to appear on the iris as rubeosis iridis. New vessels threaten vision because they are fragile and rupture easily, causing haemorrhages within the retina, in the vitreous, or in the potential preretinal (subhyaloid) space between the two. Vitreous haemorrhages appear as greyish opacities obscuring the fundus, whereas preretinal bleeds have a flat top if the red cells in the space are allowed to sediment. Extensive vitreous and preretinal haemorrhages cause sudden loss of vision in the affected eye. Small haemorrhages may resorb almost entirely, but bleeding usually recurs and ultimately impairs vision. Without treatment, 50% of patients with 'high-risk' new vessels (especially those involving the disc, which are particularly liable to bleed) will become blind within 5 years (see Figs 24.6 and 24.7, p. 1293). Advanced diabetic eye disease. Fibrous tissue proliferates with new vessels and following repeated haemor-

19

FIG. 19.19 Stages and lesions of diabetic retinopathy Maculopathy, an important cause of blindness in type 2 diabetes, can accompany any of these stages; macular oedema may be invisible on fundoscopy.

FIG. 19.20 Fluorescein angiogram Severe background retinopathy showing microaneurysms, haemorrhages, and venous beading indicating early preproliferative changes. Diffuse fluorescence outside the vessels indicates extensive capillary leakage. (Photography by courtesy of Mr R. Whitelocke.)

rhages, appearing as opaque, greyish membranes on fundoscopy. It tends to contract, so that strands attached to the retina exert traction, causing retinal detachment and tears. Detachment causes visual loss, which is permanent if

1009

the retina is not reattached within a few weeks. Warning symptoms include distortion of vision and a 'sparkling' sensation, and these therefore need urgent ophthalmological referral. Fibrosis also complicates rubeosis iridis, especially if the vessels bleed into the anterior chamber, and may block the filtration angle. This prevents reabsorption of aqueous and causes glaucoma, with a blind and extremely painful eye. Maculopathy. The macula serves high-resolution central vision, which is essential for daily activities such as reading. Unfortunately, it is particularly sensitive to damage by oedema and exudates from surrounding leaky capillaries and ischaemia. 1 Maculopathy can complicate any stage of retinopathy and is the commonest cause of blindness in type 2 diabetes. Significant maculopathy dramatically impairs vision and must be suspected if visual acuity is 6/12 or worse and cannot be explained by refraction errors, cataracts or vitreous opacities. Fundoscopy may seem deceptively normal; all patients with unexplained visual impairment must therefore be referred to an ophthalmologist. The diagnosis is confirmed by fluorescein angiography, which shows extensive capillary leakage, and slit-lamp examination, which will reveal retinal thickening. Screening and investigation of diabetic retinopathy Visual acuity and fundoscopy should be checked routinely in every diabetic patient at diagnosis, annually thereafter, and 3-6-monthly if changes other than mild background retinopathy are present. Acuity should be tested using the Snellen chart before mydriatics are given, and with any refractive errors corrected by the patient looking through his or her own distance glasses or a pinhole in a piece of card. Fundscopy must be performed through dilated pupils, as retinopathy, especially new vessel formation, often occurs far peripherally. Contraindications to mydriatics (e.g. 1% tropicamide) are glaucoma and previous eye surgery. The lens and vitreous, as well as the disc, major vessels and finally the sensitive macula ('look straight at my light'), must all be examined. Table 19.11 shows guidelines for referring the patient to the ophthalmologist. Specialized investigations include slit-lamp measurements of retinal thickness (which is increased in macular oedema), estimation of intraocular pressure, and fluorescein angiography. Fluorescein injected intravenously binds to albumin and so only leaves the circulation if the vessels are abnormally leaky. After a fluorescein bolus, rapid-sequence photographs using ultraviolet light demonstrate the retinal arteries, capillaries and veins. Fluorescence outside the vessels indicates leakage, notably in macular oedema and around new vessels (Fig. 19.20).

1

1010

Fig. 19.8

2

MCQ 19.13

TABLE 19.11 When to refer diabetic patients to the ophthalmologist • • • • • • •

Extensive or progressive haemorrhages or exudates Preproliterative changes Proliferative changes Unexplained loss of visual acuity (6/12 or worse): possible maculopathy Vitreous haemorrhage Retinal detachment urgent referral (within 24 hours) Glaucoma >

SUMMARY 9 Diabetic retinopathy • The commonest cause of blindness in Britons of working age • Background changes affect almost all cases after 20 years of diabetes • Proliferative changes develop in only 30-50% of cases • Maculopathy commonly causes blindness in type 2 diabetes; it may be invisible on fundoscopy • Laser photocoagulation prevents blindness in 50% of cases with new vessels • Vitreoretinal surgery vision in 50% of cases with advanced eye disease

Management of diabetic retinopathy With advances in laser photocoagulation and vitreoretinal surgery, many cases of severe diabetic retinopathy have become treatable. Laser photocoagulation uses blue-green argon laser light, which is absorbed by vascular structures. The laser can be used either to destroy localized targets such as clumps of new vessels or leaky capillaries, or for panretinal photocoagulation (PRP). PRP ablates the peripheral retina with 2000 or more burns, sparing the macula and maculopapillary bundle, which carries its fibres to the disc. This destroys ischaemic retina and therefore removes the stimulus to neovascularization; it also channels remaining blood flow into the macula to preserve central vision. With PRP the risks of patients with proliferative changes becoming blind within 5 years are reduced from 50 to 25%. Macular oedema can also be treated, using laser burns to seal surrounding leakage points. Vitreoretinal surgery, by removing vitreous haemorrhage and fibrous membranes and repairing detached or torn retina, can now restore vision to over 50% of eyes rendered blind by advanced diabetic eye disease. Prevention of diabetic retinopathy is a major priority. This hinges on regular screening of eyes and early ophthalmologic referral, together with improved glycaemic control, stopping smoking and treatment of hypertension. Visually impaired diabetic people should be registered as partially sighted or blind to obtain appropriate state benefits. Sympathetic counselling and practical devices such as injection aids and speaking blood glucose meters may be very helpful. 2

Other ocular complications of diabetes Diabetes accelerates the formation of senile cataracts and, rarely, 'snowflake' cataracts may develop rapidly during periods of very poor glycaemic control at any age. Cataracts must be distinguished from the blurred vision of hyperglycaemia, usually with hypermetropia, which may be due to osmotically induced changes in lens shape. Normalization of hyperglycaemia may also alter acuity for several weeks.

19

Diabetic nephropathy and other renal diseases Diabetic nephropathy is a specific microvascular disease affecting mainly the glomerulus, although tubular lesions also occur. In the UK it accounts for 25% of patients with end-stage renal failure. It is the commonest cause of premature death in type 1 diabetes, especially in patients who become diabetic before puberty, but is rarer when type 1 diabetes presents after 40 years of age. Only 30-40% of type 1 diabetes patients ever develop nephropathy, and two-thirds of these ultimately enter end-stage renal failure. Nephropathy is rarer in type 2 diabetes, but as this is commoner than type 1 diabetes the numbers of renal failure patients with type 1 diabetes and type 2 diabetes are comparable. Fortunately, the frequency of nephropathy is apparently falling. Diabetes predisposes to urinary tract infections, especially in patients with incomplete bladder emptying owing to autonomic neuropathy. Unusual organisms may be involved, including tuberculosis and gas-forming bacteria; a recognized complication is papillary necrosis, which may cause acute renal failure. Pathophysiology of diabetic nephropathy Nephropathy is one facet of generalized microvascular damage and is almost always associated with retinopathy, often proliferative. An extremely important association is with hypertension. This is present in virtually all patients with clinical nephropathy and, if untreated, accelerates the rate of decline of GFR. Susceptibility to nephropathy may relate to an inherited tendency to hypertension. Other predisposing factors include smoking and poor glycaemic control. As in other capillary beds, the glomerular basement membrane is thickened. The mesangium is expanded by amorphous material and the glomerulus ultimately becomes sclerosed, forming the pathognomonic Kimmelstiel-Wilson nodular lesions. The first functional change is increased permeability of the glomerular capillaries to albumin. Urinary albumin excretion rate (AER) rises initially into the range of 30-300 mg/24 hours, known as 'microalbuminuria'. These albumin concentrations are below the detection limits of conventional dipsticks and are demonstrable only by radioimmunoassay or other sensitive methods. In twothirds of these patients AER continues to rise, and at >300 mg/24 hours the stage of clinical nephropathy

FIG. 19.21 Evolution of albuminuria in diabetic nephropathy 'Microalbuminuria' represents an albumin excretion rate (AER) of 30-300 mg/24 hours, which is detectable by sensitive radioimmunoassay (RIA). In two-thirds of these patients AER rises into the macroalbuminuric range (>300mg/24 hours), detectable by routine dipstick testing. These patients are at risk of developing renal failure or the nephrotic syndrome.

('macroalbuminuria') becomes detectable by dipsticks. In some patients proteinuria ultimately exceeds 3.0-3.5g/day, causing the nephrotic syndrome (Fig. 19.21). GFR is initially normal, or even increased in some cases; this 'hyperfiltration' is associated with renal hypertrophy. Once AER reaches 100-300 mg/24 hours GFR starts to decline linearly, with an average loss of lOmL/min per year (Fig. 19.21). Serum creatinine levels begin to rise when GFR has fallen to 50 mL/min, and end-stage renal failure supervenes on average 5-7 years after macroalbuminuria appears. Investigations and diagnosis Microalbuminuria can now be measured easily and cheaply, and tests suitable for screening spot urine samples are available. Screening should be performed annually. Blood urea and creatinine levels can be misleadingly normal until GFR has fallen by 50% (Fig. 19.22). In about 10% of cases renal failure or proteinuria is not due to diabetic nephropathy. Atypical features, e.g. haematuria, rapid-onset renal failure, small kidney size or the absence of retinopathy, should raise this possibility. The correct diagnosis is vital for therapeutic and prognostic reasons, and may have to be established by renal biopsy. Management of diabetic nephropathy Microalbuminuric stage Much can be done at this stage to slow the pace of renal damage and delay progression to clinical nephropathy. Control of hypertension is crucial (the target is <130/80), as this significantly slows the rise in AER and fall in GFR. ACE inhibitors reduce the AER (possibly by lowering intraglomerular pressure), and should be considered in all type 1 diabetes patients with microalbuminuria. In patients with type 2 diabetes, blood pressure control (with a target

1011

SUMMARY 10 Diabetic nephropathy • The commonest cause of premature death in type 1 diabetes • Microalbuminuria precedes macroalbuminuria (clinical nephropathy) • In clinical nephropathy, GFR declines linearly with time • Treating hypertension slows deterioration in renal function • End-stage renal failure in diabetic patients should be treated as in non-diabetic people

Years FIG. 19.22 Decline in GFR in established diabetic nephropathy If untreated, GFR falls linearly at an average rate of 10ml/min per year; individual rates vary widely and may be slowed by treating hypertension, improving glycaemic control, ACE inhibitors, reducing protein intake and stopping smoking.

of <130/80) is also important. There is less strong evidence for a specific beneficial effect of ACE inhibitors in this group compared with type 1 diabetes, and renal function should be closely monitored because of the high rate of macrovascular disease and associated renal artery stenosis. The DCCT and UKPDS trials have shown the benefits of good glycaemic control in reducing the incidence of microand macroalbuminuria. Stopping smoking may also be of benefit. Clinical nephropathy (macroalbuminuric stage) Effective treatment of hypertension (present in most patients) is again essential, and ACE inhibitors may markedly reduce proteinuria. Moderate restriction of dietary protein and stopping smoking may help to maintain GFR; optimizing glycaemic control has little effect at this stage. End-stage renal failure Renal support therapy is needed when serum creatinine reaches 500u,mol/L. Prediction of this time from plots of inverse creatinine (1000 -s- creatinine in fimol/L) or GFR allows careful planning in advance (Fig. 19.22). The treatment options are the same as for non-diabetic people and are now nearly as successful. Patients must not be denied renal support simply because they have diabetes, although premature death (mainly from cardiovascular disease) is 10 times higher in diabetic than in non-diabetic patients receiving renal replacement therapy.

1

1012

MCQ 19.14

2

Case 19.3 3

MCQ 19.15

Renal transplantation is preferred for younger patients; live related donors are best, when 5-year survival exceeds 60%. Haemodialysis can be complicated by the difficulty of constructing arteriovenous fistulas in calcified arteries (which are common in nephropathy) and by postural hypotension due to fluid shifts. Chronic ambulatory peritoneal dialysis (CAPD) avoids these problems and is suitable for many patients, including the blind. Other aspects of diabetic care can be difficult for renal failure patients. Hypoglycaemia is common, as insulin and most sulphonylureas are cleared partly through the kidneys and so accumulate in renal failure. Sulphonylureas are particularly dangerous and insulin should be substituted when creatinine levels begin to rise; metformin must never be given in renal failure because of the very high risks of lactic acidosis. Proliferative retinopathy commonly coexists and may deteriorate during haemodialysis; early laser treatment is essential. Neuropathy causing foot ulceration is frequent, and autonomic neuropathy aggravates postural hypotension during haemodialysis. Cardiovascular disease ultimately kills most of these patients.12

Diabetic neuropathy Diabetic nerve damage involves both the somatosensory system, causing variable sensory and motor deficits, and the autonomic outflow to various organs (Fig. 19.23). Pathological changes affect both the Schwann cells, with segmental peeling and loss of myelin, and the axons themselves. Axonal degeneration may be accompanied by regeneration and sprouting of nerve endings. Nerve conduction velocity is decreased and smaller fibres may fire spontaneously, a possible basis of the characteristic neurogenic pain. Causative factors in diabetic neuropathy are thought to include: • Hyperglycaemia. Epidemiological studies have associated poor diabetic control with more severe nerve damage, and the DCCT has shown that good glycaemic control more than halves the incidence of clinical neuropathy in type 1 diabetes. Hyperglycaemia could damage nerves directly through glycation of proteins and/or polyol pathway overactivity. • Vascular damage. Diffuse occlusion of the capillaries supplying the nerves (vasa nervorum) occurs in human diabetic nerves and may parallel functional impairment, presumably by causing hypoxia. The sudden focal palsies

FIG. 19.23 Diabetic neuropathy Diabetic neuropathy may be classified as somatosensory or autonomic. A wide range of systems may be affected.

that affect single cranial and peripheral nerves may be due to occlusion of larger vessels, causing localized infarction and demyelination. Somotosensory diabetic neuropathy About 30% of diabetic clinic patients have evidence of neuropathy on formal testing, but this is mostly subclinical as only 10% have significant symptoms. Somatosensory nerve damage is of two types: a diffuse, symmetrical 'stocking and glove' pattern typical of metabolic or toxic neuropathies, in which the longest nerves are most susceptible to damage; and focal or multifocal neuropathies, in which individual nerves are picked off by discrete, presumably vascular, insults. Diffuse, symmetrical neuropathies These affect both sensory and motor function to a variable and overlapping extent, although the patient's symptoms often relate predominantly or exclusively to one or the other. Sensory symptoms are the commonest, typically consisting of unpleasant pins and needles, burning, shooting or electric-shock-like sensations, often with 'allodynia', i.e. pain provoked by a normally innocuous stimulus such as contact with bedclothes. The feet and legs are usually affected and the hands only rarely. Pain is often worst at night, severely disrupting sleep and causing depression. Symptoms can either develop insidiously over many months or years, or acutely within a few days or weeks. The acute presentation often follows a period of severe hyper-

glycaemia, especially if accompanied by weight loss, and tends to resolve with time and improved glycaemic control. In contrast, the chronic form is less obviously associated with poor control and does not respond to intensified treatment. Chronic sensory neuropathy also causes loss of sensation, sometimes profound. The most important loss is of pain perception, which is a major cause of damage to the neuropathic foot (see below). The patient may be unaware, for example, of full-thickness burns from hot-water bottles, scalds from bathwater, pressure damage from tight shoes, or having the foot impaled by stepping on a nail. Impaired touch and joint-position sense may give the impression of walking in thick socks, and cause a positive Romberg's sign. Physical examination may reveal symmetrical 'stocking and glove' sensory loss affecting all modalities, but this is often patchy, usually spares the hands, and may be much less impressive than the symptoms would suggest; clinical testing may be normal in acute painful neuropathy. Tendon reflexes in the legs are often reduced or absent and there may be marked muscle wasting. Neuropathic foot problems - ulceration, increased skin blood flow and Charcot's arthropathy - may develop through a combination of somatosensory and autonomic damage (see below). Motor neuropathy with asymptomatic muscle wasting often accompanies primarily sensory syndromes, and a diffuse predominantly motor neuropathy may produce severe symmetrical wasting, which is typically worst in the hands and usually accompanied by intense pain. There is little sensory deficit and tendon reflexes are usually preserved. Older type 2 diabetes patients, sometimes only mildly hyperglycaemic, are usually affected and recovery may be very poor. Focal and multifocal neuropathies These are palsies of one or more cranial or peripheral nerves. Cranial nerve palsies are common, especially affecting the third, fourth and sixth nerves. The third nerve palsy is characteristically painful and partial: diplopia and ptosis are present but the pupillary innervation is spared and pupil diameter and responses are unaffected. The palsy usually resolves spontaneously. Peripheral nerve palsies, particularly of the median, ulnar and lateral popliteral nerves, may be due to pressure damage and/or vascular insults and often recover slowly and incompletely. A phrenic nerve palsy may cause an elevated hemidiaphragm. Diabetic amyotrophy may be due to vascular damage of a large nerve trunk or root (radiculopathy) supplying the leg. The femoral nerve is usually involved, causing acute pain, weakness and wasting in the quadriceps, with loss of the knee jerk. Muscles below the knee are less often affected. For unknown reasons some patients have extensor plantar responses, a picture which must be differentiated from a spinal or cauda equina lesion. Amyotrophy often presents during a period of poor control and usually improves spontaneously within a few months, especially if diabetic control is tightened. 0

19

1013

Diagnosis and management of diabetic somatosensory neuropathy The history is usually diagnostic. Sensory modalities served by large fibres (vibration, joint-position sense, light touch) and small fibres (pinprick, light touch) should be mapped, remembering that any objective deficit may not match the severity or extent of symptoms. Tendon reflexes and muscle bulk and power must be tested. Because of their different prognoses and treatments, diffuse and focal neuropathies must be distinguished. Sensory testing can be standardized by various bedside instruments. Electrophysiological testing will demonstrate slowed conduction velocities in affected nerves. Diabetic neuropathy must be differentiated from other metabolic neuropathies, including vitamin B12 deficiency, uraemia and alcohol abuse, all of which can coexist with diabetes and require different treatments. Treatment should begin by optimizing glycaemic control, using intensified insulin regimens if necessary; this often helps acute painful syndromes but not those that develop slowly. Pain may respond to simple analgesics (paracetamol, non-steroidal anti-inflammatory drugs, codeine), tricyclic antidepressants (imipramine, especially if combined with fluphenazine), membrane-stabilizing drugs such as anticonvulsants (phenytoin, carbamazepine) or oral mexiletine. Capsaicin cream applied topically may be helpful for pain in the extremities; it acts by depleting C fibres (which carry neurogenic pain impulses) of the neurotransmitter substance P. Some patients do not respond to any of these drugs; in these cases, implantation of a dorsal-column stimulator (which exploits the 'gate' control of pain transmission proposed by Melzack and Wall) may provide dramatic relief. Autonomic neuropathy Autonomic dysfunction commonly accompanies somatosensory neuropathy and presumably has a similar pathogenesis. About 40% of unselected diabetic patients have some features of autonomic neuropathy, but most are not apparent clinically. Only a few suffer major symptoms, but these can be very debilitating; moreover, these patients have a significantly reduced life expectancy. Both sympathetic and parasympathetic divisions are involved. Clinically apparent features are commonest in patients with long-standing diabetes, and include:

1014

• Abnormal sweating: this is usually reduced in the feet, but profuse 'gustatory' sweating of the face and trunk may be provoked by eating. • Postural hypotension, with a systolic fall exceeding 20 mmHg on standing, is due to failure of the normal increase in cardiac output and vasoconstrictor tone, and causes dizziness and blackouts. • Gastrointestinal motility is disturbed, causing gastric stasis with vomiting, diarrhoea (especially at night), which may be aggravated by bacterial overgrowth, and/or constipation. • Neuropathic bladder problems include incomplete emp-

tying, sometimes with a palpable bladder, which may cause overflow incontinence and predispose to ascending urinary tract infections. • Sexual difficulties include failure of erection (a parasympathetic response mediated by the sacral nerves) and/or ejaculation (a sympathetic reflex transmitted by the lumbosacral outflow). Erectile failure in diabetic men can also be due to depression (a common cause in nondiabetic men) or atheroma of the pudendal arteries, which supply the corpora cavernosa. • Sudden unexplained death is commoner in patients with severe autonomic symptoms; possible causes include cardiorespiratory arrest and hypoglycaemia, awareness of which is blunted in many patients with long-standing diabetes. Diagnosis and management of autonomic neuropathy Autonomic neuropathy is usually diagnosed clinically from non-invasive tests of cardiovascular reflexes, which show an excessive postural drop in systolic blood pressure (>20 mmHg), loss of the normal sinus arrhythmia during deep breathing (<10bpm difference between inspiration and expiration), or loss of reflex bradycardia during the Valsalva manoeuvre. Special tests can demonstrate decreased pupillary responses, sweating, and gastric and bladder emptying. Symptomatic postural hypotension may be helped simply by raising the head of the bed at night, or by fludrocortisone, which retains sodium and water and may aggravate coexisting supine hypertension. Vomiting often responds to metoclopramide or cisapride, and erythromycin or tetracycline often cures diarrhoea when bacterial overgrowth is present. Regular bladder training may improve emptying and incontinence. Impotence may be very difficult to treat. Treatment of erectile dysfunction can be with oral sildenafil, which is effective in about 50% of diabetic patients. This should be taken about 1 hour before intercourse. As in the non-diabetic population, it is absolutely contraindicated in patients taking nitrates (e.g. GTN or isosorbide dinitrate) in any form at any time, because of the risk of profound hypotension and circulatory collapse. In patients in whom sildenafil is contraindicated or ineffective, artificial erections may be induced either by vacuum suction devices or by the injection of vasodilators such as papaverine or prostaglandin E! into the corpus cavernosum. It is important to counsel patients about the cardiovascular risks of sexual activity, before initiating any of these treatments.

Macrovascular (large-vessel) disease Atherosclerosis is very common in both type 1 and type 2 diabetes and the major cause of death in the latter. Predisposing factors are those that operate in the non-diabetic population, amplified by hyperglycaemia. • Hyperglycaemia is an independent cardiovascular risk factor. Epidemiological studies indicate that the risk of

•

•

•

•

macrovascular disease begins to increase when the 2hour blood glucose value during an OGTT exceeds 7mmol/L; this is the basis for denning the category of IGT (p. 984). The extent and severity of atheroma are related to the duration and degree of hyperglycaemia, suggesting that good glycaemic control may be preventative, but there is as yet no evidence that it can reverse established disease. Hypertension affects up to one-third of diabetic people and is two to three times more common than in the general population. The association may be partly explained by sodium retention and altered vascular reactivity. Hyperlipidaemia is common, with an atherogenic pattern of increased VLDL- and LDL-cholesterol and reduced HDL, which is often more pronounced in type 2 diabetes. Triglycerides are also increased in untreated diabetes. Smoking is at least as common in diabetic as in non-diabetic people, and many diabetic people continue to smoke because they fear overeating and weight gain if they stop. The 10-year mortality in diabetic smokers is twice as high as in non-diabetic non-smokers, and most premature deaths are from macrovascular disease. Hyperinsulinaemia has also been implicated as a risk factor for macrovascular disease, as epidemiological and experimental evidence has suggested that insulin and related molecules are atherogenic. The commonly associated features of hyperinsulinaemia, insulin insensitivity, obesity, hypertension and an atherogenic lipid profile may all stem from insulin insensitivity. This constellation of abnormalities has been termed 'syndrome X" by Reaven and others (Fig. 19.24).

Manifestations of macrovascular disease Atheroma in diabetic patients is histologically identical to that in the general population, but is often more extensive and multifocal and tends to involve more distal arteries. The main complications are as follows.

FIG. 19.24 Syndrome X This is the constellation of diseases and abnormalities associated with insulin resistance, The basis for these associations remains controversial.

Coronary heart disease. Compared to the general population, this is at least twice as common in diabetic men and four times as common in diabetic women (especially before the menopause, when women are normally protected against atheroma). There is a very strong association with microalbuminuria, which identifies most of the patients at risk of premature cardiovascular death (p. 1011). Myocardial infarction is the commonest cause of death in type 2 diabetes. In diabetic people it is commonly complicated by cardiac failure or cardiogenic shock, and carries twice the general mortality. This may be owing to a specific 'diabetic cardiomyopathy', independent of general ischaemic damage, as left ventricular function may be impaired in normotensive diabetic patients whose coronary arteries are devoid of atheroma. Cardiac failure, sometimes with normal findings on examination and chest X-ray, may cause dyspnoea. Angina and myocardial infarction may be painless in diabetic patients, especially those with autonomic neuropathy, presumably because of sensory denervation of the heart. Stroke is two to five times commoner than in the nondiabetic population. Peripheral vascular disease is common, with diffuse atheroma in the arteries below the knee as well as in the iliofemoral vessels. Claudication, rest pain and gangrene may result; the latter is usually dry and may affect one or more digits or the whole foot. Diabetes accounts for onehalf of all non-traumatic amputations. Other manifestations include mesenteric artery occlusion, which causes anginal-type abdominal pain after eating, and, occasionally, extensive infarction of the bowel.

19

Examination and investigations All the peripheral pulses must be checked for their presence, strength and bruits. Signs of hypertension, cardiac failure and poor perfusion of the legs (slow capillary return after blanching the skin, thin skin and other 'trophic' changes) must also be sought. The arteries can be further investigated by non-invasive Doppler scanning or by arteriography. Routine ECG and chest X-ray may reveal ischaemia, infarcts, cardiomegaly or pulmonary oedema, but may be deceptively normal, and a stress ECG, echocardiography or isotopic cardiac scans may be needed to demonstrate dysfunction. Angiography of the coronary or peripheral arteries will localize stenoses and indicate the feasibility of surgery or angioplasty. Blood glucose and lipid levels should be monitored regularly. Management of macrovascular disease General measures to treat cardiovascular risk factors are crucial. The benefits of stopping smoking must always be stressed, especially as smoking may aggravate microvascular as well as macrovascular disease (see Fig. 19.29). Hypertension must be treated, preferably avoiding drugs that worsen blood glucose or lipid levels, such as high-dose thiazide diuretics. Although (3-blockers may slightly

1015

worsen the lipid profile, and have tended to be avoided in diabetic patients, good clinical trial data supports their use; at least in type 2 patients they have been demonstrated in the UKPDS study to be as effective as ACE inhibitors at reducing rates of microvascular and macrovascular complications. Calcium-channel antagonists, ACE inhibitors, ablockers, indapamide and low-dose diuretics (e.g. 1.25-2.5 mg bendrofluazide) have no adverse metabolic effects. Hyperlipidaemia is treated as described on page 1024, avoiding fish oils, which aggravate hyperglycaemia in type 2 diabetes. Glycaemic control should be optimized. Reducing obesity and taking regular exercise within the patient's capacity help to correct both hypertension and hyperlipidaemia. Angina is treated conventionally (see Ch. 12, p. 546). The proportion of operable vessels and the initial outcome of bypass surgery are now comparable in diabetic and non-diabetic populations. Intermittent claudication often improves if the simple advice to 'stop smoking and keep walking' can be followed, but a rapidly shortening claudication distance or rest pain must be investigated by arteriography. The results of reconstructive surgery, including femoropopliteal bypass and the use of the saphenous vein in situ for distal disease, are now very good, although in diabetic people the amputation rate remains high.

The diabetic foot Diabetic foot disease is of great clinical and economic importance, as it is one of the commonest causes of hospital admission for diabetic patients; such admissions are often expensive, lasting several weeks. Fortunately, most problems are largely preventable by careful education, effective screening and prompt treatment of complications. Causes of diabetic foot problems There are four basic disorders: neuropathy, ischaemia, trauma and infection, which frequently coexist and reinforce each other. Neuropathy involving sensory, motor and autonomic nerves commonly causes ulceration and other foot complications. Impaired sensation prevents tissue damage from being noticed. Distal motor neuropathy weakens the intrinsic muscles of the foot, and the unopposed action of the long extensors lifts the arch, claws the foot and concentrates pressure damage on to the metatarsal heads and heel. Autonomic denervation reduces sweating, causing dry skin, which cracks and encourages infection, and opens the arteriovenous anastomoses. This shunts blood past the capillary bed, reducing oxygen and nutrient supply to the tissues, and results in warm skin (sometimes approaching core temperature) and distended veins in the feet.

1

1016

Figs 19.9,19.10

2

Figs 19.11,19.12

FIG. 19.25 The diabetic foot showing gangrene

neuropathic ulcer and

B

Ischaemia, due to peripheral vascular disease and possibly to impaired microcirculation, results in a cold, pulseless foot at risk of infarction. The commonest form of trauma is pressure damage, especially to the metatarsal heads and heels in the clawed neuropathic foot and regions compressed by tight shoes or foreign bodies in the shoes. Pressure stimulates formation of callus, in which foci of liquefactive necrosis develop and break through to the skin surface to form an ulcer. Infection enters the foot through ulcers or cracks in the skin, including self-inflicted damage from do-it-yourself chiropody. Mixed growths of pyogenic, anaerobic and occasionally gas-forming organisms are common, and may cause extensive soft-tissue infection or spread to bone to cause osteomyelitis. Clinical features Ulceration is the commonest manifestation (Fig. 19.25 A). 1 This is often multifactorial, but the main contributory factors must be identified because their treatments differ. 'Purely' neuropathic ulcers occur at high-pressure sites and appear cleanly punched out of the surrounding callus. The ulcer is generally painless and sometimes goes unnoticed by the patient, who will complain of numbness with or without neuropathic pain in the feet. The foot is typically warm (unless peripheral vascular disease coexists), with distended veins, a clawed posture and sensory loss. Ischaemic ulcers are painful and tend to affect the edges of

19

CASE STUDY 19.2 DIABETIC VASCULAR DISEASE A 47-year-old factory worker who had had type 2 diabetes for 5 years was referred to the hospital diabetic clinic because of deteriorating glycaemic control. He was not known to have any diabetic complications. He was obese, with a B MI of 32 kg/m2. His HbAlc was elevated at 8.6%. His blood pressure was 154/90 and his lipid profile showed a total cholesterol 6.5 mmol/L, HDL cholesterol 0.8 mmol/L, triglycerides 2.6 mmol/L. He had a family history of type 2 diabetes and ischaemic heart disease. He was currently taking metformin 850mg t.d.s.

Discussion This man has poor glycaemic control, is hypertensive and has dyslipidaemia. The greatest threat to his health conies from the risk of macrovascular disease (myocardial infarction, stroke and peripheral vascular disease), so each of these risk factors needs to be minimized. His 10-year coronary risk can be calculated as about 20%, so he would

the foot, which are cold and pulseless. The history may be dominated by intermittent claudication, sometimes with rest pain. Infection may not cause obvious signs of acute inflammation, but osteomyelitis may cause deep tenderness. Areas of gangrene may occur, especially in the toes (Fig. 19.25B). 2 Charcot's arthropathy is disorganization of the articular surfaces with resorption of bone, which can lead to total disruption of affected joints, sometimes accompanied by a large effusion. The metatarsotarsal, midfoot or ankle joints are usually affected. Sensory loss is usually profound, and acute flare-ups of Charcot's arthropathy, which can appear alarmingly like a septic arthritis, are often (but not always) relatively painless. Investigation of the diabetic foot Effective treatment depends on identifying the cause(s) of ulceration. Tests for neuropathy and ischaemia are described above. Swabs or curettings from deep in the ulcer should be cultured for both aerobic and anaerobic organisms. Plain radiography of the foot may show gas in the soft tissues or bony destruction due to osteomyelitis or Charcot's arthropathy. Generalized loss of bone density (osteopenia) and tapering of the phalanges and metatarsals also occur in neuropathy. Osteomyelitis must be distinguished from Charcot arthropathy; 111ln-labelled white cell scans and MRI scans are increasingly used and are highly specific for infection (Ch. 9, p. 262). More recently, MRI scans have been used and are also very sensitive at detecting osteomyelitis. An acutely inflamed joint

not qualify for statin treatment to lower plasma lipid levels under current UK guidelines, although his risk is at a level where statin treatment might be considered desirable in the future. His obesity will be contributing significantly to all of the risk factors, and one approach that could be considered is an intensive weight-management programme, combined with a drug such as orlistat if necessary, to try and achieve a weight loss of 5-10% over 6 months. Aspirin should also be considered. His glycaemic control is unlikely to improve sufficiently with weight loss alone, and additional therapy, with the addition of a sulphonylurea as well as metformin should be considered. Other options are a thiazolidenedione or acarbose.

SUMMARY 11 Features of diabetic foot ulcers Neuropathic High-pressure zones (metatarsal heads, heel) Cleanly punched Appearance out of surrounding callus Sensory function Ulcer usually painless Foot numb Circulation Foot pulses present Skin warm Site

Ischaemic Margins of foot Ragged edges Ulcer usually painful Sensation preserved Foot pulses absent Skin cold; trophic changes

N.B. Neuropathy and ischaemia often coexist, and infection often complicates ulceration.

should be aspirated to exclude infection, even if Charcot's arthropathy seems likely. Management of diabetic foot problems Predominantly neuropathic ulcers are treated with chiropody to remove callus and a lightweight plaster cast to unload pressure from the affected area, which accelerates healing while keeping the patient mobile. Extra-depth or custom-built shoes, or pressure-absorbing socks, will reduce pressure loading and help to prevent recurrence.

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Ischaemia is treated as described above; the aim is to avoid or limit amputation if at all possible. Rehabilitation after amputation is often difficult, and all too frequently the remaining limb is later threatened by ischaemia. Infection must be treated with appropriate antibiotics and repeated cultures may be needed to ensure that mixed infections, especially including delicate anaerobes, are completely covered. Soft-tissue infections may respond to oral broad-spectrum antibiotics, such as amoxycillin and flucloxacillin, or co-amoxiclav, combined with metronidazole if anaerobic infection is suspected, but extensive infections and osteomyelitis may require some weeks of intravenous treatment and surgical debridement. Amputation may be needed in refractory cases. 1 Acute Charcot's arthropathy must not be treated surgically, as the joint often disintegrates further, and usually improves with immobilization and non-steroidal antiinflammatory drugs. Some recent studies have suggested that bisphosphonates, such as pamidronate, may help delay the progression of acute Charcot's arthropathy. Even badly disrupted joints may remain functional, but chronically unstable joints require arthrodesis. Diabetic foot problems are best managed in a combined specialist clinic. Prevention is extremely important. Many problems can be avoided by teaching patients basic foot care, by regularly checking their feet and shoes, and by providing prophylactic chiropody and special footwear as appropriate. 2

Miscellaneous diabetic complications Necrobiosis lipoidica diabeticorum is a striking lesion with a sunken, atrophic yellowish centre that usually affects the skin on the shins. 3 Like granuloma annulare, a raised skin-coloured lesion with a depressed centre, necrobiosis has been regarded as a cutaneous marker of diabetes, but both conditions also affect non-diabetic people. Connective tissue complications include thickening of the skin (sometimes resembling scleroderma) and limited joint mobility of the fingers.

FURTHER READING ON DIABETES MELLITUS DCCT Research Group 1993 The effect of intensive treatment on the development and progression of long-term complications in insulin-dependent diabetes mellitus. New England Journal of Medicine 329: 977-986. UKPDS 1992 Dietary recommendations for people with diabetes. An update for the 1990s. Diabetic Medicine 9:189-202. European Diabetes Policy Group 1998 A desktop guide to type 1 diabetes mellitus. European Diabetes Policy Group 1998-1999 A desktop guide to type 2 diabetes mellitus.

1018

1

Figs 19.13-19.15

3

Fig. 19.16

2

MCQ 19.16

Pickup J C, Williams G 1996 Textbook of diabetes, 2nd edn. Blackwell. Oxford.

HYPOGLYCAEMIA Blood glucose concentrations are normally maintained between about 4 and 7 mmol/L. Lower concentrations are particularly hazardous to the brain, which depends critically on a steady supply of glucose, its sole metabolic fuel under normal circumstances. Hypoglycaemia is defined rigorously as an arterial blood glucose level of <2.2 mmol/L. In practice, the diagnosis is often made on the basis of venous blood glucose levels. The arteriovenous glucose difference may be particularly marked after meals, because high prandial insulin levels promote glucose uptake and utilization by skeletal muscle and fat.

Causes of hypoglycaemia Hypoglycaemia occurs when glucose taken up into the tissues exceeds that entering the circulation from the liver and the gut. Factors predisposing to hypoglycaemia are therefore high insulin levels; deficiencies of the counterregulatory hormones, especially cortisol and growth hormone; hypothyroidism; damage to the liver, which depletes glycogen and impairs the liver's capacity to secrete glucose; intense exercise, which mobilizes glycogen and stimulates glucose uptake into skeletal muscle; and prolonged starvation, which depletes liver glycogen. Specific causes of hypoglycaemia (Table 19.12) are discussed below. Insulinoma and nesidioblastosis Pancreatic |3-cell tumours, or insulinomas, are the commonest cause of spontaneous hypoglycaemia. Insulinomas are often small (a few millimetres in diameter), sometimes multiple, and may occur together with parathyroid and pituitary tumours in the multiple endocrine neoplasia (MEN) syndrome type 1 (p. 938). About 15% of insulinomas are malignant and metastasize to the liver, when hypoglycaemia may be profound and intractable. Diffuse (3-cell hyperplasia, rather than a discrete tumour, is termed nesidioblastosis and presents with hypoglycaemia, usually in the neonate or infant. Other tumours Large mesenchymal tumours (e.g. retroperitoneal or pleural sarcomas) and hepatomas can cause severe hypoglycaemia, by secreting insulin-like molecules (e.g. growth factors such as insulin-like growth factor II (IGF II)) which structurally resemble insulin and so activate the insulin receptor. Inadequate counter-regulatory hormone secretion Hypoglycaemia may be a presenting feature of Addison's disease or hypopituitarism (in which growth hormone deficiency exacerbates hypoglycaemia), especially during vomiting. It also occurs in congenital adrenal hyperplasia (21-hydroxylase deficiency) and isolated ACTH deficiency.

TABLE 19.12 Causes of hypoglycaemia Insulinoma (and nesidioblastosis in neonates) Other tumours Mesenchymal tumours Hepatomas

produce IGF

Counter-regulatory hormone deficiencies Addison's disease, congenital adrenal hyperplasia Pituitary failure (ACTH, TSH, growth hormone deficiency) Drugs and toxins Insulin Sulphonylureas Pentamidine Ethanol Salicylate overdose (in children) Ackee fruit poisoning (inhibits gluconeogenesis) Hepatic disease Acute hepatic necrosis, e.g. paracetamol overdose Glycogen storage disease Hereditary fructose intolerance Post gastric surgery ('reactive' hypoglycaemia) Miscellaneous Starvation very rare in Prolonged exercise I healthy subjects Falciparum malaria Neonatal (premature babies, or after diabetic pregnancy) Autoimmune (antibodies activate insulin receptor) Idiopathic (exceedingly rare)

Drugs and ethanol Insulin and sulphonylureas commonly cause hypoglycaemia in treated diabetic patients and occasionally in nondiabetic subjects who take the drugs either inadvertently or deliberately. Self-induced 'factitious' hypoglycaemia, usually with insulin, is identified most commonly in medical or paramedical subjects, or in those with a diabetic family member. Pentamidine, used to treat pneumocystis pneumonia in AIDS patients, can cause hypoglycaemia by inducing p-cell necrosis, which may then be followed by diabetes. Ethanol directly inhibits hepatic gluconeogenesis and tends to cause hypoglycaemia, especially in treated diabetic patients who are unable to suppress their circulating insulin levels on demand, and in malnourished subjects or those with alcoholic and other liver diseases in which hepatic glycogen is depleted. Hepatic diseases Severe hepatocellular damage, such as alcoholic liver disease or acute hepatic necrosis in pregnancy or following paracetamol overdose, interferes with the mechanisms

by which the liver normally secretes glucose. Certain glycogen storage diseases (p. 1028) prevent mobilization of hepatic glycogen and cause severe hypoglycaemia in infancy or childhood.

19

Gastrointestinal diseases 'Reactive' hypoglycaemia, i.e. that occurring after meals rather than during fasting, can occur following gastric and intestinal surgery and, very rarely, in normal subjects. The cause is inappropriately high insulin secretion, possibly stimulated by incretin hormones released from the gut by eating, which outlasts the absorption of glucose from the intestine (p. 979). It should be distinguished from the dumping syndrome, which occurs after gastric surgery and is due to large fluid shifts into the intestine owing to a sudden high osmotic load in the small bowel. Miscellaneous causes • Starvation and exercise both have to be extreme for healthy subjects to become hypoglycaemic. • Neonatal hypoglycaemia may occur in premature babies, whose hepatic glycogen stores are limited, and in the babies of women who had poorly controlled diabetes during pregnancy, because hypertrophied fetal islets continue to secrete excess insulin (see p. 1002). • Falciparum malaria causes hypoglycaemia, apparently by inhibiting hepatic glucose production, and this is exacerbated by quinine treatment, which directly stimulates insulin secretion. • Autoimmune hypoglycaemia is due to autoantibodies which bind to and activate the insulin receptor, analogous to the TSH-receptor antibodies that stimulate the thyroid in Graves' disease. This occurs rarely in autoimmune syndromes and following treatment with the antithyroid drug methimazole. • Idiopathic spontaneous ('functional') hypoglycaemia has long been a fashionable diagnosis, following some popular but flawed reports from the USA over 40 years. It is usually made for vague symptoms of hunger and shakiness that are relieved by eating, and usually reflects inadequate investigation. Most subjects with this history prove to have normal glucose levels after either fasting or a test meal.

EFFECTS AND CLINICAL FEATURES OF HYPOGLYCAEMIA As described on page 991, hypoglycaemia causes 'autonomic' features owing to sympathetic activation (tremor, sweating, tachycardia) and neuroglycopenic symptoms and signs, including hunger, confusion, abnormal behaviour, and specific neurological deficits which may suggest focal lesions, fitting and coma. Complaints may be non-specific and hypoglycaemia may remain unrecognized for years: recurrent or chronic hypoglycaemia has caused people to be institutionalized for suspected psychiatric disease. Most causes of hypoglycaemia will be exacerbated by

1019

lack of food and so present during fasting, the notable exception being the reactive hypoglycaemia that follows within a few hours of eating.

Investigation, diagnosis and management of hypoglycaemia Confirmation of hypoglycaemia It is crucial to document hypoglycaemia carefully, as many suspected cases, especially those with 'reactive' symptoms, will not be confirmed; the high levels of psychosocial stress that many of these patients are under may contribute to their symptoms. As a screening procedure, blood glucose levels may be measured before breakfast, but it is best to admit patients to hospital for a supervised 72-hour fast with regular exercise. This schedule will reveal over 99% of cases of spontaneous hypoglycaemia due to insulinomas (the commonest cause), and very few normal subjects will become hypoglycaemic during this time. Blood glucose levels should be checked regularly and, if symptoms develop, two blood samples should be taken for measurement of glucose (using a laboratory method, ideally in arterialized or capillary blood), insulin and C-peptide. Glucose should then be given to confirm that symptoms improve; this fulfils Whipple's triad, namely that symptoms are associated with fasting or exercise, that they are accompanied by demonstrable hypoglycaemia, and that they are relieved by glucose administration.

Investigation and treatment of causes of hypoglycaemia A flowchart for investigating suspected hypoglycaemia is shown in Figure 19.26. Hypoglycaemia not due to insulin excess normally suppresses insulin concentrations to <5mU/L and C-peptide to undetectable levels (<0.1pmol/L). Extrapancreatic tumours, endocrine diseases, gastrointestinal diseases and miscellaneous causes (Table 19.12) should be considered under these circumstances and appropriate tests performed to identify the cause. High insulin levels are due either to endogenous hypersecretion, in which C-peptide levels will also be high, or to administration of exogenous insulin, which will suppress endogenous insulin and C-peptide secretion. Factitious hypoglycaemia induced by insulin injection can therefore be easily identified because C-peptide concentrations measured during hypoglycaemia are undetectable. Endogenous insulin hypersecretion with high C-peptide levels is almost always due to an insulinoma (or nesidioblastosis), when proinsulin levels may also be elevated because of defective processing of proinsulin in neoplastic (3 cells.

O Figs 19.17-19.18 1020

0 MCQ 19.17

FIG. 19.26 Flowchart for investigating suspected hypoglycaemia

The possibility of inadvertent or deliberate sulphonylurea administration, which stimulates insulin and C-peptide release, should be considered, especially if an insulinoma cannot be localized. Sulphonylureas can be detected by screening the urine. Hypoglycaemia provocation tests, designed to demonstrate that endogenous insulin and C-peptide secretion from an insulinoma do not suppress normally during hypoglycaemia (induced by exogenous insulin), are potentially dangerous and should not now be used. A flowchart for diagnosing insulinoma is shown in Figure 19.26. The main problem is in localizing the tumour: very small insulinomas may be missed by sophisticated imaging techniques, including CT and pancreatic arteriography, and even by palpation at operation. OUltrasound imaging may be helpful, either using a probe mounted on an endoscope, which can visualize the head of the pancreas from the duodenum, or by scanning the pancreas exposed at operation. Selective venous sampling can also be used to determine which sector of the pancreas is secreting excess insulin. The sensitivity of this method can be improved by combining it with selective injection of calcium (which stimulates insulin secretion) into each of the four main vessels supplying the pancreas. An exaggerated rise is seen in the affected segment. Treatment consists of surgical removal (which is curative for benign tumours) if the tumour can be localized. Nesidioblastosis is also treated by pancreatectomy. Medical treatment, for inoperable tumours or patients unsuitable for surgery, consists of suppressing insulin secretion, usually with diazoxide, a sulphonylurea derivative; its main sideeffects are hypotension and hirsutism. Somatostatin analogues (e.g. octreotide) have been used to treat insulinoma and nesidioblastosis, but also suppress growth hormone and glucagon release so that hypoglycaemia, when it occurs, may be dangerously profound and prolonged.

19

CASE STUDY 19.3 HYPOGLYCAEMIA A 67-year-old woman was admitted with an episode of right-sided weakness, associated with transient expressive dysphasia. Her symptoms and signs resolved within an hour of admission to hospital. She was not diabetic, was normotensive, and had no other identifiable risk factors for cardiovascular disease. An ECG and echocardiogram were within normal limits, and carotid Doppler examination showed no significant stenosis. On further questioning it became apparent that she had experienced many similar episodes over a period of 3 years. These tended to occur first thing in the morning, when she complained of having a 'muzzy' head on most days, and always resolved after breakfast. She complained of occasional attacks of sweating, but was otherwise asymptomatic. Serum sodium was 130mmol/L, potassium 4.3mmol/L,

urea 3.4mmol/L, creatinine 84umol/L, and cholesterol 4.4 mmol/L. Her fasting glucose taken in hospital was 1.6 mmol/L.

Questions 1, What is the differential diagnosis at this stage? 2. What tests would establish the exact diagnosis?

Discussion This patient has clearly documented hypoglycaemia, which could explain her symptoms and signs. She was admitted to hospital for a supervised fast, and when she developed symptoms (after less than 12 hours' fasting) blood was taken for measurement of fasting glucose,

Large mesenchymal tumours and hepatomas are easily diagnosed by CT and biopsy. These tumours should be removed if possible; medical treatment consists of steroids and glucagon injections. Idiopathic spontaneous hypoglycaemia is often investigated by the extended (5-hour) OGTT, which has a fairly high yield, as about 25% of normal healthy subjects will show a fall in venous blood glucose levels to below 3 mmol/L during this test. When the diagnostic criteria for hypoglycaemia are applied strictly, true 'idiopathic' hypoglycaemia is extremely rare. The management of acute hypoglycaemia is discussed on page 991 and individual causes of hypoglycaemia require the treatments described above. ©

FURTHER READING ON HYPOGLYCAEMIA Frier B M, Fisher M 1993 Hypoglycaemia. Edward Arnold, London.

PLASMA LIPOPROTEINS AND THEIR DISORDERS Normal lipid metabolism The two major lipids are triglycerides, a valuable energy source and store, and cholesterol, an essential component

insulin, and C-peptide. A urine sample was taken to screen for sulphonylureas. A synacthen test was carried out to exclude Addison's disease, and was normal. The most likely diagnosis is an insulinoma, and this was confirmed by demonstrating elevated plasma insulin and C-peptide concentrations, the latter indicating endogenous secretion of insulin (rather than selfadministered), and a negative plasma screen for sulphonylurea ingestion. Once the biochemical diagnosis is confirmed, CT scanning of the pancreas, perhaps complemented by pancreatic arteriography, may help localize the tumour. Surgical exploration following the scan may be justified, even if the scan fails to localize the tumour. Insulinomas are usually benign (less than 1 % are malignant) and the prognosis is good following surgical resection.

of cell membranes and a precursor in the synthesis of bile salts, steroid hormones and vitamin D. Both are absorbed from dietary fat (especially in meat, eggs and dairy products) and are also synthesized by the liver. Cholesterol is synthesized from acetyl-CoA, the rate-limiting enzyme being HMGCoA reductase (hydroxymethylglutaryl coenzyme A reductase). Cholesterol suppresses its own synthesis by inhibiting HMGCoA reductase, and bile-salt synthesis is inhibited by bile salts reabsorbed from the gut and returned to the liver through the enterohepatic circulation. Triglycerides and cholesterol are insoluble and have to be complexed into soluble lipoproteins to allow their transport from the gut and liver to the tissues. The lipoproteins (Fig. 19.27) are spherical particles containing a hydrophobic core of triglyceride and esterified cholesterol surrounded by a hydrophilic coat of phospholipid, specific proteins termed apoproteins, and a little free cholesterol. Apoproteins are synthesized in the liver and gut and comprise six main classes (apos A to F). Lipoproteins can be classified by their density on ultracentrifugation, which decreases with increasing triglyceride content. The lipoproteins are metabolized by two different pathways (Fig. 19.28). The exogenous pathway begins with dietary fat in the gut and employs triglyceride-rich chylomicrons to deliver FFA to the tissues and cholesterol to the liver. The endogenous pathway uses verylow-density lipoprotein, containing triglyceride synthe-

1021

FIG. 19.27 General structure and composition of lipoproteins

sized in the liver, to supply FFA and cholesterol to the peripheral tissues. Exogenous pathway • Chylomicrons are synthesized from dietary fat in the gut and have a very high triglyceride content, together with cholesterol and specific apoproteins (apos B48, C and E). Chylomicrons enter the circulation from the lymphatics and their triglyceride content is progressively depleted by lipoprotein lipase (LPL), an enzyme of the capillary endothelium in skeletal muscle and fat, which is activated by apo CII in the chylomicrons. FFA liberated by triglyceride breakdown are used by the tissues as fuel or for storage as triglyceride. • The residual chylomicron remnants, partly stripped of triglyceride and therefore denser, are taken up into hepatocytes by specific receptors that recognize apo E, so delivering cholesterol to the liver.

1022

Endogenous pathway • Very low-density lipoproteins (VLDL) are synthesized in the liver and, like chylomicrons, have an initially high triglyceride content which is depleted by LPL in the periphery. VLDL also contain cholesterol and apos B100, C (including CII, which activates LPL) and E. Loss of triglyceride produces intermediate-density lipoprotein (IDL). • IDL is partly taken up by the liver (through receptors for apos B and E) to recycle cholesterol, and the rest is further stripped of triglyceride to yield low-density lipoprotein (LDL). • LDL is perhaps the most important lipoprotein in causing disease, as it is abundant (normally about three-quarters of total plasma cholesterol) and produces atheroma. It is taken up into the liver and other tissues by specific LDL receptors that recognize apo B100. LDL uptake has important effects on cholesterol metabolism

FIG. 19.28 The exogenous and endogenous pathways of lipid metabolism FFA, free fatty acid; LPL, lipoprotein lipase (found in capillary endothelium); IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein. The chylomicron remnant binds to the hepatocyte via the apo-E receptor, as does the IDL. The LDL binds via the apo-B100 receptor (as does IDL also).

and atherogenesis. LDL entering the liver 'downregulates' (inactivates) LDL receptors and so reduces the liver's capacity to assimilate more LDL, and also inhibits HMGCoA reductase and therefore cholesterol synthesis. LDL is the only lipoprotein to deliver cholesterol to peripheral tissues, including the arterial intima, where its deposition causes atheroma formation (see p. 543). Another atherogenic lipoprotein is lipoprotein (a), or Lp(a), a quantitatively minor species synthesized in the liver which contains apo B100 and apo(a). The latter structurally resembles plasminogen and may bind to fibrin, preventing fibrinolysis and promoting thrombosis, and inducing atherogenesis where fibrin is deposited at sites of vascular damage. The final lipoprotein is high-density lipoprotein (HDL), which is synthesized in the liver and gut and has a relatively high content of apoproteins, notably apo AI. HDL comprises about one-quarter of total plasma cholesterol; it opposes the effect of LDL in that it protects against atheroma formation, apparently by facilitating 'reverse' cholesterol transport from the arterial wall to the liver.

Measurement of plasma lipid levels Plasma lipid concentrations, especially of cholesterol, vary widely between individuals and between different populations. For example, the mean plasma cholesterol is substantially lower in Africans and Asians than in Europeans, of whom about 50% have total cholesterol levels above the recommended limit of 5.2mmol/L. Forty per cent of individual variability is genetically determined; environmental modifying factors include diet, exercise, body weight and alcohol intake. Both obesity and a diet rich in saturated fats cause the atherogenic lipid profile of increased LDL and reduced HDL levels, which can be reversed by a diet high in fibre and polyunsaturated fats and by regular exercise. Before the menopause, women have lower LDL and higher HDL cholesterol levels than men, which partly explains their relative protection against atherosclerosis. For practical clinical purposes, total, LDL and HDL cholesterol, and triglyceride concentrations should be measured. A fasting sample is needed for accurate triglyceride measurements, as chylomicron levels rise considerably after meals. Lipid levels may be disturbed for several weeks after severe stress, such as myocardial infarction. Large-scale, random population screening for hyperlipidaemia would be complicated, expensive and of doubtful benefit in the UK, where hypercholesterolaemia is so common. Plasma lipid estimations are confined to high-risk individuals with: • coronary heart disease • peripheral vascular disease (especially if present before 50 years of age) • a strong family history of vascular disease • other risk factors (smoking, hypertension, diabetes, obesity).

Pathological significance of plasma lipid abnormalities Epidemiological studies indicate that the incidence of atherosclerosis is strongly related to total plasma cholesterol and specifically to LDL cholesterol levels; as mentioned above, Lp(a) levels may also determine atherosclerosis in certain families or groups (e.g. diabetic patients with microalbuminuria). Conversely, HDL cholesterol concentrations are inversely related to coronary heart disease, especially in moderate hypercholes-terolaemia. The current view is that there is a weak association with hypertriglyceridaemia, which becomes much stronger if LDL cholesterol is raised and HDL reduced. Recent interest has focused on oxidized LDL, which may be more atherogenic, and the possible protective role of antioxidants such as vitamins C and E. See the Joint British Societies coronary risk prediction chart (Fig. 19.29).

Hyperlipidaemia Increased concentrations of specific lipoproteins may be primary, i.e. due to hereditary defects in lipoprotein metab-

olism, or secondary to certain diseases. The lipoprotein class(es) involved may be identified precisely by lipoprotein electrophoresis, but this is superfluous to the routine clinical management of hyperlipidaemia, which can be guided satisfactorily by measuring the major cholesterol fractions and triglycerides.

19

Primary hyperlipidaemios These conditions can be classified by the WHO/Fredrickson system (Table 19.13). The molecular basis of several has now been elucidated. Familial hypercholesterolaemia (FH) This is due to defects in the LDL receptor which prevent the uptake of LDL cholesterol into the liver and so increase plasma LDL levels. These are further raised by increased hepatic cholesterol synthesis, as feedback inhibition by cholesterol of HMGCoA reductase is reduced. Protective HDL cholesterol levels are reduced and triglyceride levels are either normal (type Ila) or increased owing to VLDL (type lib). These gene defects occur in about 1 in 500 in the UK. Homozygotes have grossly elevated LDL cholesterol (>15mmol/L) and suffer greatly accelerated atherosclerosis, often dying of myocardial infarction in their teens or 20s. Heterozygotes (who have moderately reduced LDL receptor activity) have lower LDL cholesterol levels (>9mmol/L) and present with coronary heart disease in their 40s. Both genotypes often have tendon xanthomata - cholesterol deposits that thicken the Achilles tendon or cause nodules over the patellar or triceps tendons - as well as the corneal arcus and xanthelasmata that can occur in milder degrees of hypercholesterolaemia, and also in people with normal cholesterol levels (see Table 19.14). Poly genie hypercholesterolaemia This is much commoner than FH and causes a similar but milder pattern of hypercholesterolaemia with normal (type Ila) or elevated (type lib) triglyceride levels. Inheritance is polygenic; coronary heart disease appears in the 40s and xanthomata do not develop. Familial combined hyperlipidaemia This is a variable combination of types Ila, lib and IV, which is inherited as an autosomal dominant and which predisposes to atherosclerosis. Familial hypertriglyceridaemia This is due to either increased endogenous triglyceride synthesis (excess VLDL is produced by the liver, Fig. 19.28), or failure of exogenous triglyceride in chylomicrons to be cleared by LPL; defects in LPL itself or in apo CII, which normally activates it, can be responsible. Plasma triglycerides are grossly elevated (10-100mmol/L); the fraction responsible can be identified simply by storing plasma for 18 hours at 4°C, when chylomicrons will form a creamy supernatant, whereas VLDL or IDL cause uniform turbidity. Severe hypertriglyceridaemia (>10mmol/L) causes acute pancreatitis, eruptive xanthomata (itchy, reddish

1023

TABLE 19.13 Primary hyperlipidaemias (WHO modification of Fredrickson classification) Type

Total plasma cholesterol

I

Normal

Ha

(LDL)

llb III IV V

(LDL)

Normal or slight Normal or slight

Total plasma triglyceride (chylo) N

(VLDL) (IDL) (VLDL) (chylo and VLDL)

Defect

Inheritance

Prevalence

Atherosclerosis risk increased

Lipoprotein lipase deficiency or apo Cll deficiency LDL receptor defect

Recessive

Rare

No

Dominant (FH) or polygenic Dominant Dominant Recessive

Polygenic is common Common Rare Common Rare

Yes

LDL receptor defect Apo E abnormality Overproduction of VLDL Lipoprotein lipase deficiency or apo Cll deficiency

TABLE 19.14 Features of hyperlipidaemia Coronary heart disease and peripheral vascular disease Lipid deposition in soft tissues: • Tendon xanthomata always indicate hypercholesterolaemia • Palmar xanthomata • Xanthelasmata • Corneal arcus

also found in subjects with normal cholesterol

• Eruptive xanthomata Lipaemia retinalis Acute pancreatitis

in hypertriglyceridaemia

triglyceride deposits) and lipaemia retinalis (a milky appearance of the retinal vessels); coronary heart disease is not generally increased (see Table 19.14). Secondary hyperlipidaemias These may arise in hypothyroidism, untreated diabetes mellitus, oral oestrogen or thiazide diuretic therapy, alcohol abuse, the nephrotic syndrome and liver disease. Those causing an atherogenic lipid profile predispose to vascular disease. These conditions must be considered and excluded in cases of lipid abnormality (Table 19.15).

Management of hyperlipidaemias 1 Hyperlipidaemia must be managed as part of a general attack on cardiovascular risk factors. Essential general measures therefore include stopping smoking (one of the most important independent risk factors); reducing excessive alcohol intake; controlling hypertension (avoiding drugs that raise blood lipid or glucose levels); lowering body

1

1024

Case 19.4

Yes Yes No No

TABLE 19.15 Secondary hyperlipidaemias Cholesterol Disorder

VLDL

Diabetes Obesity Hypothyroidism Nephrotic syndrome Cholestasis (e.g. primary biliary cirrhosis) Alcohol abuse

LDL HDL Triglycerides Complications

4 4 —

or -

-

CHD CHD CHD CHD CHD

or

Pancreatitis; not CHD

CHD, coronary heart disease.

weight towards a BMI of <25; and encouraging exercise (which raises HDL levels). Recent studies have emphasized the value of both general and specific measures in reducing mortality from coronary heart disease in hyperlipidaemic people, namely diet and stopping smoking in the Oslo Trial, gemfibrozil treatment in the Helsinki Heart Study, and finally, pravastatin in the West of Scotland Coronary Prevention Study. Lipid-modifying drugs The principal classes of drugs are shown in Table 19.16. Those that primarily affect cholesterol, lowering total and LDL cholesterol and sometimes raising HDL, include the bile-salt sequestering resins and the HMGCoA reductase inhibitors (statins). The resins (e.g. cholestyramine and colestipol) bind bile salts in the gut lumen, preventing them from returning to the liver in the enterohepatic circulation; this reduces negative feedback inhibition by the bile salts of their own synthesis and so increases cholesterol consumption by the liver. Resins are often effective in hypercholesterolaemia,

19

TABLE 19.16 Lipid-modifying drugs Effects on Side-effects

Indications

Resins Cholestyramine Cholestipol

Flatulence, gut upset Block absorption of digoxin and warfarin

Hyperchol.

Statins (HMGCoA reductase inhibitors)

Gut upset Myositis (rare) Long-term safety uncertain as yet

Hyperchol.

Drugs

LDL

HDL

TG

Simvastatin Pravastatin Probucol

4

i

-

Gut upset, QT prolongation

Hyperchol.

Fibrates Gemfibrozil Bezafibrate

i

T

I

Gut upset Gallstones Myositis (rare) Potentiate anti-coagulants

Hypertrig. Combined

Nicotinic acid Acipimox (derivative)

it

4

G u t upset, ulceration Flushing (less with acipimox) Glucose intolerance (less with acipimox)

Hypertrig. Combined

Fish oils Omega-3 marine oils

t

4

Gut upset Glucose intolerance (avoid in type 2 diabetes)

Hypertrig.

-

Hyperchol. hypercholesterolaemia; hypertrig. hypertriglyceridaemia; combined, combined hyperlipidaemia; TG, triglycerides.

including heterozygous FH, but have prominent gastrointestinal side-effects and must be introduced slowly. The resins have traditionally been first-line treatment for hypercholesterolaemia but are now being supplanted by the statins. Statins (e.g. simvastatin and pravastatin) block cholesterol synthesis and lower intracellular cholesterol levels, which upregulates LDL receptors on the liver and stimulates LDL uptake from the blood. These powerful drugs are generally well tolerated and so far seem to have no long-term toxic side-effects. Primarily triglyceride-lowering drugs are the fibrates, nicotinic acid and its derivatives, and fish oils; fibrates and nicotinic acid also improve the cholesterol profile, whereas fish oils may lower HDL levels. Fibrates, e.g. gemfibrozil, fenofibrate and bezafibrate (which have generally replaced clofibrate), block VLDL and cholesterol synthesis, whereas nicotinic acid and its derivatives (e.g. acipimox) reduce VLDL synthesis by inhibiting lipolysis and therefore the supply of FFA from fat to the liver. Fibrates are well tolerated; nicotinic acid causes troublesome flushing and mild hyperglycaemia, which appear to be less prominent with acipimox. Probucol lowers cholesterol levels and also has antioxidant properties, reducing levels of oxidized LDL and atherogenesis. The fish oils inhibit VLDL triglyceride

synthesis. They have to be taken in large doses and cause gastrointestinal upset and glucose intolerance; this argues against their use in patients with type 2 diabetes, who frequently have hypertriglyceridaemia. Management of hypercholesterolaemia - primary prevention Moderate (polygenic) hypercholesterolaemia should be treated initially for several months with a low-fat diet and general measures to reduce cardiovascular risk factors. A reduction in total fat intake and a relative increase in polyunsaturated fats (replacing fatty meats, dairy produce and fried foods with fish, chicken, vegetable oils and grilled or boiled foods) can reduce LDL cholesterol by up to 10% and be effective in mild hypercholesterolaemia. This healthy diet must be positively promoted. Most recent guidelines recommend that treatment decisions should be made on the basis of risk. Risk equations have been derived from the data collected from the Framingham study, and are the basis for most risk tables. These take into account other factors, specifically age, sex, blood pressure, smoking and diabetic status, as well as the total: HDL cholesterol ratio, to derive the risk of developing a myocardial infarct over 10 years. The current recommendations are that patients should be treated with a statin

1025

if the 10-year coronary risk is greater than 30%. If the risk is greater than 15% and the total cholesterol is greater than 5.0mmol/L, then lifestyle and other measures should be instituted, and treatment with a statin considered if these are unsuccessful (Fig. 19.29). The treatment of FH is difficult. Heterozygotes usually respond to a combination of resin and statin, but homozygotes often do not and may require regular plasma exchange or ultracentrifugation of plasma to remove LDL. Secondary prevention Patients with pre-existing coronary artery disease should be treated aggressively, with the aim of reducing cholesterol to less than 5.0mmol/L and LDL cholesterol to below 3.0mmol/L; the best trial evidence in this group supports the use of a statin, although a fibrate may be considered if the serum triglyceride level is above 5 mmol/L. Management of hypertriglyceria'aemia Dietary management of hypertriglyceridaemia should aim to achieve a BMI of <25 and a reduction in saturated fat intake. Severe hypertriglyceridaemia (>10 mmol/L) requires treatment to prevent attacks of acute pancreatitis. A fibrate or nicotinic acid are often effective, and fibrates are particularly useful in type III hyperlipidaemia. Hypertriglyceridaemia is frequently associated with glucose intolerance, and the latter may be exacerbated by either nicotinic acid (but not acipimox) or fish oils. 1

FURTHER READING ON PLASMA LIPOPROTEINS AND THEIR DISORDERS Joint British Recommendations on prevention of coronary heart disease in clinical practice. Heart Supplement 2 December 1998.

PORPHYRIA

The term porphyria refers to a heterogeneous group of inborn errors of metabolism caused by enzyme defects in the biosynthetic pathway of haem, leading to the accumulation of its precursors the porphyrinogens. These consist of four cyclized pyrrole rings and are classified into uro-, copro- and protoporphyrinogens by the distribution of side-groups around the porphyrin ring. Porphyrinogens are excreted in the urine if present in excess in blood. They are colourless compounds but are oxidized to yield highly coloured porphyrins, which in some cases of acute porphyria colour the urine dark.

1 1026

MCQ 19.18

HAEM SYNTHESIS

Porphyrin biosynthesis occurs in a variety of cell types, but predominantly in liver and bone marrow (Fig. 19.30). The initial step is the condensation of glycine and succinyl CoA to form 8-amino-laevulinic acid (8-ALA) under the influence of mitochondrial ALA synthase. The single pyrrole ring, porphobilinogen (PBG), is then formed in the cytosol from two molecules of 8-ALA. Four molecules of PBG are cyclized under the influence of PBG deaminase to form the porphyrin ring structure. There follows a series of decarboxylation and mitochondrial oxidation reactions that eventually yield protoporphyrin IX. The addition of ferrous iron, catalysed by ferrochelatase, is the final step in haem biosynthesis. The pathway's activity is controlled by negative feedback of haem on 8-ALA synthase.

CLASSIFICATION OF THE PORPHYRIAS

The porphyrias may be classified as hepatic or erythropoietic, according to the main site of the biosynthetic defect and excess precursor formation, but the clinical subdivision into acute or non-acute forms is more useful (Table 19.17). All porphyrias are associated with increased 8-ALA synthase activity because of decreased negative feedback, which is usually enhanced by an environmental factor. This is accompanied by increased PBG deaminase activity in the non-acute conditions, but normal or reduced activity in the acute varieties. The net result in the acute conditions is an accumulation of 5-ALA and PEG, which probably accounts for the neurological, psychiatric and acute gastrointestinal disturbances observed. In the non-acute conditions specific uro- and coproporphyrins accumulate without PBG excess, because increased activity of the 8ALA synthase pathway is accompanied by increased PBG deaminase activity (Fig. 19.30). Photosensitivity occurs in all porphyrias, except for the acute intermittent variety, and is due to accumulation of porphyrin within the epidermis as a result of photooxidation of porphyrinogens.

Acute porphyrias Acute porphyrias are all inherited as mendelian dominant traits. They are characterized by acute episodic neurological and gastrointestinal symptoms, usually followed by complete remission, although fatalities due to respiratory failure may occur. Episodes are rare before puberty, when a rise in the sex steroids enhances 8-ALA synthase activity. Acute attacks are precipitated by alcohol, sex steroids (e.g. oral contraceptives) and many drugs, notably barbiturates, sulphonamides and other lipid-soluble enzyme-inducing drugs, which increase S-ALA synthase activity.

19

FIG. 19.29 Examples of coronary risk tables from the joint British Recommendations

TABLE 19.1? Classification of porphyrias Acute

Non-acute

Acute intermittent porphyria

Porphyria cutanea tarda (cutaneous hepatic porphyria)

Variegate porphyria Hereditary coproporphyria

Erythropoietic - congenital porphyria - protoporphyria

cular failure (75%), sensorimotor peripheral neuropathy (50%), respiratory muscle paresis, fitting and coma. Psychiatric manifestations, which vary from depression to frank psychosis, may last throughout the acute episode. Renal impairment with proteinuria and inappropriate antidiuretic hormone (ADH) secretion (p. 1104) may also occur. The diagnosis may be suggested by a positive family history, or the passage of urine that turns red-brown on standing. Confirmation depends on testing urine for excess PBG using Ehrlich's aldehyde reagent, which produces a pink colour that is insoluble in chloroform. Genetic testing is now possible, by analysis of the PBG deaminase gene, but this does not yet have widespread clinical application.

I I I 1 I I I I

Variegate porphyria The defect is in protoporphyrinogen oxidase. Features are similar to those of acute intermittent porphyria, together with the cutaneous features of porphyria cutanea tarda (see below). The highest incidence is in South African whites.

FIG. 19.30 Porphyrin metabolism Increased 5-ALA synthetase activity leads to increased porphyrin production (porphyria). In acute porphyria porphobilinogen metabolism is normal or reduced, in contrast to non-acute porphyria, in which it is increased.

Acute intermittent porphyria Acute intermittent porphyria is due to a defect in PEG deaminase. Most cases are clinically silent; women are more likely to manifest acute attacks, consisting in 95 % of cases of abdominal pain and vomiting. Additional features include sinus tachycardia, hypertension and left ventri-

Hereditary coproporphyria Coproporphyrinogen oxidase is defective, causing features similar to those of variegate porphyria. Management of acute porphyria Prophylaxis in those at risk is of obvious importance. Suspected patients can be identified by urine testing (30% yield) and erythrocyte-enzyme assays. Those affected should avoid alcohol, barbiturates and oral contraceptives, and special observation during pregnancy is indicated. Acute attacks may be curtailed by a high carbohydrate intake (e.g. 400g/day of glucose intravenously) and perhaps intravenous haematin, both of which depress

1027

8-ALA synthase activity. Inappropriate ADH secretion may require fluid restriction. Tachycardia and hypertension should be treated with (3-blockade, psychiatric disturbances with phenothiazines, and fitting with benzodiazepines; barbiturates are absolutely contraindicated.

Liver transplantation may be required as a last resort; bone marrow transplantation may, in the future, offer hope of a cure. 1

INHERITED DISORDERS OF

Non-acute porphyrias Porphyria cutanea tare/a Porphyria cutanea tarda is caused by a defect in hepatic uroporphyrinogen decarboxylase, which has a genetic element but is predominantly acquired; alcohol abuse is often important. It may also be associated with hepatitis C infection. It is characterized by bullae following sun exposure or minor trauma, usually affecting the face, back of the neck and dorsum of the hands. The bullae heal with scarring and diffuse thickening of the skin, which can resemble scleroderma, and hypertrichosis also develops. Hepatomegaly (particularly with alcohol abuse) and hepatic siderosis and diabetes mellitus may occur. Urinary uroporphyrin excretion is increased but PBG is normal. Treatment includes avoidance of alcohol, venesection to achieve normal uroporphyrin levels in urine, and low-dose chloroquine to increase urinary uroporphyrin excretion. Congenital porphyria Congenital porphyria is a rare autosomal recessively inherited condition which presents early in childhood. It is due to a defect in uroporphyrinogen cosynthetase and is characterized by photosensitivity with bulla formation and healing with scarring. Dystrophic nail changes and brown or pink tooth discoloration may also occur, and a normochromic anaemia with normoblastic marrow hyperplasia and splenomegaly are usual features. Low-dose chloroquine may be of value in treatment, and splenectomy may improve the anaemia. Erythropoietic protoporphyria Erythropoietic protoporphyria is an autosomal dominant condition caused by a defect in ferrochelatase activity, which presents in childhood with photosensitivity (often with no rash), severe peripheral paraesthesia and hepatic dysfunction due to protoporphyrin deposition. The diagnosis is made by demonstrating characteristic erythrocyte fluorescence and elevated red cell protoporphyrin levels. Urinary and faecal protoporphyrin excretion may be increased. Treatment with oral (3-carotene may protect against the photosensitivity, and bile-salt sequestering agents (e.g. cholestyramine) may protect the liver by interrupting the enterohepatic circulation of protoporphyrin.

1 1028

MCQ 19.19

CARBOHYDRATE METABOLISM

Glycogen storage diseases Glycogen is synthesized from glucose by glycogen synthase and a branching enzyme which adds side-chains to the growing polymer. It is stored primarily in liver as a source of glucose for release into the circulation, and in muscle as substrate for glycolysis (see Fig. 19.7). Glycogen breakdown depends on several enzymes, including phosphorylase (which removes glucose residues from the polymer), a debranching enzyme (amylo-l,6-glucosidase), and oc-1,4glucosidase which cleaves glucose from glycogen stored in lysosomes. In liver, glucose-6-phosphate is converted to glucose under the influence of glucose 6-phosphatase, whereas in muscle it undergoes glycolysis and is converted sequentially to fructose-6-phosphate, fructose-1,6bisphosphate (catalysed by phosphofructokinase), pyruvate and lactate. The glycogen storage diseases are due to defects in the above enzymes, which are all inherited as autosomal recessive traits. Twelve defects have been identified, and except for muscle phosphorylase deficiency (type V, McArdle), they present in early childhood. All are extremely rare. Glycogen synthase deficiency (very rare) causes severe depletion of liver glycogen. The other defects cause glycogen to accumulate in liver, muscle, myocardium, kidney or gut, and cause features such as hepatomegaly, hypoglycaemia, muscle fatigue and cramps, and congestive cardiac failure. The commonest conditions are types I, II andV. Type I (Von Gierke) Hepatic glucose 6-phosphatase is defective, preventing hepatic glycogen mobilization and presenting with hepatomegaly in infancy. The nervous system adapts to using ketone bodies as an energy source, but intercurrent illness precipitates severe hypoglycaemia and lactic acidosis. Affected infants are characteristically obese, grow poorly and exhibit hyperlipidaemia and hyperuricaemia. Blood glucose levels fail to increase after glucagon administration and the diagnosis is confirmed by liver biopsy. Untreated, the condition is usually fatal in early childhood. Successful therapy depends on frequent glucose feeds given day and night by nasogastric tube. This can restore normal growth, but impairs neurological ketoadaptation and so increases the hazards of acute hypoglycaemia! Type II (Pompe) a-Glucosidase deficiency causes lysosomal glycogen to accumulate in cardiac and skeletal muscle and liver. Car-

diomegaly and congestive cardiac failure usually present in infancy and prove fatal within months, but variants include childhood presentations with myopathy and an indolent onset in adult life. Hypoglycaemia does not occur. Type V (McArdle) Muscle phosphorylase deficiency is a rare condition which presents in adult life with muscle cramps and myoglobinuria after exercise. Victims are easily fatigued and develop proximal muscle wasting. Physical activity is restricted but lifespan is normal.

Galactosaemia Galactosaemia is a rare autosomal recessive condition caused by deficiency of the liver enzyme galactose-1 phosphate uridyl transferase, which catalyses conversion of galactose-1 -phosphate to glucose-1-phosphate. Affected children are normal at birth but develop symptoms soon after milk feeds are started: galactose in milk cannot be metabolized, causing the accumulation of galactose-1phosphate, which is toxic to tissues. If undetected, the condition progresses from diarrhoea and vomiting to hepatomegaly and jaundice. Death within a few weeks is common, but survivors develop cataracts, cirrhosis and mental retardation. Fortunately, prompt detection in the neonate and the avoidance of galactose in the diet allows relatively normal development, although some degree of mental retardation and ovarian failure may occur. Initial diagnosis is by detection of reducing substances in the urine by a positive Clinitest but a negative result with enzyme-based sticks that are specific for glucose. Definitive diagnosis is based on assay of red-cell galactose-1phosphate uridyl transferase levels. The effectiveness of therapy is assessed by red-cell galactose-1-phosphate concentration.

storage diseases, mucolipidoses, mucopolysaccharidoses and glycoprotein storage diseases. They are autosomal recessive, except for Hunter's disease (type II) and Fabry's disease, which are both X-linked. The disorders are generally characterized by excessive deposition of substrate in brain, spleen, liver and bone, causing neurological and skeletal problems with hepatosplenomegaly. A few of the commoner disorders are briefly described below.

19

Sphingolipidoses Gaucher's disease Deficiency of |3-glucocerebrosidase causes gangliosides to accumulate in nervous tissue (in the childhood form, causing mental retardation and spasticity) or in the liver, spleen and bone (in the adult form). The adult form is more common and presents with hepatosplenomegaly, bony symptoms including severe pain and deformity, and anaemia due to bone marrow infiltration. Typical Gaucher's cells can be recognized on liver or marrow biopsy. Splenectomy may be helpful. Niemann-Pick disease, Fabry's disease and Toy-Sachs disease See Table 24.70, page 1413.

Mucopolysaccharidoses Mucopolysaccharidoses are a group of complexcarbohydrate storage disorders with abnormal accumulation in fibroblasts, chondrocytes and neural tissue. Common features include skeletal dysplasia, hepatosplenomegaly, coarse skin and corneal clouding. Gross mental retardation is present in the two best-recognized variants. Hurler's syndrome and Hunter's syndrome, which overlap to some extent.

LYSOSOMAL STORAGE DISORDERS Lysosomal storage disorders are a large group of inherited diseases in which there is an abnormal deposition of a substrate in vacuoles related to lysosomes as a result of an inborn error of metabolism. These disorders include lipid-

FURTHER READING ON LYSOSOMAL STORAGE DISORDERS Scriver C R, Beaudet A L, Sly W S, Valle D 1989 The metabolic basis of inherited disease. McGraw-Hill, New York.

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20

Renal andUrinary Disease John Cunningham

Epidemiological considerations 1031

Renal disease and hypertension 1081

Anatomy and physiology 1031

Urinary tract infection, pyelonephritis and tuberculosis 1083

Assessment of renal structure and function 1037 Major symptoms and signs of renal and urinary disease 1044 Major renal syndromes 1047 Primary glomerular disease 1068 Renal involvement in non-renal and multisystem disease 1075 Diseases of the renal interstitium 1079 Cystic diseases of the kidney 1030

Nephropathy due to physical or chemical agents 1086 Urinary stone 1086 Urinary tract obstruction 1090 Neoplasia in the kidney and urinary tract 1091 Continence and incontinence 1095 Prescribing in patients with renal disease 1097

The function of the kidney in health falls into three main areas (Table 20.1): • Excretion of waste products • Maintaining the constancy of the internal environment • Biosynthesis of hormones. The importance of these functions is vividly demonstrated in patients with kidney disease, in whom a wide variety of symptoms and signs are associated with disordered metabolism in addition. The sophistication of the various functions of the kidney is evident from the striking contrast between the limited efficacy of the various forms of artificial dialysis treatment, and the virtual normalization of body function that attends reversal of kidney dysfunction or successful transplantation.

EPIDEMIOLOGICAL CONSIDERATIONS The annual incidence rate of end-stage renal disease (ESRD) in the UK is about 150 per million population.

Of these, about 60% are accepted for renal replacement therapy (RRT). In December 2000 the number of patients in the UK receiving treatment for ESRD by means of dialysis or transplantation was approximately 32 000. Patients with the various forms of glomerulonephritis form the largest group receiving RRT, followed by those with tubulointerstitial diseases (including pyelonephritis) and diabetic nephropathy. The incidence of ESRD rises rapidly with age; its frequency is similar in males and females. Urinary tract infection (UTI), though often not serious, is a considerable source of morbidity. It has been estimated that 1-2% of all general practice consultations are in relation to symptoms suggestive of UTI. Women are most frequently affected, and prevalence studies have shown symptoms of dysuria in as many as 21% of females aged between 20 and 65 years. Demonstrable infection has a prevalence of 4% among females between the ages of 16 and 45, rising to 10% between the ages of 55 and 64 and 15% in those over 65. For some renal diseases there are marked racial and regional differences in incidence. For example, ESRD resulting solely from severe hypertension is much commoner in blacks than in whites. In Asians from the Indian subcontinent the incidence of type 2 diabetes mellitus is very high and an unusually large proportion of these acquire diabetic nephropathy, which is by far the commonest cause of renal failure in this group. Renal amyloid is an uncommon cause of ESRD in western Europe and the USA, but in Israel, with its large population of Sephardic Jews, familial Mediterranean fever leading to amyloidosis accounts for 7% of patients reaching ESRD. In some parts of the world endemic parasite infection may be associated with an unusually high incidence of certain types of renal or urinary disease. Examples are East Africa, where immune complex glomerulonephritis with nephrotic syndrome due to chronic infection with Plasmodium malariae is common (accounting for up to 2% of all hospital admissions); and Egypt and Sudan, where Schistosoma haematobium infection is associated with immune complex glomerulonephritis, obstructive uropathy and carcinoma of the bladder.

ANATOMY AND PHYSIOLOGY THE KIDNEY AS AN ORGAN In humans, the kidneys are paired bean-shaped structures measuring 10-12 cm in length, 5-6 cm in width and 3-4 cm in depth. The renal parenchyma consists of an outer cortex and inner medulla (Fig. 20.1A). The kidneys weight about 150 g each and are situated retroperitoneally on either side of the vertebral column, at the level of T12-L3, where they underlie the costovertebral angles posteriorly. The right kidney is about 1.5cm lower than the left, and both move up and down about 3cm during respiration. The functional

1031

TABLE 20.1 Functions of the kidney Excretion of products of metabolism Urea Creatinine Urate Oxalate Sulphate Phosphate Hydrogen ion 'Uraemic toxins' Water of metabolism Excretion of substances ingested in excess of requirement Water Sodium Potassium Calcium Phosphate

Homeostasis Body water Body sodium Body potassium Acid-base status Calcium Phosphate

Production of hormones Benin Angiotensin Erythropoietin 1,25-dihydroxyvitamin D

unit of the kidney is the nephron. Each kidney contains about 1000000 nephrons, each one made up of a glomerulus, a proximal tubule, a loop of Henle, a distal tubule and a collecting tubule (Fig. 20.IB). Nerve supply. The renal capsule and ureters are innervated via the T10-T12 and LI roots, and pain arising from the upper renal tract may be perceived over the corresponding dermatomes. The blood supply is from the renal arteries, which may be single or multiple, and which undergo a series of divisions within the kidney, forming in succession interlobar arteries running radially as far as the corticomedullary junction; arcuate arteries running circumferentially along the corticomedullary junction; and interlobular arteries running radially through the cortex towards the surface of the organ (Fig. 20.IB). Afferent arterioles arise from the interlobular arteries and supply the glomerular capillaries, which in turn drain into efferent arterioles (Fig. 20.2). The subsequent movement of blood depends on the location of the glomeruli within the kidney. Efferent arterioles from outer cortical glomeruli drain into a peritubular capillary network within the cortex, and thence into progressively larger and more proximal branches of the renal vein. In contrast, blood from juxtamedullary glomeruli passes into vasa recta in the medulla, where it maintains close proximity with the medullary portion of the tubules before turning back towards the area of cortex from which the vasa recta originated. The vasa recta have fenestrated walls

1

1032

MCQ 20.1

which facilitate the movement of diffusable substances through the thin and thick limbs of Henle's loop. Renal blood flow and glomerular filtration rate (GFR). Renal blood flow is high: about 25% of the resting cardiac output, or 1300mL/min. This corresponds to a renal plasma flow of about 700mL/min, of which 25% is ultrafiltered at the glomeruli, giving a GFR of 120mL/min (180L/day). Collection of urine. The collecting tubules merge in the inner medulla to form the papillary ducts of Bellini, which in turn empty at the apices of the papillae into the calyces. The calyces are lined by a transitional cell epithelium which is continuous with that of the renal pelvis, ureters and bladder. Urine is passed to the bladder by active peristalsis in the ureters, pending intermittent discharge to the exterior by the process of micturition. 1

MIGROANATOMY AND PHYSIOLOGY The glomerulus Each glomerulus consists of vascular and epithelial elements and is made up of three basic cell types: • Glomerular capillary endothelial cells. These are unusual in that they are fenestrated with 500-1000 A pores (Fig. 20.1E). • Epithelial cells. These are designated parietal or visceral, depending on their location (Fig. 20.1E). • Mesangial cells. These specialized cells secrete the mesangial matrix of the glomeruli and modify the filtration characteristics of the glomerulus, probably by the distribution of blood flow within the glomerulus. They are phagocytic, and are considered to be related to the macrophages of the reticuloendothelial system. The basement membrane lies between the capillary endothelial and the visceral epithelial cells; this triad comprises the glomerular sieve across which glomerular filtration occurs.

The tubule Throughout its length the tubule is lined with epithelial cells which are cuboidal, except in the thin limb of Henle's loop where they are flat. A luminal brush border distinguishes the proximal tubular cells from those elsewhere in the tubule. The anatomical arrangement of the different parts of the nephron and its blood supply is such that there is the potential for events in a renal tubule to influence the behaviour of its own glomerulus. This phenomenon is called tubuloglomerular feedback. It is evident at the macula densa, where each distal tubule is in close proximity to the afferent arteriole of its own glomerulus, forming the juxtaglomerular apparatus (JGA) from which renin is released. Although the nephrons differ in their anatomical location within the kidney and in their structure and function, each nephron is capable of undertaking most, if not all, of

20

FIG. 20.1 Gross and microscopic anatomy of the kidney A Longitudinal section B Note that the loop of Henle dips deeply into the hypertonic medulla and, in the case of juxtamedullary nephrons (i.e. those with their glomeruli closest to the cortico-medullary junction area), the efferent arteriole is linked to the vasa recta, also dipping deeply into the medulla. C A juxtamedullary nephron is shown on the left, and a cortical nephron on the right. D and El Microanatomy of the renal glomerulus.

the functions of the complete organ. These functions are centred on the need for selective excretion in a regulated manner. Each nephron achieves this by producing a plasma ultrafiltrate and then modifying its composition to ensure the reclamation of useful compounds and the excretion of waste. These processes are conducted respectively in the glomerulus (formation of ultrafiltrate) and the tubules (modification of composition of the ultrafiltrate).

Formation of the glomerular filtrate Hydrostatic, oncotic and electrostatic forces predominate in the formation of the glomerular filtrate (GF). The resistance to flow in the afferent and efferent arterioles is such that the hydrostatic pressure in the glomerular capillaries is much higher than in other capillary beds, approximating 40-60 mmHg. This favours the movement of water and other substances from the capillary lumen to the lower-pressure Bowman's space (Fig. 20.1D), and easily overcomes the opposing plasma oncotic pressure. Such

movement requires passage across a functional 'sieve' which, as noted above, comprises the capillary endothelial cells, the visceral epithelial cells of Bowman's capsule, and the basement membrane between them. The effective pore size in the sieve ensures that macromolecules are selectively retained within the capillaries, whereas water and other small and intermediate-sized molecules and ions pass through. Molecular charge is also important in determining movement across the sieve. The inner surface of the sieve is negatively charged and therefore repels anionic molecules such as albumin. The ease with which a substance will cross the glomerular sieve and so form a constituent of the GF thus depends on both its size and its charge. Plasma proteins are either too big (globulins), or both too big and unfavourably charged (albumin) to allow significant passage into the GF. However, immunoglobulin light chains (MW 22 kD) and many other small proteins cross the sieve and form part of the glomerular filtrate. Most are cleared from the filtrate by tubular reabsorption, unless the filtered load of, for example, immunoglobulin

1033

TABLE 20.2 Tubular transport Substance

Reabsorbed

Secreted

Water Sodium Potassium Calcium Phosphate Hydrogen ion Bicarbonate Glucose Amino acids

Yes Yes Yes (proximal ly) Yes Yes No Yes Yes Yes

No No Yes (distal ly) No No Yes No No No

TABLE 20.3 Quantitative aspects of tubular transport

FIG. 20.2 Scanning electron micrograph of normal glomerulus A, afferent arteriole; E, efferent arteriole; CL, capillary loop (one of many). (From: Brenner and Rector, The kidney, Vol 1, published by W B Saunders.)

light chains is so great as to overload the reabsorptive capacity. Approximately 180 L of GF are formed each day in an average man. As the composition of the GF is very close to that of plasma from which the macromolecules have been removed, the daily GF contains enormous amounts of low and middle molecular weight plasma constituents (in addition to water). Many, but not all, of these must be reclaimed from the GF if rapid depletion is to be avoided.

Substance

Filtered load (per 24 hours)

Water Sodium Potassium Calcium Bicarbonate Glucose

25000mmol 720 mmol 234mmol 4300 mmol 810mmol

180 L

Typical urinary excretion (per 24 hours)

% reabsorbed

0.75-2.5 L

98.6-99.6

100-250 mmol 60-1 20 mmol 5 mmol 5 mmol 1mmol

99.0-99.6 83.0-92.0

98 99.9 99.9

are given in Table 20.2 and an indication of their scale in quantitative terms in Table 20.3. Selective filtration at the glomerulus, followed by tubular reabsorption and secretion, leads to the 'final urine'. Effective regulation of the processes of glomerular filtration, tubular reabsorption and tubular secretion ensures that the composition of the final urine is appropriate to the prevailing needs of the individual. O

Modification of GF by tubular action As the GF passes along the renal tubule its composition is progressively altered by two simultaneous processes: • Tubular reabsorption, i.e. the selective movement of substances from the tubular lumen prior to intrarenal catabolism or passage to the peritubular capillaries; • Tubular secretion, i.e. the selective secretion of substances into the tubular lumen.

The specific homeostatic functions of the kidney are shown in Table 20.1.

Both these processes may be passive or active, and both change qualitatively and quantitatively along the length of the renal tubule. Important examples of tubular transport

Body water, usually accounting for about 50% of adult body weight, is kept constant by a homeostatic system (see also Ch. 21) in which both thirst and the renal handling of water are closely linked to the osmolality of the extracellular fluid (ECF). An increase in ECF osmolality is detected by osmoreceptors in the hypothalamus, stimulating both thirst and the release of ADH (antidiuretic hormone/vasopressin) from the posterior pituitary. ADH activates an adenylate cyclase in the distal part of the

1

1034

SPECIFIC HOMEOSTATIC FUNCTIONS

MCQ20.2

Regulation of body water content

Regulation of body sodium content

FIG. 20.3 Modification of the glomerular filtrate by tubular action

nephron, increasing its permeability to water. Water then moves from the tubular lumen to the hyperosmolar medullary interstitium, the result being water conservation by the kidney (Fig. 20.3). In the absence of ADH, the distal nephron is relatively impermeable to water, and the reabsorption of Na+ and Cl~ without water results in the formation of dilute urine. In health, the kidney can adjust the rate of water excretion over an enormous range (0.5-25 L/day) in response to changing water intake and non-renal water losses. The lower limit is imposed by the need to excrete the daily load of 600-900 mmol of solute (made up largely of urea and sodium chloride), and the inability of the kidney to increase urine concentration above 1200mmol/kg water. There is thus an obligatory water loss of 500-750 mL per day, the exact amount depending on dietary protein and sodium intake. Abnormalities of body water content are described in Chapter 21.

Body sodium content is governed by the balance between intake (from the diet) and output (mainly in the urine, but also to a variable extent in sweat and faeces) (see Ch. 21). As with water, sodium ingestion varies widely, and the kidney is capable of modifying its handling of sodium in such a way as to maintain the constancy of body sodium levels (see Ch. 21, p. 1101). About 25000 mmol of sodium is filtered at the glomeruli each day; to prevent overwhelming sodium depletion, the vast bulk of the filtered sodium must therefore be reabsorbed. To achieve a urinary sodium output of 100250mmol/day (the range typically seen in normal subjects eating a UK diet), 99% or more of the filtered sodium must be reabsorbed. When there is a need for extreme sodium conservation, as in subjects with a low sodium intake, or who have become sodium-depleted as a result of non-renal sodium losses, tubular reabsorption can be increased further still, until a urinary sodium concentration as low as 1-2 mmol/L is reached. Most (50-75%) of the filtered sodium is reabsorbed isoosmotically with chloride and water in the proximal tubule, the remainder being reabsorbed in the ascending limb of Henle's loop and in the distal nephron (Fig. 20.3). The control of sodium reabsorption, and hence its excretion, is complex and incompletely understood, and is probably the result of a combination of hormonal (both systemic and local), neurogenic and vascular factors. Mineralocorticoids (predominantly aldosterone) are of great importance and act on the distal nephron to promote sodium reabsorption. These hormones are regulated in part by the activity of the renin-angiotensin system (itself influenced by the amount of sodium in the distal nephron in the vicinity of the macula densa) and in part by ACTH. Atrial natriuretic peptide (ANP) is stored in, and released from, the atria and promotes renal sodium excretion.

20

Regulation of body potassium content As with sodium and water, the body content of potassium depends on the balance of intake (from the diet) and excretion, the latter being almost entirely renal. Potassium excretion by the kidney can also be varied over a wide range (approximately 10-700mmol/day). Typical dietary intake (and thus urinary excretion rate) in the developed countries is about 60-120 mmol/day. The amount of potassium appearing in the GF is much lower than that of sodium because of its relatively low concentration in blood plasma - about 720 mmol/day, assuming a GFR of 180 L/day and a plasma potassium concentration of 4mmol/L (180 x 4 = 720). About 75% of the filtered potassium is reabsorbed in the proximal tubule, and further potassium reabsorption occurs along the ascending limb of Henle's loop (Fig. 20.3). Potassium secretion into the tubular fluid occurs in the distal nephron, and it is here that the excretion rate of potassium is regulated by a combination of factors, of which the action of

1035

mineralocorticoids, especially aldosterone, is the most important. Aldosterone increases potassium secretion in the distal nephron, but this effect is not entirely subjugated to the control of aldosterone by body sodium. Potassium itself also influences aldosterone secretion; high plasma potassium concentration stimulates aldosterone secretion by the adrenal cortex directly, and also indirectly by augmenting potassium-dependent renin secretion. By this mechanism, potassium excess thus tends to correct itself. Additional control of potassium excretion is exerted by the prevailing requirements for sodium excretion and acid-base status (Ch. 21).

Regulation of acid-base status In quantitative terms, by far the most important acidic product of metabolism is CO2, derived mainly from aerobic respiration, but also from the hepatic metabolism of lactic acid, and the oxidation of free fatty acids (FFA) and ketone bodies. An adult produces some 15 000-20 000 mmol of CO2 per day, and virtually all of this is eliminated via the lungs. However, in addition to CO2, the body produces a much smaller amount of non-volatile acid, some of which (amounting to 50-100mmol/day, or approximately Immol/kg body weight per day) can only be excreted by the kidney. This is the result of the metabolism of cystineand methionine-containing proteins and also of the incomplete oxidation of fat, carbohydrate and protein; all of these processes yield inorganic acids. A helpful way to consider the role of the kidney in the maintenance of acid-base homeostasis (see Ch. 21) is in terms of balance. The kidney generates and releases into the circulation an amount of bicarbonate that precisely balances the net production of non-metabolizable, nonvolatile acidic products of metabolism (i.e. 50-100 mmol of bicarbonate per day). To achieve this, a precisely equivalent amount of hydrogen ion (50-100 mmol/day) is excreted in the urine, the exact amount being regulated according to the prevailing production rate of non-volatile acids of metabolism. The kidney achieves this balance in two ways (Fig. 20.4): • Proximal 'reclamation' of filtered bicarbonate • Urinary acidification in the distal nephron.

1036

Proximal 'reclamation' of filtered bicarbonate. Bicarbonate ions in plasma are filtered at the glomerulus. The daily filtered load of bicarbonate is very large (about 4300 mmol/day) and, because its loss would rapidly lead to overwhelming bicarbonate depletion and acidosis, nearly all the filtered bicarbonate is reclaimed following titration in the tubular lumen by actively secreted H+. The carbonic acid so formed is dehydrated to CO2 and water (under the influence of brush border carbonic anhydrase). The CO2 diffuses into the tubular cells and then combines with OFT ions to form bicarbonate, before passing on to renal venous blood. Between 80% and 90% of the bicarbonate reclamation occurs in the proximal tubule.

FIG. 20.4 Mechanisms of tubular action Blue = proximal tubular cell; grey = distal tubular cells. The functions of the latter are separated for clarity.

Urinary acidification in the distal nephron. Reclamation of the 10-20% of the filtered bicarbonate load that reaches the distal tubule is also dependent on active secretion of H+ ions. Additional H+ secreted is trapped in the tubular lumen by two urinary buffers, ammonia (NH3) and phosphate, although the role of ammonia as a urinary buffer is becoming controversial. It has been thought that ammonia (produced from the deamination of glutamine by the

tubular cells) acts as a proton acceptor in the tubular lumen, being converted to ammonium (NH4+) and trapping secreted H+ in the lumen. Monohydrogen phosphate (HPO42~), derived from the GF, accepts H+, forming dihydrogen phosphate (H2PO4 ). These mechanisms allow substantial amounts of acid to be excreted in the urine, while at the same time limiting the resulting decrease in urinary pH. Certain features of this classic description of distal acidification mechanisms are, however, controversial. It is now clear that most renal NH4+ production occurs in the proximal tubular cells, and that NH4+ is then transported to distal sites. The pK of ammonia is 9.4, indicating that, at physiological pH, nearly all the ammonia is present as NH4+. Thus, the ammonia produced from glutamine in the proximal tubular cells is immediately converted to NH4+. The tubular cell membranes are relatively impermeable to NH4+, but permeable to ammonia, and so NH4+ could only pass into the lumen by means of its equilibrium with ammonia (Fig. 20.4). Once in the tubular lumen, ammonia can accept FT and thereby act as a urinary buffer. However, the generation of ammonia in this way also leads to the production of an equivalent amount of H+. Thus, although the mechanism allows the buffering of urinary H+ by ammonia, it cannot directly influence overall acid-base status. The regulation of acid secretion is extremely complex. From the foregoing account, it is apparent that changes in the filtered load of bicarbonate and/or its reabsorption, or alteration of the distal secretion of hydrogen ions or of the availability of the urinary buffers, ammonia and HPO42~, can, singly or in combination, affect the return of bicarbonate ions to the renal venous blood.

Regulation of calcium and phosphorus metabolism Calcium Body calcium homeostasis (see Ch. 18) is dependent on: • The movement of calcium between body fluids and the skeleton under the control of parathyroid hormone (PTH) and active metabolites of vitamin D; • The intestinal absorption of dietary calcium, also under the control of PTH (acting indirectly via the vitamin D endocrine system); • The PTH-dependent regulation of the renal handling of calcium. Ultrafiltrable calcium in blood plasma amounts to about 1.3mmol/L of the 2.4mmol/L of calcium normally present in plasma. This means about 230mmol of calcium appears in the GF each day. Of this, 50-60% is re absorbed in the proximal tubule and the remainder in the thick ascending limb of Henle's loop, the distal convoluted tubule and the collecting tubule. In health, the reabsorption is almost complete, only some 5mmol of the initial 230mmol of filtered calcium appearing in the urine per day. The most important controlling influence on urinary calcium excretion is PTH, which increases tubular calcium reabsorption.

Additional effects are exerted by the level of sodium excretion and acid-base status (both natriuresis and acidosis increase calciuria). Increases in the filtered load of calcium, such as occur in hypercalcaemic states, also increase the urinary output of calcium.

20

Phosphate Renal phosphate handling is the major determinant of ECF phosphate concentration. The 80% of plasma phosphate that is not protein bound is filtered at the glomerulus, and 80-90% of this is then reabsorbed by tubular transport. The percentage of filtered phosphate that is reabsorbed can be varied over a wide range, which in health is mainly in response to changes in dietary phosphate intake and PTH. The latter acts via cAMP to decrease tubular phosphate transport in both the proximal and distal nephrons; PTH is thus a phosphaturic hormone.

THE ENDOCRINE FUNCTION OF THE KIDNEY Hormone synthesis by the kidney. The hormones produced by the kidneys are listed in Table 20.4. They may act locally in the kidney or on remote target tissues. In the cases of 1,25 -dihydroxyvitamin D, renin and erythropoietin, the kidney is the sole, or major, site of production. Hormone metabolism by the kidney. Polypeptide hormones (PTH, insulin), steroid and thyroid hormones are subject to varying degrees of renal catabolism, which may be altered in the presence of kidney disease. Hormones with major renal actions. The kidney is a target organ for many hormones (Table 20.4), all acting to influence the kidney's performance of its various homeostatic functions.

ASSESSMENT OF RENAL STRUCTURE AND FUNCTION

Examination of the urine Quantity Most normal adults in temperate climates pass between 750 and 2500 mL of urine per day. Anuria is the complete absence of urine flow. Oliguria implies diminished urine flow and is present when the urine flow rate is less than the minimum required to allow excretion of the daily solute load (about 500mL/day in an adult). Polyuria is a nebulous term indicating the passage of large volumes of urine, but implying nothing about the appropriateness (or otherwise) or cause of the high flow rate. Specific gravity/osmolality Measurements of the specific gravity and osmolality of the urine provide similar information and, in the absence of

1037

TABLE 20.4 Hormones and the kidney Synthesized in kidney

Hormone

TABLE 20.5 Conditions associated with extremes of urinary pH Action on kidney

Acid

Alkaline

High protein diet Acid ingestion (ascorbic acid, ammonium chloride) Metabolic acidosis Respiratory acidosis (acute) Water deprivation Potassium depletion Hyperaldosteronism

Vegetarian diet Alkali ingestion (sodium bicarbonate, potassium citrate) Infection with urea-splitting organisms Metabolic alkalosis Respiratory alkalosis (acute) Renal tubular acidosis (type I) Water diuresis

1,25-dihyroxyvitamin D/ calcitriol

Yes

Increases tubular calcium reabsorption

Renin/angiotensin

Yes

Autoregulation and distribution of renal blood flow

Prostaglandins (PGE2 and PGI2)

Yes

Autoregulation and distribution of renal blood flow Increase renin release Influence water handling

Erythropoietin

Yes

None

Kallikrein

Yes

Autoregulation and distribution of renal blood flow Influences sodium and water handling Increases phosphaturia Increases bicarbonaturia Increases tubular calcium reabsorption Increases synthesis of 1,25-dihydroxyvitaminD

PTH

Vasopressin/ADH

No

Increases antidiuresis

Aldosterone

No

Increases tubular Na+ reabsorption Increases tubular K+ and H+ secretion

Catecholamines

Increase renin release

Atrial natriuretic peptide

No

Increases sodium/water excretion

significant glycosuria, are functions of the urinary concentrations of sodium, chloride and urea. The range of specific gravity is 1.001-1.035 (equivalent to 50-1300 mmol/kg water). Even heavy protein excretion alters these figures only minimally.

pH Urinary pH varies from 4 to 8 and may be measured using paper strips impregnated with an indicator or, more accurately, by means of a pH electrode. Conditions associated with extremes of urinary pH are shown in Table 20.5.

1 1038

MCQ 20.3

Glucose The use of glucose oxidase-impregnated dipsticks provides a simple and specific semiquantitative test for glucose in urine. The commonest cause of abnormal glycosuria is elevation of the plasma glucose concentration to above 8.3-10 mmol/L, at which point the tubular reabsorptive capacity for glucose is exceeded. In addition, a number of rare disorders of tubular function may be associated with glycosuria at normal plasma glucose concentrations; these disorders are collectively designated renal glycosuria. Protein Most people excrete less than 150 mg of protein per day in the urine and, with the exception of orthostatic proteinuria (see below), levels above this imply disease of the kidney or urinary tract. Semiquantitative testing is done using dipsticks (sensitive to 200-300 mg protein per litre) or by the more cumbersome salicylsulphonic acid test (sensitive to 100-150mg protein per litre). The latter has the advantage of detecting Bence-Jones' protein (immunoglobulin light chains). Additional information may be obtained from quantitative measurement of the protein content of timed urine collections. Variation in the albumin excretion rate below the threshold for detection by dipsticks can be followed using sensitive specific assays for urinary albumin. Normally, albumin excretion measured in this way is less than 20mg/day. This is increasingly employed to detect very early glomerular damage. For example, in diabetics, urinary albumin excretion above the normal range (microalbuminuria - 20-200 mg/day) predicts the later development of clinical diabetic nephropathy. The protein excretion rate is generally increased in the upright posture, and on occasion this may lead to abnormally high protein measurements in timed collections or spot measurements in normal ambulant subjects. This is termed orthostatic proteinuria and the diagnostic difficulty may be resolved by demonstrating that an early-morning urine specimen is normal, whereas a specimen taken later in the day with the subject ambulant contains excess protein. The diagnostic implications of abnormal protein excretion depend on both its magnitude (Table 20.6) and, to

TABLE 20.6 Diagnostic implications of proteinuria Degree of proteinuria

Diagnostic implications

Mild (up to 500mg/day)

Fever Benign hypertensive nephrosclerosis Renal tumour Obstructive nephropathy Prerenal uraemia Tubulointerstitial nephropathy Chronic pyelonephritis Early diabetic nephropathy Orthostatic proteinuria

Moderate (up to3g/day)

Heavy (more than 3g/day)

Urinary tract infection Chronic pyelonephritis Acute tubular necrosis Acute glomerulonephritis Chronic glomerulonephritis Obstructive nephropathy Accelerated phase hypertension Orthostatic proteinuria Pre-eclampsia Myeloma Acute glomerulonephritis Chronic glomerulonephritis Diabetic nephropathy All causes of nephrotic syndrome

a lesser extent, its selectivity. Heavy proteinuria is always glomerular in origin, and albumin predominates over larger molecular weight proteins such as globulins. In highly selective proteinuria only albumin is present in significant amounts, whereas with non-selective proteinuria the much larger globulins are present as well. Protein selectivity measurements are of little use in adults, but in children are helpful in predicting the nature and likely response to treatment of nephrotic syndrome (p. 1062). O Blood Blood in the urine may lead to a visible red or brown discoloration or a smoky appearance when present in quantities exceeding 0.5mL/L. Potentially confusing appearances may be seen in haemoglobinuria (as a consequence of haemoglobinaemia), porphyria, and dye or drug ingestion (e.g. beetroot, rifampicin). Smaller amounts of blood, insufficient to cause visible discoloration, may be detected by chemical tests for haemoglobin using dipsticks. A positive test for haemoglobin should always be followed by microscopic examination for red blood cells. This will distinguish haematuria from haemoglobinuria (in which no red cells will be seen). Careful assessment of red cell morphology using phase-contrast microscopy may indicate whether they are derived from the renal parenchyma (dys-

morphic red blood cells) or from the collecting system, ureters or bladder (normal red blood cells).

20

Culture Although bladder urine should be sterile, voided urine is not, and interpretation of bacteriological studies of the urine must take account of this. Contamination is minimized (though not eliminated) by use of the midstream urine (MSU) or clean catch technique, in which the initial part of the voided stream is discarded and the midportion of the stream collected in a sterile container. In females this should be preceded by cleansing of the external genitalia. The likelihood of significant infection is high if: • A pure growth of a single organism is obtained (multiple organisms often indicate contamination) • The number of bacteria exceeds 105/mL • Leukocytes are present in the spun deposit of fresh urine (pyuria). Deposit The microscopic examination of a fresh unstained deposit of spun urine is an important part of the examination of any patient in whom disease of the urinary tract is suspected, especially if dipstick testing has shown blood or protein. A search is made for cells, tubular casts and crystals (Table 20.7). Urinary casts consist of Tamm-Horsfall protein derived from the tubular epithelium, and are probably formed in the distal nephron. Cellular casts, in which the Tamm-Horsfall matrix is studded with red or white blood cells, are indicative of parenchymal renal disease. Granular casts are probably degenerate cellular casts and have a granular or grainy appearance. Hyaline casts contain no cellular elements or debris and may be seen in very small numbers in normal urine. The number of cells and casts seen is usually expressed per high-power field.

Measurement of GFR The renal clearance of a substance is calculated from the formula: UV/P

where U = urinary concentration, V = urine flow rate (usually expressed in mL/min) and P = plasma concentration. Calculation of GFR requires a test substance that is freely filtered at the glomerulus, but neither reabsorbed nor secreted by the tubules (Table 20.8). The polysaccharide inulin has ideal characteristics but the methodology is cumbersome, precluding its use in clinical practice. However, the renal handling of endogenously produced creatinine is similar to that of inulin, and reliable estimates of GFR can generally be obtained from measurements of creatinine clearance. This requires only the measurement of plasma creatinine concentration in plasma and in a timed urine collection of known volume. GFR can also be calculated simply from knowledge of the plasma creatinine concentrations and reference to 'normal values'. The formula for calculating creatinine

1039

TABLE 20.7 The urinary sediment In various renal conditions Condition

RBC

WBC

RBC casts

Granular casts

Hyaline casts

Acute glomerulonephritis Chronic glomerulonephritis 'Minimal change' nephrotic syndrome Acute tubular necrosis Prerenal uraemia Acute pyelonephritis Chronic pyelonephritis Benign hypertensive nephrosclerosis Acclerated phase hypertension Pre-eclampsia Urinary tuberculosis Diabetic nephropathy Tumour

4

0-4

1-4

1-3

1-3

1-3

0-1

0-2

1-3

1-3

0-1

0

0

0-1

0-3

1-3

1-3

0-2

1-3

1-3

0-1

0-1

0

4

0

0-1 0-1

0

0

0

0

0-1 1-2 0-1 0-1

0-2

0-2

1-4

0-1

0-2

0-2

0-2

0-1 0-4

0-1 2-4

0 0

0-3 0-2

0-1 0-4

0

0

0-1

0

0-1 0-2 0-1 0

1-2 0-1 0-1

0-2 0-1

The numbers 0-4 refer to the extent of the abnormality in each case. RBC, red blood cells; WBC, white blood cells.

TABLE 20.8 Characteristics of compounds used to measure GFR Characteristic

Ideal marker

Inulin

Creatinine

Urea

Freely filtered at glomerulus Tubular reabsorption Tubular secretion Ease of assay Endogenously produced

Yes

Yes

Yes

Yes

No

No

No

Yes (slight)

No

No

Yes (slight)

No

Easy Yes

Difficult No

Easy Yes

Easy Yes*

* But variable rate.

1040

clearance (UV/P) indicates that GFR is inversely related to plasma creatinine concentration (Fig. 20.5). Thus, assuming a constant production rate of creatinine, a halving of GFR will lead to a doubling of plasma creatinine concentration, a fourfold decrease in GFR to a fourfold increase in plasma creatinine concentration, and so on. This method is very useful for monitoring changes in GFR in the same subject, but substantial individual variations in muscle bulk (and hence creatinine production rate) necessitate the inclusion of several correction factors before reason-

FIG. 20.5 Relationship between glomerular filtration rate (GFR) and plasma creatinine concentration (PCr) The normal range of PCr is shown by the blue bar. At high levels of GFR, changes of GFR are associated with relatively small changes of PCr, which remains within the normal range until GFR falls to about 45mL/minute. At low levels of renal function, PCr becomes a much more sensitive indicator of GFR.

ably accurate GFR estimates can be made. Nevertheless, plasma creatinine measurement is one of the most frequently performed and useful tests of renal function. Similar measurements can be made using urea instead of creatinine, but these are much less informative owing to wide fluctuations in urea production rate and substantial and variable tubular reabsorption of urea (Table 20.8). Radionudide methods The GFR can be measured by injecting a radioactive substance that is handled by the kidney in the same way as inulin and then following its disappearance from plasma. 51 Cr-EDTA is a suitable radiopharmaceutical, and allows easy and reproducible calculation of GFR. Range of GFR and effect of ageing The GFR in a normal adult is about 120mL/min (Fig. 20.6). In children over 2 years of age, GFR is closely related to body surface area and should be expressed in relation to this. GFR peaks between the ages of 20 and 30 years, subsequently decreasing by ImL/min/year (Fig. 20.7). In most people this decrease runs more or less in parallel with the slow decrease in muscle mass commensurate with ageing, such that plasma creatinine concentration changes little with advancing age. Appreciation of these age-related changes in GFR is important in clinical practice, particularly when considering dose modification of drugs prescribed to the elderly. Measurement of renal plasma flow The estimation of renal plasma flow requires a test substance that is both filtered at the glomerulus and rapidly

20

FIG. 20.6 Changes in glomerular filtration rate with age

FIG. 20.8 Intravenous urogram showing obstructed right kidney The IVU shows normal morphology on the left and dilation of the pelvicalyceal system on the right, due to pelviureteric junction obstruction.

Imaging of the kidney and urinary tract Plain radiographs In many people one or both kidneys may be visible on plain abdominal radiographs or plain nephrotomograms, giving information about the presence, location, size and shape of the kidneys, as well as revealing certain types of renal stone or other calcifications. Intravenous urography (IVU) The injection of organic iodine compounds that are excreted by the kidneys opacities first the renal parenchyma (nephrogram), and later the collecting system (pyelogram), ureters and bladder. As well as providing important structural information, the IVU also demonstrates the presence or absence of excretory function (Fig. 20.8). The quality of images may be poor if excretion is slow, as in severe renal disease, but can be enhanced by the administration of large doses of contrast medium and by nephrotomography. Although the IVU is commonly employed and is often very useful, it carries a mortality of about 1 in 40000 studies, with a substantial incidence of non-fatal adverse reactions to the injected contrast medium. Ironically, one of the most common of these is nephrotoxicity - rare if renal function is normal, but common if function is already compromised or in the presence of certain coexisting diseases, especially diabetes mellitus or myeloma. FIG. 20.7 Age-related decrease in renal function - men and women.

secreted by the tubules, such that none reaches renal venous blood. Para-aminohippuric acid has the required characteristics, but this measurement is almost never required in clinical practice; it remains important as a research tool, however. Semiquantitative measurement of renal blood flow can also be made by colour flow Doppler. The success of this technique is both operator and patient dependent; adequate images of the renal vasculature are not always possible.

Antegrade and retrograde urography The morphology of the collecting system and ureters may not be demonstrated adequately by IVU if excretory function is poor. The direct introduction of contrast medium into the kidney (antegrade pyelography) or lower ureter during cystoscopy (retrograde pyelography) may yield further information if these invasive procedures are deemed appropriate (Fig. 20.9). Such investigations are most commonly used in the detailed assessment of patients with obstruction of the urinary tract. Cystography In cystography the bladder is filled with contrast medium via the urethra and radiographs are taken before, during

1041

and after micturition, usually to see whether urine refluxes up the ureters. The investigation is invasive, carrying the risk of introducing infection. It is usually performed in children with urinary infections in whom reflux nephropathy is suspected.

Ultrasonography Ultrasonography allows totally non-invasive evaluation of gross renal morphology and visualization of adjacent tissues (Fig. 20.10). It is useful in the diagnosis of cystic diseases of the kidney, renal tumours and renal obstruction. Unlike the IVU, renal ultrasound does not depend on the presence of excretory function, and so non-functioning kidneys can be seen just as well as functioning ones. On the other hand, Ultrasonography yields no direct information on the relative function of the kidneys. Computed tomography Computed tomography (CT) gives detailed structural information about the kidneys and surrounding tissues, and the ureters and bladder. It is particularly useful in assessment of the retroperitoneum in cases of obstruction.

FIG. 20.9 Antegrade pyelograms showing obstruction of the right kidney due to a stricture in the lower part of the ureter A] Contrast medium has been introduced directly into the dilated collecting system of the kidney via a percutaneously inserted catheter. b The obstruction is shown in the lower ureter.

1042

Radionuclide studies Radionuclide studies allow both structure and function to be evaluated and have the advantage of low associated radiation exposure compared to IVU. "Tc-DMSA (dimercaptosuccinic acid) is used to show gross renal morphology, and either "Tc-DTPA (diethylenetriamine penta-acetic acid), MAGS or 131I hippuran renograms to investigate function. In isotope renography, simultaneous counting over both kidneys is done and analysis of the resulting renograms (Fig. 20.11) may indicate the relative contribution of the two kidneys to total function (divided renal function), delay in perfusion (suggestive of renal vascular disease), or a progressive increase in activity with time (suggestive of obstruction).

FIG. 20.10 Renal ultrasound examinations fAl Longitudinal scan of a normal kidney. The characteristic renal outline can be seen with the echogenic centre area representing the normal pelvicalyceal system and its associated fat. The surrounding elliptical renal parenchyma produces low level echoes and appears much darker. ITI A dilated and obstructed collecting system. The large echo-free (i.e. black) renal pelvis and widened upper ureter can be seen in the centre of the picture.

Arteriography and venography The arterial and venous vasculature of the kidneys can be seen following direct injection of contrast medium into the renal artery and vein, respectively (Fig. 20.12). These procedures are invasive and are used when compromise of the renal blood supply, leading to hypertension or impairment

of renal function, is suspected. Pathological circulation to a renal tumour can be demonstrated in this way, although the advent of good-quality ultrasonography and CT has made most arteriography redundant, except when the tumour is to be embolized. Venography is performed in cases where ultrasonography and/or CT have failed adequately to exclude renal vein thrombosis.

20

Magnetic resonance imaging (MRI) MRI can provide good-quality images of the major renal vasculature. It has the obvious advantage of being totally non-invasive and also of permitting the projection of the images in many planes, which is particularly useful when examining tortuous or otherwise abnormal renal arteries (Fig. 20.13).

Renal biopsy The kidneys may be biopsied with relative safety using a cutting biopsy needle passed into the kidney through the renal angle under local anaesthetic. Preconditions that should be satisfied before biopsy is undertaken are: • • • •

FIG. 20.11 DTPA isotope renograms typical of various conditions In obstruction, the increase in activity up to 20 minutes results from the progressive accumulation of isotope within the obstructed collecting system. In renal artery stenosis, arrival of the bolus of isotope is delayed, leading to a delayed peak and subsequently slow clearance. In chronic renal parenchymal disease, arrival of the bolus is not delayed compared with normal, but is of much reduced intensity, reflecting low renal blood flow and low GFR.

An appropriate indication (Table 20.9) A cooperative patient Absence of bleeding disorder Prompt availability of blood for transfusion in the event of haemorrhage • Prior knowledge of the position, size and function of both kidneys. A solitary functioning kidney should rarely be biopsied. The procedure is carried out with the patient lying prone using simultaneous ultrasound localization of kidney and biopsy needle. One or two small samples of renal cortex are taken, each containing 10-50 glomeruli, and used for

FIG. 20.12 Renal arteriograms A Conventional renal digital subtraction arteriogram (DSA) showing mild renal stenosis (arrowed) on the right. B Magnetic resonance angiogram (MRA) of the same patient. The stenosed segment (arrowed) is clearly seen in this coronal projection, (Photographs provided by Dr W. Gedroyc.)

1043

B

FIG. 20.13 Magnetic resonance imaging of the renal arteries A Conventional digital subtraction arteriogram (DSA) showing normal renal vasculature. fil Magnetic resonance angiogram (MRA) of the same patient. Pel Axial projection MRA of the same patient. (Photographs provided by Dr W. Gedroyc.)

light microscopy, electron microscopy and immunoperoxidase studies, allowing the presence and distribution of fibrin, complement, IgG, IgA and IgM to be defined. The safety of renal biopsy is difficult to determine. Mortality appears to be well below 0.1% and serious morbidity, e.g. bleeding necessitating nephrectomy, occurs in about 0.1-0.2% of cases. Minor morbidity, such as significant pain or bleeding requiring transfusion, may arise in about 2% of cases.

I

1044

1

MCQ 20.4

MAJOR SYMPTOMS AND SIGNS OF RENAL AND URINARY DISEASE The symptoms and signs associated with renal and urinary disease are diverse and often non-specific. In many patients these features may remain subtle and nebulous, even when renal impairment is moderately severe, leading to the patient seeking medical advice late in the course of the disease. Haematuria The pattern and characteristics of haematuria are useful pointers to the underlying cause. For example, haematuria may be macroscopic or microscopic, painful or painless, continuous or intermittent, persist throughout the act of

TABLE 20.9 Usefulness of renal biopsy

TABLE 20,10 Symptoms and signs of uraemic syndrome

Often helpful Acute renal failure of uncertain cause Rapidly progressive renal disease (especially if crescentic nephritis suspected) Collagen disease, e.g. SLE, polyarteritis Renal haematuria (cause unclear) Proteinuria (cause unclear) Nephrotic syndrome Transplant assessment Suspected amyloid

Nervous system Fatigue, malaise, depression, impaired thought, involuntary movements, nausea, fits, coma, pruritus, paraesthesiae, neuropathy Cardiopulmonary Pericarditis, pleurisy, Kussmaul breathing, dyspnoea Dermatological Pruritus, purpura, pallor, pigmentation, urea frost Gastrointestinal Anorexia, nausea, vomiting, Gl bleeding, constipation, diarrhoea, peptic ulceration, angiodysplasia, colitis, foetor

Sometimes helpful Slowly progressive renal disease (with kidneys of normal size) Diabetic nephropathy

Haematological Anaemia (normochromic, normocytic), bleeding (disordered platelet function)

Not indicated Suspected renal infection End-stage renal disease, especially if kidneys are small Renal cystic disease

TABLE 20.11 Causes of renal pain

micturition or be present only at the beginning or end of micturition. Haematuria due to renal parenchymal disease is usually continuous, painless and microscopic, although it may on occasion be macroscopic or intermittent. In contrast, haematuria arising from renal tumours is usually intermittent and painless, and that from bladder tumours may be intermittent and sometimes painful. Proteinuria Protein does not discolour the urine, although it often causes increased frothing. It is therefore usually noticed as a result of routine urine examination, following the development of associated symptoms of renal disease or, in the case of heavy proteinuria, the development of the nephrotic syndrome (p. 1062). Hypertension Hypertension is much more common in people with renal disease than in those without. As many as 80% of patients with abnormal renal function, or who are receiving RRT by dialysis, will have experienced significant (and in many cases severe) hypertension at some stage during their illness. Conversely, there are occasions when severe hypertension may, by leading to vascular changes within the kidney, be the cause of renal disease (p. 1081). Oedema Renal disease may give rise to oedema either as a consequence of inappropriate retention of sodium and water, leading to overexpansion of the ECF, or by reduction in plasma oncotic pressure as a result of heavy urinary protein losses (nephrotic syndrome, see p. 1062). In some cases both these mechanisms are operative. Overexpansion of the ECF (in the absence of severe hypoalbuminaemia) may be accompanied by hypertension and

20

Obstructive

Non-obstructive

Stone (kidney, ureter) Tumour Sloughed papilla Blood clot Pelviureteric obstruction

Renal swelling ± inflammation Acute pyelonephritis Renal vein thrombosis Renal cysts Renal tumour Acute nephritis (rare) Renal infarction Trauma

expansion of the vascular compartment to the point where pulmonary oedema develops. This is particularly likely to occur in subjects with diminished cardiac reserve. Uraemia The uraemic syndrome is a group of symptoms and signs (Table 20.10), some or all of which are found in patients with serious reduction of excretory capacity (i.e. of GFR), from any cause. 1 The uraemic syndrome rarely manifests itself clinically until the GFR has fallen to 20% of normal or less. The pathogenesis and management of the uraemic syndrome are discussed on pages 1052-1056. Renal pain Renal pain is usually felt in the loin or flank, although in the case of ureteric obstruction leading to renal pain, discomfort may be felt in the iliac fossa, testicle or labia, depending partly on the level of the obstruction. The commonest, and most spectacular, cause of renal pain is acute obstruction by a stone; usually this is fairly rapid in onset and very severe. Other causes of renal pain are listed in Table 20.11. Oliguria/anuria Oliguria is often defined as the passage of less than 500 mL of urine per day. A more precise and physiological defini-

1045

TABLE 20.12 Causes of polyuria Excessive water intake Psychogenic polydipsia Beer drinking

Abnormal tubular water handling Pituitary diabetes insipidus Inherited nephrogenic diabetes insipidus (rare)

Osmotic diuresis Diabetes mellitus (glucose)* Chronic renal failure (urea)* Diuretics (NaCI)*

Acquired nephrogenic diabetes insipidus Hypokalaemia Hypercalcaemia Obstructive uropathy Tubulointerstitial diseases

'The respective osmotic diuretics are given in parentheses.

TABLE 20.13 Causes of frequency and nocturia Cause

Example

Infection*

Cystitis/urethritis/prostatitis Bacteria, including tuberculosis Fungal Parasitic (schistosomiasis) Bladder tumour Prostatic hypertrophy Urethral stricture Multiple sclerosis

Neoplasia* Anatomical Neurological 1

tion would be a reduction of urine flow to the point where even with urine maximally concentrated the requirements for solute excretion cannot be met, thereby reflecting the influence of body size and diet on the definition. Anuria means cessation of urine flow. The causes may conveniently be divided into: • Prerenal, where primary decrease in renal blood flow leads to compromise of function in an otherwise normal kidney; • Renal, i.e. intrinsic renal disease of any type; • Postrenal, owing to mechanical obstruction, which may be at any point from the collecting system in the kidney to the urethra. Acute obstruction to bladder outflow only results in impairment of renal function when the maximum bladder capacity is reached. In general, the causes of anuria and oliguria are the same as those of acute renal failure (see Table 20.15). Polyuria The causes of polyuria (increased urine flow rate) fall into three categories (Table 20.12). In some patients with diabetes insipidus polyuria may be spectacular, with daily urine output as great as 25 L. O Frequency Frequency of micturition results from polyuria or decreased functional bladder capacity (Table 20.13). Nocturia The absence of nocturia depends on the normal reduction in urine flow rate during the night and an adequate functional bladder capacity. Polyuria of any cause may thus result in nocturia, as may acute and chronic renal diseases, certain drugs such as corticosteroids and diuretics, and the ingestion of large volumes of fluid late in the day; all of these, in one way or another, interfere with the normal diurnal variation in urine flow rate.

1

1046

MCQ 20.5

2

MCQ 20.6

Often associated with dysuria also.

Reduction of functional bladder capacity due to local (e.g. infection, contracted bladder, outflow obstruction, tumour) or remote (e.g. neurological diseases) factors will also result in nocturia, in this case not associated with polyuria. Dysuria Dysuria is pain immediately before, during or immediately after micturition. The discomfort is often perceived as a 'burning' or 'scalding' sensation from the urine, and may be associated with frequency, decreased functional bladder capacity, urgency or hesitancy of micturition. Strangury, when present, is the painful desire to micturate despite the bladder being empty or nearly so. Infection and neoplasia are the main causes; these and other causes of dysuria may also be associated with frequency. Urgency of micturition, incontinence and enuresis Urgency is the inability to postpone micturition significantly beyond the moment when the desire to micturate is first perceived. It may lead to urge incontinence if the patient cannot get to an appropriate place to void quickly enough. Incontinence is the involuntary passage of urine and may result from disorders of the bladder, its nerve supply, or within the CNS (see also p. 1095). Incontinence occurring exclusively at night is termed enuresis and may be primary

SUMMARY 1 Symptoms and signs of renal and urinary tract disease Uraemia Renal pain Oliguria/anuria Polyuria Frequency Nocturia Dysuria Incontinence

Haematuria Macroscopic Microscopic Proteinuria Asymptomatic Symptomatic (nephrotic syndrome) Hypertension Oedema Peripheral Pulmonary

TABLE 20.14 Diagnostic features distinguishing between acute and chronic renal failure Favour acute • Known recent onset • Known precipitating factor(s) • Near normal haematology • Normal size kidneys (ultrasound, plain X-rays, IVU)

Favour chronic • History of nocturia • Pigmentation • Small kidneys • Bone disease (radiographic or biochemical) • Normochromic anaemia

SUMMARY 2 Major renal syndromes • • • • • • •

Acute renal failure (including acute tubular necrosis) Acute nephritic syndrome Rapidly progressive glomerulonephritis Chronic renal failure Nephrotic syndrome Recurrent gross haematuria Persistent, asymptomatic proteinuria and/or microscopic haematuria • Renal tubular syndromes

(failure to attain nocturnal bladder control in childhood) or secondary (development of enuresis following previous nocturnal continence). The above conditions are discussed further on page 1095.

TABLE 20,15 Causes of acute renal failure Prerenal Any cause of shock Hypovolaemia:

20

haemorrhage, burns, salt and water depletion, perforated viscus, pancreatitis, postoperative (especially aortic, cardiac and biliary surgery)

Sepsis Cardiogenic Renal arterial or venous disease: renal artery stenosis, renal vein thrombosis Inappropriate renal vasoconstriction, e.g. hepatorenal syndrome Renal Acute tubular necrosis following hypovolaemia or shock of any cause Acute glomerulonephritis Acute glomerulonephritis with multisystem disease, e.g. SLE, Henoch-Schb'nlein purpura, infective endocarditis Disease of small/medium-sized blood vessels, e.g. haemolytic uraemic syndrome, thrombotic thrombocytopenic purpura, disseminated intravascular coagulation, vasculitis, systemic sclerosis, accelerated phase hypertension Acute tubulointerstitial disease Exogenous nephrotoxins, e.g. drugs, ethylene glycol, heavy metals, X-ray contrast media Endogenous nephrotoxins, e.g. myoglobin, haemoglobin, bilirubin, uric acid, Bence-Jones' protein Postrenal Any cause of obstruction Stone (bilateral or affecting solitary kidney) Ureteric obstruction by pelvic malignancy (cervix, bladder, prostate, rectum) Bladder outflow obstruction Retroperitoneal disease (lymphoma, aortic dissection, retroperitoneal fibrosis)

MAJOR RENAL SYNDROMES Patients with renal disease usually present with one of the renal syndromes discussed below (listed in Summary 2), and categorization by syndrome is an essential first step towards making a definitive diagnosis.

ACUTE RENAL FAILURE Acute renal failure (ARF) is the rapid deterioration of renal function over a period of hours or days. Although oliguria and anuria are frequent accompaniments, this need not be the case: the cardinal index is a rapid decline in GFR, leading to nitrogen retention. This may arise de novo, or against a background of pre-existing stable chronic renal impairment (Table 20.14); distinguishing between these two possibilities is an important part of the diagnostic process. 2 The causes of ARF may be prerenal, renal or postrenal, and it is helpful to bear these categories in mind when assessing a patient with apparent ARF (Table 20.15).

Prerenal ARF Prerenal ARF is associated with a low cardiac output (of any cause), intense renal vasoconstriction and reduced GFR with resulting oliguria, and avid salt and water retention. The kidney is structurally normal but functionally compromised. Removal of prerenal factors leads to rapid and complete recovery of renal function. The necessary measures may include correction of hypovolaemia with blood or saline, treatment of sepsis, or improvement of cardiac function (if possible). If severe and/or prolonged, renal vasoconstriction may be severe enough to lead to ischaemic renal injury (acute tubular necrosis,ATN). Thus the identification and rapid correction of prerenal factors is of paramount importance in the management of these patients. An intractable type of prerenal ARF - the hepatorenal syndrome - is sometimes seen in patients with severe liver disease. Renal recovery is unusual in the absence of hepatic recovery. The nature of the interaction between the liver and kidney is obscure. In the rare cases where a patient dying with hepatorenal

1047

CASE STUDY 20.1 ABDOMINAL PAIN, VOMITING, FEVER AND HYPOTENSION IN A 44-YEAR-OLD WOMAN A 44-year-old woman with five children presented to the Accident & Emergency department with a 48-hour history of upper abdominal pain and vomiting. During this time she had felt increasingly unwell, initially with flu-like symptoms and latterly with severe weakness, prostration and rigors. About 1 year previously she had experienced less severe right upper quadrant pain which had lasted for approximately 4 days. At that time she had noted that her urine had become unusually dark. All these symptoms resolved spontaneously and she had remained well since then. There was no previous medical history of note and she was taking no medications. On examination she was extremely unwell, with clinical evidence of shock - pulse 110 beats per minute, blood pressure 80/40, with sweating, cold peripheries and core temperature of 38.5°C. She was clinically jaundiced, with moderate tenderness to palpation in the epigastrium and right upper quadrant. There were no signs of chronic liver disease. A specimen of urine obtained following catheterization showed 2+ protein and y blood on stick testing. Subsequent microscopy of this urine revealed granular and occasional red cell casts. Plasma urea and creatinine concentrations were 28mmol/L and 430 mmol/L, respectively. Plasma electrolytes showed the following: sodium 138, potassium 6.1, chloride 99, bicarbonate 13 mmol/L. Bilirubin was 85 mmol/L, AST 90IU/L, ALT 65IU/L, alkaline phosphatase 480 IU/L. Haemoglobin was normal, WBC 16000 with left shift, and platelets 90000.

Fig. 20.1

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Questions 1. What is the most likely renal diagnosis? 2. What is the cause of the renal disturbance? 3. Give an estimate of the urine sodium concentration. 4. What is the nature of the acid-base disturbance? 5. Consider what further investigations are required (a) in relation to the renal disturbance, and, (b) in relation to the general disturbance. Discussion This woman presents with a story strongly suggestive of severe sepsis resulting in acute renal failure. The history of abdominal pain 1 year previously with transient discoloration of the urine suggests an episode of obstructive jaundice then. The spontaneous resolution points to gallstones as the most likely cause, raising the strong possibility that the present illness is also the result of obstructive jaundice with stones in the common bile duct. This patient is clearly very ill, suggesting an infection complicating the obstruction - cholangitis. Gram-negative bacteraemia is a frequent complication of this, and blood cultures would stand a good chance of identifying the offending organism. Further evidence for the severity of the infection comes from the low platelet count - this raises the possibility of disseminated intravascular coagulation. A blood film should be examined for fragmented RBCs, together with a clotting screen. This patient also has a metabolic acidosis with increased anion gap.

This indicates that the reduction of plasma bicarbonate reflects titration by accumulated non-volatile acid, rather than primary bicarbonate depletion. In patients with shock, blood lactate concentration rises lactic acidosis. This is likely to have been the principal cause of the metabolic acidosis in this case, with an additional contribution from the renal failure - uraemic acidosis. Hepatobiliary and kidney ultrasound should be undertaken as a matter of urgency. This is a good way of visualizing the biliary tree, identifying the presence of stones and also assessing the calibre of the common bile duct and intrahepatic ducts - these would normally be dilated in a patient with extrahepatic obstruction due to gallstones. Ultrasound is also used to image the kidneys - the clinical picture is of acute renal failure, and it is important to ensure that both kidneys are present and that there is no obstruction. Management would centre on rapid and vigorous treatment of the shock with intravenous fluids and broad-spectrum antibiotics, focusing particularly on Gram-negative organisms. ERCP with, if possible, removal of obstructing stone, should be undertaken as early as possible. The question now arises as to whether this patient has prerenal acute renal failure, or whether she has progressed to established acute renal failure with underlying acute tubular necrosis. The latter explanation is favoured by the floridly abnormal urine with significant proteinuria, and is supported by the finding of relatively high urine sodium concentration. Conversely, had urine sodium been low, particularly if the urine dipstick showed only small amounts of blood

syndrome has been used as a kidney donor, prompt recovery of function after transplantation has been observed, suggesting that neurohumoral factors are important in the genesis of this condition.

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CASE STUDY 20.1 CONTINUED or protein, prerenal uraemia would have been suggested, in which case prompt recovery would have been expected to follow effective treatment of the circulatory shock. Following the establishment of euvolaemia it is appropriate in these patients to maintain euvolaemic volume status. Improvement of plasma biochemistry and/or increase in urine output heralds the beginning of recovery of kidney function or, conversely, if this is delayed, indicates the need for supportive treatment by dialysis. Choice of dialysis modality is governed principally by the general state of the patient. If circulatory instability and sepsis persist, continuous haemofiltration is the preferred modality, whereas if the patient recovers circulatory stability but remains in established renal

failure intermittent haemodialysis is normally favoured until kidney function recovers spontaneously. Most patients will eventually revert to normal or near normal levels of renal function following acute tubular necrosis. In this patient the blood pressure responded well to volume expansion with colloid and normal saline and urgent ERCP revealed obstructing stones in the common bile duct. These were removed via a sphincterotomy. Renal function did not improve, adding further support to the diagnosis of acute tubular necrosis. The metabolic acidosis improved without recourse to intravenous bicarbonate therapy, although moderate acidosis persisted. Plasma urea and creatinine concentrations rose progressively, but hypervolaemia was successfully

Renal ARF In renal ARF there are established structural abnormalities in the kidney. In some cases (e.g. postinfectious glomerulonephritis, acute tubulointerstitial nephropathy), the disease process may primarily involve the kidney with little evidence of disease elsewhere. Alternatively, there may be evidence of multisystem disease, such as systemic lupus erythematosus, infective endocarditis, polyarteritis nodosa, Henoch-Schonlein purpura, or of nephrotoxic exposure. The coexistence of any of the prerenal factors (given in Table 20.15) raises the possibility of established ATN, and these factors should always be corrected as far as possible in the hope that progression from prerenal ARF to ATN can be averted. The distinction between established ATN and prerenal ARF in an oliguric patient is important: fortunately, it is generally straightforward. It may be made on the basis of one or more of the features listed in Table 20.16. Renal hypoperfusion is the commonest cause of ATN, 1 although in some cases the lesion appears to develop as a result of a combined insult due to hypoperfusion and exposure to a nephrotoxin (Table 20.15). The renal vasoconstriction may be very severe, and in many cases seems out of proportion to accompanying increases in systemic vascular resistance. Prevention of this 'inappropriately' severe renal vasoconstriction is a frequent therapeutic goal, but is difficult to achieve other than by avoiding or rapidly correcting shock states. The renal lesion is tubular necrosis with subsequent regeneration. The

avoided by careful fluid management. With plasma urea and creatinine concentrations of 39mmol/L and 618mmol/L, respectively, dialysis treatment was started. By that time the patient's circulation was stable and treatment took the form of intermittent haemodialysis via a double-lumen internal jugular catheter. Initially daily sessions were required, decreasing thereafter to alternate days. Altogether 10 days of renal replacement therapy were required before renal function had recovered sufficiently to maintain independence from dialysis. A brisk diuretic phase during recovery required intravenous fluid support with normal saline, and the patient was discharged home 4 weeks after admission. Six months later plasma urea and creatinine concentrations were normal.

TABLE 20.16 Distinction between prerenal and renal causes of acute renal failure in an oliguric patient Favours prerenal cause

Favours renal cause

Yes

No

Urine Protein Red blood cells White blood cells Casts Osmolality (mosmol/kg/H20) Sodium (mmol/L)

0-1 0 0 0-1 >500 <20

1-4 1-3 1-3 1-3

Feature Identifiable prerenal factor, e.g. shock, hypovolaemia

<400

>35

Urine/plasma urea ratio

>8

<3

Urine/plasma creatinine ratio

>40

<20

Fractional excretion of sodium*

<1%

>1%

* Fractional excretion of sodium is the percentage of the total filtered load of sodium that appears in the final urine (Table 20.3). The numbers 0-4 indicate the degree of urinary abnormality.

glomeruli are relatively spared. The process of repair may last from a few days to several weeks, and generally leads eventually to complete or near complete recovery of renal function. If the ischaemic damage is very severe, however,

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varying degrees of cortical necrosis may occur, and recovery of function is then limited or negligible. For reasons not fully understood, cortical necrosis is particularly likely to occur in relation to shock occurring during pregnancy, such as may arise following antepartum haemorrhage. Postrenal ARF

Important causes of postrenal ARF are given in Table 20.15. ARF will only develop if the obstruction is bilateral, or if it affects a solitary functioning kidney. Thus, obstruction of one ureter by a stone does not lead to ARF, whereas obstruction of both ureters by pelvic malignancy does. Early identification of postrenal factors in a patient with ARF is most important if therapy is to be appropriately directed and irreversible obstructive injury to the kidneys averted. Assessment may be aided by prior knowledge of the presence of one of the potentially obstructing lesions. Physical examination may reveal a pelvic mass, or enlarged kidneys or bladder. Ultrasound examination of the kidneys is valuable, both to give a positive diagnosis of obstruction and to exclude obstruction as a likely factor in patients with ARF. In some cases IVU may be undertaken, but the pictures can be equivocal and delayed films (up to 24 hours following the injection) may be needed. Invasive imaging of the urinary tract by antegrade or retrograde ureterography is rarely needed to make the diagnosis but, along with cystoscopy, may be of help in the detailed assessment of the obstructed patient.

Management Prerenal ARF will, by definition, respond promptly to correction of the prerenal factor(s). Renal ARF may be of a type in which resolution usually occurs within days or weeks (e.g. ATN, postinfectious glomerulonephritis (GN), some toxic nephropathies), or it may lead to irreversible renal failure (e.g. renal infarction, some types of acute GN and renal vasculitis). In some cases (e.g. renal vasculitis) resolution of the renal lesion may follow therapy with steroids, cytotoxic drugs or plasma exchange. Postrenal ARF is treated by relief of the obstruction, usually by mechanical means (e.g. insertion of ureteric stent, percutaneous nephrostomy, removal of stone) pending further assessment of the feasibility of definitive relief of the obstructing lesion. In a few patients non-mechanical measures, such as radiotherapy, antitumour chemotherapy or steroids, may obviate the need for mechanical relief of obstruction. Regardless of the underlying cause, any patient with prolonged ARF will require energetic supportive measures. These may be conservative, or involve the use of dialysis.

O MCQ 20.7

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O MCQ 20.8

Conservative Fluid intake Fluid intake must be adjusted to ensure that the patient is neither hypovolaemic nor overloaded. Euvolaemia is the objective, and careful clinical assessment of volume status is of the utmost importance (p. 1100). Hypovolaemia must be avoided at all costs - its presence inevitably reduces further the already compromised renal function, as well as greatly increasing the risk of acute tubular necrosis (if not already present). The volume of fluid given will depend initially on the patient's state of hydration at presentation. If overloaded, the patient must be fluid-restricted to the lowest attainable level; conversely, hypovolaemia must be corrected promptly by oral or intravenous fluids. Maintenance of euvolaemia requires repeated clinical assessment of volume status, monitoring of external fluid losses - both measured (urine, faeces, nasogastric tube, fistula etc.) and unmeasured (sweat, respiration) - daily weighing (aiming to keep body weight near constant), and appropriate replacement. Sodium intake The hypovolaemic patient will require volume replacement with normal saline (and/or colloid fluids depending on the clinical circumstances) until euvolaemia is reached; sodium intake must then be adjusted to balance sodium losses. These may be very small (<30mmol/day) in an oliguric, afebrile patient, or very large (e.g. from the gastrointestinal tract). The external losses of sodium should be quantified by measurement of the sodium concentration and volume of the fluid, although in many cases knowledge of the source of fluid allows a reasonable estimate of its likely sodium concentration (p. 1104). Sodium intake is then adjusted to match the total sodium loss. Potassium intake Potassium intake usually has to be reduced in an oliguric patient, typically to 30-40 mmol/day or less. The adequacy of potassium restriction may be monitored by serial measurements of plasma potassium concentration. Frequently, potassium restriction alone is insufficient to prevent hyperkalaemia: this progresses as a result of loss of potassium from the ICF owing to accelerated tissue catabolism, and also by movement of potassium from the ICF to the ECF under the influence of developing renal acidosis. Sodium bicarbonate may be useful in this setting and, provided its use is not precluded by body sodium and water overload, is very effective. Cation exchange resins (e.g. calcium resonium) given orally or rectally may increase external potassium loss, and the combination of insulin and glucose can also be useful in the short term for management of hyperkalaemia (p. 1112). Protein and energy provision Many patients with ARF have severe associated disease (such as shock, sepsis and trauma), so that the usual considerations regarding protein restriction in renal failure (p. 1056) may not apply. The management of isolated ARF in

an otherwise well and stable patient should include dietary protein restriction to about 0.6 g protein/kg body weight per day. This should be accompanied by generous energy provision from carbohydrate and fat, to a total of at least 30kcal/kg body weight per day. This limits the accelerated tissue catabolism required to make up any shortfall in energy provision. In contrast, the patient with ARF and severe associated illness is likely to be in a hypercatabolic state and require as much as 50kcal/kg body weight per day or more. Protein restriction has no place here: indeed, intake should be high (1.5g/kg body weight per day). Dialysis

Dialysis may be needed for one or more of the following indications: • Uraemic syndrome (p. 1052) • Adverse biochemistry (urea levels > 40-45 mmol/L) • Severe hypervolaemia with hypertension and/or pulmonary oedema • Hyperkalaemia (potassium levels > 6.5 mmol/L) • Severe symptomatic acidosis • The need to remove fluid to allow intensive feeding with high-energy/high-nitrogen diets or total parenteral nutrition (TPN). Such feeding usually requires an intake of at least 2500 mL/day. Slow continuous haemodialysis or slow continuous haemofiltration is usually the preferred treatment, especially in the presence of multiple organ failure and circulatory instability. Intermittent haemodialysis is suitable for stable patients and, less commonly, peritoneal dialysis is used this has the advantage of simplicity and, unlike the others, avoids the need for anticoagulation.

ACUTE NEPHRITIC SYNDROME Acute nephritic syndrome is characterized by the abrupt appearance of blood and protein in the urine, in association with a decline in GFR, sodium and water retention and hypertension. The haematuria may be macroscopic or microscopic, and the spun deposit of fresh urine contains red blood cells and casts which are cellular, granular, or both. The syndrome is often mild and transient, but may also be severe enough to present as ARF. The renal lesion is usually acute GN, which may be primary or secondary (discussed on pp. 1068 and 1072), although a minority of patients will be found to have acute tubulointerstitial disease (p. 1080). The causes of acute nephritic syndrome are listed in Table 20.17. 1 The management of the disease causing this syndrome is discussed on pages 1069-1075.

RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS The pathological process of rapidly progressive glomerulonephritis (RPGN) often appears confined to the kidney

TABLE 20.17 Causes of acute nephritic syndrome Primary postinfectious Bacterial Streptococci Bacterial endocarditis Ventriculo-atrial shunt ('shunt nephritis') Typhoid Brucella Meningococci Viral Cytomegalovirus Hepatitis virus Epstein-Barr virus

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Secondary with underlying multisystem disease SLE Polyarteritis Wegener's granulomatosis Goodpasture's syndrome Henoch-Schonlein purpura Haemolytic-uraemic syndrome Other Idiopathic (RPGN) Acute tubulointerstitial nephropathy

Parasitic Plasmodium falciparum

(idiopathic RPGN), but may also be present on a background of a multisystem disease such as polyarteritis, Henoch-Schonlein purpura, systemic lupus erythematosus (SLE) or infective endocarditis. There is usually a distinctive epithelial crescent within the glomerulus, leading to the alternative designation 'crescentic nephritis'. Fibrin deposition may be prominent. In this syndrome, renal function deteriorates progressively over days, weeks or months, usually with urine containing many casts, red blood cells and protein. The course is relentlessly downhill, and although some patients appear to respond to aggressive therapy with steroids, cytotoxic drugs, plasma exchange and, in some cases, antiplatelet and anticoagulant drugs, many progress to ESRD and require dialysis. Diagnosis is based on renal biopsy. The individual diseases causing RPGN, and their management, are discussed on pages 1068-1075.

CHRONIC RENAL FAILURE Aetiology Chronic renal failure (CRF) can result from any cause of parenchymal renal disease, including unrelieved obstruction (Table 20.18). 2

Clinical features and investigation Assessment of the patient with suspected CRF is described in Table 20.19. In all cases it is important to decide whether the renal impairment is indeed chronic or whether it is acute (Table 20.16). CRF rarely has the potential to improve significantly (although appropriate treatment may slow or arrest progression), but many patients with ARF have potentially recoverable lesions. It follows that a diag-

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TABLE 20.18 Causes of chronic renal failure Vascular Renal artery stenosis (only when bilateral or affecting solitary functioning kidney) Hypertensive nephrosclerosis Systemic sclerosis Haemolytic uraemic syndrome/thrombotic thrombocytopenic purpura Vasculitis (polyarteritis, Wegener's) Glomerulopathy All causes of primary glomerulopathy (except minimal change) All causes of secondary glomerulopathy (with associated multisystem disease, e.g. SLE, Henoch-Schonlein purpura) Toxic glomerulopathy (gold, penicillamine) Tubulointerstitial nephropathy (TIN) Idiopathic Associated with multisystem disease (Sjb'gren's, sarcoidosis) Associated with metabolic disorders (e.g. urate, nephrocaicinosis) Toxic TIN, e.g. analgesic abuse, Bence-Jones' protein in myeloma Infection and/or reflux Chronic pyelonephritis Renal tuberculosis Cystic disease Adult polycystic disease Obstructive nephropathy Diabetic nephropathy Amyloid Renal dysplasia, hypoplasia, agenesis

nosis of CRF does not usually require more than general information regarding the renal pathology. Thus, renal biopsies are seldom of value in patients with CRF. There are, however, certain factors that require careful consideration, and attention should be directed in particular to the following: • Is a prerenal factor exacerbating the CRF? The most likely of these is salt and water depletion (which may itself be a consequence of a concomitant renal concentrating defect), and its correction may dramatically improve the level of renal function. • Has coexisting hypertension been adequately controlled? • Have postrenal factors been adequately excluded? The importance of this is clear: relief of an obstructing lesion is likely to halt progression of the CRF, and may lead to its partial reversal. Advanced CRF is always associated with the development of the uraemic syndrome. 1

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MCQ 20.9

TABLE 20.19 Assessment of the patient who appears to have chronic renal failure Clinical Symptoms or signs of uraemia Length of history Family history of renal disease Pointers to underlying multisystem disease (diabetes, SLE, etc.) Symptoms and/or signs of obstruction Palpably enlarged kidneys Volume depletion or expansion Blood pressure/signs of accelerated hypertension Laboratory Urine analysis

- for blood/protein - microscopy of fresh spun deposit - culture Assessment of GFR (plasma creatinine/clearance) 24-hour protein excretion Full blood count, ESR Immunological studies (optional, depending on case), e.g. immunoglobulins, complement, immune complexes, autoantibodies, ANCA Infection - HBsAg, Hep. C virus antibodies, and blood cultures (where appropriate) Imaging Plain abdominal X-ray with/without nephrotomography (renal size) Ultrasound of kidneys (renal size, obstruction) Radionuclide studies (level of renal function, obstruction) IVU (renal size, gross morphology and function) Hand X-rays (secondary hyperparathyroidism) Histology Renal biopsy - only if kidneys are not small and there is doubt over chronicity

Uraemia The uraemic state eludes precise definition. A working description would be 'the constellation of symptoms, signs and altered body physiology and chemistry that arises when renal function is substantially impaired'. These features are listed in Table 20.10 (p. 1045). Uraemia results mainly from the toxic accumulation of waste products, but depletion of essential compounds and failure of biosynthetic functions of the kidney also contribute. Most organ systems are affected in one way or another. The conservative management of CRF is outlined in Table 20.20. Uraemic toxins There are many potential uraemic toxins, although urea itself is probably not one of them, at least in clinical practice. Other candidates are peptide hormones (PTH, gastrin, glucagon and calcitonin), purine metabolites, aliphatic and aromatic amines, phenols and indoles, all of which are demonstrably toxic in vitro. The demonstration of increased quantities of compounds of molecular

TABLE 20.20 Conservative management of the uraemic syndrome Item

Comments

Identify and treat prerenal factors

Many patients with CRF cannot conserve sodium/water

Identify and treat postrenal factors

Exclude obstruction in all cases

Restrict dietary protein

GFR usually less than 25mL/min, Early restriction might protect remaining nepnrons

Adjust dietary sodium/ potassium

Severe restriction unnecessary except in oliguria. Sodium supplementation needed in some cases

Fluids

Aim for urine flow rate of 1500-2000 ml/day

Prophylaxis or treatment of osteodystrophy

Restrict dietary phosphate. Give phosphate binders (calcium carbonate and/or aluminium hydroxide). Give calcium supplements. Consider vitamin D analogues (calcitrol, alfacalcidol)

Control blood pressure

Adjustment to body sodium/water by diet and diuretics. Beta-blockers, angiotensin-converting enzyme inhibitors, calcium antagonists if necessary

Look out for deficiency of vitamins and minerals

Iron is the most likely to require supplementation

Acidosis

Treat with sodium bicarbonate if (a) severe and (b) no contraindication

weight 0.5-5kDa (so-called 'middle molecules') in uraemic patients has led to speculation that one or more of these may be involved. Both small molecules, such as urea, and middle molecules are removed by dialysis (p. 1059), and this is associated with amelioration of the uraemic syndrome. However, evidence relating these compounds directly to clinical uraemia remains circumstantial. Haematopoietic system in uraemia Anaemia The majority of patients with significant renal impairment have normochromic normocytic anaemia. The following contribute to the anaemia (see also Ch. 23, p. 1205): • Decreased production of erythropoietin by the diseased kidney • Direct marrow suppression by uraemic toxins • Shortened red cell survival • Increased blood loss. Most patients approaching ESRD or being treated by haemodialysis have haemoglobin concentrations in the region of 6-10 g/dL, although in those who have been nephrectomized the anaemia is usually more severe. Patients with polycystic kidney disease often continue to

make erythropoietin and may have completely normal haemoglobin concentrations, even when on dialysis. Haematinic deficiency may exacerbate the anaemia of CRF: iron and folate supply is often marginal in patients on restricted diets and, in addition, renal patients malabsorb iron and have increased iron needs as a result of mucosal bleeding. 1

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Bleeding Bleeding in uraemia is mainly from capillaries and is due to abnormal platelet function (platelet numbers are usually normal in uraemia). Treatment of uraemia by dialysis improves, but does not normalize, the platelet defect. The bleeding tendency manifests itself clinically with cutaneous ecchymoses and mucosal oozing. Cardiovascular system in uraemia Cardiovascular disease is by far the most common cause of death in patients with renal failure, regardless of whether they are treated by haemodialysis, peritoneal dialysis or transplantation. Heart Many patients with CRF, particularly those maintained for long periods on dialysis, appear to develop impaired cardiac function. Although this usually occurs as a consequence of hypertension or coronary artery disease, this is not always the case. Chronic anaemia, volume overload, nutritional deficiency, high circulating levels of angiotensin II and uraemic toxins may all contribute to a 'uraemic cardiomyopathy'. Rigorous control of intravascular volume, blood pressure (by dialysis and/or drugs) and anaemia (using erythropoietin) offers the best hope of prevention or amelioration of the condition. If necessary, symptomatic ischaemic heart disease and valve disease can be managed surgically with no great excess in morbidity or mortality. Arteries Chronically uraemic patients, whether treated by dialysis or not, have a greatly increased incidence of arterial disease, and cardiovascular disease is by far the largest single cause of death among patients on dialysis programmes. This is paralleled by striking increases in vascular calcification affecting the coronary arteries and other vessels. Uraemia is often accompanied by hyperlipidaemia, in which plasma triglycerides and very low-density lipoproteins are elevated and high-density lipoproteins are reduced (p. 1022). These abnormalities, in combination with hypertension, may account for the accelerated arterial disease that appears to be part of the uraemic state. It is not yet known whether biochemical improvements from lipid-lowering diets and drugs translate to a reduction in vascular disease in uraemia, but current practice is to treat both hypertension and hyperlipidaemia vigorously. Pericardium Haemorrhagic pericarditis is a frequent complication of terminal uraemia, but may also arise in the less uraemic patient approaching ESRD or receiving dialysis. Its occur-

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FIG. 20.14 Renal osteodystrophy The process is dominated by a combination of phosphate retention (its consequences shown on the left side of the figure) and failure of the diseased kidney to synthesize 1,25-dihydroxyvitamin D (its consequences shown in the centre and right of the figure).

rence is loosely related to the severity of uraemia, as judged by plasma urea concentration. The onset may be insidious or abrupt, the latter leading to severe pain or cardiac tamponade, which may be fatal. Management is that of any pericardial effusion (p. 587) combined with intensive dialysis. Surgical relief of tamponade or chronic constrictive pericarditis is occasionally needed. Skeletal and mineral metabolism in uraemia: renal osteodystrophy Skeletal abnormalities are an invariable accompaniment of uraemia and comprise hyperparathyroid bone disease, osteomalacia and osteosclerosis. The pathogenesis of these conditions is dominated by two distinct processes: phosphate retention and lack of 1,25-dihydroxyvitamin D (calcitriol) (Fig. 20.14), both leading to secondary hyperparathyroidism.

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Deficiency of 1,25-dihydroxyvitamin D/calcitriol Calcium malabsorption develops when renal damage has progressed to the point where the production of 1,25dihydroxyvitamin D, the active hormonal form of vitamin D, from its precursor 25-hydroxyvitamin D (under the influence of 25-OHD-loc-hydroxylase) becomes significantly impaired (Fig. 20.15). Early in renal failure plasma concentrations of 1,25-dihydroxyvitamin D are normal, probably because the accompanying hyperparathyroidism has the effect of stimulating the diseased kidney

FIG. 20.15 Renal and hormonal control of calcium metabolism PTH, secreted in response to decreasing ECF calcium, stimulates the production of 1,25(OH)2D in the kidney. 1,25(OH)2D in turn stimulates bone resorption and intestinal calcium absorption, and feeds back negatively to inhibit PTH secretion.

to maintain 1,25-dihydroxyvitamin D production (pp. 962, 964). In advanced renal failure (GFR <20mL/min) 1,25dihydroxyvitamin D concentration falls to low or undetectable levels. This is partly as a result of decreased renal mass and loss of the cells that contain 25-hydroxyvitamin D la-hydroxylase (the proximal tubular cells), and partly as a result of the suppressive influence of hyperphosphataemia on the la-hydroxylase enzyme. The consequent intestinal calcium malabsorption further exacerbates the secondary hyperparathyroidism, and the lack of direct 1,25-dihydroxyvitamin D action in the parathyroid glands leads to inappropriate increases of PTH synthesis and to parathyroid hyperplasia. Phosphate retention Phosphate retention is a consequence of the decreasing filtered load of phosphate as GFR falls. This has several consequences for the parathyroids, all of them stimulatory:

• Augmentation of PTH synthesis and parathyroid cell mitotic activity • Inhibition of renal synthesis of 1,25-dihydroxyvitamin D • Increased skeletal resistance to PTH: the skeleton is less responsive to PTH during hyperphosphataemia • Reciprocity with calcium: high phosphate reduces ECF calcium concentration. The dominant skeletal lesion is thus that of hyperparathyroid bone disease, with increased numbers and activity of osteoclasts, accelerated bone resorption, a coupled increase in osteoblastic activity, high bone turnover and variable degrees of peritrabecular brosis (osteitis fibrosa). These lesions can usually be reversed by therapy that alleviates the hyperparathyroidism (p. 1057). In addition, a proportion of patients show features of impaired mineralization (osteomalacia), either in combination with hyperparathyroid bone disease or in isolation. The pathogenesis of uraemic osteomalacia is less well understood than that of hyperparathyroidism, but it may be a direct consequence of a lack of 1,25-dihydroxy vitamin D, or a reflection of abnormal collagen synthesis, or failure of transformation of calcium phosphate to hydroxyapatite in the presence of uraemia. Aluminium derived from aluminium-containing phosphate binders may accumulate in the bone of some patients with uraemia and has been associated with severe and refractory osteomalacia. Although hyperparathyroidism and osteomalacia both lead to osteopenia, some patients show regional osteosclerosis, particularly involving the trabecular bone of the spine. Its pathogenesis is poorly understood but it usually develops on a background of severe hyperparathyroidism. Soft tissue calcification, generally vascular, subcutaneous or corneal, may occur, especially in patients with chronic elevation of plasma phosphate concentration. The vascular calcification is found even in adolescent and young adult dialysis patients and may be an important contribution to the high vascular morbidity and mortality in these patients. Metabolic acidosis - from which all uraemic patients suffer to some extent, and which is buffered by skeletal alkali - also contributes to the development of renal osteodystrophy, especially when the acidosis is severe and prolonged. Clinical features are usually subtle when the disease is mild or moderate, especially when hyperparathyroidism dominates the picture. In the presence of significant osteomalacia, however, bone pain, deformity and pathological fractures may occur. Radiological evidence of hyper-

SUMMARY 3 Calcium, phosphorus and calciumregulating hormones in untreated uraemia Calcium Phosphate 25-hydroxyvitamin D 1,25-dihydroxyvitamin D PTH

parathyroidism (p. 971; subperiosteal erosions affecting particularly the phalanges and spinal osteosclerosis - the rugger jersey spine) or osteomalacia (osteopenia, Looser zones, non-healing fractures) may be present. Plasma biochemistry shows normal or low calcium concentration, raised inorganic phosphate and, often, raised alkaline phosphatase, reflecting increased osteoblastic activity. If measured, PTH is high, 25-hydroxyvitamin D normal and 1,25-dihydroxyvitamin D low, indicating failure of renal bioactivation of vitamin D.

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Gastrointestinal system ana1 uraemia Peptic ulcer disease is possibly more common in uraemic patients. Serum gastrin is elevated in uraemia, but basal and stimulated gastric acid secretion is often normal. Haemorrhagic complications of peptic ulcer disease are more likely in uraemia because of the associated haemostatic defects (p. 1053) and, in the case of haemodialysis patients, exposure to anticoagulants. Treatment is along conventional lines with antacids and H2-receptor antagonists. Small and large bowel changes are usually mild and of little functional significance, except in near-terminal uraemia, when bleeding may be severe. Angiodysplasia (Ch. 15, p. 772) is relatively common in uraemia and accounts for bleeding in a number of cases. Nervous system in uraemia Uraemic encephalopathy is a syndrome of global CNS dysfunction, probably resulting from retained uraemic toxins, although it is not clear which of these underlie the clinical manifestations. Its onset depends in part on the severity of uraemia (judged biochemically), but also on the rate of onset of uraemia, rapid onset being associated with earlier CNS decompensation. Higher mental functions are the first affected; poor concentration, apathy, insomnia and irritability occur frequently. Motor disturbances become evident later, leading to slurring of speech, tremors, asterixis (the 'uraemic flap'), myoclonus and even seizures. Nausea and vomiting are prominent in advanced uraemia and may respond to antiemetic drugs. 'Dialysis dementia' is a rare and usually fatal complication of severe aluminium intoxication in uraemic patients. Peripheral nervous system Uraemic neuropathy is a frequent complication of terminal uraemia. Symptomatic neuropathy may also develop in patients in whom the initiation of dialysis has been deferred for too long, or who are underdialysed; clinical and electrophysiological evidence of asymptomatic neuropathy is very common. The neuropathy is mixed sensory and motor - axonal degeneration is the underlying pathology. A variable degree of improvement follows treatment of the uraemia. Metabolic and nutritional considerations in uraemia Protein. A mixed picture with elements of both deficiency and toxicity emerges. Protein-restricted diets pre-

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dispose to protein malnutrition, whereas the accumulation of nitrogenous compounds, some of which may be 'uraemic toxins', results from impaired renal catabolism and excretion of waste. Additional problems may be present in specific diseases (e.g. massive protein losses in nephrotic syndrome). Carbohydrate. As a group, uraemic patients are slightly hyperglycaemic compared to normals, both when fasted and following glucose challenge. Peripheral insulin resistance appears to be the major cause, and this may be further exacerbated by a tendency of uraemia per se to inhibit insulin secretion. Conversely, the renal catabolism of insulin is normally considerable and decreases as renal disease progresses. As a result, although uraemic patients have mild carbohydrate intolerance, overtly diabetic patients with nephropathy require less insulin as nephropathy progresses. Lipids. Plasma triglycerides and very low-density lipoproteins are increased and high-density lipoproteins decreased in uraemia. All these changes potentially contribute to the observed increase in atherogenesis among uraemic patients.

Conservative management of chronic renal failure This section deals with the clinical management of the patient who has severe impairment of renal function but who has not yet reached ESRD and the need for renal replacement therapy (RRT). Because of the serious limitations of adaptive capacity in the diseased kidney, the central principles of conservative management are: • To minimize the functional stresses and strains imposed on the kidney by attempting to define the appropriate intake of food, minerals and water in such a way as not to exceed the kidney's limits of adaptation; • To identify and treat any coexisting factors that may further compromise renal function, e.g. hypertension, prerenal factors, postrenal factors; • To anticipate and, if possible, avoid future complications of uraemia, such as malnutrition, osteodystrophy, soft tissue calcification; • To anticipate and prepare for the initiation of RRT if needed. Specific aspects of clinical management are as follows (and are summarized in Table 20.20).

Diet

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Protein Protein restriction is considered only when symptoms and/or signs of the uraemic syndrome become evident; this does not usually happen until GFR falls to 25 mL/min or less. Protein restriction decreases the rate of production of uraemic toxins and the acid products of metabolism, and is very effective in alleviating the uraemic syndrome (although it has no immediate effect on underlying renal

SUMMARY 4 Checklist for management of chronic renal failure • Adjust salt and water intake to maintain euvolaemia, if necessary with loop diuretic also • Maintain urine flow at >1500 ml/day • Restrict dietary potassium if hyperkalaemic • Restrict dietary protein • Restrict dietary phosphorus and give phosphate binder (usually calcium carbonate) • Control blood pressure, if possible by using ACE inhibitors • Correct haematinic deficiency and give erythropoietin if needed • Correct acidosis, using sodium bicarbonate if tolerated

function). In the UK, normal dietary protein intake is 70-140g/day. This can be reduced in a step wise fashion (as GFR decreases) to a lower limit of 30g/day (0.6g/kg body weight per day) without serious risk of nutritional deficiency, provided that it is accompanied by adequate energy intake in the form of carbohydrate and fat and that there is no additional catabolic stress. At these very low protein intakes it is important that the protein is of animal origin, in order to avoid selective deficiency of essential amino acids: these may only be present in small amounts in vegetable protein. The essential amino acids in animal protein are present in proportions that approximate to their minimum daily requirement in humans. This represents an ideal scenario. In practice, patients are also at risk of malnutrition (anorexia or poor compliance with diet) and increasingly are managed with only modest dietary protein restriction to about 1 g/kg body weight per day. Conversely, although it is conventional practice to restrict protein only for symptomatic treatment of the uraemic syndrome, there is convincing laboratory evidence that much earlier protein restriction will retard, and in some cases halt, the progression of renal deterioration (p. 1057). Although this has been difficult to establish convincingly in the clinical arena, there is an increasing tendency for protein restriction to be implemented earlier in the course of chronic renal failure. Sodium In many patients urinary sodium excretion is reasonably well maintained even at very low levels of GFR. However, in the salt-consuming developed countries, sodium restriction often becomes necessary; the indications are hypertension, or evidence of expansion of body sodium and water. The dietary intake may be set at about 60mmol/ day (moderate salt restriction), compared to the 100250mmol/day in a 'normal' diet. More severe sodium restriction can be used but renders the diet increasingly unpalatable. Fortunately, potent loop diuretics often obviate the need for unpleasantly low-sodium diets. Conversely, there are cases where inappropriate salt losses through the diseased kidney may dictate a high dietary sodium intake in order to avoid sodium and water depletion and prerenal exacerbation of the uraemic state.

Potassium Even in advanced renal failure the kidney is usually able to maintain adequate potassium excretion, provided that urinary flow remains generous. A modest reduction of dietary potassium is required: 60-80 mmol/day is usually appropriate, compared to a typical 'normal' intake of 80-120 mmol/day. Severe hyperkalaemia may develop if there is oliguria, gross dietary indiscretion, acidosis (with a shift of body potassium from ICF to ECF), or severe intercurrent illness with accelerated catabolism. Potassium-sparing diuretics (e.g. spironolactone, amiloride, triamterene) severely impair potassium excretion in uraemia and should be avoided; this also applies to 'combination' preparations (thiazide/furosemide (frusemide) and amiloride/triamterene/spironolactone). The treatment of hyperkalaemia is described on page 1112, but in patients with severely impaired renal function a sudden rise in serum potassium may necessitate emergency dialysis. Fluids Fluid restriction is rarely necessary in a patient with CRF, unless oliguria or anuria supervenes. On the contrary, it is important to ensure that the fluid intake is set at a level adequate to keep up with the relatively high obligatory urine flow rate in CRF, thereby preventing water depletion and prerenal exacerbation of the renal disease. In practice, the fluid intake should be such as to maintain urine flow at around 1500-2000 mL/day, i.e. minimum daily fluid intake should be 2000-2500 mL/day. A minority of patients with more severe urinary concentrating defects will require larger amounts of fluid to maintain water balance. Calcium, phosphorus and vitamin D CRF is associated with a tendency towards hyperphosphataemia, hypocalcaemia, hyperparathyroidism and impaired production of 1,25-dihydroxyvitamin D and consequent intestinal calcium malabsorption (p. 1054). A number of therapeutic measures are employed. • Moderate dietary phosphate restriction; • Administration of oral 'phosphate binders' with food. Calcium carbonate and magnesium carbonate are routinely used as phosphate binders. Aluminium hydroxide was the standard therapy but is now hardly used on account of its toxicity in some uraemic patients. Sevelamer hydrochloride is a new phosphate binder that contains neither calcium nor aluminium, is easy to use, and has the added benefit of reducing plasma LDL and total cholesterol via its action as a bile salt sequestrant; • Maintenance of a high oral calcium intake. Calcium carbonate is convenient here. Doses of 25-150 mmol/day (2.5-15 g/day) given with food will often control plasma inorganic phosphate adequately, and also increase vitamin D-independent intestinal calcium absorption, thereby lessening hyperparathyroidism; • Use of potent analogues of vitamin D. The requirement is that they should bypass the vitamin D resistance of

CRF by not requiring renal 1-hydroxylation to achieve activity (see Fig. 20.14). 1,25-dihydroxy vitamin D (calcitriol), loc-hydroxyvitamin D (alfacalcidol) and dihydrotachysterol are all effective. However, because they also augment intestinal absorption of phosphate, they should not be given until plasma phosphate has been controlled as described above.

20

A note of caution on the use of large doses of calcium salts in these patients: recent studies point to the early development of coronary artery calcification in dialysis patients, especially those previously maintained on a high calcium intake (see Recent Advances in the approach to renal osteody strophy). Other vitamins and minerals Clinical deficiency is rare in the well managed patient with CRF, although subtle deficiency states may be more common. Iron status in particular may be marginal reflecting intestinal iron malabsorption and increased requirements owing to blood tests and occult bleeding. Overzealous and prolonged dietary protein restriction may lead to difficulties, but this usually reflects inappropriate persistence with conservative measures in a patient in whom dialysis should have been started earlier. Acidosis In some patients uraemic acidosis is sufficiently severe, even after appropriate dietary protein restriction, to warrant attempts to relieve it. This may be done with sodium bicarbonate, although the need for concomitant sodium restriction may preclude or limit its use. Potassium bicarbonate is never used in this setting for fear of causing hyperkalaemia. Control of blood pressure The control of blood pressure is discussed on page 1081. Its importance cannot be overemphasized.

Anaemia Evidence of iron and folate deficiency should be sought and treated if appropriate. Replacement of the deficient hormone can be achieved by regular injections of synthetic human erythropoietin; this approach is extremely effective. Occasional, or even regular, blood transfusion is used in some patients. Symptoms (e.g. weakness, lethargy) and complications (angina, cardiac failure) of anaemia dictate the need for treatment, as well as the absolute level of haemoglobin. Target haemoglobin is in the range 11.513.5g/dL. Successful transplantation leads to a rapid return of normal haematopoietic activity. Measures to halt or retard the progression of chronic renal failure Progressive renal disease usually causes a decrease in the number of functioning nephrons; therefore, it follows that each of the remaining nephrons must process an unusually large amount of water and solute. Adaptive

1057

RECENT ADVANCES IN THE APPROACH TO RENAL OSTEODYSTROPHY For many years the conventional approach has been to utilize a combination of dietary phosphate restriction, the administration of oral phosphate binders and the replacement of deficient calcitriol with synthetic calcitriol or a similarly active metabolite of vitamin D. When correctly applied, these measures have proved effective in a large proportion of patients with end-stage renal disease. Patients with severe parathyroid hyperplasia (often with underlying nodular hyperplasia), in whom parathyroid autonomy has progressed to the point where the synthesis and release of PTH cannot be adequately suppressed by standard treatment, are frequently encountered. In these patients continued stimulation of the parathyroid glands (by a combination of high ambient phosphate concentration, low ambient calcium concentration and a relative deficiency of calcitriol), has led to striking parathyroid enlargement following extended periods of increased parathyroid cell mitotic activity. Within such enlarged parathyroid glands areas of nodular hyperplasia develop in which there is evidence of chromosomal abnormalities and monoclonal proliferation. Functionally, these nodules possess the machinery to produce, synthesize and secrete parathyroid hormone, but to a variable degree lack the machinery that would enable them to respond appropriately to suppressive inputs. Thus in these areas there is reduced expression of the vitamin D receptor (an essential part of cellular responses to calcitriol) and of the extracellular calcium receptor. The parathyroid cells are therefore unable to respond fully to the normal suppressive influence of high ambient calcium and/or calcitriol. Runaway stimulation therefore continues and is often refractory to the standard treatment and practices outlined above. These patients usually require parathyroidectomy. Modified vitamin D analogues have been synthesized and evaluated clinically in the hope that they will exhibit potent suppression of the parathyroid glands without dose-limiting hypercalcaemia. To achieve this, such metabolites would need to exert a selective action on the parathyroid glands with little or no action on calcaemic target tissues, principally intestine and bone. To date, despite much encouraging experimental evidence, none of these compounds has been shown to be superior to current best practice in properly conducted clinical trials. Phosphate control was initially achieved using aluminium salts (aluminium hydroxide or aluminium carbonate) given with meals. The extremely low gastrointestinal absorption of aluminium was thought to protect patients from aluminium toxicity in this setting, but in the early 1980s it became apparent that, particularly in

1058

patients with advanced renal disease and negligible aluminium excretory capability, the small amounts of aluminium absorbed during this type of treatment led to significant accumulation, with important toxicity to the skeleton and to the central nervous system (sometimes fatal in the case of the CNS). Thus aluminium salts were quickly abandoned as first-line treatment for phosphate control and were replaced with calcium salts - calcium carbonate and calcium acetate. These also are effective phosphate binders, but have the disadvantage of significant calcium absorption and a tendency for episodes of hypercalcaemia. A new approach, and one showing much early promise, is the use of calcimimetic agents. These compounds bind to the extracellular calcium receptor and increase its sensitivity to calcium. Thus the parathyroid cells are tricked into thinking that extracellular calcium concentration is higher than it really is, hence the term 'calcimimetic'. Both experimentally and clinically, these agents significantly reduce parathyroid hormone while simultaneously reducing serum calcium concentration. This combination of effects is ideally suited to the scenario that exists in patients with severe hyperparathyroidism. Phase 2 clinical trials have been completed and show great promise: it is likely that these agents will form an important part of the treatment of hyperparathyroid disorders in renal disease, and probably in other clinical scenarios as well. Of great concern has been the realization that the extensive vascular calcifications seen in patients with long-standing chronic renal disease is associated with, among other things, previous use of calcium salts as treatment for hyperphosphataemia. It appears that the risk of calcium salts may be significant even in patients without overt hypercalcaemia. These findings have lead to a search for aluminiumand calcium-free phosphate binders. One such is sevelamer hydrochloride (Renagel). This is a polymeric compound which binds dietary phosphorus well and, because of its unrelated action as a bile acid sequestrant, also reduces serum cholesterol and LDL cholesterol by as much as 30%. It remains to be seen whether sevelamer hydrochloride will be associated with a reduction in the amount of vascular calcification in patients treated long term. Initial studies are encouraging, with evidence that the progression of vascular calcification (measured by electron beam CT scanning) in dialysis patients is halted when they are converted from calcium salts to sevelamer hydrochloride. Whether or not this will translate to a reduction in cardiovascular morbidity and mortality remains to be seen.

changes in the residual nephrons are many, but there is good evidence that single-nephron GFR (i.e. GFR per nephron) is increased in chronic renal disease, and that this is associated with a raised hydrostatic pressure in the glomerular capillaries (glomerular hypertension). If sustained, this leads to glomerular sclerosis, further loss of nephrons and progressive renal deterioration. In animals, this sequence of events can be completely prevented by dietary protein restriction or angiotensin-converting enzyme (ACE) inhibition, and it is likely (though not yet proven), that the same holds for some types of chronic renal disease in humans. Experimentally, glomerular hypertension can be reduced by ACE inhibitors acting on the renal production of angiotensin II. Although the clinical utility of these measures is not fully established, modest protein restriction (0.6-1.Og/kg body weight per day) and early use of ACE inhibitors is reasonable. By the same reasoning, most nephrologists aim to include an ACE inhibitor in the antihypertensive regimen given to diabetics with nephropathy or microalbuminuria (p. 1011). It is likely that similar benefits will be seen with angiotensin II receptor antagonists.

FURTHER READING ON CHRONIC RENAL FAILURE Brenner B M, Mayer T W, Hostetter T H 1982 Dietary protein intake and the progressive nature of kidney disease: the role of hemodynamically mediated glomular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation and intrinsic renal disease. N Engl J Med 307:652-660. Nath K A 1998 The tubulointerstitium in progressive renal disease [Editorial]. Kidney Int 54:992. Hunsicker L G, Adler S, Caggiula A et al 1997 Predictors of the progression of renal disease in the modification of diet in renal disease study. Kidney Int 51: 1908. Kimmel P L 1994 Management of the patient with chronic renal disease. In: Greenberg A, ed. Primer on kidney diseases, San Diego: Academic Press, 289. Hruska K A, Teitelbaum S L 1995 Mechanisms of disease: renal osteodystrophy. N Engl J Med 333:166.

Renal replacement therapy for chronic renal failure Renal replacement therapy (RRT) for CRF can be achieved by haemodialysis, peritoneal dialysis or renal transplantation. Most centres offering RRT integrate all three treatment modalities, with the aim of providing each patient with the most appropriate management. The requirement for RRT In 1999 the acceptance rates into UK dialysis and transplant programmes was 90 per million population - less than the 150 per million population estimated to develop renal failure. Those not treated (probably about 40% of the whole) are usually too fragile to withstand dialysis, frequently because of serious comorbid conditions. These figures are lower than in most countries in Europe and much lower than in the USA. Consequently, many people in the UK die from renal failure without receiving RRT.

20

FIG. 20.16 Age-related increase in the incidence of end-stage renal disease

Virtually all of these are elderly and have serious comorbid conditions (Fig. 20.16). The current UK dialysis and transplant population is 32000, 47% of which is transplanted and 53% dialysed. Dialysis treatment Dialysis involves placing a large volume of artificial fluid (dialysate) in very close proximity to a large volume of the patient's blood, separating the two with a semipermeable membrane. Haemodialysis In haemodialysis the membrane is synthetic and semipermeable, and is arranged to form an 'artificial kidney' through which blood passes at about 300mL/min before being returned to the patient (Fig. 20.17). The chemical composition of the dialysate is similar to that of ECF. Urea and other waste products, which are present only in plasma, diffuse down a concentration gradient across the membrane and into the dialysate. Changes in the composition of the dialysate and in the hydrostatic pressure gradient across the membrane allow the rate of removal of a variety of substances to be tailored according to the patient's needs. Adequate access to the circulation is a prerequisite. This is obtained by percutaneous placement of large-bore central venous catheters (short-term treatment only), or by the creation of an arteriovenous fistula at the wrist, thereby increasing forearm blood flow and allowing large-bore needles to be placed in forearm veins (longterm treatment). Treatment is intermittent - typically three sessions of 4 hours each per week. In the UK, many patients undergoing haemodialysis conduct their own treatment at home. Peritoneal dialysis In peritoneal dialysis the dialysate is fed into the peritoneal cavity via a flexible tube, and the peritoneum itself acts as a semipermeable membrane. The dialysate is replaced with fresh fluid when chemical equilibrium is reached. The most usual form is continuous ambulatory peritoneal dialysis (CAPD), in which 2-L exchanges are performed four times per day. The technique is simple to learn and the vast majority of patients can carry out and supervise their own

1059

TABLE 20.21 Indications for initiation of dialysis treatment Suitability for long-term treatment and/or reversible cause of renal failure

FIG. 20.17 Physical principles of haemodialysis

treatment at home. An alternative and increasingly used form of peritoneal dialysis is APD - automated peritoneal dialysis. Here the peritoneal fluid cycling is done by a machine, usually at night. Limitations of dialysis Although dialysis can remove waste products, sodium, potassium and water reasonably well and thus control some aspects of the uraemic syndrome, for the following reasons, it is, inferior to normal functioning kidneys: • The average clearance of urea or creatinine achieved by intermittent haemodialysis (approximately 12 hours' treatment per week) is only 6mL/min, and by CAPD about 7mL/min, compared to 100-120 mL/min by normal kidneys. With CAPD in particular, patients who are larger often cannot be provided with adequate weekly clearance unless they are fortunate enough to maintain significant residual renal function. In practice, this usually means patients in their first 2 or 3 years of CAPD: it is rare for residual renal function to be maintained beyond that time, and there is a tendency for CAPD to become increasingly inadequate thereafter. • The permeability characteristics of the artificial membrane in haemodialysis and, to a lesser extent, the peritoneum in peritoneal dialysis (CAPD), are inferior to those of the physiological glomerular sieve. • Dialysis has no equivalent of 'tubular action'; the dialysis membrane must therefore strike a compromise between being permeable enough to allow waste products to cross and not so permeable that excess loss of physiologically important compounds occurs. In practice, the membrane fails on both counts. • Dialysis has essentially no adaptive capability. • Endocrine functions of the kidney are not provided by dialysis. The anaemia (erythropoietin) and osteodystrophy (1,25-dihydroxyvitamin D) continue. For these reasons, most of the management considerations that apply to the non-dialysed patient with CRF also apply to the dialysed patient (see Table 20.20).

1060

Initiation of dialysis treatment Because dialysis is inherently unnatural and invasive, it should not be undertaken lightly. The optimum time to

Uraemic syndrome Neurological Coma, stupor, fatigue, abnormal mentation, fits, myoclonus, asterixis, peripheral neuropathy Cardiovascular/pulmonary Pericarditis, pleurisy, volume overload unresponsive to conservative measures Skin Pruritus Gastrointestinal Anorexia, nausea, vomiting, unremitting diarrhoea Metabolic Unremitting acidosis Chemistry Plasma urea more than 40mmol/L on protein restricted diet Plasma creatinine more than 1200^imol/L Creatinine clearance less than 5 mL/min Hyperkalaemia unresponsive to conservative measures

convert a patient with CRF from conservative management to dialysis is a finely judged clinical decision and is reached just before the development of uraemic complications (Table 20.21). Renal transplantation Compared to maintenance dialysis, successful renal transplantation is a vastly superior form of treatment. There is little that normal native kidneys can do in the way of excretory, homeostatic or endocrine function that cannot be done equally well by a good transplanted kidney. This is reflected in the clinical outcome: it is apparent that many transplanted patients are returned to a state of virtual normality. However, two problems continue to bedevil renal transplantation. These are the inadequate supply of kidneys, and graft rejection. Kidneys are obtained from cadavers (usually those with irreversible CNS injury due to trauma or stroke) or from fit, first-degree relatives. In a small number of cases the living donor is unrelated (usually a spouse). In 2000,1658 renal transplants were performed in the UK. Of these, 1323 were cadaveric, 267 were from relatives and 68 from unrelated living donors. In December 2000 the UK waiting list for kidney transplants was 4900. The median waiting time on the list was 20 months. ABO compatibility is essential and outcome is improved by good HLA matching. The transplanted kidney is placed in the left or right iliac fossa and anastomosed to the iliac vessels; the donor ureter is implanted into the recipient bladder (Figs 20.18, 20.19, 20.20). Immunosuppressive treatment is given routinely and consists of ciclosporin,

20

FIG. 20.18 Anatomy of a renal transplant 1 The donor kidney is taken in continuity with the upper ureter. To facilitate the surgical anastomosis, the donor renal artery is attached to a patch of aorta in cadaveric donation.

FIG. 20.19 Anatomy of a renal transplant 2 The kidney is placed through an oblique incision in the left or right iliac fossa in an extraperitoneal location.

often with steroids and/or azathioprine. A number of new immunosuppressive drugs are entering the clinical arena. Tacrolimus (an agent with a similar mode of action to ciclosporin but with somewhat different side-effects) and sirolimus (rapamycin) are already widely used. It is too early to know whether they confer significant new benefits in renal transplantation. Acute rejection usually occurs during the first few weeks after transplantation and is treated with high doses of intravenous steroids (0.5g methylprednisolone i.v. on 3 consecutive days) in the first instance, with recourse to 'biological' immunosuppressants, such as antithymocyte globulin (polyclonal) or anti-CD4 antibody (monoclonal), in resistant cases. These powerful agents carry with them the danger of overly suppressing the immune system and a risk of serious opportunistic infection and malignancy. These drugs are toxic; this is particularly unfortunate with ciclosporin which, as well as being an excellent immunosuppressive agent, also has marked acute and chronic

FIG. 20.20 Anatomy of a renal transplant 3 The donor renal artery and vein are anastomosed to the external iliac artery (end to side) and the common iliac vein (end to side) respectively. The donor ureter is implanted into the recipient bladder,

nephrotoxicity. About 80% of cadaveric grafts function for 2 years or more, and because most graft loss occurs early, the majority of this 80% will continue to do well thereafter (Fig. 20.21). Living related-donor transplants do even better. Most patients receiving kidney transplants are already being dialysed and can return to dialysis treatment if the transplant fails. A major problem with kidney transplantation is illustrated in Figure 20.21B, where a continuing linear rate of graft loss is apparent even many years after transplantation. This is principally the result of 'chronic allograft nephropathy', in which it is thought that persisting lowgrade immunological injury (chronic rejection) leads to cumulative damage and eventual failure of the graft. No effective prevention has been found, and this remains a damaging influence on renal transplant programmes. Xenotransplantation As indicated elsewhere in this chapter, the shortage of human organs for transplantation has led to a long waiting list for grafting. In the case of heart and liver transplantation this leads to increased mortality, and in the case of kidney transplantation to substantially increased morbidity associated with long-term dialysis, and possibly increased mortality also. For medical, sociopolitical and religious, reasons the shortfall is unlikely ever to be made up using human organs. This implies that either artificial organs, or living organs procured from other species (xenotransplantation) will be needed. Successful Xenotransplantation presents formidable scientific problems, as well as logistic and ethical ones. Choice of species is heavily constrained by issues of animal size, functional characteristics of the potential xenograft, availability in sufficient numbers and ethical acceptability. Although primates might be assumed to be the best option, at present the pig is the favoured choice. Primates breed slowly and some are already endangered species, fuelling concern about their acceptability as a source of xenografts.

1061

FIG. 20.21 Improving survival results between 1981 and 1993. Note that the biggest change is seen during the first 6 months after transplantation Thirteen years transplant survival after first cadaveric kidney transplant in the UK and Republic of Ireland, 1 January 1981 to 31 December 1993: A by year of transplant. B by HLA matching. (Data from UKTSSA, with permission.)

It is estimated that some 20000-40000 animals per year will be needed to sustain the world's current transplant programmes in this way, and it will take at least half a century to create a sufficiently large stock of primate organ donors. In contrast, the pig grows fast, reaches sexual maturity quickly and, being a major source of food already, would in most people's eyes give rise to fewer ethical concerns if used in this way. Rejection of discordant xenografted issue is hyperacute (occurring within minutes) and is mediated by preformed natural antibody-activating complement. Immune suppression of the type used to control allograft rejection is largely without effect. In contrast, xenografts between highly concordant species (e.g. rat and mouse, or man and ape) are rejected more slowly by predominantly cellular mechanisms that are controllable by conventional antirejection therapies such as cyclosporin. Current efforts to circumvent the problem of hyperacute rejection centre on the manipulation of the donor. A colony of transgenic pigs has been produced in Cambridge, in which constructs of the human decay-accelerating factor (DAF, CD55) and the membrane cofactor protein (MCP, CD46) have been incorporated into the pig genome. These act on both classic and alternative pathways of complement activation: DAF accelerates the decay and inactivation of C3 convertases, and MCP is a cofactor to factor 1 in the breakdown of C3 convertases to inactive forms. These regulators of complement activation normally serve to prevent runaway activation of the alternative pathway and catastrophic self-destruction of normal endothelium, and the 1 1062

MCQ 20.10

0 Case 20.1

2

Figs 20.2, 20.3

hope is that xenografts from the transgenic pigs will therefore be able to provide the same normal 'brake' on complement activation that exists in the recipients' own tissue. Hearts from these transgenic pigs have now been transplanted into monkeys. None of the transgenic hearts was hyperacutely rejected and 20% of them functioned for more than 60 days. In contrast, all the 'normal' pig hearts were hyperacutely rejected in under 60 minutes. These are encouraging results that point the way forward to 'pig to man' xenografting, probably within the next few years.

FURTHER READING ON RENAL TRANSPLANTATION Morris P J (ed) 1994 Kidney transplantation. Principles and practice, 4th edn: Philadelphia: W B Saunders. Suthanthiran M, Stram TB 1994 Renal transplantation. N Engl J Med 331:365. Schnuelle P, Lorenz D, Trede M, Van der Woude FJ 1998 Impact of renal cadaveric transplanatation on survival in end-stage renal failure: evidence for reduced mortality risk compared with hemodialysis during long-term follow-up. J Am Soc Nephrol 9:2135.

NEPHROTIC SYNDROME Nephrotic syndrome is best defined as the presence of heavy proteinuria (usually >3g/day), hypoalbuminaemia, hyperlipidaemia and oedema. It is not helpful to pursue the definition beyond this semiquantitative statement, because there is much interpatient variation in the clinical response to a given level of proteinuria.

Aetiology Nephrotic range proteinuria, leading to the nephrotic

TABLE 20.22 Causes of nephrotic syndrome Primary glomerular disease Minimal change GN Membranous GN Focal segmental glomerulosclerosis Mesangiocapillary GN Drug/toxin-induced Gold Other heavy metals Penicillamine Intravenous drug abuse

Secondary glomerular disease Infection (infective endocarditis, visceral sepsis, quartan malaria, hepatitis B)

Neoplasia (carcinoma, lymphoma, leukaemia, myeloma)

TABLE 20.23 General measures in the treatment of nephrotic syndrome • • • • •

20

High protein diet Dietary sodium restriction Water restriction (rarely necessary) Diuretic therapy Intravenous proteins

Multisystem diseases (SLE, HenochSchonlein purpura, rheumatoid arthritis, amyloid, diabetes mellitus)

syndrome, may result from a variety of different types of insult to the functional glomerular sieve (Table 20.22). 1 The glomerular changes that result in nephrotic syndrome may reflect disturbances to the size selectivity or the charge selectivity (or both) of the glomerular sieve, such that substantial amounts of plasma proteins, particularly albumin, appear in the GF.

Pathophysiology The amount of oedema is variable, but correlates better with the severity of hypoalbuminaemia than with the magnitude of proteinuria. The oedema is generalized and may be associated with pleural effusion and/or ascites, especially in children. The pathophysiological processes leading to oedema in the nephrotic syndrome are illustrated in Figure 20.22. This sequence predicts that the nephrotic patient has an expanded ECF, a contracted vascular compartment, high plasma renin activity and aldosterone concentration, and avid renal sodium and water retention. This is indeed the case in many (though not all), nephrotic patients.

Investigation In children, minimal change GN is the usual lesion. In such cases the diagnosis can usually be made without recourse to renal biopsy. In a typical case there is a normal GFR, an absence of significant numbers of red cells or casts in the urine, and a highly selective urine protein excretion (p. 1039). The abolition of proteinuria by steroid therapy is confirmatory. In children with steroid-resistant disease, or who have impaired GFR and/or red blood cells and casts in the urine, and in the majority of adults, identification of the renal lesion (Table 20.22) and appropriate management will usually necessitate renal biopsy. 2

Complications and management 3 The complications of the nephrotic syndrome may be serious, and an important therapeutic objective is therefore the amelioration or elimination of the proteinuria. (The

FIG. 20.22 Pathogenesis of oedema in nephrotic syndrome

specific glomerulopathies causing nephrotic syndrome are discussed on pages 1069-1075.) Often this is not possible, but certain general measures remain appropriate regardless of the underlying renal lesion (Table 20.23). Diuretics should be used judiciously and in conjunction with dietary sodium restriction. Although in some cases very large doses of a potent loop diuretic will be needed to effect a diuresis, these drugs carry the risk of inducing severe contraction of the vascular compartment (hypovolaemia) and may lead to prerenal uraemia, shock, and even ARF in some cases. Severe hypovolaemia can be corrected temporarily by administration of colloid in the form of plasma proteins, a manoeuvre that is also employed occasionally to initiate a diuresis. The use of the aldosterone antagonist spironolactone in these patients is both logical and helpful. Vasopressin antagonists are being developed and show early promise. Protein malnutrition is a major hazard in patients with nephrotic syndrome; the patients should maintain the highest possible protein intake while ensuring adequate

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SUMMARY 5 Complications of nephrotic syndrome • • • •

Massive oedema Effusions/ascites Hypovolaemia (reduced blood volume) Protein malnutrition - growth retardation - poor wound healing - osteoporosis • Hyperlipidaemia - probable increased atherogenesis • Hypercoagulability - renal vein thrombosis - stroke • Susceptibility to infection (especially in children)

energy provision to prevent further acceleration of protein catabolism. Despite these measures, growth retardation, poor wound healing and reduced immune competence are frequent. The hyperlipidaemia is refractory to dietary measures, but responds to HMG CoA reductase inhibitors (e.g. atorvastatin). Thrombotic problems resulting from the hypercoagulable state that attends the nephrotic syndrome are common. The hypercoagulability may be the result of urinary losses of antithrombin III. Thrombosis is particularly likely to involve the renal veins, leading to an abrupt decline in GFR that must be distinguished from progression of the underlying nephropathy. Diagnosis of renal vein thrombosis in a nephrotic is important, because anticoagulation almost certainly reduces the risk of subsequent pulmonary embolism and may allow eventual recanalization of the occluded vessel and improvement in GFR. Careful ultrasound or CT examination of the renal veins may reveal the clot, but in some cases renal venography is required. 1

membrane disease' (reflecting appearances on electron microscopy) and Alport's disease (hereditary nephropathy), for example. In blacks, sickle cell anaemia (or trait) is an important possibility. In older patients, stones, urothelial malignancy and prostatic disease become increasingly likely.

Investigation and management Investigations should include measurement of GFR, examination of the urine and quantification of protein output. An IVU should be performed in all cases. Children and young adults with a typical presentation can usually be spared cytoscopy, but middle-aged and elderly patients (in whom urological cancer becomes increasingly common) should undergo full urological assessment. Renal biopsy is needed to establish the diagnosis with certainty, especially if there is depression of the GFR, heavy proteinuria, hypertension, a low C3 complement, or a family history suggestive of hereditary nephritis (p. 1075). The course is often benign, although a proportion of patients go on to develop progressive renal disease. There is no specific treatment, and management is therefore directed towards identifying and treating secondary hypertension and monitoring renal function.

PERSISTENT ASYMPTOMATIC PROTEINURIA AND/OR HAEMATURIA The finding of abnormal proteinuria or microscopic haematuria in an apparently healthy person usually results from a routine medical examination for employment or insurance purposes, or is picked up incidentally during an unrelated illness. Table 20.24 lists the large number of conditions that may be associated with this syndrome.

RECURRENT HAEMATURIA Recurrent haematuria most frequently affects boys and young men. The syndrome is dominated by recurrent episodes of macroscopic haematuria, sometimes associated with loin pain, and with a tendency to exacerbations following intercurrent viral upper respiratory infections or strenuous exercise. Microscopic haematuria usually persists between attacks and proteinuria is absent or modest (<1.5g/24h). In most cases the renal pathology is characteristic, with florid mesangial deposition of IgA or IgM in the glomeruli; the nephropathy is then termed IgA (or IgM) nephropathy or Berger's disease (p. 1074). A number of other glomerulopathies manifest themselves in this way: 'thin basement

1

1064

MCQ 20.11

Investigation Inevitably, the question arises as to how far investigation should proceed in these otherwise healthy individuals. Assessment of renal structure and function by plasma biochemistry, creatinine clearance, 24-hour protein output, urine microscopy and culture, and either renal ultrasound or IVU, should be undertaken in all cases. Dysmorphic red cells in the urine increase the probability of renal parenchymal disease rather than urological disease. Provided radiological investigation and GFR are normal, proteinuria is modest and the urinary sediment does not show granular or cellular casts, it may be appropriate to adopt a 'wait-and-see' policy, only proceeding to invasive investigation, such as renal biopsy, if there is evidence of disease progression. However, early recourse to renal biopsy is usually justified in order to define prognosis, or if there is suspicion that an active and progressive process may be present, particularly if this might be amenable to therapy.

TABLE 20.24 Causes of asymptomatic persisting proteinuria and/or haematuria in an apparently healthy person Primary glomerular disease Mesangial proliferative GN Mesangiocapillary GN Membranous GN Focal segmental glomerulosclerosis IgA nephropathy (often causes intermittent gross haematuria) Multisystem disease Henoch-Schonlein purpura SLE

Miscellaneous renal Tubulointerstitial nephropathy Cystic diseases of the kidney Renal tumours Renal tuberculosis Non-renal Urothelial tumours Prostatic disease

RENAL TUBULAR SYNDROMES Although most patients with renal disease will have evidence of disordered tubular function if a sufficiently diligent search is carried out, other manifestations of renal disease usually dominate the clinical picture. Of note is that most pathologies that damage the renal parenchyma reduce the number of functioning nephrons, implying that the remaining nephrons each have to process an increased amount of water and solute. Invariably this reduces the kidney's capacity to operate at extremes of solute and water conservation or excretion. The resulting reduction in adaptive capacity is a common and often important feature of patients with renal disease. In a minority of patients, however, clinical disorders result directly from tubular dysfunction. In these cases the disorder may be inherited, with presentation generally in childhood, or acquired.

Renal glycosuria Inheritance of renal glycosuria is autosomal recessive. The syndrome results from diminished proximal tubular glucose reabsorption, allowing glycosuria with normal blood glucose concentration. No clinical sequelae occur. Normal pregnant women exhibit glycosuria - here the high GFR overwhelms the tubular reabsorptive capacity.

Aminoaciduria The defects involved in aminoaciduria may be single or multiple. The most important is cystinuria, leading to recurrent cystine stone formation. Cystine solubility increases at alkaline pH and the disease is treated by a combination of high fluid intake and alkali ingestion. Penicillamine is also effective, although potentially toxic. Inheritance is autosomal recessive.

Phosphate transport defects There are several types of phosphate transport defects,

TABLE 20.25 Causes of aspired Fanconi's syndrome

20

• • • •

Myeloma kidney Sjogren's syndrome Nephrotic syndrome Heavy metal poisoning Lead Mercury (organic and inorganic) Copper (Wilson's disease) • Drugs Outdated tetracycline Salicylates Cisplatin

which result in inappropriate phosphaturia, hypophosphataemia and rickets. Inheritance is usually X-linked (the disorder is known as vitamin D-resistant rickets (VDRR) or X-linked hypophosphataemic rickets} but sporadic inherited cases also occur. Treatment usually takes the form of oral phosphate supplementation with pharmacological doses of vitamin D, or smaller doses of 1,25dihydroxyvitamin D (calcitriol). The latter combination is particularly effective in ameliorating the hypophosphataemia and healing rickets. A rare acquired form also exists and is associated with production of a humoral factor by certain mesenchymal tumours, such as cavernous haemangiomas, giant cell tumours of bone, and neurofibromas. In such cases of oncogenous rickets the disordered phosphate metabolism is corrected by removal of the tumour.

Multiple tubular defects (Fanconi's syndrome) Patients with Fanconi's syndrome have abnormal urinary excretion of amino acids, phosphate, bicarbonate, glucose and small proteins. The classification of this disorder is complex, reflecting its many inherited and acquired causes. All are relatively uncommon; some of the more important acquired ones are shown in Table 20.25. The defects of phosphate reabsorption and proximal bicarbonate reclamation often lead to clinical disease - hypophosphataemic rickets and proximal 'type IF RTA, respectively - requiring treatment with phosphate, 1,25-dihydroxyvitamin D or alkali, as appropriate (pp. 1065-1067).

Renal tubular acidosis Renal tubular acidosis (RTA) is metabolic acidosis of renal origin and is unrelated to the acidosis associated with severe impairment of GFR (uraemic acidosis). It is generally divided into three categories, depending on the nature and site of the acidification disturbance (Table 20.26). Although the pathogenesis of the different types of renal

1065

TABLE 20.26 Classification of renal acidosis Renal tubular acidosis (RTA)* Proximal RTA (type II)

Distal RTA with hypokalaemia (type I)

Distal RTA with hyperkalaemia (type IV) +

+

Uraemic acidosis

Delect

Decreased H secretion

Decreased H secretion

Decreased H and K secretion

Decreased nephron mass and decreased ammonia synthesis (controversial)

Acidosis Type Anion gap Severity Plasma K+ GFR Treatment

Hyperchloraemic Normal Moderate Decreased Usually normal Diuretics and alkali

Hyperchloraemic Normal Moderate or severe Decreased Normal or decreased Alkali

Hyperchloraemic Normal Moderate Increased Usually decreased Mineralocorticoids K+ restriction

Normal plasma chloride Increased Usually moderate Normal or increased Decreased Protein restriction, sometimes alkali, dialysis

*Type III RTA (not shown) is a rare condition where a patient has manifestations of both type I and type II RTA.

tubular acidosis differs, all cause hyperchloraemic metabolic acidosis (low plasma bicarbonate, raised plasma chloride with a normal anion gap), in contrast to the acidosis of uraemia (low bicarbonate, normal chloride and increased anion gap; p. 1045). Distal RTA (type I RTA) The causes of distal RTA are listed in Table 20.27. There is selective impairment of the distal tubules' ability to secrete H+, such that urinary pH cannot be lowered below 5.5. Other distal tubular functions are unimpaired. The resulting inability of the distal tubule to reclaim all of the 5-20% of filtered bicarbonate that normally escapes proximal reclamation leads to continuing bicarbonaturia, even in the presence of severe acidosis. It also limits the utility of urinary buffers such as HPO42 , which require a low urinary pH if they are to act as efficient proton acceptors. Distal potassium ion secretion is unimpaired and is often enhanced by mild ECF volume contraction and secondary aldosteronism, leading to hyperchloraemia and hypokalaemia. Diagnosis depends on demonstrating an inappropriately high urinary pH (>5.5) during spontaneous or ammonium chloride-induced acidosis. Other diagnostic manoeuvres are available, but are rarely needed in clinical practice. Treatment takes the form of alkali given as potassium or sodium bicarbonate and/or citrate in amounts sufficient to restore plasma bicarbonate and chloride concentrations as close to normal as possible. Severe hypokalaemia is often 1

1066

MCQ 20.12

present and should be treated before the administration of alkali, to avoid the further drop in plasma potassium that would follow correction of the acidosis. The amount of alkali required is small (l-3mmol/kg body weight per day) because bicarbonaturia is not severe and does not increase as plasma bicarbonate concentration rises on treatment. Proximal RTA (type II RTA) Proximal RTA may occur in several rare inherited diseases but is more commonly acquired in association with myeloma, Sjogren's syndrome or toxic nephropathy (especially lead or mercury). There is a diminished capacity of the proximal tubule to reclaim filtered bicarbonate ions. The resulting bicarbonaturia leads to progressive metabolic acidosis and decreased plasma bicarbonate concentration, in turn lessening the filtered load of bicarbonate. This chain of events progresses until the filtered load of bicarbonate has fallen to the point where the abnormal proximal tubule can again reclaim a normal percentage of the filtered bicarbonate load. This creates a new steady state in which bicarbonate losses cease, but only at the expense of stable metabolic acidosis. Administration of sufficient bicarbonate to these patients will reverse the sequence of events described above. Treatment comprises long-term administration of bicarbonate. Large amounts (10-30mmol/kg/day) are needed, because as plasma bicarbonate rises so the magnitude of the bicarbonaturia also increases. The bicarbonate requirement can often be reduced by concomitant therapy with a thiazide diuretic. Hypokalaemia is often worsened by therapy, but can be countered by giving some of the bicarbonate as potassium bicarbonate, or by the use of potassium-sparing diuretics.

the distal tubule are impaired (Tables 20.26 and 20.27), resulting in hyperchloraemic metabolic acidosis accompanied by disproportionately severe hyperkalaemia. This is the commonest form of RTA, and although the acidosis is mild the accompanying hyperkalaemia may be severe or even life-threatening. Type IV RTA may result from the following:

FIG. 20.23 Nephrocalcinosis in a patient with long-standing renal tubular acidosis Plain abdominal X-ray.

TABLE 20.27 Causes and classification of distal renal tubular acidosis With hypokalaemia (type I) Inherited Associated with nephrocalcinosis Primary hyperparathyroidism Sickle cell anaemia Medullary cystic disease Vitamin D toxicity Autoimmune disease Tubulointerstitial nephropathy secondary to: Cryoglobulinaemia Obstruction Sjb'gren's syndrome Chronic pyelonephritis Systemic lupus erythematosus Renal transplantation Chronic active liver disease Drugs Amphotericin 8 Analgesics (in analgesic nephropathy) With hyperkalaemia (type IV) Primary deficiency of Secondary deficiency of mineralocorticoid mineralocorticoid Isolated familial Hyporeninaemic hypoaldosteronism hypoaldosteronism (rare) with underlying: Generalized Hypertensive nephrosclerosis adrenocorticoid deficiency Diabetic nephropathy Addison's disease Obstructive nephropathy Adrenalectomy Renal transplantation Tubular resistance to mineralocorticoid Some cases of chronic renal impairment Spironolactone or amiloride therapy

Distal RTA with hyperkalaemia (type IV RTA) In type IV RTA there is generalized impairment of distal tubular function, usually on a background of a mild or moderate reduction in GFR. Both H+ and K+ secretion in

20

• Primary lack of mineralocorticoid owing to adrenal disease in the presence of potentially normal distal tubular function (isolated hypoaldosteronism and Addison's disease); • Disease of the juxtaglomerular apparatus (JGA), leading to impaired production of renin and secondary hypoaldosteronism (hyporeninaemic hypoaldosteronism). This is associated particularly with hypertensive nephrosclerosis or diabetic nephropathy; • Resistance of the distal tubule to mineralocorticoid action. This is usually partial rather than complete, and may arise in some patients with chronic renal impairment. It is also, of course, a direct (and deliberate) consequence of Spironolactone therapy. Treatment depends on the underlying abnormality. Deficiency of mineralocorticoid - whether isolated, part of Addison's disease, or secondary to hyporeninaemia requires replacement with mineralocorticoid in the form of 9a-fludrocortisone. When there is renal resistance to mineralocorticoid, control may often be achieved with pharmacological doses of 9a-fludrocortisone. 1

Other causes of renal potassium wasting By far the most common are diuretic use and osmotic diuresis in hyperglycaemic diabetics. Two important, albeit rare, conditions are Bartter's syndrome and Gitelman's syndrome. Both are characterized by hypokalaemia, but their associations differ. In Bartter's syndrome chloride reabsorption in the loop of Henle is impaired, resulting in a functional defect similar to that produced by loop diuretics (furosemide [frusemide]). In Gitelman's syndrome the renal lesion mimics that of thiazide diuretic treatment, in which sodium and chloride transport is impaired distally. Important drug-induced causes of renal potassium wasting include aminoglycosides, amphotericin and platinum-containing cytotoxic agents.

Salt-losing nephropathy and nephrogenic diabetes insipid US In adults, salt-losing nephropathy and nephrogenic diabetes insipidus (failure to conserve sodium and/or water) are nearly always acquired. They can result from almost any cause of renal disease, particularly those predominantly affecting the renal medulla, such as urinary obstruction, papillary necrosis, chronic pyelonephritis and tubulointerstitial diseases. Hypercalcaemia and hypokalaemia cause a functional nephrogenic diabetes insipidus which is initially reversible on correction of the meta-

1067

bolic abnormality. The severity of the polyuria in these acquired tubular syndromes rarely approaches that of pituitary diabetes insipidus but, in contrast, accompanying salt losses may be massive. The importance of inappropriate renal salt and water loss is its tendency to cause severe volume contraction and prerenal uraemia; one should not be misled by the continuing production of large amounts of urine. Treatment is usually straightforward. Underlying hypercalcaemia or hypokalaemia should be investigated and treated. In chronic renal disease it is essential to ensure an adequate intake of dietary salt and water, using salt tablets if necessary. This is especially important at times of intercurrent illness, when oral intake may fall. Some of these patients also have disordered renal acidification mechanisms (renal tubular acidosis), and it is then convenient to give the sodium supplementation as sodium bicarbonate.

PRIMARY GLOMERULAR DISEASE

other parts of the body and be deposited or 'planted' in the glomerulus. In either case, the formation of an antigen-antibody complex may occur in situ if an appropriate antibody is generated (Fig. 20.24). Circulating complexes. The second mechanism of injury involves the generation of antibody directed against an antigen derived from sources other than the kidney. In this case the antigen might be endogenous or exogenous. When the resulting antigen-antibody complex gains access to, or is produced in, the circulation, it can be deposited in the kidneys and there activate mediators of inflammation. Antigens suspected of mediating human glomerular disease through this mechanism are listed in Table 20.29. The production of glomerular injury is complex and probably depends on linked cellular and non-cellular mechanisms. Immunohistopathological study of renal tissue obtained from renal biopsies or at postmortem sometimes reveals antibody (IgG, IgM or IgA) and complement components, the precise location and pattern of which can yield valuable diagnostic information. Furthermore, the common finding of monocytes/macrophages (producers of TNF and interleukin-1) and T-helper

IMMUNOLOGICAL AND OTHER MECHANISMS OF GLOMERULAR INJURY Many glomemlar diseases, whether occurring in isolation (primary) or as part of a multisystem disease (secondary), are associated with demonstrable immunological abnormalities. Most may therefore be regarded as a form of autoimmune disease, implying loss of tolerance to autoantigens (self-antigens). Although it is not always clear whether these are directly involved in the pathogenesis of the glomerular disease, much attention has been directed towards identification of the immunological disturbances and their manipulation as part of treatment. The final common path of immunologically mediated glomerular injury is the activation of various inflammatory mediators, both cellular and soluble, which then inflict damage on the glomerulus or, less frequently, on other tissue elements in the kidney (Fig. 20.24). It is likely that the production and activation of the mediators (Table 20.28) requires the presence of antigen-antibody complexes in the kidney, and also of specific cell types. Clearly, the source of these immune complexes, the identification of their antigen component(s), and the factors that control the behaviour of the involved cells are of great importance in the understanding of the diseases, and in the development of rational treatment. Two general mechanisms of immunological injury to the glomerulus are proposed. In situ complex formation. The antigens may be an intrinsic part of the glomerulus, or may be derived from

1

1068

Figs 20.4, 20.5

FIG. 20.24 Mechanisms of immunological glomerular injury

TABLE 20.28 Initiators and mediators of glomerular injury Cellular • Polymorphs • Macrophages/monocytes • Lymphocytes (esp. T helper cells) • Platelets

Non-cellular • Antibody • Complement • Fibrinogen • Histamine • Kinins • Prostaglandins • Some interleukins (esp. IL-1, IL-2 and IL-6) • Tumour necrosis factor (TNF-a) • Free radicals

TABLE 20.29 Non-renal antigens linked with immune complex nephritis Exogenous • Bacterial Streptococcus Staphylococcus Meningococcus Treponema pal/idum • Viral Hepatitis B and C Cytomegalovirus (CMV) • Parasitic Plasmodium malariae Schistosoma haematobium • Drugs Penicillin • Exogenous proteins Serum sickness

Endogenous • DNA

• • • •

Tumour specific Rbc membrane Thyroglobulin IgG

• • • • • • •

Postinfectious GN Infective endocarditis Shunt nephritis Quartan malaria Syphilis Hepatitis B or C infection Systemic lupus erythematosus

20

Because some of these glomerular diseases may be part of a multisystem disease (e.g. SLE), problems unrelated to the kidney may dominate the clinical picture. ACUTE POSTINFECTIOUS GLOMERULONEPHRITIS

TABLE 20.30 Involvement of immune complexes In pathogenesis of nephritis Probable

• Acute nephritic syndrome, with or without acute renal failure (p. 1051) • Rapidly progressive glomerulonephritis (p. 1051) • Chronic glomerulonephritis (p. 1051) • Nephrotic syndrome (p. 1062) • Hypertension (p. 1081) • Asymptomatic haematuria and/or proteinuria (p. 1064) • Recurrent macroscopic haematuria (p. 1064).

Possible • Henoch-Schonlein purpura • IgA nephropathy (Berger's disease) • Mesangiocapiliary GN • Idiopathic rapidly progressive GN • Membranous GN • Focal segmental glomerulosclerosis

Acute postinfectious GN is common in children of school age, though it also arises in adults and, rarely, the very young. Males are more often affected. The preceding infection is usually in the upper respiratory tract, but can be in the skin or at other sites. There is usually a latency of 1-3 weeks. Group A, type 12, [3-haemolytic streptococci are those most likely to cause acute GN, with shigellae, meningococci, staphylococci and Strep, pneumoniae also implicated in some cases.

Pathogenesis and pathology Much circumstantial evidence points to a role for immune complexes, either circulating or formed in situ within the kidney. Immune complexes are demonstrable in serum in most cases, and activation of serum complement is frequent. A diffuse generalized proliferative glomerulonephritis is present, often with an infiltrate of polymorphs. The tubules and interstitium are relatively spared. Immunofluorescence studies show granular deposits of C3 complement and IgG in the glomeruli.

Clinical features and diagnosis lymphocytes (producers of interleukin-2) suggests (but does not prove) a role for these cells and cytokines in pathogenesis. Similarly, in only a minority of cases has it been possible to identify the antigenic component of the immune complexes, and even in cases where this has been achieved with certainty it is still not clear what triggers the sequence of events that leads ultimately to glomerular injury; many patients with circulating immune complexes do not develop nephritis. Examples of human nephritis in which immune complexes are thought to play a role are given in Table 20.30.

CLINICAL PRESENTATION AND

MANAGEMENT OF GLOMERULAR DISEASE The principal presentations of the specific glomerular diseases described below are as follows - all are seen frequently in nephrological practice:

The illness typically presents as an acute nephritic syndrome with oliguria, fluid retention, hypertension, proteinuria and haematuria. The degree of renal impairment is variable. The diagnosis is usually easy on clinical grounds alone. The urine is 'active', with red blood cells, cellular casts and protein. Evidence for a preceding streptococcal infection is sought by means of swabs of throat or any suspicious skin lesion, and serological tests for streptococcal infection, such as the ASO titre and anti-D-Nase B antibody. Hypocomplementaemia (low haemolytic complement and C3, with variable reduction of C2, C4 and Clq) due to alternative pathway activation (p. 80) and the presence of circulating immune complexes support the diagnosis. Renal biopsy is seldom required in children, although it may be in adults. 1

Management and prognosis Antistreptococcal antibiotics (penicillin or erythromycin)

1069

are generally given, although there is no evidence that they influence the nephritis. In most cases observation and general supportive measures are sufficient. In oliguric patients fluid retention is controlled by appropriate restriction of dietary salt and water; protein and potassium are restricted if uraemia or hyperkalaemia threaten. Hypertension is best managed by avoiding or correcting overexpansion of the ECF, with the aid of loop diuretics if necessary. Careful control of blood pressure is particularly important in children, in whom hypertensive encephalopathy may develop when the blood pressure is only moderately elevated. Rarely, severe renal failure may require temporary dialysis treatment (p. 1051) pending recovery of renal function. Long-term antistreptococcal prophylaxis is not required. Children have a better prognosis than adults. The early mortality is about 1% or less in children, but the minority in whom severe oliguria or proteinuria persist has a less favourable outcome. Long-term prognosis is uncertain, but a significant minority (up to 30%) may ultimately develop progressive renal disease, often 10 or more years later. Adults are more likely to show incomplete resolution after the initial attack and to progress thereafter to CRF. O

GLOMERULONEPHRITIS IN ASSOCIATION WITH OTHER INFECTIONS Pathology The bacterial, viral or protozoan infections that may be complicated by GN are listed in Table 20.31. In most of these the GN is in association with current rather than past infection. Bacterial The most important bacterial-associated GN is that seen in

TABLE 20.31 Infections which may cause glomerulonephritis Bacterial Group A, (3-haemolytic streptococci Other streptococci Staphylococci Salmonella typhi Treponema pallidum

Viral Hepatitis B and C HIV Cytomegalovirus Epstein-Barr

Protozoan Plasmodium malariae Plasmodium falciparum Schistosoma haematobium

1 1070

MCQ 20.13

2

CQ20.14

patients with infective endocarditis. These patients usually have only mild impairment of GFR, with microscopic haematuria, proteinuria and urinary casts, in association with clinical and laboratory manifestations of endocarditis. In some the renal disturbance dominates the clinical picture, with the syndrome of RPGN and renal failure. Circulating immune complexes are present and complement (C3 and C4) is reduced (classic pathway activation). Cryoglobulins are often present in the circulation. Renal biopsy is only needed if the underlying diagnosis is in doubt, or if renal impairment is severe and unremitting. A variety of renal lesions may be seen, but focal proliferative and focal necrotizing GN are the most common. Deposits of C3, IgG and IgM are conspicuous. Other important chronic bacterial infections that may lead to GN include those arising on implanted devices (e.g. ventriculoatrial shunts and synthetic vascular grafts) and in association with visceral abscesses. Viral The most important are HIV and chronic hepatitis B or C. HIV. This may cause HIV glomerulopathy, acute renal failure and electrolyte disturbances. About 10% HIVinfected subjects have proteinuria, in most cases with an underlying glomerulopathy (usually focal segmental glomerulosclerosis; FSGS). In most, this progresses to renal failure. The likelihood of HIV-associated glomerulopathy is greatest in full-blown AIDS, less so in AIDS-related complex, and infrequent in asymptomatic HIV infection. ARF (with ATN) is seen in critically ill patients with sepsis and shock. Nephrotoxic drugs (pentamidine, aminoglycosides, amphotericin B) are important contributors. Hyponatraemia is the most common electrolyte disturbance, usually resulting from gastrointestinal sodium losses, or the syndrome of inappropriate ADH secretion in cases of pulmonary or CNS involvement. Treatment. Progressive nephropathy is inevitable: no effective therapy has yet been found, and survival on dialysis or after transplantation is poor (see also Recent advances in HIV-associated renal disease, p. 1071). Hepatitis B. This may lead to a variety of glomerular lesions (membranous GN is the most common), either in isolation or in association with hepatic involvement, or a more generalized process such as systemic vasculitis or

SUMMARY 6 HIV and the kidney Glomerulopathy:

Present in 10% most likely in AIDS lesion is focal segmental glomerulosclerosis

Acute renal failure:

ATN sepsis, shock drug induced

Electrolyte disturbance:

hyponatraemia due to - sodium losses - inappropriate ADH

cryoglobulinaemia. The virus itself is probably the antigen in the immune complex. Successful elimination of the hepatitis B virus does not necessarily lead to resolution of the nephropathy. Hepatitis C. The identification of hepatitis C virus (HCV) has led to the recognition of several extrahepatic manifestations of the infection, particularly when it is chronic. These include mixed cryoglobulinaemias, arthritis, a Sjogren's like sicca syndrome, and immune thyroiditis. They also include glomerulonephritis and polyarteritis. The usual renal lesion is mesangiocapillary glomerulonephritis type I (p. 1073), with other lesions or vasculitis also found in some cases. Presentation is usually with proteinuria, often with full-blown nephritic syndrome and/or progressive renal failure. That there are renal manifestations of HCV is not at all surprising. The propensity for patients with mixed cryoglobulinaemias to develop glomerulonephritis has long been known, and it is now clear that HCV is a major cause of essential cryoglobulinaemia. In the past, recognized associations with essential cyoglobulinaemias have been, in addition to glomerulonephritis, various connective tissue diseases (especially Sjogren's syndrome), malignancy, chronic infections (e.g. endocarditis), and chronic liver disease. In the 30% of cases without any of these conditions the mixed cryglobulinaemia would be termed 'essential'. It is now known that virtually all patients with essential mixed cryoglobulinaemia have evidence of HCV infection, with positive tests for antibody to HCV and also for HCV

mRNA, the latter indicative of active viral replication. Some 70% have evidence of continuing hepatic involvement and about 30% have renal disease, this conferring a more ominous prognosis. The pathogenesis is thought to include the deposition in the glomeruli of circulating immune complexes containing HCV antigen and HCV antibody, with resulting cellular proliferation and leukocyte infiltration and tissue injury. Other processes that may be operative in some cases are the formation of autoantibodies (known to occur frequently, but of uncertain role in the pathogenesis of the renal lesion) and impaired clearance of circulating immune complexes by an HCV-damaged liver. As with hepatitis B, elimination of the virus has an unpredictable effect on the nephropathy.

20

Parasitic Plasmodium malariae and Schistosoma haematobium infections are important causes of nephrotic syndrome in endemic areas. This is particularly the case in children, where they must be distinguished from idiopathic nephrotic syndrome due to minimal change disease. 2

Management Removal of the offending antigen, if possible, usually leads to resolution, although this may be incomplete in some cases, especially the viral ones. Renal failure is managed along conventional lines. There is no evidence that other

RECENT ADVANCES IN HIV-ASSOCIATED RENAL DISEASE Renal disease is an important complication in HIVinfected patients. It takes several forms. The most important is HIV-associated focal glomerulosclerosis. These patients present with nephrotic syndrome and, when biopsied, are usually found to have a combination of collapsing focal glomerulosclerosis and a varying degree of tubulointerstitial injury. These lesions can be found across the full spectrum of HIV infection, but are most common in those with advanced disease and a profound reduction in CD4 count. It is likely (although not certain) that HIV is implicated directly in the genesis of this lesion. Thus HIV DNA has been found in the glomeruli of patients with HIV nephropathy (and also those without nephropathy). Transgenic mice with HIV-DNA constructs in their genome develop collapsing focal glomerulosclerosis and tubulointerstitial damage similar to the lesions in humans. Active viral gene replication was identified in the renal cortex of these animals. Genetic factors are clearly important: HIV-associated nephropathy occurs with much higher frequency in blacks than in other racial groups. Additionally, there is evidence of a familial predisposition to the development of this lesion. The frequency across the spectrum of HIV in the developed world ranges between 2 and 10%. Presentation is with nephrotic syn-

drome and progressive deterioration of kidney function to end-stage renal disease. The natural history - often between 1 and 4 months - is considerably shorter than is seen in focal glomerulosclerosis patients without associated HIV infection. Until recently this progression has been inexorable and refractory to treatment. Combined highly active antiretroviral therapy is likely to change the course of this illness, however. Early reports suggest that, in parallel with other manifestations of HIV infection, nephropathy may also be halted or even reversed in patients receiving combination antiretroviral therapy. Other important nephropathies may arise in HIVinfected patients. Acute and subacute renal failure is common, usually resulting from other complications of HIV, such as infection, shock, and various nephrotoxic antibiotics. Pentamidine, amphotericin B and aminoglycoside are frequently implicated. Tubulointerstitial disease as a result of cytomegalovirus infection has been reported, as have other glomerulopathies: membranous nephropathy with associated hepatitis B infection, and mesangiocapillary glomerulonephritis with associated hepatitis C infection (often with essential mixed cyroglobulinaemia).

1071

manoeuvres, such as immunosuppressive drugs or plasma exchange, are of benefit.

FURTHER READING Klotman P E 1999 HIV-associated nephropathy. Kidney Int 56:1161. Weiss M A, Daquioage Margolin E G, Pollak V E 1986 Nephrotic syndrome, progressive irreversible renal failure, and glomerular 'collapse'. A new clinicopathologic entity? Am J Kidney Dis 7:20.

most common. Renal function is usually normal, or nearly so, at the time of presentation, but progression to CRF is frequent, although difficult to predict. A proportion of patients, particularly those with underlying neoplasia, die of the non-renal cause of the disorder. Other complications, such as renal vein thrombosis and pulmonary emboli, are also a cause of morbidity and mortality. Hypertension becomes increasingly prevalent as the disease progresses. The diagnosis rests on renal biopsy.

Management MEMBRANOUS NEPHROPATHY The majority of cases of membranous nephropathy are idiopathic, but this lesion may also arise in a variety of underlying diseases (Table 20.32). It accounts for about 25 % of cases of nephrotic syndrome in adults.

Pathogenesis and pathology The pathogenesis is unknown. Renal biopsies show thickening of the glomerular basement membrane, with a spike and dome pattern visible using special stains. 1 Diffuse deposits of IgG, IgM and C3 complement are present in glomerular capillary walls. The presence of immune complexes in serum is variable and their role in the pathogenesis unsubstantiated. In Europe (but not elsewhere) there is an association with HLA-A1 138 DR3.

Clinical features and diagnosis Most patients present with asymptomatic proteinuria or nephrotic syndrome. A significant minority of adults will have an underlying neoplasm, colonic carcinoma being the

TABLE 20.32 Causes of membranous nephropathy Idiopathic

Drugs/toxins Mercury Organic gold (in treatment of rheumatoid arthritis) Penicillamine Captopril

Infections Malaria Syphilis Hepatitis B

Multisystem disease Systemic lupus erythematosus Rheumatoid arthritis

Neoplasia Lymphoma rare|y Leukaemia Various carcinomas, especially of the colon

1

1072

Fig. 20.6

2

MCQ 20.15

The nephrotic syndrome is managed conventionally (p. 1062) and a watchful eye kept for renal vein thrombosis or pulmonary embolism, both of which are indications for anticoagulation. Treatment of the nephropathy is controversial. There is evidence that intensive immunosuppression (using corticosteroids and chlorambucil or cyclophosphamide) given for 6 months improves the longterm outlook. The aim is to induce remission of the nephrotic syndrome and to prevent progressive renal failure.

MINIMAL CHANGE NEPHROPATHY Minimal change nephropathy (known in the past as 'lipoid nephrosis') is by far the most common cause of childhood nephrotic syndrome. It is also an important cause of nephrotic syndrome in adults.

Pathogenesis and pathology The pathogenesis and aetiology of the condition are unknown. There is evidence of disordered T-lymphocyte function, but the relevance of this to the pathogenesis is unproven. Of note, however, is the response of the lesion to steroids, alkylating agents and cyclosporin, all of which interfere with T-cell function. The glomeruli are normal by light microscopy; immunofluorescence is negative. Electron microscopy shows fusion of the epithelial cell foot processes, but this is also seen in many other glomerular diseases; it is significant only when the glomeruli appear normal under light microscopy. These features in the presence of nephrotic syndrome favour a diagnosis of minimal change nephropathy.

Clinical features and diagnosis Children and adults usually present with oedema and are found to have nephrotic syndrome. Hypertension is rare, and renal function is usually normal. Among young children males predominate, but the sex incidence in adults is approximately equal. Progression to CRF is exceedingly rare, although ARF may supervene, particularly following excessive use of diuretics. In adults the diagnosis usually depends on renal biopsy. In children, however, the relative infrequency of other

deaths are the result of complications of treatment, particularly infection. ©

20

FOCAL SEGMENTAL GLOMERULOSCLEROSIS Focal segmental glomerulosclerosis (FSGS) is the second most common cause of nephrotic syndrome in children and, in contrast to minimal change GN, tends to progress to renal failure, especially in children. Most cases are idiopathic, but some arise in association with underlying collagen vascular diseases. A particular variant is seen in patients with HIV infection.

Pathogenesis and pathology

FIG. 20.25 Prognosis in various types of glomerulopathy

causes of nephrotic syndrome justifies a more empirical approach, especially if the proteinuria is highly selective (p. 1039). In all age groups, urinary cells and cellular casts are infrequent or absent.

Management and prognosis In 80-90% of cases the lesion responds to steroids given at moderate to high dose for 8 weeks, most patients showing a response in less than 4 weeks. Subsequent withdrawal of steroids may be followed by prolonged remission, or lead to relapse of the nephrotic syndrome, necessitating a further course of steroid treatment. In steroid-resistant patients, or in those in whom remission can only be maintained by unacceptably heavy exposure to steroids (steroid dependence), cyclophosphamide or chlorambucil given for 8-10 weeks has led to prolonged remission or improved steroid responsiveness. The immunosuppressive agent ciclosporin is also capable of inducing remissions in previously refractory patients. The renal lesion virtually never progresses to CRF, and since the introduction of steroids and cytotoxic therapy the prognosis has been very good (Fig. 20.25), especially in children. An important proviso concerns those cases that appear to 'progress' to focal segmental glomerulosclerosis (FSGS, see below). Here the prognosis is more ominous. It is not clear whether true progression occurs, or whether minimal change nephropathy is sometimes diagnosed in error in patients with very early FSGS. Initial failure to respond to steroids heralds a less favourable outcome. Despite the benefits of these therapies, a small number of

The cause of FSGS is unknown. Although immune complexes may be found in as many as 70% of cases, there is no direct evidence of their involvement in the pathogenesis. The lesion often recurs after renal transplantation, suggesting the presence of a circulating factor. The abnormal glomeruli are segmentally sclerosed, i.e. only a part of each glomerular tuft is affected. Early in the disease only deep juxtamedullary glomeruli may be involved. IgM deposits are usually present, often with C3 complement.

Clinical features, diagnosis and treatment Children present with nephrotic syndrome and adults with asymptomatic proteinuria and hypertension. The diagnosis invariably depends on renal biopsy. In early cases there may be confusion with minimal change nephropathy unless the biopsy contains juxtamedullary glomeruli; these may be the only ones affected early in the course of FSGS. Proteinuria is usually non-selective and urine often contains red blood cells and casts, helping to distinguish it from minimal change nephropathy. Some cases respond to steroids, but this is unpredictable. Often such responses are delayed and follow only after prolonged (3 months at least) high-dose steroids. Cytotoxic drugs have been tried without established benefit.

MESANGIOCAPILLARY GLOMERULONEPHRITIS Mesangiocapillary glomerulonephritis (MCGN) comprises at least two, and possibly three, distinct diseases, each with its own characteristic glomerular pathology. The diseases best characterized are designated types I and II MCGN.

Pathogenesis and pathology The pathogenesis is unknown and may well be different in the two types of MCGN. The glomerular pathology is characteristic. In type I disease mesangial cell proliferation is

1073

marked and the glomerular basement membrane is intact, with subendothelial deposits easily visible on electron microscopy. Type II disease usually shows a lesser degree of mesangial cell proliferation and the electron-dense deposits appear to be intramembranous. IgG and complement are present, more consistently so, and in greater amounts, in type I MCGN. Persistent depression of plasma C3 complement is often found, particularly in patients with type II disease, and indicates complement activation by the alternative pathway. Circulating immune complexes are detectable in some patients and viral antigens have been identified in affected tissues of cases associated with hepatitis B and C virus.

Clinical features Both types of MCGN may present with nephrotic syndrome, nephritic syndrome, hypertension or asymptomatic proteinuria/haematuria, and the majority of the presentations are in children or young adults. Slow progression to CRF is usual, though unpredictable. A minority of patients, usually with the type II variant, progress more rapidly, and in a few patients there is a fulminant course to ESRD. It appears that those patients presenting with full-blown nephrotic syndrome do worse than those with asymptomatic urinary abnormalities.

Diagnosis and management The diagnosis depends on renal biopsy. The glomerular morphology of type I MCGN may be seen in patients with underlying SLE, hepatitis B or C infection and chronic bacterial infection (such as infective endocarditis), and steps should be taken to identify or exclude these conditions. Steroids, with or without cytotoxic drugs, are probably not useful and may be harmful. Antiplatelet drugs and anticoagulants have also been tried and may be of benefit, but this remains to be confirmed. a-Interferon may be helpful in some virus-associated cases.

IgA NEPHROPATHY (BERGER'S DISEASE) Pathogenesis and pathology In IgA nephropathy (Berger's disease) the glomeruli show extensive mesangial deposits of IgA, often accompanied by C3 complement. This pattern is also seen in patients with Henoch-Schonlein purpura. Diffuse mesangial proliferation with superimposed segmental lesions are seen on light microscopy. 1 The lesion can recur in transplants, pointing to a role for host factors. Disturbances of IgA production (accelerated) and clearance (reduced) have been

1

1074

Fig. 20.7

2

MCQ 20.16

found, but despite much circumstantial evidence for an immune aetiology, the details remain obscure. A closely related variant, differing only by the presence of IgM in place of IgA, also exists, and has the same clinical features and management as IgA nephropathy.

Clinical features This is predominantly a disease of young adult men, many of whom present with recurrent macroscopic haematuria, sometimes accompanied by loin pain (p. 1064). Proteinuria is variable, and cellular casts in the urine confirm the glomerular origin of the red blood cells. Relapses may show a temporal relation with upper respiratory infections. The condition has had a benign reputation, but undoubtedly may progress to CRF, particularly if hypertension or proteinuria is present early in the course. Occasionally, the disease may manifest itself with an acute nephritic syndrome.

Diagnosis and management Although the clinical picture is often highly characteristic, renal biopsy is nearly always performed to establish the diagnosis with certainty. The IgA deposits that characterize the renal lesion are also evident in skin capillaries and this finding supports the diagnosis, even in the absence of renal biopsy. These patients should be spared fruitless and inappropriate urological investigation: a careful history and examination of the urinary deposit will usually indicate whether or not the haematuria is glomerular. In many cases the lesion is benign and observation only is required. No therapeutic intervention has been shown to alter the course of the progressive or relapsing disease. ©

IDIOPATHIC RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS Idiopathic RPGN is a serious condition which, as its name suggests, frequently progresses to renal failure.

Pathogenesis and pathology There is little to suggest involvement of the immune system in this disease: neither circulating immune complexes nor glomerular deposits of immunoglobulin and C3 are evident in most cases. The hallmark is the presence of glomerular crescents containing large amounts of fibrin. Similar crescentic lesions are found in some patients with other types of GN, including those associated with polyarteritis, SLE and infective endocarditis.

Clinical features and diagnosis The usual presentation is a subacute nephritic syndrome with malaise, hypertension, haematuria and proteinuria. Middle-aged and older adults predominate. Without treatment, the outlook is very poor.

RPGN should be suspected in any patient with apparent acute or subacute onset of renal impairment, particularly if the urine is 'active', with red blood cells and cellular casts. Assessment of renal size will identify those patients with normal-sized kidneys in whom CRF is unlikely. Renal biopsy is then required to establish the diagnosis.

Management Empirical treatment with high doses of steroid drugs appears to be of some benefit, but these agents should not be given for more than 4 weeks unless there is clear evidence of a response. Cytotoxic drugs and plasma exchange have been tried and there are many anecdotal reports of success. Limited controlled studies suggest that standard therapy should comprise high-dose steroids, a cytotoxic drug such as cyclophosphamide or azathioprine (the latter possibly being less effective), and intensive plasma exchange.

THIN MEMBRANE NEPHROPATHY This condition takes its name from the characteristic thinning of the glomerular basement membrane seen on electron microscopy. In most cases there is an autosomal dominant inheritance pattern, leading to an alternative designation - benign familial haematuria.

TABLE 20.33 Renal involvement in multisystem diseases Collagen vascular

Metabolic

Dysproteinaemia/ neoplasia

Systemic lupus erythematosus Vasculitis Polyarteritis Wegener's Henoch-Schonlein purpura Cryoglobulinaemia (essential mixed) Systemic sclerosis Rheumatoid arthritis Sarcoidosis Sjb'gren's syndrome

Diabetes mellitus Gouty nephropathy

Lymphoma/leukaemia Adenocarcinoma

Hypercalcaemia

Myeloma

Hypokalaemia

Amyloid

20

Ponticelli C, Zucchelli P, Paserini P, Cesana B et al 1992 Methylprednisolone plus chlorambucil as compared with methylprednisolone alone for the treatment of idiopathic membranous nephropathy. N Engl J Med 327:599-603. Couser W G 1999 Glomerulonephritis. Lancet 353:1509.

RENAL INVOLVEMENT IN NON-RENAL AND MULTISYSTEM DISEASE

Clinical features Presentation is with microscopic or intermittent macroscopic haematuria and an appropriate family history. The course is benign.

HEREDITARY NEPHRITIS (ALPORT'S SYNDROME) Alport's syndrome is an inherited disorder with a prevalence of about 1 in 5000. It is characterized by progressive renal impairment and nerve deafness. Presentation is usually with microscopic or gross haematuria. Males tend to be more severely affected than females, particularly with regard to the nephropathy, and associated deafness is variable or even absent in some patients. The mode of inheritance is inconsistent, with some families showing a dominant and others an X-linked dominant pattern. The renal lesion is predominantly glomerular; although there are no specific features on light microscopy, electron microscopy reveals a thin, fragmented and sometimes split glomerular basement membrane. There is no known treatment.

FURTHER READING ON PRIMARY GLQMERULAR DISEASE Appel G B 1993 Immune complex glomerulonephritis - deposits plus interest. N Engl J Med 328:505-506.

Involvement of the kidney occurs in many diseases (Table 20.33). In most of these the glomerulus is the site of damage, with a GN that may give rise to any of the syndromes of glomerular disease. The renal manifestations are variable in severity, but in some cases dominate the clinical picture.

SYSTEMIC LUPUS ERYTHEMATOSUS Renal involvement in SLE is common: 50% of adults, and even more children, have clinical evidence, and more still have abnormal renal histology. It manifests itself with haematuria/proteinuria, acute nephritic syndrome, nephrotic syndrome or chronic renal impairment. At least five glomerular lesions are described, all associated with deposition of complement and immunoglobulins within the glomeruli, and with activation of complement and the presence of circulating immune complexes. The most benign lesion comprises deposition of Igs and complement in an otherwise normal, or slightly abnormal, glomerulus. Focal and segmental proliferative GN and membranous GN both have an unpredictable prognosis, but diffuse proliferative GN with SLE progresses to renal failure in the majority of cases. In a few patients tubulointerstitial involvement dominates, with demonstrable Ig and C3 deposition on the tubular basement membrane.

1075

Treatment. The need to treat is dictated by evidence of progressive renal disease and/or the presence of a renal lesion that is likely to progress. Steroids, often in combination with cytotoxic drugs such as cyclophosphamide or azathioprine, are used, sometimes with plasma exchange. Induction regimens that include a cytotoxic drug, especially cyclophosphamide, are more effective than are steroids alone. Three months of intensive induction therapy is usual. Subsequent maintenance therapy is usually needed for at least 5 years - a combination of azathioprine and prednisolone (at the lowest effective dose) probably offers the best compromise between efficacy and toxicity. These regimens have transformed the outlook in lupus nephritis: uniformly progressive renal lesions can now be controlled effectively in about 80% of cases.

POLYARTERITIS Polyarteritis usually affects the middle-aged and elderly, with males predominating. Renal involvement is frequent, and in some cases the disease may appear to be limited to the kidneys at the time of presentation. Patients with involvement of medium-sized vessels - so-called polyarteritis nodosa, or classic polyarteritis - suffer the consequences of renal ischaemia, with hypertension, renal infarction and renal failure. Diagnosis can be made by skin biopsy, by visceral arteriography, which may show multiple small aneurysms in the kidney or other viscera, or by renal biopsy, in which arteritic lesions may be seen. Microscopic polyarteritis, on the other hand, usually presents with an acute or subacute nephritic syndrome, often with purpura, arthropathy and myopathy. Clinically it may resemble Henoch-Schonlein purpura. Renal biopsies show a florid necrotizing GN. Antineutrophil cytoplasmic antibodies (ANCA) are often present in serum. Treatment. Both types usually respond to treatment with high-dose steroids and cyclophosphamide. (Polyarteritis is discussed further in Ch. 22, p. 1181.)

WEGENER'S GRANULOMATOSIS 1 Wegener's granulomatosis (see also Ch. 22, p. 1182) has features in common with microscopic polyarteritis, including the presence of ANCA, but may be distinguished by its propensity to involve the upper airways and lungs (pulmonary-renal syndrome) and by the granulomatous nature of the arteritic lesions. Renal biopsies show necrotizing glomerulitis, which usually manifests itself clinically with rapidly progressive glomerulonephritis. 2 The prog-

1

1076

Case 20.2

2

Fig. 20.8

nosis has improved greatly with the use of cyclophosphamide and steroids, which control the disease in the majority of cases.

HENOCH-SCHONLEIN PURPURA Henoch-Schonlein purpura is a condition of children and young adults, who present with some or all of the following: GN, skin purpura, arthralgia/arthritis, abdominal pain. The renal lesion is a mesangial-proliferative GN with prominent IgA deposits. IgA is also deposited in skin and other tissues, in this respect resembling IgA nephropathy (Berger's disease). Disease activity is intermittent and tends to involve several organs at once. The GN is usually benign, especially in children, but may progress rapidly or slowly following a series of acute episodes with incomplete resolution. An immune complex aetiology is probable and no treatment has proven efficacy; immunosuppression with steroids, cytotoxic drugs and plasma exchange is often tried in severe cases.

SYSTEMIC SCLEROSIS Visceral involvement in systemic sclerosis frequently includes the kidneys, in which marked thickening of the walls of the medium-sized arteries occurs (see also p. 1178). The glomerular lesions are those of ischaemia, and severe accelerated-phase hypertension is a frequent complication. The aetiology is unknown and there is no effective treatment for the underlying condition. ACE inhibitors allow effective blood pressure control in most of these patients, and this results in a greatly improved renal prognosis, although other manifestations of the disease, particularly cardiac, remain potentially lethal.

RHEUMATOID ARTHRITIS Renal disease in patients with rheumatoid arthritis is usually the result of secondary amyloid (AA type) or of adverse reaction to antirheumatic drugs such as gold, penicillamine or non-steroidal anti-inflammatory agents. However, a few patients, particularly those with widespread vasculitis, may develop GN or renal vasculitis. Steroids and cytotoxic drugs have been effective in some cases.

GOODPASTURE'S SYNDROME The term Goodpasture's syndrome refers to a disease in which the following features are present: lung haemorrhage, GN, and the formation of antibody to glomerular basement membrane (anti-GBM antibody). A pulmonary-renal syndrome can also arise in several other

diseases, such as Wegener's granulomatosis, SLE and legionnaire's disease, and often has clinical features indistinguishable from Goodpasture's syndrome. Anti-GBM antibody is absent in these conditions. The reason for the formation of anti-GBM antibody is unknown; it probably plays a central part in the pathogenesis of the disease, and renal biopsies show linear deposits of IgG and C3 complement along the glomerular capillary walls, accompanied by a proliferative GN, often with crescent formation. The anti-GBM antibody is also demonstrable in the lung, and deposits there probably mediate the lung haemorrhage. The disease predominates in young male adults and there is considerable case-to-case variation. Either the pulmonary or the renal lesions may dominate the clinical picture. Treatment centres on attempts to remove the offending antibody by means of plasma exchange, and to prevent its reappearance by the use of cytotoxic drugs. This approach, with dialysis support when needed, has greatly improved the outlook.

TABLE 20.34 Mechanisms of renal disturbance in malignant disease Mechanism

Example

Obstruction

Carcinoma of prostate, bladder, cervix, rectum Para-aortic lymphadenopathy Intrarenal, e.g. urate, Bence-Jones' proteinuria

Direct invasion of kidney

Leukaemia Hodgkin's disease and other lymphomas Myeloma

Secondary glomerulopathy Membranous nephropathy Minimal change glomerulopathy

Associated with carcinoma of lung, stomach, colon, breast, ovary Associated with Hodgkin's disease, lymphoma or leukaemia

Tumour-induced metabolic disturbance

Hypercalcaemia Urate nephropathy Syndrome of inappropriate ADH secretion (SIADHS)

20

OTHER ACQUIRED COLLAGEN

VASCULAR DISEASES Mixed connective tissue disease (p. 689), essential mixed cryoglobulinaemia (p. 1262), sarcoidosis (p. 682) and Sjogren's syndrome (p. 1137) may all be associated with GN, in addition to the more frequent association between Sjogren's syndrome and interstitial nephropathy (p. 1079).

NEOPLASTIC DISEASE Malignancy may disturb kidney function in a number of ways (Table 20.34). Both isolated solid tumours and diffuse neoplasms of lymphoid tissue may be involved. Tumour lysis syndrome results from the very rapid release of urate and phosphate from a tumour undergoing necrosis, and may lead to acute renal failure from acute uric acid nephropathy. The specific instance of multiple myeloma and the dysproteinaemias is discussed below.

DYSPROTEINAEMIA, MULTIPLE

MYELOMA AND RENAL AMYLOID Multiple myeloma and the other dysproteinaemias may all involve the kidneys, and at least 50% of patients with multiple myeloma will ultimately die of renal failure. The most important renal manifestations are amyloid (p. 1263) and myeloma kidney (Table 20.35). Amyloid in patients with myeloma is of the AL type and its presence in the kidney (and an associated nephrotic syndrome) may antedate other clinical manifestations of

TABLE 20.35 Renal damage in multiple myeloma • • • • • • • • •

Bence-Jones' proteinuria Myeloma kidney Hypercalcaemia Hyperuricaemia (especially at initiation of chemotherapy) Renal amyloid Dehydration ± X-ray contrast media (combination prone to induce ARF) Plasma cell infiltration Glomerulonephritis (immunologically mediated) Hyperviscosity syndrome (e.g. in macroglobulinaemia) may cause papillary necrosis • Obstruction (by stone or sloughed papillae)

myeloma. The nature of the renal lesion is similar whether the amyloid is associated with underlying multiple myeloma, unassociated with malignant disease, or secondary to a chronic inflammatory process, such as sepsis or rheumatoid arthritis (amyloid of A A type). There is no specific treatment for the renal lesion, which usually progresses inexorably, although it is possible that chemotherapy of the myeloma or the chronic inflammatory process at an early stage of the disease may slow or halt the progression of the amyloid as well. Myeloma kidney is a tubulointerstitial nephropathy caused by nephrotoxic immunoglobulin light chains (Bence-Jones' protein) in the glomerular filtrate. Recovery is unpredictable and depends on successful treatment of the myeloma and reduction of the urinary Bence-Jones' protein load. Even so, this lesion is often irreversible.

1077

DIABETES MELLITUS Diabetic glomerulopathy

Renal involvement in diabetes becomes progressively more common with increasing duration of disease, such that after 20 years some 30% of diabetics will have proteinuria or other evidence of nephropathy. Surprisingly, the emergence of nephropathy more than 30 years after the initial diagnosis of diabetes is unusual, i.e. most diabetics who are destined for nephropathy will develop it within 20-30 years. Diabetics who are affected usually (though not always) have associated malignant vasculopathy and other vascular complications of diabetes mellitus. In type 2 patients the duration of impaired glycaemic control usually antecedes the clinical diagnosis, probably by several years in many cases. This may account for the onset of nephropathy and other complications quite soon after the first detection of the diabetic state. Contrary to earlier belief, it is now clear that the risks faced by type 1 and 2 diabetics are similar, and are related to the duration of diabetes. Further, the risk of renal failure is also related to microalbuminuria and, in turn, to overt proteinuria. Glomerular changes predominate and are of two types: • Diffuse glomerulosclerosis, in which there is thickening of the glomerular basement membrane, capillary wall and mesangium. This lesion is common, but is not specific for diabetes mellitus; • Nodular glomerulosclerosis (Kimmelstiel-Wilson lesion), which is specific for diabetes mellitus but is present in only a minority of patients. O The pathogenesis of diabetic nephropathy is unknown but attention has focused on two main possibilities, which are not mutually exclusive: • Genetic. This is clearly part of the story: for example, diabetic siblings of propositi with diabetic nephropathy have a fourfold greater chance of developing nephropathy than do those of propositi without nephropathy. • Acquired. The renal lesion is acquired and is secondary to either lack of insulin, hyperglycaemia or both. Various observations make this likely, in particular the finding of diabetic nephropathy in some 'non-genetic' cases, e.g. following pancreatectomy, and the appearance of diabetic lesions in 'normal' kidneys transplanted into diabetic recipients. Poor glycaemic control also favours the development of nephropathy. The disease generally passes through four recognizable phases:

1

1078

Fig. 20.9

2

MCQ 20.17

• • • •

Hyperfiltration with supranormal GFR Microalbuminuria (but still dipstick negative) Proteinuria (dipstick positive) Heavy proteinuria (with nephrotic syndrome or renal failure).

Hypertension develops in virtually all these patients, and there is some evidence of an association between the inheritance of type 2 diabetes mellitus and essential hypertension. Deterioration is inevitable, though its rate is unpredictable. There is now, however, great interest in the possibility that reduction of the glomerular hypertension that is known to coexist with hyperfiltration early in diabetes may slow the development of nephropathy. In the short term this can be achieved by means of very tight glycaemic control, protein restriction or the use of ACE inhibitors (p. 1059). Coexistent arterial hypertension accelerates progression; conversely, intensive antihypertensive therapy to the point of absolute normotension retards progression. 2 Other renal complications of diabetes Urinary tract infection (UTI) is more common in diabetics and is also more likely to be complicated by acute pyelonephritis, papillary necrosis and pyonephrosis. Autonomic neuropathy may impair bladder function, increasing the risk of ascending UTI. Renal replacement therapy in diabetics Haemodialysis, CAPD and renal transplantation are all used in diabetes, but coexisting retinopathy, cardiac and arterial disease (all frequently present) greatly reduce the success of these treatments, and the survival prospects of diabetics with renal failure are poor.

FURTHER READING ON DIABETES MELLITUS Anderson S, Brenner B M 1988 Pathogenesis of diabetic glomerulopathy: the role of glomerular hyperfiltration. In: Mogensen C E, ed. The kidney and hypertension in diabetes mellitus. Boston: Martinus Nijhoff, 139-146. Brenner B M (ed) 1995 The kidney, 5th edn. Philadelphia: W B Saunders. Parving H H, Smidt U M, Anderson A R, Svendsen P A 1983 Early aggressive antihypertensive treatment reduces rate of decline in kidney function in diabetic nephropathy. Lancet 1:1175-1179.

SICKLE CELL DISORDERS The most important renal complications seen in sickle cell disorders (discussed in Ch. 23, p. 1218) are recurrent gross haematuria, papillary necrosis and glomerulonephritis. INTRAVASCULAR COAGULATION

Several conditions may lead to intravascular coagulation

(`Ch. 23, p. 1270) and renal impairment, but these two features are especially characteristic in haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopenic purpura. In both these conditions there is evidence of microangiopathic haemolytic anaemia (MAHA) and thrombocytopenia. Although laboratory features are similar, HUS is mainly a disease of children, with prominent renal involvement (in fact, the commonest cause of acute renal failure in children in the UK), whereas thrombotic thrombocytopenic purpura usually affects adults and renal disease is more variable. The aetiology is uncertain, although HUS appears to follow viral or bacterial infections in children and has also shown case clustering in schools or families. Recent evidence has implicated verucytotoxin-producing Escherichia coli infection: patients with HUS produce antibody to verucytotoxin and the toxin itself can produce similar angiopathic lesions in rabbits. A rare disease indistinguishable from haemolytic uraemic syndrome has been recognized following apparently normal pregnancy, and also in women taking the contraceptive pill. Treatment of these conditions is difficult, and the best prospects are offered by a combination of antiplatelet drugs and infusions of fresh plasma.

FURTHER READING ON INTRAVASCULAR COAGULATION Milford D V, Taylor C M 1990 New insights into the haemolytic uraemic syndromes. Arch Dis Child 65:713-715. Kaplan B S, Meyers K E, Schulman S L 1998 The pathogenesis and treatment of hemolytic uremic syndrome. J Am Soc Nephrol 9:1126.

GOUTY NEPHROPATHY Humans excrete urate/uric acid in amounts that are very high considering the low solubility of uric acid at acid pH. Three types of clinical problem may arise: • Uric acid stone formation (p. 1086). • Acute uric acid nephropathy. This is caused by massive deposition of uric acid crystals in the tubules, renal pelvis and ureters, and arises as a complication of accelerated uric acid production during treatment of widespread malignancy, such as lymphoma or leukaemia (Ch. 23, p. 1238). The xanthine oxidase inhibitor allopurinol usually provides adequate prophylaxis. • Chronic urate (gouty) nephropathy. This is a common accompaniment of prolonged hyperuricaemia, itself strongly associated with clinical gout. The renal damage is mainly interstitial, although glomerular changes also occur. Sodium urate crystals may be demonstrable in renal tissue in some cases. Management is prophylactic, using allopurinol to decrease plasma and urine urate levels. Established chronic urate nephropathy is irreversible, although progression may be halted or slowed by allopurinol therapy.

DISEASES OF THE RENAL INTERSTITIUM

20

Diseases of the renal interstitium are sometimes collectively termed 'tubulointerstitial disease' or 'interstitial nephropathy'.

Aetiology and pathology The tubulointerstitial nephropathies are distinguished from the glomerulopathies by relative sparing of the glomeruli and prominent changes affecting the nonglomerular components of the renal parenchyma, i.e. the interstitium and tubules. The causes of tubulointerstitial disease are given in Table 20.36.

TABLE 21.36 Causes of tubulointerstitial disease Cause

Acute

Chronic

Idiopathic Drug hypersensitivity Penicillin Cephalosporins Sulphonamides Diuretics NSAIDs Toxin-induced Aminoglycoside antibiotics Cisplatin Pentamidine Analgesic abuse (including NSAIDs) Lithium X-ray contrast media Heavy metals Immunological disorders Sjogren's syndrome SLE Neoplasia Myeloma kidney Leukaemic infiltration Metabolic Hypercalcaemia Hypokalaemia Uric acid Other Acute pyelonephritis Chronic pyelonephritis Reflux Obstruction Sickle cell disorder

1079

Acute tubulointerstitial nephropathy is characterized by prominent interstitial oedema with a heavy infiltrate of inflammatory cells, among which neutrophils, eosinophils or mononuclear cells may predominate. 1 In contrast, chronic tubulointerstitial nephropathy is associated with marked tubular atrophy, interstitial fibrosis and an infiltrate of mononuclear cells. Patients may present with ARF (p. 1047), CRF (p. 1051) or a tubular syndrome (p. 1065). Heavy proteinaemia (>3 g/day) is exceedingly uncommon. In general (although by no means always), tubulointerstitial diseases are less likely to be associated with oliguria or anuria and are more likely to give rise to one or more of the renal tubular syndromes than are the glomerulopathies. Many nephrotoxins act primarily on the interstitial tissues. In some cases toxicity may be confined to the kidney, whereas others may involve several organs. Drugs are an important cause of toxicity, antibiotic and antirheumatic agents being particularly important (see p. 1086). Analgesic nephropathy is a tubulointerstitial disease that results from prolonged exposure to certain mild analgesics. Phenacetin (now withdrawn) was implicated, but there is also evidence that aspirin and NSAIDs may be involved in some cases. The disease eventually leads to ischaemic necrosis of the renal papillae and CRF; in the past, analgesic nephropathy was one of the major causes of ESRD in a number of developed countries. Conditions such as renal obstruction (p. 1090), reflux nephropathy and infection (p. 1086) and multisystem diseases of the kidney (p. 1086) may lead to severe interstitial damage. Obstruction (p. 1090), reflux and infection (p. 1083) are discussed in detail elsewhere, but nevertheless fall into the broad category of tubulointerstitial nephropathy.

Diagnosis and management The frequency of drug-induced acute or chronic tubulointerstitial nephropathy indicates that the diagnosis should be carefully considered in any patient presenting with an unexplained acute or chronic renal disturbance. A history of relevant drug exposure should be sought, and in many cases a renal biopsy will be needed to define the renal lesion and the potential for recovery. In most cases treatment is expectant, with the removal or avoidance of any relevant nephrotoxin if possible, and treatment of any underlying immunological disorder. Acute idiopathic cases and those associated with hypersensitivity reactions to drugs, such as penicillin, may benefit from a short course of steroids and generally have a good prognosis. Chronicity and the presence of marked tubular atrophy or interstitial fibrosis on biopsy are adverse features, although progression may be very slow.

CYSTIC DISEASES OF THE KIDNEY Renal cysts are relatively common and vary greatly in significance. Table 20.37 gives a classification of the important types, of which the most important are: • Adult polycystic kidney disease • Simple cysts (single or multiple) • Neoplastic cysts. Less common are medullary cystic disease (MCD) and juvenile nephronopthisis.

ADULT POLYCYSTIC KIDNEY DISEASE (PKD) Adult polycystic kidney disease is an important cause of renal failure, accounting for 5-10% of all cases of ESRD. It is inherited as an autosomal dominant and the penetrance is 100%. Genetic counselling is therefore important. Two main variants exist. In PKD-1 the gene has been localized to chromosome 16 close to the oc-globin locus, enabling presymptomatic and prenatal diagnosis by DNA markers in some families. The PKD-2 variant has the same inheritance pattern but tends to present later.

Clinical features Presentation may be with microscopic or macroscopic haematuria, hypertension, renal pain (associated with

TABLE 20.37 Cystic diseases of the kidney Cystic disease Polycystic kidney disease Adult polycystic kidney disease Juvenile polycystic kidney disease

1080

2

MCQ 20.18

Common. Dominant inheritance. Renal failure. Associated with hepatic cysts but no hepatic disease Rare. Recessive inheritance. Hepatic cysts, renal and hepatic failure

Simple cysts Single Multiple

Common. Often asymptomatic

Neoplastic cysts

Renal cell tumour (hypernephroma)

Medullary cysts Medullary cystic disease Juvenile nephronopthisis

1 Fig. 20.10

Clinical and pathological features

Medullary sponge kidney

Usually dominant inheritance; presents in adolescence. Renal failure Recessive; presents in childhood. Renal failure Tubular ectasia. Nephrocalcinosis. Recurrent urinary infections

haemorrhage into a cyst or infection), CRF, or identification of enlarged kidneys. Progressive enlargement of the cysts leading to impairment of renal function is the rule, about 10-20 years elapsing between presentation and ESRD in most cases. About 30% of patients also have hepatic cysts; these are not associated with hepatic dysfunction. There appears to be an increased incidence of subarachnoid haemorrhage in patients with adult polycystic kidney disease, and 10-22% of patients may have intracranial aneurysms.

Diagnosis and management Diagnosis is easy in advanced cases, where the enlarged kidneys may be palpated and their gross morphology assessed by renal ultrasound. However, in early cases, particularly in children and young adult relatives of affected patients presenting for screening, diagnosis may be extremely difficult. Good-quality renal ultrasound offers the best combination of accuracy, sensitivity and acceptability to the patient, although the sensitivity of CT scanning may be slightly better than that of ultrasound. Renal biopsy is not appropriate in these patients. Complications include hypertension, urinary infections and stone formation, and bleeding into cysts or the urine. Energetic treatment of these problems probably retards progression, but at present there are no means of slowing or preventing the underlying process of cyst enlargement and renal damage. ©

SIMPLE CYSTS Simple cysts may be single or multiple. If large enough, they may present with loin pain or a loin mass, but they are more frequently detected incidentally during the course of renal imaging for other reasons.

NEOPLASTIC CYSTS Some renal tumours may exhibit cyst formation and it is therefore most important to distinguish accurately between benign simple cysts and neoplastic cysts. This can often be achieved with acceptable certainty by careful imaging, ultrasound or CT. However, it may be necessary to aspirate the cysts percutaneously and perform cytological examination of the fluid or renal arteriography in doubtful cases.

JUVENILE POLYCYSTIC KIDNEY DISEASE Juvenile polycystic kidney disease is an uncommon recessively inherited disorder also associated with hepatic fibrosis and cysts. Renal and/or hepatic failure develop early.

MEDULLARY CYSTIC DISEASE AND JUVENILE NEPHRONOPTHISIS

20

Medullary cystic disease (autosomal dominant) and juvenile nephronopthisis (autosomal recessive) are causes of renal failure in early adulthood and childhood, respectively. The prominent tubulointerstitial involvement leads to urinary concentrating defects and other tubular syndromes. There is no specific treatment.

FURTHER READING ON CYSTIC DISEASES OF THE KIDNEY Brenner B M (ed) 1995 The kidney, 5th edn. Philadelphia: W B Saunders. Reeders S T et al 1985 A highly polymorphic DNA marker linked to adult polycystic kidney disease on chromosome 16. Nature 317:542-544.

RENAL DISEASE AND HYPERTENSION The kidney and blood pressure interact in a number of ways, and the final common paths of these interactions are such that: • The kidney may cause hypertension • The kidney may be damaged by hypertension.

RAISED BLOOD PRESSURE AS A CONSEQUENCE OF RENAL OR RENAL VASCULAR DISEASE Hypertension is much commoner in patients with renal diseases than in the population at large, and the incidence of hypertension in such patients increases as renal function declines. By the time that CRF occurs, at least 80% of patients will be, or will have been, hypertensive. It appears that two major processes, acting either in isolation or (probably more frequently) in concert, underlie the raised blood pressure in these patients. These are: Increases in body sodium and water content Inappropriately increased activity of the reninangiotensin-aldosterone system. Increased body sodium and water content. The most clear-cut example is the anephric patient receiving regular dialysis treatment. Here, the renin-angiotensin system is essentially non-functioning and blood pressure is found to be closely related to the level of ECF expansion, rising as body sodium/water are allowed to increase and falling when sodium/water are removed by dialysis. Inhibition of the renin-angiotensin system by converting-enzyme inhibitors has only minor effects on blood pressure. Increased activity of the renin-angiotensin-aldosterone system. In some patients in whom there is no evidence of

1081

increasingly severe glomerular ischaemia is interrupted by means of effective hypotensive treatment.

Management' Hypertension with underlying renal parenchymal disease The aim of treatment is the normalization of blood pressure, achieved in most cases by a combination of dietary manipulation and drugs. The following possibilities must be considered: • Is the patient fluid-overloaded? (Physical signs include raised JVP, peripheral oedema, pulmonary oedema.) • Is the patient in the benign or the accelerated phase of hypertension? (The signs are mainly in the optic fundi: grade III or grade IV changes indicate accelerated phase and the need for immediate treatment.) FIG. 20.26 Renal hypertension

excess body sodium and water, ACE inhibition dramatically reduces blood pressure, implying dependence of the elevated blood pressure on the renin-angiotensinaldosterone system. In practice, hypertension in most renal patients is probably a result of both mechanisms outlined above. Impaired ability to excrete sodium/water favours ECF expansion and a rise in blood pressure. In a normal individual this would trigger a pressure-induced natriuresis and neurohumoral responses (including decreased renin release and increased release of atrial natriuretic peptide (ANP), both of which favour natriuresis (Fig. 20.26). The abnormal kidney, however, may show a blunted natriuretic response and may also fail to demonstrate appropriate suppression of renin release under these circumstances. Thus, volume expansion develops, the renin-angiotensin-aldosterone system is unsuppressed, and hypertension ensues.

RENAL DAMAGE AS A CONSEQUENCE OF RAISED BLOOD PRESSURE

1082

The effect of raised blood pressure on the kidney depends on its severity and chronicity, and whether or not the hypertension is in the benign phase or the accelerated phase (p. 592). It is doubtful whether hypertension in the benign phase poses a serious threat to renal function in the short or medium term, although there is evidence that black races may be more susceptible to renal damage in this setting. In contrast, the accelerated phase of hypertension is associated with florid changes in the renal circulation, with fibrinoid necrosis and very marked endothelial cell proliferation giving rise to the so-called 'onion peel' appearance of the small blood vessels. These lesions are remarkably similar to those seen in patients with systemic sclerosis (p. 1076). Rapid progression to renal failure is the rule, unless the spiral of increasing blood pressure and

Those patients in whom volume expansion is a major factor will respond well to a combination of dietary sodium restriction and a loop diuretic such as furosemide (frusemide) (thiazides do not work well in patients with significant impairment of renal function). It is important not to cause excessive reduction in body sodium/water: to do so would introduce a 'prerenal factor' which could further compromise renal function. Patients in whom there is no evidence of volume overload, or who have not responded adequately to therapeutic reduction of body sodium/water, will usually respond well to inhibition of the renin-angiotensin system (ACE inhibitors), reflecting the overactivity of this system in the genesis of their hypertension. Hypertension with underlying renal vascular disease Regardless of the site of the arterial lesion (renal artery, branches of the renal artery, arcuate or interlobular vessels), the result is reduced renal blood flow, reduced pulse pressure at the baroreceptor in the JGA, and consequently increased release of renin by the JGA. In these patients, overactivity of the renin-angiotensin system is usually the dominant factor. Body sodium/water status is variable and successful inhibition of the renin-angiotensin system with a ^-blocker or ACE inhibitor is likely to control blood pressure, if necessary with the help of a diuretic or additional hypotensive agents. ACE inhibitors may cause a profound (and usually reversible) reduction in GFR in patients with critical renal artery stenosis, and are contraindicated if the stenosis is bilateral, or affects a solitary functioning kidney. Disease of the renal artery Disease of the renal artery (see Fig. 20.10) poses a particular therapeutic problem because in some cases correction of the stenotic lesion will cure or ameliorate the hypertension and, if the stenotic lesion is severe, improve renal function. Stenosis of the renal artery is most often atheromatous and is therefore likely to be seen in middle-

aged and elderly people with risk factors for arterial disease. A smaller number arise in young women, in whom the pathology is fibromuscular hyperplasia of the renal artery. In both instances the disease may be unilateral or bilateral. Treatment, when indicated (see below), may be by open operation or balloon dilatation (angioplasty), usually followed by stenting. Two considerations may lead to a decision to undertake angioplasty or surgery for renal artery stenosis: • The belief that correction of the lesion will cure or ameliorate the hypertension. This is often very difficult to predict, but is more likely when the patient is young, when the hypertension is very recent in onset, when the disease is unilateral and confined to the renal artery, and when renal venous blood sampling shows plasma renin activity much higher on the affected side than elsewhere in the circulation. • The hope that renal function can be improved by correction of the stenotic lesion. This usually involves patients with bilateral atheromatous lesions in whom progression of the atheroma may lead to total occlusion, with catastrophic loss of renal function. Unilateral renal disease and hypertension Unilateral renal disease of any kind can cause hypertension. Nephrectomy may be considered in such cases, when the following indications apply: • The kidney is dangerous, such as with renal tumour. • The kidney is useless and there is a good chance of 'surgical cure' of hypertension.

FURTHER READING ON RENAL DISEASE AND HYPERTENSION Klahr S 1989 The kidney in hypertension - villain or victim? N Engl J Med 320:731-733. Raine AEG (ed) 1992 Advances in renal medicine. Oxford: Oxford University Press. Joint National Committee on Detection, Evaluation, and the Treatment of High Blood Pressure (JNC V) Sixth Report 1997 Arch Intern Med 157:2413.

URINARY TRACT INFECTION, PYELONEPHRITIS AND TUBERCULOSIS URINARY TRACT INFECTION Infection of the urinary tract is exceedingly common, but in the vast majority of cases it is mild and easily treated. Table 20.38 lists the most common infecting organisms. A working definition of urinary tract infection (UTI) is the presence, in an appropriately collected midstream specimen of urine (MSU), of more than 10-5 colony

TABLE 20.38 Urinary pathogens • • • • •

£ coli Enterococci Proteus Enterobacter Pseudomonas

20

Staphylococci Klebsiella Candida (usually catheter associated) Mycobacterium tuberculosis

TABLE 20.39 Causes of sterile pyuria Recently treated urinary infection Tuberculosis Acute interstitial nephritis Chronic interstitial nephritis (including analgesic nephropathy) Chronic pyelonephritis

forming units per mL of urine. However, this is merely an arbitrary limit above which significant infection is likely and below which infection is less likely. Exceptions are frequent. The diagnosis is made more likely if there is accompanying pyuria (evident on microscopic examination of the urine), and much less likely if more than one organism is isolated. Sterile pyuria is defined as white cells in the urine in the absence of significant bacterial growth. The causes of sterile pyuria are shown in Table 20.39. As UTI most frequently arises by means of ascending infection, faecal organisms predominate (Table 20.38). M. tuberculosis usually reaches the kidney by the haematogenous route.

Predisposing factors Several factors predispose to the development of UTI: • Female sex. The male urethra is longer than the female one, which, together with the antibacterial action of prostatic secretions, probably accounts for the substantially higher incidence of UTI in females of all ages than in males. • Failure of complete bladder emptying. The most important causes are outflow obstruction due to prostatic hypertrophy in males, and neurological diseases leading to functional disturbances of micturition in either sex. • Anatomical disorders of the bladder. These may be congenital or acquired (e.g. bladder diverticulum, cystocoele). • Vesicoureteric reflux. Reflux of urine into the ureters or kidney during micturition is abnormal and, as well as predisposing to UTI, also renders ascent of the infection to the kidney much more likely. It is commonest in children, and its importance lies in its likely role in the aetiology of chronic pyelonephritis (p. 1085). • Pregnancy. The ureters and renal pelves dilate during normal pregnancy, and it is probable that this contributes

1083

•

. • • •

to the substantially increased incidence of UTI and pyelonephritis seen in pregnant women. Diabetes mellitus. Diabetics as a whole suffer more UTIs than non-diabetics. This increase is confined largely to those patients with long-standing disease and neuropathic bladder dysfunction. Young diabetics are not at risk of UTI. Tumours. UTI may be the first sign of an underlying bladder tumour. Stones. The presence of stones anywhere in the urinary tract makes infection more likely, and also renders it much harder to eliminate. Foreign body. Indwelling bladder catheters, nephrostomy tubes and ureteric stents all favour infection.

Clinical features The presentation of UTI depends on the location and type of infection, although the relationship between apparent location of infection based on symptoms (i.e. bladder or kidney) does not always correlate with definitively demonstrated site of infection. Urethra! syndrome. Urethral syndrome is the combination of dysuria, frequency, urgency and strangury without demonstrable UTI as defined above. Women are affected exclusively and the disorder is probably heterogeneous, resulting from mechanical factors (sexual intercourse), chemical irritation (toiletries) or atypical infection (chlamydia, viruses, or bacteria in small numbers). Cystitis. 1 Symptoms are those of the urethral syndrome and range from trivial to severe. They are accompanied by pyuria and significant bacteriuria. The urine is usually cloudy and may be foul-smelling. A variable degree of constitutional disturbance is usually present, and in a minority of cases the infection may ascend, leading to acute pyelonephritis (see below). Asymptomatic bacteriuria. In adults, the incidental finding of significant bacteriuria is generally of little consequence, although pregnant women show a propensity for the asymptomatic bacteriuria to progress to cystitis and acute pyelonephritis. However, in children the position is less clear, in that a significant minority will prove to have associated abnormalities of the urinary tract. In both children and adults spontaneous resolution is quite common, and with the exception of pregnant women and children with vesicoureteric reflux, antibiotic therapy is not of value. Acute pyelonephritis. This usually results from ascending infection and may be preceded by a clinical episode of cystitis. Rarely, it may be acquired haematogenously. There is usually a substantial constitutional disturbance, with fever, rigors and malaise. Renal pain and tenderness is usual, and the infection may occasionally be very severe, 1 1084

Case 20.3

1

MCQ 20.19

1

MCQ 20.20

FIG. 20.27 CT scan of renal abscess in a solitary kidney: haematogenous spread The position of the abscess is shown by the square cursor.

with bacteraemia, shock and even death. Two types of patient are at particular risk of overwhelming acute pyelonephritis: diabetics, who may suffer papillary necrosis during the course of such an infection; and subjects with obstruction of the urinary tract and acute pyelonephritis above the obstruction (most commonly arising in association with renal or ureteric stones). The latter may develop severe and permanent renal damage (pyonephrosis) over a very short period of time (hours or days), as well as being at high risk of bacteraemia.

Investigation Investigation should focus on the isolation, identification and antibiotic sensitivity of the infecting organism. Fresh urine should be examined under the microscope for leukocytes and other formed elements. Patients with clinical evidence of acute pyelonephritis should have blood cultures. Additional investigations to be considered during or after treatment are ultrasound, IVU and cystourethroscopy. Ultrasound. Often helpful during an acute episode of pyelonephritis to exclude obstruction. IVU. This should be undertaken after the first infection in adult males and after the second or third in females, particularly if there was clinical evidence of pyelonephritis. Its purpose is to exclude the possibility of a functional or structural abnormality of the kidneys or urinary tract. Cystourethroscopy. In men this will often be needed after even a single infection because of the rarity of UTI in the absence of significant prostatic or bladder disease.

Management General measures. Fluid intake should be generous and achieve a urine flow rate of at least lOOmL/h. Analgesics may be required. Antibiotic therapy. This is often begun before the results of bacteriological investigations are available, though it

may be modified subsequently if the bacteriological results so dictate. Conventionally, a course of 5 days is given for clinical cystitis, but effective treatment may also comprise a large single dose of an appropriate antibiotic. The most frequently used agents are: • Amoxicillin (250 mg t.d.s. for 5 days, or 3 g as a single dose by mouth) • Trimethoprim (300 mg once daily for 5 days) • Norfloxacin (200mg o.d., or 800mg single dose). In complicated or severe infection, and where there is presumptive evidence of acute pyelonephritis, at least 7 days of high-dose chemotherapy should be given. The treatment of the urethral syndrome is empirical and often unsatisfactory. Symptoms often fluctuate spontaneously, making it difficult to assess the response to therapy. Some patients appear to benefit from alkalinization of the urine with citrate salts or urethral dilatation, even when no objective evidence of outflow obstruction exists. 0

TUBERCULOSIS OF THE URINARY TRACT Tuberculosis of the urinary tract almost always results from haematogenous spread, usually from a pulmonary focus, and involves one or both kidneys. A progressive interstitial nephropathy develops, with extensive fibrosis and distortion of the gross anatomy of the kidney. Renal calcification is frequent, though not invariable. The disease spreads down the urinary tract, involving the renal pelves and ureters, and ureteric strictures frequently result. The bladder may be involved, leading to tuberculous cystitis and a contracted bladder, as may the epididymis, leading to tuberculous epididymitis. Renal damage is common, and may result from progressive destruction of parenchyma by the infection, or from stricture formation leading to obstruction.

Clinical features and diagnosis Unfortunately, some of these patients present with irreversible CRF. Others come to attention following painless haematuria, frequency or nocturia due to tuberculous cystitis, or with constitutional symptoms such as fever, malaise and weight loss. The urine shows a sterile pyuria. The epididymis may be hardened and calcified, and renal imaging often shows intrarenal calcifications with irregular loss of renal parenchyma and, in some cases, obstruction. Ultimately, the diagnosis depends on successful isolation of acid-fast bacilli from the urine. Early morning urine specimens are used, and at least three should be obtained and examined by microscopy and culture for 6 weeks before excluding active infection.

Management Treatment is with antituberculous chemotherapy (p. 645).

Careful assessment of the anatomy of the renal tract is essential to exclude obstruction, and follow-up IVUs should be performed during the first year to identify late stricture formation. Surgical reimplantation of the ureters may be needed in some cases, and severe contraction of the bladder may require an enlargement procedure (caecocystoplasty) or urinary diversion to alleviate frequency and protect against further renal damage. 3

20

CHRONIC PYELONEPHRITIS AND VESICOURETERIC REFLUX Chronic pyelonephritis (CPN) is a diagnosis based on abnormalities of gross morphology of the kidney (either at postmortem or by IVU or other forms of imaging). The cardinal features of the condition are: • Unilateral or bilateral parenchymal scars which give the kidney an irregular outline; • Flattening of the renal papillae, giving a 'clubbed' appearance to the calyces. The parenchymal scars overlie the clubbed calyces. Microscopically, there is severe interstitial fibrosis and scarring, with tubular atrophy. The calyces and collecting system show mucosal thickening and inflammation. Glomerular lesions are variable.

Aetiology and pathogenesis The aetiology of CPN is controversial. In the past, it was assumed that the scarring was the result of intermittent acute or chronic infection of the kidney. The main problem with this explanation is the absence of infection in many cases, and also the clear evidence that the disease may progress in the absence of persistent infection in the urine or in the kidney. It is now thought that a number of different factors, probably in association with transient infection in early life, may initiate and perpetuate the lesion that results in CPN. Of these, vesicoureteric reflux and obstruction are the two with the most clear-cut involvement, and it is therefore helpful to categorize CPN as follows. CPN with vesicoureteric reflux. This association is far too frequent to be coincidental. It is likely that the repeated, and individually trivial, insults to the kidney following each episode of reflux (particularly in infancy, when the kidney is highly susceptible to damage) cause cumulative damage. It appears that reflux of infected urine is particularly harmful, but whether the injury is mechanical, chemical or immunological is unclear. CPN with obstruction. Evidence of obstruction is found in a proportion of patients who satisfy the diagnostic criteria for CPN; some of these have functional and structural disorders of the bladder. CPN in isolation. In a sizeable proportion of cases reflux is absent, and there is no evidence of back pressure or obstruction. In these idiopathic cases of CPN an explanation that is increasingly accepted is that reflux in early

1085

childhood (probably associated with UTI), with resolution in adolescence, may be the underlying cause.

Clinical features, investigation and treatment Many patients present for the first time with symptoms and signs of CRF or hypertension. In addition, severe reflux may give rise to renal pain or predispose to clinically evident attacks of acute pyelonephritis. In addition to the general assessment of renal function, a search should be made for factors that might accelerate the progression of the disease, in particular obstruction, the presence of stone, and active urinary infection. Reflux may be documented by micturating cystography, but surgical correction is rarely warranted and does not appear to retard progression of the disease, even though it may make control of infection easier. As in all patients with renal disease, close attention to maintenance of appropriate fluid and electrolyte balance and control of blood pressure are essential.

NEPHROPATHY DUE TO PHYSICAL OR CHEMICAL AGENTS RADIATION NEPHRITIS Radiation nephritis most often arises in the context of radiotherapy for tumours in or adjacent to the kidneys, such as ovarian or testicular cancer, lymphoma, neuroblastoma or Wilms' tumour. Pathological changes are widespread and involve glomeruli, tubules, interstitium and vascular elements. There is no treatment other than general supportive measures and control of blood pressure. Dialysis and/or transplantation may be appropriate in some cases.

NEPHROPATHY DUE TO CHEMICAL TOXINS The importance of chemical toxins as a cause of nephropathy is illustrated by studies showing that nephrotoxins are implicated in 20-25% of cases of ARE It is salutary to note that the vast majority of these cases are iatrogenic, with prescribed drugs identified as the offending agents. Chemical insult to the kidney may lead to any of the major renal syndromes. The nephrotoxicity of many of the agents discussed below is enhanced by concomitant volume contraction; identification and correction of this and other 'prerenal

1

1086

Case 20.4

2

MCQ 20.21

factors' (see Table 20.15) is thus of great importance when known nephrotoxins are being administered therapeutically.

Drug-induced nephrotoxicity (therapeutic) Antibiotics are the major contributors, with those of the aminoglycoside group (gentamicin, tobramycin) being prominent. Other frequently prescribed agents with nephrotoxic potential are NSAIDs 1- penicillamine, gold and lithium. Withdrawal of the offending agent will often allow renal function to return to normal, but in some cases the renal damage is permanent (Table 20.40).

Nephrotoxicity resulting from drug abuse In epidemiological terms, by far the most important example is analgesic nephropathy (p. 1080) following the habitual consumption of large amounts of certain proprietary analgesic mixtures. Phenacetin (now withdrawn), paracetamol, aspirin and ibuprofen can be obtained over the counter without prescription. Of these, paracetamol is the least toxic. Heroin abuse may lead to immune complex GN or acute myoglobinuric renal failure due to rhabdomyolysis.

Other environmental nephrotoxins X-ray contrast media are associated with a small risk of ARF, especially in patients with established renal disease, diabetes, jaundice and multiple myeloma. In these groups, an important predisposing factor is volume contraction, which should be corrected prior to injection of X-ray contrast media. Other toxins include mercury, lead, organic solvents, ethylene glycol (antifreeze), paraquat and paracetamol (in large overdose). 0

FURTHER READING ON NEPHROPATHY DUE TO PHYSICAL OR CHEMICAL AGENTS Brenner B M (ed) 1995 The kidney, 5th edn. Philadelphia: W B Saunders. Murray M D, Brater D C 1993 Renal toxicity of the non steroidal anti-inflammatory drugs. Annu Rev Pharmacol Toxicol 33, 435-465.

URINARY STONE Urinary stone, or urolithiasis, and the dramatic symptoms that may be associated with it, has been recorded for at least two millennia. The true incidence is difficult to assess, but it is likely that clinical stone events afflict about 1 % of the population at some time during their lives. Men are

20

TABLE 20.40 latrogenic toxic nephropathy Drug

Renal disturbance

Aminoglycosides (gentamicin, tobramycin, amikacin) Penicillins (methicillin, benzylpenicillin, ampicillin) Sulphonamides Cephalosporins (especially cephaloridine) Demeclocycline Amphotericin B

ARFwith or without oliguria

Pentamidine NSAIDs Penicillamine Organic gold Diuretics (thiazides, furosemide [frusemide]) Lithium carbonate Cisplatin X-ray contrast media

Acute interstitial nephropathy Precipitation in tubules ARF Nephrogenic diabetes insipidus Decreased renal blood flow; tubular toxicity ARF Acute or chronic interstitial nephropathy Nephrotic syndrome Nephrotic syndrome Interstitial nephropathy Tubular syndromes, chronic interstitial nephropathy Interstitial nephropathy ARF with or without oliguria

TABLE 20.41 Types of urinary stone Composition

Radio-opaque

Frequency (%)

Calcium oxalate Calcium oxalate + hydroxyapatite Calcium phosphate Magnesium ammonium phosphate + calcium phosphate (struvite) Uric acid Cystine

++++-

35 45 1-3 10

0 +

5 1-2

affected about four times more often than women, and in both sexes stone formation tends to be recurrent and unpredictable, putting a substantial onus on doctors to devise effective means of prophylaxis.

Types of stone Details of the major stone types are given in Table 20.41, from which it can be seen that the large majority are made up of calcium oxalate or a mixture of calcium oxalate with hydroxyapatite. Struvite stones (magnesium ammonium phosphate) usually contain calcium phosphate as well, and are invariably associated with infection. Uric acid stones and cystine stones are associated with elevated urinary excretion rates of these compounds.

Pathogenesis Stone formation is frequent because of the precariously

FIG. 20.28 Operative removal of 'staghorn' calculus

high urinary concentration of compounds of relatively low solubility. Certain protective mechanisms are built in, such that immediate precipitation is not an inevitable result of supersaturation. Inhibitors of crystal formation in urine are inorganic (magnesium, pyrophosphate, citrate) and organic (glycosaminoglycans, nephrocalcin), and it is possible that the action of these is at least as important a determinant of stone formation as the absolute concentrations of, for example, calcium, phosphate and oxalate in the urine. Uric acid is of particular importance, in that not only is it capable itself of precipitating and forming stones, but it also appears to interfere with the action of the organic inhibitors, thereby also predisposing to non-uric acid stone formation. Calcium About 30% of patients with calcium-containing stones will have hypercalciuria (arbitrarily defined as more than 7.5mmol/day in men and more than 6.5mmol/day in women). A minority of these will also be hypercalcaemic because of underlying hyperparathyroidism, sarcoidosis, vitamin D intoxication, milk alkali syndrome, malignant disease or hyperthyroidism. In these cases the objective is to treat the underlying metabolic abnormality, thereby resolving the hypercalciuria. However, the vast majority of hypercalciuric stone formers will be found to be normocalcaemic, and provided there is no identifiable cause for hyperabsorption of calcium by the intestine (e.g. mild vitamin D intoxication), or of renal tubular disorder leading to hypercalciuria (e.g. renal tubular acidosis, high salt intake, chronic furosemide (frusemide) therapy), they are designated as suffering from idiopathic hypercalciuria. Detailed investigation of these patients suggests that they fall into three main groups: • Absorptive hypercalciuria, i.e. primary intestinal hyperabsorption of calcium with compensatory 'spillover' into the urine, leading to hypercalciuria; • Renal hypercalciuria, i.e. primary renal calcium leak with compensatory intestinal hyperabsorption of calcium (rare);

1087

• Resorptive hypercalciuria, i.e. primary acceleration of skeletal resorption with compensatory 'spillover' of calcium into the urine, leading to hypercalciuria. Oxalate There is a positive relationship between urinary oxalate excretion and the likelihood of calcium oxalate stone formation.

Uric acid Hyperuricosuric individuals have a greatly increased incidence of uric acid stone formation and a moderately increased incidence of calcium oxalate stone formation. This association probably reflects interference by uric acid with the action of urinary inhibitors of crystal formation. Cystine Cystinuria is inherited as an autosomal recessive and is

CASE STUDY 20.2 A 63-YEAR-OLD MAN WITH A POOR URINARY STREAM, MALAISE AND ANKLE SWELLING A 63-year-old man presented with increasing malaise, tiredness and mild ankle swelling. Over the past 3 years he had noted a deteriorating urinary stream and an increasing frequency of micturition. Nocturia had been troublesome, and on many occasions over the past 4 months he had noted a tendency to leak small amounts of urine while asleep. Micturition had not been painful and he had not noted an abnormal appearance of the urine.

Questions p 1. What|s the most likelf^ cause of the poor urinary stream? 2. What is the significance of tMe intermittent bed-wettiti| at night? 3. Why has he developed general malaise, tiredness and oedema? I

Discussion This man describes symptoms that should immediately set alarm bells ringing. The story is highly suggestive of slowly progressive bladder outlet obstruction, most likely the result of benign prostatic hypertrophy. The deteriorating urinary stream, increased frequency of micturition and nocturia are all typical of this common condition. Such a patient would normally receive definitive treatment by means of transurethral resection of the prostate gland, and would have few important long-term

1088

sequelae apart from a degree of residual frequency of micturition and retrograde ejaculation. In this case, however, the bedwetting at night points to a more ominous scenario. This symptom is highly suggestive of overflow incontinence, in which the bladder outlet obstruction has become so severe that progressive bladder enlargement has ensued, with increasingly severe back pressure on the kidneys. Physical examination in a patient with overflow incontinence will always reveal a markedly enlarged bladder. Further investigations would usually confirm significant renal damage - plasma urea and creatinine concentrations would be elevated, and imaging of the urinary tract by ultrasound would, in addition to confirming the existence of a grossly enlarged bladder, also demonstrate dilatation of the upper urinary tract with bilateral hydronephroses. This structural damage to the kidneys (obstructive nephropathy) may often be irreversible or only partially reversible. In the case described here the damage has been sufficiently severe to lead to symptoms of the uraemic syndrome - malaise and tiredness. The development of oedema reflects the low glomerular filtration rate and the impairment of salt and water excretion by the damaged kidneys. Other pathologies to be considered include carcinoma of the prostate: any patient with bladder outlet obstruction ascribable to prostatic enlargement should undergo tests to

exclude prostate cancer. Clinical examination may give a clue - the benign prostate is smooth and rubbery to palpation, whereas the malignant prostate is irregular, sometimes nodular, and hard on digital palpation. Prostate-specific antigen (PSA) should be measured in all such patients, and prostatic tissue resected at surgery should always be examined for evidence of malignancy. Investigations in this patient confirmed significant renal insufficiency, with plasma creatinine 460mmol/L and urea 34mmol/L. The haemoglobin was 10.8g/dL with normal red cell indices normochromic normocytic anaemia as seen in chronic disorders, including uraemia. Clinically the prostate felt benign and the PSA was within normal limits. Bladder ultrasound was not performed, the urinary tract having already been drained by a urethral catheter. The initial drainage volume was 950 mL. Ultrasound of the upper urinary tract showed marked bilateral hydronephrosis, with dilatation of the upper ureters. The patient subsequently underwent a transurethral resection of the prostate gland and renal function improved slowly but incompletely: 1 year after the procedure the plasma creatinine and urea were still elevated at 230mmol/L and 15mmol/L, respectively. The patient continued to manifest moderate proteinuria (1.6g/24h), this pointing to residual glomerular damage with hyperfiltration and the likelihood of slowly progressive renal insufficiency - the 'remnant nephropathy' scenario.

associated with elevated excretion of other dibasic amino acids. Cystine stone formation is the only important clinical sequela.

20

Clinical features Presentation is usually with renal or ureteric colic, resulting from partial or complete obstruction to the flow of urine. The pain is usually intense and is nearly always accompanied by haematuria, which may be macroscopic. If the stone has obstructed a single functioning kidney, ARF of postrenal type is inevitable. However, less dramatic presentations are also common, with passage of tiny stones or gravel, usually with some associated discomfort. Symptoms may even be absent, or comprise merely dull backache which may lead to the erroneous diagnosis of a mechanical back lesion. Fortunately, severe permanent renal damage is rare, and arises only when acute infection is present above an obstructing stone (leading to pyonephrosis) or following neglect of an obstructing stone.

Diagnosis and management The diagnosis and treatment of urinary stone falls into an early phase of assessment and management of the immediate problems posed by the stone, and a late phase, concerned with the aetiology of the offending stone and strategy to prevent future episodes. Early Diagnosis is usually easy and is often made on clinical grounds alone. Plain X-ray of the abdomen will reveal the majority of calcium-containing stones, but their location in relation to the kidney and ureter requires an IVU. The IVU will also allow identification of non-radio-opaque uric acid stones, and usually demonstrates the position of the stone and the consequent dilatation of the upper urinary tract above the level of obstruction. Ultrasound examination of the kidney may be helpful in identifying stones within the kidney (Fig. 20.29). Urine should be examined for blood and cultured, and all urine passed should be strained in the hope of catching the stone, which can then be analysed. Renal or ureteric colic requires strong analgesia: opiates should be given promptly and in adequate dosage. The role of 'antispasmodics' such as anticholinergic drugs is not clear, but inhibitors of prostaglandin synthesis (e.g. indometacin [indomethacin]) may be highly effective. A generous fluid intake is maintained and the patient mobilized as quickly as possible. These measures alone will allow spontaneous passage of the stone in many cases. Factors favouring spontaneous passage are small size (<5mm), and location in the lower third of the ureter. Active intervention is required for unremitting obstruction and pain, associated infection, a large stone that is unlikely to pass, and ARF of postrenal type. Intervention may take the form of open surgery (nephrolithotomy or ureterolithotomy), endoscopic snaring from below during

FIG. 20.29 Renal stone Ultrasound examination showing acoustic shadow cast by the stone.

cystoscopy, or percutaneous removal from above via a nephrostomy. Many stones in the kidneys or ureter can be fragmented in situ by external Shockwave lithotripsy (ESWL). Here, appropriately directed ultrasound is used to shatter renal or ureteric stones in vivo, allowing spontaneous passage of the fragments. Late Analysis of the stone is desirable but not always possible. Routine metabolic tests to be undertaken in all cases are: • Plasma calcium, phosphate, alkaline phosphatase, urea, urate, creatinine, electrolytes; • 24-hour urine collection for simultaneous measurement of calcium, uric acid, oxalate, citrate, creatinine and sodium; • Nitroprusside test for cystine. Abnormalities in the initial screen may dictate measurement of serum PTH, fasting urinary calcium excretion, and tests of urinary acidification and plasma 25-hydroxyvitamin D concentrations to exclude vitamin D intoxication. Depending on the results of the above assessment, the following specific measures should be taken (in addition to general advice to achieve fluid intake sufficient to maintain a urine output of at least 2L/day): • Hypercalciuria with hypercalcaemia. Treat underlying cause of hypercalcaemia. • Idiopathic hypercalciuria. Treat with thiazide/amiloride diuretic combinations (both reduce urinary calcium excretion). In selected cases this may be combined with cellulose phosphate given orally (to decrease intestinal calcium absorption), with allopurinol (to reduce urinary uric acid excretion), or with potassium citrate. • Calcium stones with no metabolic abnormality. The patient should avoid excessive oxalate-rich foods (tea, coffee, nuts, spinach, rhubarb). Treatment is with oral potassium citrate. • Uric acid stones. Allopurinol.

1089

TABLE 20.42 Causes of urinary tract obstruction Level of obstruction

Pathophysiology

Any Renal parenchyma Collecting system

Stone, sloughed papilla, blood clot, trauma Uric acid, Bence-Jones' protein, cysts Urothelial tumour, TB, pelviureteric obstruction (stricture, aberrant vessel, fibrous band) Retroperitoneal or pelvic malignancy (carcinoma of bladder, prostate, cervix, rectum, lymphoma, carcinoma of ureter), aortic aneurysm, idiopathic retroperitoneal fibrosis, TB, schistosomiasis, obstetric trauma Benign prostatic hypertrophy, carcinoma of prostate or bladder, neurogenic bladder, TB, foreign body, trauma Urethral valves, phimosis, stricture, meatal stenosis, trauma, foreign body

Ureter

Bladder

Urethra

• Cystine stones. Alkalinize urine with sodium or potassium citrate. Maintain urine flow at 3L/day minimum. Consider penicillamine if the above measures are ineffective. • Struvite stones. Surgical removal is the only effective treatment. • Hyperoxaluria and hypocitraturia. When documented, hyperoxaluria should be countered by a low-oxalate diet and hypocitraturia should be treated with potassium citrate. Dietary calcium restriction is sometimes recommended in patients with calcium-containing stones. However, this therapeutic dogma is of unproven benefit and may in some cases be harmful (predisposing women, in particular, to osteoporosis). A sensible compromise is to limit calcium intake only when excessive, and not to attempt to reduce it below 25 mmol/day (1 g of elemental calcium per day) except in those subjects shown to have absorptive hypercalciuria. 1

URINARY TRACT OBSTRUCTION

Aetiology Some of the main causes of urinary tract obstruction are given in Table 20.42. The clinical presentation is varied and depends on age at onset and the site, severity and rate of onset of obstruction.

Clinical features The following clinical features are important in the assess-

1090

1

MCQ 20.22

4

MCQ 20.24

2

MCQ 20.23

0 Fig. 20.11

ment and management of patients suspected of having an obstructing lesion. It is of the utmost importance that this diagnosis is not missed or delayed, as avoidable or irreversible renal damage may ensue. • Pain. Acute obstruction is usually associated with pain, regardless of the site of the lesion. In contrast, slowly progressive obstructions are likely to be pain-free and hence more likely to cause obstructive renal injury, which may be severe and irreversible by the time the patient seeks help. • Renal failure resulting from obstruction implies that both kidneys are obstructed, or that a solitary functioning kidney is obstructed. • Volume of urine. The fact that a patient is passing normal volumes of urine does not exclude obstruction. Whereas complete obstruction of the urinary tract necessarily causes anuria, the patient with partial obstruction will usually continue to pass normal, or even increased, volumes of urine, at the expense of damaging back pressure on the kidney. • Renal impairment. Because the early recognition and relief of obstruction is so important if unnecessary renal damage is to be avoided, the diagnosis must be considered in all patients presenting with acute or chronic renal impairment. • Urinary infections that are recurrent or difficult to eradicate should raise the suspicion of an anatomical and possibly obstructing lesion.

Effects of obstruction on the kidney The earliest functions to be compromised by progressive obstruction are urinary concentration and acidification, followed by a decrease in GFR. Relief of obstruction may sometimes be followed by temporary concentrating defects, leading to inappropriate salt and water losses.

Diagnosis and management Clinical assessment may reveal symptoms and signs that point to obstruction, and may also indicate its likely site and aetiology. This is particularly so in patients with urethral disease or bladder outflow obstruction. Alternatively, the clinical picture may suggest a disorder known to be associated with urinary obstruction, e.g. carcinoma of the cervix or lymphoma in a patient with unexplained renal failure. Although the existence of obstruction is usually clear-cut, major problems arise in some cases. These fall into three groups. • Is the 'obstruction' significant? The finding of a dilated collecting system does not necessarily imply current obstruction, but may be an anatomical hangover from previous obstruction. • Extent of renal damage. Is renal function likely to improve following relief of the obstruction? This problem arises when, in the presence of clear-cut obstruction, it remains uncertain whether renal damage has

20

FIG. 20.30 Age-adjusted incidence of urinary tract cancer in the UK in 1983

progressed beyond the point where useful recovery of function is likely. A variety of non-invasive and invasive tests can be helpful, but in some cases the answer is only obtained following a trial of palliative drainage by means of a nephrostomy tube or bladder catheter. • Advanced malignancy. Should obstruction be relieved when it is the result of advanced malignancy? Malignant disease is an important cause of obstructive nephropathy (Table 20.42), and in these patients thought should be given to the likely prognosis of the tumour. If this is exceedingly poor, it may be kinder to allow the patient to die in uraemic coma, rather than as a result of uncontrolled pelvic malignancy. Techniques used in the relief of obstruction include surgical bypass or urinary diversion through the skin, direct drainage from above via a nephrostomy tube, or internal stenting of an obstructing lesion. ©

NEOPLASIA IN THE KIDNEY AND URINARY TRACT Cancers of the urogenital tract are common. The agespecific incidence rates for the UK are shown in Figure 20.30. In the kidney, renal cell carcinoma is the most common tumour (75% of cases), with transitional cell carcinoma accounting for 15% of cases. Carcinoma of the prostate is the third largest cause of death from cancer in males.

RENAL TUMOURS Renal adenocarcinoma Renal adenocarcinoma is three times commoner in men and may be related in part to cigarette smoking. It is also

FIG. 20.31 Large renal carcinoma shown by CT scanning The multicystic morphology of the tumour is clearly seen on the anterior border of the right kidney.

commoner in patients with von Hippel-Lindau syndrome (p. 1356). The tumour arises from the renal tubule cells. Lymphatic and haematogenous spread, and local spread through the capsule, mean that 30-40% of patients are inoperable when first seen.

Clinical features 0 Half of the patients have haematuria. Loin pain and an abdominal mass are frequently present. Presentation may also be with bone pain or cough and dyspnoea from metastases. Renal adenocarcinoma may also present with a variety of paraneoplastic symptoms, including fever and night sweats, humoral hypercalcaemia, and polycythaemia due to excess erythropoietin production. Investigation Diagnosis can be difficult if the tumour is small. An IVU may show a space-occupying mass, but a negative X-ray does not exclude a small tumour. Ultrasound is more sensitive and a CT scan is helpful in difficult cases (Fig. 20.31). These techniques have reduced the need for renal angiography. Management and prognosis Surgical resection offers the only hope of cure, but over 30% of renal tumours are inoperable. Opinion is divided as to the extent of the operation. Lymph node dissection is usually carried out. Radiotherapy has a limited role, but is often used if extrarenal extension of the tumour is found at operation. Chemotherapy is of little value. a-Interferon, interleukin-2 and vinblastine may cause regressions, and the tumour may spontaneously fluctuate in size. Although regression of metastases has been seen following removal of the primary, this is a rare event. Of patients with small localized disease, 50% are alive at 10 years. Only 20% of patients with stage II disease (large tumours but no local or node spread) will be alive, and 5% of stage III cases (extracapsular spread). Cancer staging is discussed in Chapter 6, pages 155-157. 4

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Nephroblastoma (Wilms' tumour) Wilms' tumour is an embryonic renal tumour usually found in children, in whom it presents as an abdominal mass. Hypertension is common. Treatment is surgical, with adjuvant chemotherapy and radiotherapy in many cases. The

combined approach has led to major improvements in the prognosis of the neoplasm.

Transitional cell carcinoma of kidney This is a tumour arising from the renal part of the

CASE STUDY 20.3 A SINGLE EPISODE OF PAINLESS HAEMATURIA IN A 58-YEAR-OLD MAN A 58-year-old man presented with a dull ache in the left flank and, on questioning, reported a single episode of red discoloration of the urine approximately 3 months previously. In other respects he had felt well, but for 2 weeks had noted increasing thirst and frequency of micturition. He had been a heavy cigarette smoker for most of his adult life. Examination revealed a healthylooking individual in whom the only abnormal physical finding was a palpably enlarged and moderately tender left kidney. Examination of the urine showed 1+ haematuria on stick testing, with no abnormal proteinuria. Bacteriological culture of a midstream urine was negative.

Questions

1. What is the most likely diagnosis? 2. Is the patient's lifestyle relevant to this diagnosis? 3. What metabolic disturbance is characteristically associated with this diagnosis and how could it be treated?

Discussion The history of painless haematuria and the finding of a palpably enlarged left kidney points to left renal pathology. The most important diagnosis to consider is renal cell carcinoma (Grawitz tumour) or a transitional cell carcinoma of the renal calyces or collecting system. The latter in particular is predisposed to by tobacco use, and in a much smaller number of patients by exposure to aniline dyes or to

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previous cytotoxic chemotherapy with cyclophosphamide. In the Middle East and North Africa chronic infection with Schistosoma haematobium is an important risk factor for urothelial cancer, especially of the bladder. Renal cell carcinoma is often associated with humoral hypercalcaemia of malignancy, in which tumour-derived PTH-rp acts on parathyroid hormone receptors to elevate the plasma calcium concentration. The diagnosis of renal malignancy depends on adequate imaging. In this case kidney ultrasound would be undertaken first, and the presence of a single or multiple solid lesion(s) within the kidney would point strongly to tumour. Further imaging would be undertaken by CT scanning, chest Xray and radioisotope bone scanning. Treatment would usually comprise surgical resection (radical nephrectomy in the case of adenocarcinoma of the kidney, and radical nephroureterectomy in the case of transitional cell tumours), with adjunctive chemotherapy in some cases. Other important diagnoses to consider are cystic disease of the left kidney and obstructive hydronephrosis. Renal cysts, the majority of which are 'morphologically simple' and benign (but occasionally malignant), may become very large and also have the potential to cause macroscopic haematuria. Renal cysts are easily diagnosed by ultrasound and, depending on the appearances of the cyst and the perceived likelihood of malignancy, the cyst fluid may be aspirated for cytological examination.

Polycystic kidney disease (dominant inheritance) is never unilateral and so should not be a source of confusion. Painless renal enlargement due to obstruction may reflect a pelviureteric junction stricture (PUJ obstruction), or ureteric obstruction further downstream as a result of retroperitoneal disease (malignancy, retroperitoneal fibrosis, for example), or a primary urothelial tumour located in the ureter itself. Obstruction from stone is usually painful, although not always. In this patient ultrasound examination revealed a 7 x 5 cm mass in the left kidney. CT scanning of the upper abdomen and chest confirmed the existence of the mass and revealed no evidence of extrarenal spread. The plasma calcium in this patient was 3.3 mmol/L, with plasma creatinine 114umol/L and urea 15 mmol/L. In the context described here, hypercalcaemia of malignancy is suggested, probably humoral mediated by parathyroid hormonerelated peptide (PTHrp). This would explain the polydipsia and polyuria. Disproportionate elevation of urea relative to creatinine points to renal insufficiency of prerenal type - water depletion in this case is caused by hypercalcaemia-induced nephrogenic diabetes insipidus. Treatment should comprise volume expansion and intravenous pamidronate. PTH was low, reflecting suppression of the parathyroid glands by the hypercalcaemia. The patient underwent a radical left nephrectomy and 2 years later remained well, with no evidence of tumour recurrence or metabolic disturbance.

transitional cell epithelium (urothelium) and, like bladder cancer, it is strongly associated with cigarette smoking. The main symptoms are haematuria and renal pain, often with unilateral obstruction. The IVU shows a filling defect in the collecting system and the kidney may be obstructed. Cytological examination of the urine reveals malignant cells in 50% of cases. Treatment is by nephroureterectomy where possible. Because the whole urothelium is unstable, stump recurrences are quite common. Radiotherapy may slow local progression but is not curative.

Transitional cell carcinoma of the bladder Transitional cell carcinoma of the bladder was shown to be more common in workers in the aniline dye industry. The carcinogen was identified as b-naphthylamine. The tumour is also more common in the rubber industry, and in cigarette smokers. Worldwide, the major predisposing cause is bladder schistosomiasis (p. 370). Staging The staging notation (Fig. 20.32) is based on the mode of spread through the bladder wall.

Clinical features and investigation The major symptom is haematuria, which is usually painless. Urinary frequency, nocturia and back pain may all occur. Diagnosis is by cystoscopy. An IVU is essential to show renal anatomy, and simple renal function tests should be performed. Lymphography and CT scanning are increasingly used in staging.

20

Management Small superficial lesions are treated transurethrally by cystodiathermy, and intravesical chemotherapy is increasingly being used. Up to 15% of such patients will develop more generalized intravesical recurrence, requiring surgery. For more advanced (T2-T3) tumours, treatment is with surgery or radical radiotherapy or a combination of the two. Partial cystectomy may be possible in some cases, but in others total cystectomy (with an ileal conduit for the ureters) may be needed. Recently, several studies have shown that radical radiotherapy produces results as good as radical cystectomy. Chemotherapy is increasingly used in advanced and metastatic disease, with long survival in a minority of patients.

Carcinoma of the prostate The age-specific incidence of this very common cancer is shown in Figure 20.30. In the last 50 years, mortality from this disease has increased in the UK. Little is known of its aetiology. The tumour is nearly always an adenocarcinoma. The majority are well-differentiated cancers, anaplastic tumours being only 15% of the total. The tumour grows in the gland (T1/T2) and then invades the capsule (T3) and, finally, adjacent structures (T4). Spread is to regional lymph nodes and then to bone and lung.

FIG. 20.32 Staging of bladder cancer T1 tumours involve the bladder mucosa. T2 tumours involve the superficial muscle (dashed line), T3a extend into deeper muscle, and T3b involve the whole wall. T4a tumours invade the prostate (or vagina), and T4b the rectum and pelvic wall. (After: Blandy J P 1986 Operative urology. Blackwell Scientific, Oxford.)

Clinical features and diagnosis The tumour is often asymptomatic and may be diagnosed on rectal examination for some other reason. The commonest local symptoms are related to bladder outflow obstruction or infection, but presentation with backache from metastases is also frequent. Measurements of serum prostate-specific antigen (PSA) are useful for diagnosis and treatment monitoring. Its role in screening is controversial. Although there is no doubt that the serum PSA can detect asymptomatic ('preclinical') cancer, it is not clear whether early diagnosis has a useful bearing on morbidity or mortality. The argument hinges on the best management for early disease: in the USA, radical prostatectomy (significant morbidity from impotence and incontinence) is favoured, whereas in Europe management is more symptom-orientated and therefore less influenced by early diagnosis in asymptomatic cases. Histological confirmation may be obtained by biopsy, usually taken transrectally, or from curettings taken at transurethral prostatectomy. Further staging will include a chest X-ray

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CASE STUDY 20.4 HAEMATURIA AND RIGHT LOIN PAIN IN A 35-YEAR-OLD MAN A 35-year-old man presented with an abrupt onset of very severe right loin pain with macroscopic haematuria. He had experienced a series of similar episodes over the preceding 15 years and all of these had been ascribed to the presence of kidney stones. On all but two occasions the stones had passed spontaneously, but when he was aged 22 a ureteric stone required endoscopic removal, and 2 years ago a large stone in the right kidney was disintegrated using extracorporeal Shockwave lithotripsy. He had been told that, apart from maintaining a high fluid intake, there was little that could be done to prevent further episodes of stone formation. Questions 1. What is the most likely reason for his recurrent stone formation? 2. Was the advice given appropriate? 3. What investigations and management are required, (a) to assess and resolve the acute episode, and (b) to identify the best preventative strategies for the future? Discussion The history is strongly suggestive of acute ureteric obstruction, probably by stone. Added weight is given to this view by the extensive history of recurrent episodes of stone formation. The immediate priorities are to establish the diagnosis with certainty and to administer appropriate (and almost invariably strong) analgesia the pain of acute ureteric obstruction is characteristically extremely severe. Pain relief is best achieved using a combination of an NSAID (intramuscular diclofenac is commonly used) together with opiate analgesia if required. Imaging by ultrasound, and if necessary by intravenous urography, usually establishes the diagnosis satisfactorily. A plain X-ray of the abdomen may reveal an opacity overlying the

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kidney or in the line of the ureter, but confirmation that this is an obstructing stone requires intravenous urography - IVU. Complementary information can also be obtained by ultrasound, which will reveal obstruction of the kidney if present, and may also demonstrate acoustic shadow from a stone. Obstructing renal and ureteric stones frequently pass spontaneously - the smaller the stone and the lower its position in the ureter the more likely is spontaneous passage to occur. Active measures to remove the stone may comprise one or more of endoscopic snaring from below via a cystoscope, percutaneous removal directly from the renal pelvis, or extracorporeal Shockwave lithotripsy. In this patient plain radiographs showed a 0.6cm opacity in the line of the right ureter just below the level of the pelvic brim. Ultrasound examination showed moderate hydronephrosis of the right kidney, with normal appearances on the left and no bladder enlargement. IVU confirmed normal appearances on the left, with greatly delayed appearance of contrast material on the right. Hydronephrosis was confirmed and the opacity was seen to lie in the right ureter. The patient was observed for 48 hours and given strong analgesia. Because a follow-up X-ray showed no further movement of the stone, it was removed endoscopically from below. Following resolution of the acute episode, this patient requires screening for metabolic predispositions to stone formation. These can be identified in a large majority of patients with recurrent stone formation, most of whom have normal plasma biochemistry and the abnormalities are found in the urine. If available, the stone should be subjected to biochemical analysis. Metabolic assessment of the urine is conducted on 24-hour specimens and is designed to exclude cystinuria (nitroprusside test) and to quantify the excretion rates of calcium, oxalate and urate - increased output of any of these predisposes to stone

formation. In addition, the urine citrate output should be measured: citrate is an important inhibitor of stone formation and hypocitraturia is a potent risk factor for the development of calcium-containing stones. Identification of the relevant risk factor allows targeted therapy, in addition to general advice to maintain a high fluid intake. Blood biochemistry assessment is usually less rewarding - hypercalcaemia and metabolic acidosis, if present, both predispose to stone formation, but note that hyperuricaemia does not, unless accompanied by hyperuricosuria. Hypercalciuria is managed by a reduction of dietary calcium intake if excessive (a low-calcium diet confers no additional benefit), reduction of dietary sodium intake (a high salt intake increases calciuria), and hypocalciuric diuretic agents (thiazides and amiloride, conveniently given as co-amilozide). These measures effectively reduce urine calcium output in most hypercalciuric stone formers and substantially reduce the frequency of stone episodes. Note that loop diuretics (furosemide (frusemide) and bumetanide) increase calciuria. Hyperuricosuria is treated with allopurinol, hyperoxaluria by dietary adjustment to avoid oxalate-rich foods, and hypocitraturia by oral supplementation with potassium citrate. In this patient the urine calcium output was elevated at 13.7 mmol/ 24 h, and urine citrate markedly reduced at 0.8mmol/24h. In the first instance treatment comprised coamilozide (hydrochlorothiazide plus amiloride combination). The urine was reassessed 2 months later, at which time the measured calcium output had fallen to 7.9mmol/24h just above the upper limit of normal. Citrate output remained low and long-term therapy with potassium citrate was added to the prophylactic regimen. Sixteen months later the patient remained clinically well and plain abdominal radiographs showed no evidence of new stone formation.

and bone scan. An IVU may show back pressure effects on the bladder and kidneys. Management For localized small tumours, both radical prostatectomy and radical radiotherapy have been used. With radical treatment 30-40% of patients will be alive at 10 years, the proportion falling if there is extracapsular extension of the tumour. The mainstay of treatment is hormone manipulation, using the inhibitor of LH release, buserelin or diethylstilbestrol. For more advanced disease, radiotherapy may palliate both local symptoms and symptoms from bone metastases.

some cases further investigations are needed to define the potential for pharmacological, urological or neurological treatment. Measurement of urine flow rate during the voiding phase is valuable in the assessment of bladder

20

CONTINENCE AND INCONTINENCE NORMAL MICTURITION Functionally, micturition occurs in three phases: • Bladder filling • Postponement, comprising perception of the need to void; movement to a suitable place to void; adoption of voiding posture • Voiding of urine. Thus, micturition may be disturbed by intrinsic disease of the bladder or its outlet, disordered afferent or efferent nerve supply of the bladder, spinal cord lesions, intracranial disease, psychological disturbance or locomotor disturbance. Neuropathic bladder is a widely used (and abused) term denoting no more than bladder dysfunction resulting from any type of neurological disturbance; it implies nothing about the nature of that neurological disturbance. The detrusor muscle of the bladder (parasympathetic innervation) and the bladder outlet (sympathetic innervation) act in a coordinated fashion, such that outflow resistance is high and detrusor tone low during filling. When the bladder is full and voiding is appropriate, micturition is accompanied by simultaneous contraction of the detrusor (mediated by increased parasympathetic activity) and relaxation of the bladder outlet (mediated by decreased sympathetic and pelvic floor activity) (Fig. 20.33). This is coordinated by a micturition centre in the brainstem, which is itself subject to a degree of cortical control (Fig. 20.34).

INCONTINENCE Many of the causes of incontinence also result in a reduced functional bladder capacity which, of necessity, leads to frequency of micturition and/or nocturia (p. 1046). The history and examination often yield a diagnosis, but in

FIG. 20.33 The micturition cycle Bladder emptying occurs at any time when bladder pressure is greater than urethral pressure (shaded area). During filling - (A) to (B) - bladder pressure rises little. Initiation of micturition at points (B) and (F) leads to a synchronous increase in bladder pressure and decrease in urethral pressure until, at (C), emptying begins. When emptying is complete (D), bladder and urethral pressures revert - points (A) and (E) - and filling resumes. (After Yeates WK in Hinman F (ed) 1983 Benign prostatic hypertrophy. Springer-Verlag, New York.)

FIG. 20.34 Neurological control of micturition The sympathetic efferent relaxes the detrusor muscle of the bladder and constricts the bladder outflow. The cholinergic efferent promotes contraction of the detrusor muscle. The pelvic nerve supply to the external sphincter stimulates further constriction of the bladder outflow. (After Yeates WK in Hinman F (ed) 1983 Benign prostatic hypertrophy. Springer-Verlag, New York.)

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outflow obstruction. An IVU or ultrasound is often needed to determine the effects of the disordered bladder function on the upper urinary tract and kidneys. Residual urine after micturition can be demonstrated by IVU and/or ultrasound. Cine cystography shows the relevant anatomy during bladder filling and emptying, and may be combined with simultaneous pressure measurements to give a filling and voiding cystometrogram.

Stress incontinence Stress incontinence is the involuntary passage of urine when intra-abdominal pressure is raised, as in coughing, lifting, standing up etc. In the main it is a disease of women, in whom pelvic floor laxity, often the result of pregnancy and/or childbirth, compromises the closure of the bladder outlet. There is no neurological defect. The dysfunction should be confirmed by performing a cine voiding cystometrogram. Treatment with pelvic floor exercises may be effective, and some patients are improved by a-agonist drugs, such as phenylpropanolamine. However, surgical intervention is often needed and is usually effective.

Urge incontinence In urge incontinence the perception of the desire to void is followed within seconds or minutes by voiding, even though the patient attempts to delay it. Voiding is usually complete. This problem may reflect: • Increased afferent stimulation from local disease, e.g. infective cystitis, bladder tumour, bladder hypertrophy; • Failure of central inhibition, e.g. multiple sclerosis, cerebrovascular disease, cerebral tumour, spinal cord lesion; • Cortical stimulation, e.g. incontinence provoked by the sound of running water. In many female cases there is no detectable organic cause of incontinence (idiopathic 'bladder instability'). Sacral reflexes are preserved, and so usually is sacral sensation and voluntary control of the anal sphincter. Instability of the detrusor muscle is usually demonstrable in the neuropathic group. Treatment should be directed at the underlying pathology when feasible. Pharmacological attempts to decrease detrusor hyperexcitability using anticholinergic drugs (e.g. propantheline), tricyclic antidepressants or calcium channel blockers (e.g. nifedipine) are sometimes successful. In severe cases of neurological origin in women (particularly multiple sclerosis), the bladder activity may be greatly reduced by the injection of phenol into the pelvic autonomic nerves through the bladder base.

Reflex incontinence Reflex incontinence is where voiding occurs periodically without advance warning. The most important causes are spinal lesions above the level of the sacral outflow. Depending on the severity of the spinal lesion, neurological examination may show exaggerated sacral reflexes, a perianal sensory deficit and/or impairment of voluntary sphincter control. The interruption, not only of central inhibition but also of coordination, leads to detrusor hyperexcitability coupled with failure to relax the bladder outlet, a potentially dangerous combination that results in a highpressure bladder and the risk of renal damage. Adequate decompression, by reducing the resistance of the bladder outlet, is essential in these cases. Sometimes this can be achieved pharmacologically by a-adrenergic blocking drugs, such as phenoxybenzamine, or by endoscopic resection of the bladder neck and/or the external sphincter. The absence of bladder sensation, however, precludes the restoration of bladder control. In these circumstances male patients nearly always require incontinence appliances. Female patients require continuous or intermittent catheterization, and it is sometimes necessary to divert the urine by means of an ileal conduit.

Overflow incontinence Overflow incontinence usually manifests itself with leakage of small amounts of urine, initially often at night only. The symptom is often quite subtle, but it is important to recognize it because of the severe obstructive renal damage that usually ensues if the condition is neglected. The incontinence is always associated with a residual urine volume approaching that of the bladder capacity, usually resulting in a manifestly distended bladder. It is most often seen in a man with prostatic hypertrophy causing outflow obstruction. Other cases result from neurological lesions, either as an acute condition in spinal shock, or as subacute or chronic bladder dysfunction from prolapsed intervertebral disc, sacral plexus lesions or autonomic neuropathy (diabetes mellitus, tabes dorsalis) that decreases normal detrusor excitability. The urinary stream is slow. Treatment is directed at correction of the mechanical outlet obstruction, e.g. by prostatectomy. In some neuropathic cases a-blocking drugs (phenoxybenzamine, prazosin), or endoscopic resection or incision of the bladder neck or external sphincter, may improve matters by reducing outlet resistance. The outlook in those patients with local mechanical causes that increase bladder outlet resistance (e.g. prostatic hypertrophy) is usually excellent, whereas the prognosis in the long-standing neuropathic group is usually poor.

Enuresis 1

1096

MCQ 20.25

Enuresis denotes bed-wetting in, or beginning in, childhood, though strictly it means merely the voiding of urine. Bed-wetting is universal in infancy and affects

about 50% of children at age 3, and about 15% at age 10. It is commoner in children with psychological problems and in those with organic diseases of the kidney and/or urinary tract. Primary nocturnal enuresis (i.e. present from birth) does not usually require detailed investigation, provided that daytime micturition is normal and there is no evidence of present or past infection, or of urinary tract obstruction. Treatment, in the absence of associated abnormalities of the urinary tract, may involve bladder training, with voluntary postponement of voiding by day, or alteration of sleep pattern by means of a bell set to sound when the child wets a sensor pad in bed. The tricyclic antidepressants (e.g. imipramine) are effective in many cases, probably by multiple actions on the depth of sleep and on the detrusor muscle. An alternative approach is to give the vasopressin analogue desmopressin intranasally last thing at night. This decreases urine output during the night and is successful in selected patients.

TABLE 20.43 Therapeutic considerations in renal disease

20

Pharmacological consideration Example Decreased therapeutic efficacy Target organ resistance Diuretics less effective in patients with renal disease Failure of diseased kidney Vitamin D not bioactivated to 1,25(OH)2D to bioactivate agent in severe renal disease Increased nephrotoxicity

X-ray contrast media, aminoglycoside antibiotics more nephrotoxic to previously damaged kidneys

Decreased excretion of drug or metabolite

Digoxin, many antibiotics

Incontinence in the elderly The overall problem of incontinence in the elderly is considerable. It has been estimated to afflict 5-15% of the elderly in the general population, and many more in institutions. The mechanism is often multifactorial, particularly neuropathic; however, in depressed or demented patients it may include loss of the will to be continent, and loss of appreciation of what is a socially acceptable micturition site. Treatment is similar to that in younger patients, but therapeutic options may be constrained by drug sideeffects or unacceptable risks of surgery. As a result, relatively more of the elderly will require palliation in the form of incontinence appliances, pads or indwelling catheters. The latter, though an easy option for the doctor and nursing staff, should be avoidable in most cases. More detailed discussion is given in Chapter 7. O

FIG. 20.35 Effect of changes of GFR on the elimination of different drugs Drug A is cleared by both the kidney and the liver, and drug B by the kidney alone. Drug C is cleared by the liver alone; its clearance rate is unaffected by changes in the GFR.

PRESCRIBING IN PATIENTS WITH

RENAL DISEASE The extensive renal excretion of therapeutic agents and their metabolites means that the prescription of drugs to patients with renal disease must often be modified with regard to both the choice of drug and its schedule of administration. The main considerations (Table 20.43) are: • Decreased therapeutic efficacy • Increased nephrotoxicity • Decreased excretion of drug or metabolite. Thus, some agents may have to be given in unusually large doses to patients with renal disease (e.g. diuretics), whereas others require dose reduction (e.g. digoxin) or should not be given at all if the risk of toxicity is too high.

Body clearance As applied to a particular drug, body clearance is the sum of the clearances (i.e. hepatic, renal, skeletal, muscle etc.) of that agent in all organs contributing to its removal. When the kidney is the sole route of exit the renal clearance approximates the body clearance, whereas in the case of the drug that is removed exclusively by hepatic metabolism, the hepatic clearance approximates the body clearance and the renal clearance is zero. The effect of decreasing GFR on body clearance of different types of drug is illustrated in Figure 20.35.

Principles of dose modification The decision to reduce the dose of a drug is based on both

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its potential to accumulate in renal failure and the potential for toxicity if accumulation occurs. Drugs with a very high therapeutic index (e.g. penicillin) require dose modification only if very large doses are being given, or if renal function is near zero. Conversely, drugs with a low therapeutic index (e.g. digoxin or aminoglycoside antibiotics) require dose modification even in the presence of slight impairment of renal function. Depending on the pharmacokinetics of the drug, dose

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reduction may take the form of normal dose/increased dose interval, reduced dose/normal dose interval, or a combination of the two. Appropriate modification can be aided by tables, nomograms and monitoring. In practice, tables and nomograms, used with an understanding of the relevant pharmacology, allow an educated guess of the correct dosage to be made; and subsequent monitoring of plasma concentrations of the drug helps to guide further dose adjustments.

21

Salt andWater

Homeostasisand Acid-BaseBalance Disorders of water homeostasis 1101 Disorders of sodium homeostasis 1107

WATER HOMEOSTASIS Total body water is maintained primarily through the action of antidiuretic hormone (ADH), also called arginine vasopressin (AVP), and by the sensation of thirst (Fig. 21.3).

Antidiuretic hormone

John P Monson

Water and sodium homeostasis 1099

losses are frequently accompanied by loss of water, the osmolar changes will be slight and marked changes in intracellular volume will not occur. Net water loss will, however, result in an increase in extracellular osmolality, consequent free diffusion of water from the intracellular space, and therefore loss of water from all compartments.

Potassium homeostasis 1110 Acid-base homeostasis 1113 Investigation of acid-base status 1114 Acid-base disorders 1114

WATER AND SODIUM HOMEOSTASIS Total body water and sodium are maintained within narrow limits by neural and hormonal homeostatic mechanisms which ensure that water and salt intake and excretion are equal. Disease states may perturb salt and water balance either by exerting direct effects on one or more of these homeostatic mechanisms or by altering water or sodium loss or intake. The distribution of water between intracellular and extracellular fluids depends on the osmolality of the two compartments (Fig. 21.1). Sodium is quantitatively the most important extracellular cation and, as 80% of total sodium is present in the extracellular space owing to active sodium-potassium (Na+/K+ ATPase) and sodium-hydrogen ion exchange across cellular plasma membranes (Fig. 21.2), the extracellular osmolality is determined primarily by the molar concentrations of sodium and its anion equivalents, chloride and bicarbonate. It follows that extracellular fluid volume is largely dependent on the total body sodium. This applies to both intravascular and interstitial spaces, although the water distribution between these two components of extracellular space is further dependent on the osmotic effects of plasma proteins (oncotic pressure) and on hydrostatic pressure. Net sodium loss will result in shrinkage of both interstitial and intravascular volumes, but because such

The net change in osmolality that follows any tendency to total body water deficit constitutes the most important stimulus to the secretion of ADH by neurosecretory cells in the supraoptic and paraventricular nuclei of the hypothalamus. Sensitive receptors which mediate this phenomenon are localized primarily in the hypothalamus. These osmoreceptors are particularly sensitive to increased sodium concentrations, but less so to glucose or urea. Additional receptors, present in capacitance vessels near the heart and in the left atrium, mediate ADH release in response to vascular volume changes independently of changes in osmolality. This mechanism is less sensitive than that mediated by osmolar changes, but will override the osmolar modulation of ADH secretion when circulating volume is decreased for any reason. ADH release may also be influenced by circulating angiotensin II, catecholamines and endogenous opiates. ADH formed in the hypothalamus is transferred, as secretory granules, along the axons of the neurosecretory cells to the posterior pituitary, where it is released into the circulation in response to the stimulation of osmo- or volume receptors. The major sites of action of ADH are the V2 receptors in the distal tubules and collecting ducts of the kidney. Permeability to water is increased by a cyclic AMP-mediated phosphorylation mechanism, and water reabsorption occurs by virtue of medullary hypertonicity achieved by means of the countercurrent system. In addition to its effect on the kidney, ADH may have a regulatory role in glucose and urea production in the liver. The latter is of particular interest in view of the importance of urea in maintaining renal medullary hypertonicity.

The sensation of thirst The sensation of thirst is mediated predominantly by hypothalamic osmoreceptors distinct from, but in close proximity to, those subserving ADH secretion. Vascular volume receptors may also contribute. However, except when water supplies are limited, much of everyday fluid intake occurs out of habit or on a social basis. For this reason, urine flow rates are generally far in excess of, and

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Extracellular Mag.(O.8) Calc.(2.5) CI(100) HCO 3-(25) PO42-(1.0)

FIG. 21.1 The distribution of total body water Osmolality is equal in all compartments.

urine osmolality lower than, the values found when a significant degree of renal concentration occurs as a result of the action of ADH. Ageing is associated with a modest reduction in thirst sensation; under conditions of regular habitual and social fluid intake, this is not clinically important. Normal pregnancy results in a reduction in thirst threshold (so that thirst is perceived at a lower plasma osmolality) and a parallel reduction in the osmotic threshold for vasopressin secretion, the net effect being a fall in plasma osmolality of approximately l0mmol/kg during the first trimester, which persists throughout pregnancy.

FIG. 21.2 The intra/extracellular ion distribution Concentrations in mmol/L are shown in parentheses and those for calcium indicate the total of ionized and un-ionized. The solid arrows represent active transport mechanisms and the broken arrows passive diffusion, which depends on the electrochemical gradient.

SODIUM HOMEOSTASIS Sodium is lost to the body in cutaneous sweat and, via the kidney, in the urine. The former cannot be regulated and is determined solely by environmental conditions. Approximately two-thirds of sodium filtered by renal glomeruli is reabsorbed in the proximal renal tubule, but regulation of sodium excretion depends on the modulation of sodium reabsorption by the ascending limb of the loop of Henle and by the distal tubule. Maintenance of a constant total body sodium in the face of wide variations in sodium intake is therefore entirely dependent on appropriate variations in the rate of renal sodium excretion. This can achieve a constant total body sodium when daily intake ranges from 20 to several hundred millimoles. However, this mechanism is incompletely understood. There is evidence for an intrarenal feedback loop between the macula densa cells of the ascending limb and glomerular pressure, such that tubular sodium concentration may partly determine glomerular filtration rate. Changes in adrenal aldosterone production, dependent on the renin-angiotensin system (p. 1081), are undoubtedly important in the regulation of active sodium reabsorption

1

1100

MCQ21.1

FIG. 21.3 Determinants of total body water balance Water intake is initiated by habit and thirst. Total body water is maintained at a constant level by the thirst mechanism and by ADH modulation of renal water excretion; denotes inhibition.

in exchange for potassium and hydrogen ions in the distal tubule. These mechanisms alone cannot explain the observed capacity for variation of renal sodium excretion, however. At least two additional mechanisms may be important in determining this. First, vascular receptors can sense changes in circulating volume and mediate the secretion of a circulating peptide, atrial natriuretic peptide (ANP), produced in the atrium, which promotes renal sodium excretion. It would appear that secretion is stimulated by atrial stretch receptors activated by increases in blood volume due, for example, to increased sodium intake, congestive cardiac failure or renal failure. The precise mechanism of action of ANP is not known; specific receptors have been identified in glomeruli, the renal medulla and collecting ducts. Its actions probably involve an increase in both renal blood flow and glomerular filtration rate, together with inhibition of the renin-angiotensinaldosterone system. ANP also has a vasodilatory action. In addition, ouabain-like substances which inhibit renal Na+/K+ ATPase are candidates as regulators of renal

SUMMARY 1 Indicators of disturbed sodium and water homeostasis Sodium and water retention • • • •

Raised venous pressure Weight gain Oedema Chest radiography (information on cardiac status)

Sodium and water depletion • • • •

Postural hypotension Weight loss Skin turgor and intraocular pressure (unreliable) Reduction in urine output (if profound salt and water depletion)

DISORDERS OF WATER HOMEOSTASIS

21

In some pathological conditions dramatic changes in total body water may occur with little or no alteration in total body sodium or potassium; in others, water loss may be accompanied by significant losses of electrolytes. Even in the latter circumstance, however, the water deficit will usually be relatively greater than the sodium deficit, which has important implications for the interpretation of plasma sodium estimations (p. 1110).

WATER DEPLETION sodium excretion; biochemical characterization and the precise mode of action remain to be elucidated. Renal sodium handling is also influenced by locally produced prostaglandins, dopamine and bradykinin; the algebraic summation of these effects remains unclear.

CLINICAL ASSESSMENT OF WATER AND SODIUM BALANCE Derangements of sodium and water homeostasis are often obvious from the clinical history which may, for example, indicate abnormal losses of fluid and electrolytes from the gastrointestinal tract. Alternatively, symptoms of oedema or orthopnoea may suggest circulatory overload or heart failure. Primary derangements in sodium balance alter the extracellular fluid volume and thus give rise to early alterations in circulating volume and consequent physical signs. Mild to moderate changes in water balance, on the other hand, are borne by intra- and extracellular compartments and are less obvious clinically. As a general principle, expansion or contraction of the circulating volume may be determined by examination of the jugular venous pressure (low in sodium depletion, raised in sodium excess) and of the lying and standing blood pressure (postural drop in sodium depletion). Peripheral oedema may also indicate a sodium-retaining state (p. 1107). Estimating the state of hydration by clinical assessment of skin turgor or intraocular pressure is unreliable. Daily weighing, on the other hand, provides a sensitive index of changes and is often used to monitor intensive diuretic therapy. Further investigation of the patient's circulating volume and cardiac status may include chest radiography, which will demonstrate cardiac enlargement and pulmonary venous congestion in heart failure, and the measurement of central venous or left atrial (pulmonary artery wedge) pressure. Profound sodium and water depletion results in a reduction in urine output. The distinction between this prerenal oliguria and renal failure is discussed on page 1110.

Water depletion may occur: • As a result of failure of renal concentrating capacity; • By obligatory insensible water loss (through the skin, lungs, and as concentrated urine) in situations when oral fluid intake is inadequate; • Via the kidney, when osmotically active solutes are present in tubular fluid in increased quantity; • Via the gut; • By increased pulmonary loss in acute respiratory disease. Because water depletion is borne by both intra- and extracellular compartments, the physical signs of fluid depletion may not be marked and, in particular, signs of reduced circulating volume occur late. With a severe reduction in total body water, a decreased level of consciousness is common and may persist for a considerable time after the deficit has been corrected. Severe water depletion results in both extra- and intracellular hyperosmolality (the rise in intracellular osmolality being highest in the central nervous system) and an increased risk of intravascular thrombosis. Water depletion is accompanied by a rise in plasma sodium.

DIABETES INSIPIDUS This condition arises when the kidneys lose - usually partially - the capacity to produce a concentrated urine. The classic presentation is with excessive thirst (polydipsia) and the passage of large volumes of dilute urine (polyuria). The history is usually short, although a mild failure of concentrating capacity may be present for months or even years prior to diagnosis.

Causes Diabetes insipidus occurs as a result of either deficiency of ADH secretion or failure of ADH action at renal tubular level. Important causes are listed in Table 21.1. In cranial or neurogenic diabetes insipidus, postsurgical and so-called

1101

TABLE 21.1 Causes of diabetes insipidus Example/comment

Cause Cranial (neurogenic) diabetes insipidus Idiopathic Familial

Postsurgical Traumatic Tumours

] j

(Some autoimmune) Autosomal dominant Autosomal recessive and including one or more of diabetes mellitus, optic atrophy, high tone deafness (DIDMOAD syndrome) May be temporary Pituitary adenoma (very rare as a presenting feature) Craniopharyngioma Dysgerminoma rare hypothalamic Teratoma tumours Secondary carcinomas, esp. lung, breast Sarcoid TB

Granulomata Inflammatory/neoplastic Infections Vascular Nephrogenic diabetes Familial Hypercalcaemia Hypokalaemia Drug-induced

Langerhans' cell histiocytosis Lymphocytic hypophysitis Meningitis/encephalitis e.g. Sheehan's syndrome - postpartum pituitary infarction (now rare) insipidus X-linked recessive Malignancy, hyperparathyroidism Diuretic therapy, Conn's syndrome Lithium salts Demethylchlortetracycline

Investigation of polyuria and polydipsia

idiopathic causes are by far the most common. There is now considerable evidence that a proportion of apparently idiopathic examples are in fact due to autoimmunity and fit into the spectrum of organ-specific autoimmune diseases, which include autoimmune thyroiditis, adrenalitis, pernicious anaemia, ovarian failure and some cases of diabetes mellitus. Pituitary adenomas very rarely present with diabetes insipidus and, as a result of improvements in obstetric care, postpartum pituitary infarction is now rare. Diabetes insipidus secondary to pathological processes affecting the neurohypophysis, but sparing the pituitary stalk and neurosecretory cells, is frequently transient. As adequate glucocorticoid is essential for water excretion, adrenocorticotrophic hormone (ACTH) deficiency may mask associated diabetes insipidus. The latter condition only becomes clinically evident when steroid replacement therapy is begun. Failure of ADH action on renal tubules (nephrogenic diabetes insipidus) may occur as a primary inherited disorder, as a consequence of certain drugs, or secondary to

1 1102

MCQ 21.2

& CD Case 21.1 3

hypercalcaemia or hypokalaemia (see Table 21.1). Familial nephrogenic diabetes insipidus is a rare X-linked recessive condition that presents in infancy. The underlying mechanism may either be an inactivating mutation in the renal tubule ADH V2 receptor, or in postreceptor activity. The disease is fully expressed in males inheriting the affected X chromosome, but subclinical defects in renal concentrating capacity may be found in female carriers. Common drug-induced causes of failure of renal concentrating ability include lithium salts (used to treat manic-depressive disorders) and the long-acting tetracycline demethylchlortetracycline. This action of demethylchlortetracycline is used to treat the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) typically found in small-cell lung cancer. These agents probably produce their effects by impairing ADH-induced cyclic AMP formation in renal tubular cells. Hypercalcaemia reduces renal concentrating capacity by inhibiting chloride transport in the loop of Henle, with a consequent reduction in medullary hypertonicity, and by inhibiting the action of ADH on renal tubular cells. These effects may be marked in severe hypercalcaemia, and contribute to the vicious circle of dehydration and accelerating hypercalcaemia that may develop. Chronic hypokalaemia may produce the same effect, although usually to a lesser extent. O

Fig. 21.1

The approach to this combination of symptoms is outlined in Figure 21.4. Prolonged water deprivation is usually unnecessary, it being sufficient to continue only until 2hourly measurements of osmolality have reached a maximum (normally achieved within 8 hours). It is important that the patient is weighed at hourly intervals and that the test is discontinued if weight loss exceeds 3% of total body weight. The latter outcome is virtually diagnostic of diabetes insipidus. Renal responsiveness to ADH is tested with an intranasal test dose (20-40 ug) of the synthetic ADH V2 receptor analogue desmopressin (1-desamino8-D-arginine vasopressin, DDAVP). Urine osmolality is measured in all specimens passed in the ensuing 9 hours. The most difficult distinction to make is that between partial degrees of diabetes insipidus and compulsive water drinking. The latter, which represents an extreme of habit-mediated fluid consumption, results in renal medullary hypotonicity and a consequent secondary renalconcentrating defect. Some assistance in diagnosis may be provided by the plasma osmolality (or plasma sodium), which is characteristically less than 290mmol/kg at the start of water deprivation in compulsive water drinkers (because of some degree of overhydration), but is frequently higher than normal in partial diabetes insipidus, because of water depletion. When the history and preliminary investigations still fail to distinguish between these possibilities, there is a place for measurement of plasma ADH (by radioimmunoassay) in response to a continuous intravenous infusion of hypertonic saline. In this test,

thereby ensuring that fluid intake is adequate and that overhydration and consequent intra- and extracellular dilution are avoided. Difficulties may arise with hypothalamic disorders that interfere with normal thirst mechanisms as well as ADH production. In these situations a fixed regimen of fluid intake, regular weighing and a carefully titrated dose schedule of desmopressin must be provided. Failure to maintain fluid intake in the presence of adipsia and diabetes insipidus exposes the patient to severe water depletion, manifest as hypernatraemia 2 3 Nephrogenic diabetes insipidus, by definition unresponsive to desmopressin, is treated with thiazide diuretics and some limitation of sodium intake. The rationale is that the induced mild sodium depletion results in enhanced proximal renal tubular sodium and water reabsorption.

21

OTHER CONDITIONS IN WHICH WATER DEPLETION PREDOMINATES Because of the effectiveness of the renal mechanism of sodium conservation, water depletion may predominate in a number of conditions simultaneously, threatening to deplete both body salt and body water.

FIG. 21.4 The investigation of polyuria and polydipsia

patients with compulsive water drinking show a normal rise in plasma ADH as plasma osmolality increases; any rise in patients with partial degrees of cranial diabetes insipidus is demonstrably less. It is vital that fluid intake should be controlled when test doses of DDAVP are administered, because of the danger of water intoxication in patients with compulsive water drinking.

Management Cranial diabetes insipidus is most conveniently treated with the synthetic ADH analogue desmopressin (DDAVP). This has a greater weight-for-weight antidiuretic activity than ADH and lacks its potentially hazardous vasopressor effects. It also has a prolonged half-life, so that single doses act for up to 18 hours. For maintenance therapy, desmopressin is administered intranasally in doses of 2.5-20ug once or twice daily. In partial disease a single nocturnal dose may be sufficient. An oral preparation of desmopressin is also available, but high doses are required (100-600 ug/day). When intranasal and oral administration are contraindicated, desmopressin may be given intramuscularly or subcutaneously once or twice daily (0.25-2.0 u.g). The aim of treatment is to partially replace antidiuretic activity in the presence of normal thirst mechanisms,

• It is most common in patients unable to maintain an adequate oral intake because of either upper gastrointestinal obstruction or a reduced level of consciousness. In this situation, continued obligatory insensible and renal loss of water results in slow, progressive intra- and extracellular dehydration. Urinary sodium loss is reduced to a minimum. • Obligatory gastrointestinal loss of water also occurs in response to a large solute load. This may be produced by the administration of hyperosmolar solutions via a nasogastric tube to a partially conscious or paralysed patient. • Virtually pure water loss may also occur as exaggerated insensible loss, via the lungs, in acute respiratory disorders such as asthma. • Water depletion may be a feature of untreated diabetes mellitus, and is most likely to occur in the previously undiagnosed non-insulin-dependent diabetic who maintains a high intake of refined sugar (Ch. 19). A vicious circle of osmotic diuresis and rising extra- and intracellular osmolality may occur, especially if there is an intercurrent illness. Some increased renal loss of sodium occurs, but this is relatively less than the water deficit. In the absence of ketosis, vomiting and consequent marked salt depletion are uncommon. • High-protein nasogastric feeds in the presence of protein catabolism may induce a solute diuresis.

Management When oral fluid replacement is impractical, mild water depletion is treated by intravenous infusion of an iso-

1103

osmolar electrolyte-free solution (5% dextrose is the standard choice). However, this is unsatisfactory if some degree of salt depletion has also occurred, and in this situation infusions of isotonic saline (0.9% 'normal' saline) are usually given. Provided cardiac and renal functions are adequate, any excess sodium replacement will be excreted via the kidneys. Alternatively, combinations of dextrose and saline solutions may be used. Maintenance daily intravenous fluid replacement for an adult patient taking nothing by mouth would aim to provide approximately 2.0-2.5 L of water with 70 mmol of sodium and 60-80 mmol of potassium. This could be given as 2 L of 5% dextrose and 0.5 L of isotonic saline, with potassium chloride added in even distribution. When water depletion has been sufficiently severe to elevate plasma osmolality markedly, there is a theoretical risk of cerebral oedema if water is rapidly replaced as 5 % dextrose alone or in the form of hypotonic saline (e.g. 'half normal', 0.45%). For this reason, isotonic saline (0.9%) is often used to avoid an excessively rapid change in plasma osmolality. This policy may need to be modified, however, if the plasma sodium concentration continues to increase during isotonic saline administration. This may arise as a result of persistent water losses and of continuing aldosterone-mediated renal sodium reabsorption (stimulated by hypovolaemia). None the less, profound water depletion should be corrected slowly, although the rate of fluid administration must keep pace with continuing renal loss of water in conditions of osmotic diuresis.

WATER EXCESS An excess of total body water arises when water intake exceeds renal, cutaneous and pulmonary losses. Water excess is unlikely in the presence of normal renal function,

except in situations of increased water intake determined by psychological disturbance or, rarely, by hypothalamic disease. When water excretion is impaired, however, a rise in total body water is relatively common (Table 21.2) and is accompanied by a fall in plasma sodium (dilutional hyponatraemid). The tendency to water excess in cardiac failure is usually compounded by diuretic therapy. This further impairs urinary dilution, and may result in stimulation of thirst as a result of increased activation of the renin-angiotensin system. In the syndrome of inappropriate ADH secretion (SIADH), ADH secretion occurs despite hypotonicity of extracellular fluid and in the absence of depletion of circulating volume. The common causes are listed in Table 21.3. 1 In many of these situations the severity of the relative water excess and its clinical consequences may be aggravated by inappropriate administration of intravenous fluids. There is increasing evidence that, particularly in the postoperative situation, women may be more at risk of potentially fatal neurological sequelae of moderate hyponatraemia.

Clinical features and diagnosis Mild degrees of water excess cause few symptoms and the clinical features of the underlying disease predominate. However, with severe water excess, as may occur in some cases of SIADH, the reduction in intracellular osmolality in the central nervous system may produce symptoms ranging in severity from general lassitude to decreased levels of consciousness, coma and generalized convulsions. The diagnosis of water excess is usually suggested at routine investigation by finding hyponatraemia in the absence of clinical or other evidence of volume depletion. Although sodium-depleting states may also result in hyponatraemia, this is only the case if the losses are marked. However, hyponatraemia may occur without water excess when the contribution of glucose to plasma

TABLE 21.3 Causes of inappropriate ADH secretion (SIADH)

1

1104

MCQ 21.3

Source

Cause

Ectopic Hypothalamic

Malignancies, especially small cell bronchial carcinoma Inflammatory lung diseases CNS infections Drugs Carbamazepine Chlorpropamide Tricyclics Phenothiazines Syntocinon Cytotoxic drugs Cyclophosphamide Vincristine Wasting diseases Postsurgical

CASE STUDY 21.1 POLYURIA AND POLYDYPSIA IN A 54-YEAR-OLD WOMAN A 54-year-old woman presented to her GP with a 6-week history of increasing thirst and passing large volumes of urine. She described the passage of urine every 1-2 hours overnight, and also noted the persistence of severe thirst on rising. There was no dysuria but she had noted some reduction in appetite and had lost 5 kg in weight over the preceding month. There was no significant previous medical history and no family history of diabetes mellitus. She was not taking any medication. Her menses had ceased at the age of 49. On examination she was noted to be slightly pale; breast examination demonstrated a firm, fixed mass 3 cm in diameter in the left breast, with enlarged lymph nodes in the left axilla. The remainder of the examination was unremarkable, and in particular there were no neuroophthalmic signs. Dipstick urinalysis was negative for glucose and protein; haemoglobin was 10.3g/dL with MCV 86, WBC 6.8 x 109/L with normal differential and platelets 168 x 109/L; a preprandial plasma glucose was 5.3mmol/L; serum urea was 5.3mmol/L, creatinine 103umol/L, sodium 143 mmol/L, potassium 4.2mmol/L, calcium 2.56 mmol/L and albumin 39g/L. Her total urine output over 24 hours was measured at 4.8 L.

symptoms are unlikely to be due to primary over-drinking. It is therefore probable that the symptoms are due to a defect in urine concentrating capacity. The normal serum potassium excludes hypokalemia as a cause of reduced responsiveness to antidiuretic hormone. Similarly, the serum calcium, although at the upper end of the reference range, is unlikely to be implicated as a cause of her symptoms. The overall features suggest a diagnosis of diabetes insipidus; this might be central or nephrogenic in origin. The associated mild normochromic anaemia could be a result of deficiencies of anterior pituitary hormones giving rise to secondary hypothyroidism and/or hypoadrenalism, although the latter would tend to mask the effects of ADH deficiency. Alternatively, it would be consistent with the presence of an underlying pathology such as malignancy. The finding of a breast mass lesion with the characteristics of a carcinoma is highly relevant to her presenting symptoms. Breast carcinoma may result in thirst and polyuria, either by causing hypercalcaemia or as a result of metastatic deposits in the pituitary; the former was not detected in this case. Further investigation of possible diabetes insipidus should commence with simultaneous measurement

21

of serum and urine osmolality; this yielded values of 295 and 310mmol/kg, respectively. These results suggested subnormal urine concentration, and absolute confirmation was obtained by a carefully supervised water deprivation test with regular weighing to avoid profound dehydration. The patient produced a maximum urine osmolality of 456mosmol/kg during 8 hours of water deprivation, and a subsequent increment to 820mosmol/kg after the administration of desmopressin. Commencement of intranasal desmopressin, 10ug nocte, resulted in complete resolution of the symptoms of thirst and polyuria. Magnetic resonance imaging of the pituitary region demonstrated a mass lesion and loss of the normal posterior pituitary bright spot consistent with the diagnosis of central diabetes insipidus (Case Fig. 21.1.1). Serum cortisol at 0900 hours was 506nmol/L and serum free thyroxine 19.6pmol/L, indicating normal ACTH and TSH reserve. She underwent transsphenoidal biopsy of the pituitary lesion, histology demonstrating metastatic breast carcinoma, and subsequently underwent radiotherapy and chemotherapy, including local irradiation to the pituitary fossa.

Questions 1, What is the most likely cause for the patient's thirst and polyuria? 2. What further investigations would you Undertake? Discussion The most common cause of increased thirst and polyuria is diabetes mellitus. Although the absence of glycosuria cannot definitely exclude this diagnosis, it indicates that the symptoms in this patient are not due to a glucose-induced osmotic diuresis. The relatively short history, the nocturnal thirst, the presence of weight loss and the high-normal serum sodium indicate that the

CASE FIG. 21.1.1 Coronal crania! MR scan demonstrating a sellar mass lesion extending to the right cavernous sinus and into the suprasellar cistern to abut the optic chiasm.

1105

osmolality is increased in untreated diabetes mellitus. The potential rise in plasma osmolality results in a movement of water from the intracellular to the extracellular spaces, and a consequent fall in plasma sodium. Furthermore, an apparent hyponatraemia (pseudohyponatraemid) may be evident if marked hyperlipidaemia contributes significantly to plasma volume, thus reducing the water content per unit volume. The latter artefact is not encountered with the use of modern ion-sensitive electrode measurements. The assessment of the hyponatraemic patient is outlined in Figure 21.5. It will be noted that SIADH is characterized by hypotonicity of plasma (osmolality <280mmol/kg) with inappropriate urinary concentration (>200mmol/kg). This condition is associated with a normal or slightly increased circulating volume, so that the activity of the renin-angiotensin-aldosterone axis is low and urine sodium excretion approximates to sodium intake. Measurements of plasma and urine osmolality in sodiumdepleted patients (p. 1109) may be similar to those in SIADH, because of the hypovolaemic stimulus to ADH secretion. However, these patients will usually be distinguished by clinical evidence of sodium loss and consequent depletion of circulating volume. In addition, non-renal saltdepleting conditions (e.g. gastrointestinal loss) will be associated with renal sodium conservation and a low urinary sodium excretion. In renal salt-wasting conditions and in the sodium depletion of adrenal insufficiency, plasma

h may be indistinguishable from measurements in patients with SIADH. This latter point serves to emphasize the importance of clinical assessment of the extracellular fluid and circulating volumes in the hyponatraemic patient. An approximate assessment of plasma osmolality may be made from the following calculation: 2Na+ +2K + + glucose (mmol/L) + urea (mmol/L) where Na+ and K+ represent the millimolar concentrations of sodium and potassium and are doubled to account for their anion equivalents in plasma. Precise measurements of osmolality in the laboratory depend on depression of freezing point techniques.

Management of relative water excess Severe water intoxication with associated neurological problems requires emergency treatment in an attempt to correct profound hyponatraemia (usually less than 115 mmol/L). Hypertonic saline infusions (2-5 x isotonic; 1.8-4.5%) are temporarily effective, but carry the dangers of precipitating circulatory overload and of overly rapid corrections of hypo-osmolality. The most important potential adverse effect of reversal of hypo-osmolality is central pontine myelinolysis (see p. 1441). This is a potentially fatal condition characterized by central nervous system demyelination, particularly involving the pons; the risk of this complication is greater in patients with a history

RECENT ADVANCES POTENTIAL HAZARDS IN TREATING HYPONATRAEMIA

1106

FIG. 21.5 The clinical and biochemical evaluation of hyponatraemia

The particular hazard of postsurgical hyponatraemia in females has been demonstrated over the past few years. The mechanisms underlying sexual dimorphism in susceptibility to hyponatraemia are currently unclear. In the cases reported, the patients were otherwise fit and well premenopausal women. The single most important avoidable factor remains the excessive administration of intravenous fluids in the postoperative period. Much debate has surrounded emergency therapy for severe hyponatraemia, a condition which may be fatal if untreated. Rapid reversal of hypo-osmolality may be associated with central pontine myelinolysis (CPM) (see p. 1441), probably as a result of rapid shifts of water from hypotonic brain cells to the extracellular space. It is probable that the risk of CPM is minimal in the situation of reversing acute hyponatraemia, in contrast to hyponatraemia which has developed over periods of >24 hours; this probably reflects time-related osmolality changes which are unique to the central nervous system. In all other circumstances correction of hyponatraemia should be limited to an increment in plasma sodium of <12mmol per 24 hours.

21

CASE STUDY 21.2 HYPONATRAEMIA A 63-year-old man presented to his GP with a history of weight loss and decreased appetite over the preceding 6 weeks. He had smoked approximately 30 cigarettes per day for most of his adult life but had no significant previous medical history. Clinical examination demonstrated wasting and firm irregular liver enlargement. There was no abnormal pigmentation and no postural fall in blood pressure. Preliminary investigation yielded the following: haemoglobin 9.6g/dL (MCV 83), serum sodium 123mmol/L, potassium 3.6mmol/L, urea 1.9mmol/L, albumin 29g/L and alkaline phosphatase 720IU/L; bilirubin and transaminases were within normal limits. Chest Xray revealed an opacity in the right lower zone. Urine osmolality was 368mmol/kg.

Questions 1, What is the explanation for the biochemical abnormalities? 2. What further investigations would you undertake to confirm the cause of the hyponatraemia? Discussion This patient's presentation is strongly suggestive of metastatic carcinoma, with bronchus as the most likely primary source. The presence of hyponatraemia would be consistent with ectopic (inappropriate) ADH secretion by the tumour, and would therefore point to a small cell bronchial carcinoma. The low serum urea would be consistent with malnutrition, and specifically with a low protein intake, and the substantial elevation of serum alkaline phosphatase supports the diagnosis of multiple hepatic metastases. Confirmation of a diagnosis of inappropriate ADH secretion requires the demonstration of any degree of urine concentration in the presence of hyponatraemia and hypo-osmolality,

of alcohol abuse and in situations where the hyponatraemia is chronic. As an approximate guideline, one should aim to increase plasma sodium by a maximum of 12 mmol per 24 hours unless the hyponatraemia is known to have developed acutely. Dexamethasone is frequently prescribed on an empirical basis to reduce cerebral oedema, but there is little evidence for its efficacy. Intermediate degrees of water excess, most often due to SIADH, are best managed by treatment of the underlying cause. When this is impossible, modest water restriction (1000-1500 mL/day) is usually effective in elevating plasma sodium to safe levels. In some cases, however, an increase in plasma osmolality can only be achieved by very strict limitations of water intake, which the patient may find intolerable. In this situation, treatment with demethylchlortetracycline (demeclocycline), which reduces renal tubular responsiveness to ADH, is particularly useful. This long-acting tetracycline derivative exerts its full effect within a week of the commencement of therapy. It is especially useful in profound SIADH associated with carcinomas.

provided renal function is normal and there is no evidence of circulating volume depletion. Adrenal failure, occurring as a rare metastatic complication or coincidentally, may also present with hyponatraemia but is usually accompanied by pigmentation and evidence of volume depletion. Secondary adrenal failure (ACTH deficiency) may also complicate metastatic carcinoma of the bronchus and will not be accompanied by evidence of mineralocorticoid depletion. Therefore, measurement of 0900 serum cortisol should be undertaken and more extensive endocrine investigation performed if necessary. The diagnosis of small cell carcinoma of the bronchus was confirmed and treatment commenced with chemotherapy. The serum sodium fell further to 119mmol/L and was treated with restriction of fluid intake to l.OL per day. Serum sodium improved to 126mmol/L. Chemotherapy was associated with initial clinical improvement and decrease in hepatomegaly. However, 3 months later his disease relapsed and progressed rapidly with a fatal outcome.

Mild degrees of water excess and consequent hyponatraemia (plasma sodium 125-135 mmol/L) do not require specific treatment.

DISORDERS OF SODIUM HOMEOSTASIS There are many conditions associated with marked changes in total body sodium and hence extracellular fluid volume. Changes in total body water are also often present, but are of secondary importance at the time of clinical presentation. Changes in plasma sodium concentration are not impressive unless the alteration in body sodium is marked, is accompanied by decreased renal water excretion, or hypotonic fluid rehydration has been administered.

SODIUM EXCESS This may occur iatrogenically as a result of massive sodium

1107

TABLE 21.4 Causes of sodium retention in disease

TABLE 21.5 Effects of increased mineralocorticoid activity

Decreased glomerular filtration rate Cardiac failure Renal failure

Cause of increased activity

Secondary mineralocorticoid excess Cardiac failure Liver disease Nephrotic syndrome

Primary mineralocorticoid excess Cushing's syndrome Conn's syndrome

replacement with hypertonic saline infusions in hyponatraemic states. More commonly, however, sodium retention occurs as a result of decreased glomerular filtration rate in cardiac or renal failure, or under conditions of increased mineralocorticoid activity (Table 21.4). The latter arises as a primary phenomenon in Cushing's syndrome (mineralocorticoid effect of increased circulating glucocorticoids) and Conn's syndrome (increased aldosterone production from the adrenal zona glomerulosa due to tumour or hyperplasia). In these conditions the blood pressure is usually elevated, plasma sodium concentrations are at the upper limit of normal, and plasma potassium is decreased. Mineralocorticoid activity may be secondarily increased in any condition resulting in stimulation of the reninangiotensin system. This so-called secondary hyperaldosteronism occurs with the reduced renal perfusion in chronic cardiac failure, liver disease with portal hypertension, and various hypoalbuminaemic states (e.g. nephrotic syndrome) in which circulating volume is reduced, thereby stimulating the renin-angiotensin mechanism. The sodium retention of Conn's and Cushing's syndromes does not result in oedema. This only arises if there is an associated increased intracapillary pressure (as in heart failure) or a reduced plasma oncotic pressure (due to hypoalbuminaemia) (Table 21.5). Secondary hyperaldosteronism is a contributory factor in the oedema that occurs in these conditions.

Differential diagnosis of oedema Oedema (or expansion of the interstitial fluid volume) may occur in a number of distinct conditions: • Heart failure, reflecting the generalized increase in intracapillary pressure; • Hypoalbuminaemic states (e.g. nephrotic syndrome) in which plasma oncotic pressure is reduced;

1 1108

MCQ 21.4

Blood pressure

Primary Conn's syndrome Cushing's syndrome (ectopic ACTH) Secondary Cardiac failure Portal hypertension Nephrotic syndrome

Oedema/ ascites

Plasma K+

±

I 4

Peripheral venous insufficiency, Idiopathic oedema may occur in women, often on an apparently cyclical basis, being worst premenstrually. The oedema is often maximal in the hands, breasts and abdomen and may be associated with mastalgia. The precise cause is unknown, but some evidence exists for increased capillary albumin leakage, which leads to shrinkage of the intravascular volume and secondary renal sodium retention. Many patients with this condition have neurotic personality traits, but whether these are primary or secondary is unclear. In a proportion of patients the primary abnormality may be intermittent diuretic abuse, with consequent secondary hyperaldosteronism.

SODIUM DEPLETION A net sodium deficit may result from gastrointestinal or renal loss. The former, occurring as vomiting or diarrhoea, is usually obvious from the clinical history, whereas a diagnosis of renal salt loss is generally made only after investigation (Fig. 21.6). In the earliest stages pure sodium deficiency may be associated with some suppression of ADH secretion because of the tendency to decreased extracellular osmolality. Eventually, however, the fall in total body sodium results in a decrease in extracellular fluid volume sufficient to stimulate ADH secretion (Fig. 21.3). Water excretion is further diminished by increased sodium reabsorption in the proximal tubules, with a consequent reduction in solute delivery to distal tubular diluting sites. It should also be borne in mind that, although dietary sodium intake is potentially unlimited in affluent societies, this may not be the case in poorer countries. Despite the homeostatic mechanisms for renal sodium conservation described above, chronic dietary sodium depletion will inevitably exacerbate total body sodium depletion during intercurrent gastrointestinal disease, or when renal sodium conservation is compromised.

Clinical features Sodium depletion is manifest clinically by signs of a reduction in extracellular fluid and circulating volumes. Upper gastrointestinal salt and water loss may be associated with metabolic alkalosis owing to loss of gastric acid. Hydrogen ion depletion results in hypokalaemia (p. 1111) and an increase in renal potassium excretion, because of decreased hydrogen ion availability for the shared renal tubular electrochemical exchange of potassium and hydrogen ions for sodium. Conversely, loss of bicarbonate-rich duodenal contents may result in metabolic acidosis. Gastrointestinal sodium loss is distinguished from renal loss by the clinical history and measurement of urinary sodium excretion, which is very low when there is a gastrointestinal cause. The causes of renal salt loss are given in Table 21.6. 1 Sodium balance is particularly vulnerable in those forms of chronic renal disease that affect the medulla. Such patients lose the capacity to vary sodium excretion and are susceptible to dramatic salt depletion in the event of intercurrent gastrointestinal disturbance, with a resultant further and rapid reduction in glomerular filtration rate. In different circumstances, however, these

patients are in potential danger of sodium retention (p. 1108). As a consequence of the reduction in circulating volume that accompanies marked sodium depletion, there is a fall in glomerular filtration rate and hence a rise in plasma urea and creatinine concentrations (Fig. 21.7). This is termed prerenal uraemia (Ch. 20), and may in some cases prove difficult to distinguish from acute renal failure. In general, prerenal states are associated with a disproportionate rise in the concentration of plasma urea compared to that of creatinine, and the haematocrit may also be raised consistent with haemoconcentration. However, other factors that affect plasma urea concentration, e.g. quantity of dietary protein or rate of body protein catabolism, may limit the usefulness of this comparison. A low urinary sodium concentration distinguishes non-renal sodium depletion from acute renal failure (in which urine sodium concentration is normal or increased). In the diuretic phase of acute tubular necrosis, or after the relief of urinary obstruction, the aetiology of the sodium loss is usually obvious. The possibility of adrenal insufficiency should be borne in mind in any patient who presents with evidence of unexplained salt depletion. Isolated aldosterone deficiency may occur in the absence of glucocorticoid deficiency. This is a rare but well recog-

21

TABLE 21 .6 Causes of net renal sodium loss Intrinsic renal disease Recovery phase of acute tubular necrosis Relief of long-standing urinary obstruction Some forms of chronic nephropathy, particularly tubulointerstitial disease Mineralocorticoid deficiency Adrenal failure Isolated aldosterone deficiency Diuretic therapy

FIG. 21.6 The clinical and biochemical evaluation of sodium depletion

FIG. 21.7 The renal consequences of sodium depletion The percentage increase in plasma urea exceeds that of creatinine by the mechanism shown, provided intrinsic renal function remains normal.

1109

nized complication of long-standing diabetes, particularly when complicated by autonomic neuropathy, and is related to reduced renin secretion (hyporeninaemic hypoaldosteronism).

Management A clinically obvious salt and water deficit almost always requires intravenous replacement with isotonic saline (sodium chloride, 0.9%). Potassium supplements are required for gastrointestinal losses. When it is impossible to distinguish definitely between salt depletion and established acute renal failure as the cause of the presenting oliguria and uraemia, it may be of benefit to administer 500 mL 0.9% saline rapidly and monitor urine output in response to this. Salt-depleting chronic renal disease may necessitate regular oral sodium supplements (Ch. 20).

TABLE 21.7 Interpretation of the plasma sodium concentration

Diagnosis SIADH

Adrenal failure Renal failure Non-renal sodium loss Primary water deficit Diabetes insipidus Hyperosmolar diabetes mellitus

Plasma Na+

Urine sodium (mmol/L)

Urine osmolality (mmol/kg)

>20 >20 >20

>200 >300 <300

<20

>300

N or

>20

>300

N or

<20

<300

Variable

>300

Plasma creatinine

Low Low Low/

normal Low/ normal High/ normal High/ normal High

N = normal.

Interpretation of plasma sodium concentrations The plasma sodium concentration reflects the degree of dilution of extracellular sodium. It thus tells us a great deal about total body water but relatively little about total body sodium. We learn more about the latter from clinical examination, from indirect indicators of glomerular filtration rate (dependent on circulating volume) such as plasma urea and creatinine, and from urine sodium excretion rates (Table 21.7).

POTASSIUM HOMEOSTASIS

Potassium ions are predominantly intracellular, the concentration gradient depending on active Na+/K+ exchange across the plasma membrane (see Fig. 21.2). Cellular uptake of potassium is stimulated by insulin, which enhances the activity of Na+/K+ ATPase, and by adrenergic mechanisms which serve to increase intracellular sodium uptake via the Na+/H+ antiport mechanism and thus secondarily stimulate Na+/K+ exchange. The other major determinant of the distribution is pH. Alkalosis, associated with a fall in intracellular hydrogen ion concentration, results in a net flux of potassium into cells, with a consequent fall in plasma potassium; acidosis has the reverse effect (Fig. 21.8). The mechanism of these changes is unknown, but may be related to intracellular changes in hydrogen ion binding of negatively charged proteins.

1

1110

MCQ21.5

FIG. 21.8 The effect of acid-base changes on the distribution of potassium across cell membranes The steady-state distribution is altered by either acidosis or alkalosis in the directions shown.

Maintenance of total body potassium depends on dietary intake (approximately l00mmol per day in western diets) and on control of renal potassium excretion. Potassium is actively reabsorbed in the proximal renal tubule. In the distal tubule, potassium excretion occurs by diffusion down its electrochemical gradient (Fig. 21.9). In the collecting ducts the passage of potassium into tubular fluid appears to be an active process shared with hydrogen ions, apparently in exchange for sodium ions in tubular fluid. This exchange is enhanced by increased concentrations of sodium in the tubular lumen and by aldosterone. Changes in intra- and extracellular pH alter concentrations of potassium in renal tubular cells and thus indirectly affect renal potassium excretion, both by diffusion and in exchange for sodium. Under conditions of high potassium intake renal tubular potassium secretion is increased.

TABLE 21.8 Causes of hypokalaemia Cause

Mechanism

Alkalosis

Intracellular shift of K+ in exchange for H+; increased renal excretion Increased renal excretion secondary to enhanced distal tubular sodium delivery and increased tubular flow Increased aldosterone effect Mineralcocorticoid effect of increased glucocorticoids

Diuretics Diabetes mellitus *Conn's syndrome *Cushing's syndrome (esp. ectopic ACTH from malignant source) *Steroid therapy (esp. high-dose hydrocortisone) *Carbenoxolone therapy for peptic ulcer

FIG. 21.9 The influence of acid-base changes on intracellular potassium concentration and renal excretion in the distal renal tubule Diffusion of potassium into the tubular lumen is increased by alkalosis and decreased by acidosis as a consequence of changes in potassium concentration in renal tubular cells.

HYPOKALAEMIA A significant reduction in plasma potassium usually indicates profound depletion of total body potassium, but may be due to temporary shifts of potassium ions from the extra- to the intracellular spaces, particularly under the influence of adrenergic mechanisms, for example after myocardial infarction. The important causes of hypokalaemia and the proposed underlying mechanisms are outlined in Table 21.8. 1

*Congenital adrenal hyperplasia (11-hydroxylase deficiency) 11 -hydroxysteroid dehydrogenase deficiency Renal tubular acidosis (distal type) Bartter's and Gitelman's syndromes Vomiting (esp. pyloric stenosis and bulimia nervosa) Secretory diarrhoea Laxative abuse Villous adenoma of rectum Hypokalaemic periodic paralysis

21

Mineralocorticoid effect of increased glucocorticoids Mineralocorticoid effect of cortisol due to inhibition of renal 11 -hydroxysteroid dehydrogenase Mineralocorticoid effect of deoxycorticosterone Reduced renal tubular conversion of cortisol to cortisone Decreased Na+/H+ exchange in distal tubule (see Ch. 20) Defective chloride absorption in loop of Henle with consequent solute loss and secondary hyperaldosteronism Loss of gastric contents and effects of alkalosis Direct loss of potassium Direct loss of potassium Enhanced potassium loss from tumour cells Intermittent shift of potassium into cells

*See Chapter 17.

losis. In addition, potassium deficiency may increase collecting duct expression of an H+/K+ ATPase that reabsorbs potassium in exchange for hydrogen ion excretion.

Clinical features Non-specific symptoms of lethargy and weakness may accompany mild to moderate hypokalaemia (c. 2.83.5mmol/L). Lower levels may give rise to marked muscular weakness, gut hypomotility, increased myocardial excitability and arrhythmias, and nephrogenic diabetes insipidus. A shift of hydrogen ions from extra- to intracellular spaces is thought to be responsible for the metabolic alkalosis that accompanies most cases of hypokalaemia. This apparent hydrogen ion shift may be due to a relative failure of cell membrane proton pumps (H+ extrusion). In addition, chronic hypokalaemia may reduce renal chloride conservation, with a consequent increased delivery of sodium to distal tubular sites. This promotes sodium exchange for hydrogen ions, with accentuation of the alka-

Investigation In many instances the mechanism of hypokalaemia is obvious from the history and clinical observations. When this is not the case, investigation is directed initially at distinguishing gastrointestinal from renal loss of potassium by means of total 24-hour urine potassium estimations. These are very low in all non-renal mechanisms of potassium loss, with the exception of repeated vomiting, which is complicated by alkalosis. It may prove very difficult to diagnose surreptitious vomiting, or diuretic or laxative abuse. A finding of hypokalaemia with a low plasma bicarbonate always suggests the possibility of renal tubular acidosis and should prompt measurement of urinary pH (which will be inappropriately high in this condition). The rare combina-

1111

tion of acidosis and hypokalaemia is also seen in the most severe examples of diabetic ketoacidosis, when potassium depletion is particularly marked.

Management Hypokalaemia is usually corrected by oral potassium chloride in wax base (e.g. Slow K) or effervescent potassium chloride; if potassium depletion is profound and lifethreatening, potassium chloride is given intravenously. The rate of administration depends on any continuing losses, but it should rarely be necessary to exceed 30mmol/hour even at the start of therapy. Plasma potassium concentrations should be monitored regularly.

Rare causes of hypokalaemia Bartter's syndrome This rare syndrome, which may present in childhood, comprises a combination of hypokalaemic alkalosis, hyperreninaemia and secondary hyperaldosteronism. The condition is inherited as an autosomal recessive trait and is due to a mutation in the gene encoding the bumetanide-sensitive Na+-K+-2C1 cotransporter. This results in a selective defect in active chloride reabsorption in the loop of Henle, leading to renal losses of sodium, potassium and chloride. Increased urinary prostaglandin excretion has been noted but is probably a secondary phenomenon. It is important to exclude diuretic abuse and surreptitious vomiting, which may also present with unexplained hypokalaemic alkalosis and activation of the renin-angiotensin system. Potassium supplementation and prostaglandin synthetase inhibition with indomethacin are effective in partially reversing the hypokalaemia. Inhibition of renin secretion with propranolol may be a useful addition. Gitelman's syndrome, caused by a defect in the thiazidesensitive Na+-C1- cotransporter located on chromosome 16q, presents in adults and produces a similar biochemical picture to Bartter's syndrome, with the additional features of hypomagnesaemia and hypocalciuria. Hypokalaemic periodic paralysis In this condition paroxysmal episodes of profound muscular weakness may occur, accompanied by hypokalaemia. 1 The underlying mechanism is unknown, but precipitating factors include high-carbohydrate meals, sepsis, exercise and stress, all of which may promote a shift of potassium into cells. The condition may be dominantly inherited. Certain susceptible patients with thyrotoxicosis may develop hypokalaemic periodic paralysis; this is rare in Caucasians but occurs in approximately 10% of oriental

1

Case 21.2

2

MCQ21.6

patients with Graves' thyrotoxicosis. Treatment of the thyroid disorder is curative. / / -hydroxysteroid dehydrogenase deficiency In this condition, which may present in childhood, there is a deficiency in the renal isoform of ll -hydroxysteroid dehydrogenase (11b-HSD type 2), the enzyme responsible for conversion of cortisol to cortisone and which therefore protects the renal tubular mineralocorticoid receptor from exposure to cortisol. There is a consequent increased renal mineralocorticoid effect of cortisol, leading to hypertension and suppression of the renin-angiotensin system. Treatment with spironolactone or amiloride is effective. Inhibition of 11b-HSD may also occur secondary to carbenoxolone therapy or excess liquorice (glycerrhitinic acid) consumption, with similar consequences to the inherited deficiency.

HYPERKALAEMIA Increases in plasma potassium usually arise against a background of decreased renal potassium excretion. Moderate increases are symptomless, but at levels exceeding 6.5mmol/L the risk of cardiac arrest increases, and severe hyperkalaemia constitutes a medical emergency. Aetiological factors and mechanisms are outlined in Table 21.9. The possibility of haemolysis of the sample causing artefactual hyperkalaemia should be considered in instances of isolated hyperkalaemia in the presence of normal renal function. Occasionally increased potassium leakage from red cells may occur in blood stored at room temperature; this is a dominantly inherited phenomenon (familial pseudohyperkalaemia) of no clinical significance and is diagnosed by maintaining the sample at 37°C prior to potassium measurement.

Management Marked hyperkalaemia (>7mmol/L) should be reduced as a matter of urgency because of the risk of cardiac arrest. Simultaneous intravenous administration of glucose (50 g) and soluble insulin (15 units) is temporarily effective, and intravenous bicarbonate (50mmol) will cause some shift of potassium from the extracellular to the intracellular compartment. The associated sodium load may be poorly tolerated, however, and dialysis may be necessary. Renal potassium losses may be increased by loop diuretics such as frusemide. Intravenous calcium salts afford some protection against the cardiac consequences of hyperkalaemia. ECG monitoring is useful for acute assessment. Moderate hyperkalaemia is associated with peaking of T waves; more sinister changes include increasing width of QRS complexes. Longer-term control may be achieved by means of cation exchange resins (e.g. Resonium A-sodium, Calcium Resonium), which are given either orally or by retention enema. 0

TABLE 21.9 Causes of hyperkalaemia

TABLE 21.10 Acid generation and elimination

Cause

Mechanism

Source

Acid

Elimination

Acute renal failure

Decreased excretion, which may be compounded by acidosis, cell necrosis (esp. when infection present), transfusions of stored blood and potassium-retaining diuretics Shift of potassium from intra- to extracellular spaces Release of cellular potassium

Aerobic respiration Glycolysis

C02 Lactic acid

Lipolysis

Free fatty acids

Hepatic metabolism

Ketone bodies

Impairment of K+ secretion in the distal nephron caused by: (a) Decreased mineralocorticoid activity due to adrenal failure (b) Reduced activity of renin-angiotensin system ('hyporeninaemic hypoaldosteronism'), e.g. in diabetic neuropathy (c) Angiotensin-converting enzyme inhibitors (d) Potassium-retaining diuretics, i.e. direct inhibition of aldosterone action (spironolactone) or of Na+/K+ distal tubular exchange (amiloride, triamterene) (e) Tubular resistance to mineralocorticoid action

Dietary protein catabolism

Inorganic acids

Pulmonary Hepatic metabolism to glucose or C02 (pulmonary elimination) Oxidation to C02 (pulmonary elimination) Oxidation to C02 (pulmonary elimination) Renal

Acidosis Cell necrosis (e.g. after cancer chemotherapy) Type 4 renal tubular acidosis (see Ch. 20)

The management of adrenal failure and hypoaldosteronism are considered in Chapter 17.

21

Lactic acid metabolism provides an interesting example of immediate buffering with subsequent hydrogen ion consumption and bicarbonate regeneration. Lactic acid (pK 4.6) is fully dissociated in plasma, and protons are consumed by normal buffering mechanisms (e.g. bicarbonate). The subsequent hepatic metabolism of lactate ions to produce glucose requires the stoichiometric consumption of hydrogen ions, with the consequent formation of bicarbonate from carbon dioxide and hydroxyl ions. Henderson-Hasselbalch equation The equilibrium relationship between the protonated and anionic forms of a buffer pair such as bicarbonate/carbonic acid may be indicated as follows:

ACID-BASE HOMEOSTASIS

A large number of metabolic events are pH sensitive and maintenance of a stable acid-base status is therefore critically important. In the healthy individual, extracellular pH is held within narrow limits (pH 7.38-7.42). Intracellular pH is generally lower than extracellular pH and varies both from one tissue to another and according to nutritional status and exercise state (mean range pH 6.7-7.3). Under normal circumstances homeostatic mechanisms are generally concerned with the buffering and disposal of hydrogen ions generated by intracellular metabolic events, particularly aerobic respiration (CO2 production), glycolysis (lactic acid production) and lipolysis (fatty acid and eventual ketoacid production, see Table 21.10). The acceptance of hydrogen ions by intra- or extracellular buffer base constitutes the first line of defence against deviations from normal pH. Important buffer systems include bicarbonate/carbonic acid, red cell haemoglobin, phosphate and intracellular proteins. Exhaustion of buffer capacity is prevented by short- or long-term elimination of hydrogen ions or by regeneration of bicarbonate. This occurs through respiration (acid eliminated in the form of CO2); metabolism (hepatic metabolism of lactic acid, tissue metabolism of ketone bodies and free fatty acid); and renal excretion (buffered by ammonia and phosphate).

This is the classic Henderson-Hasselbalch equation, which can be applied to all physiological buffer systems. Reference to this equation indicates the change in concentration of a given buffer component that is required for pH to remain constant following a primary alteration in acid-base status. Thus, metabolic production of acid that leads to an immediate fall in HCO3 will lead to a fall in pH unless Pco2 also decreases by increased respiration. Increases in Pco2 consequent upon respiratory failure necessitate a rise in HCO3 concentration (by increased renal conservation of bicarbonate) if pH changes are to be minimized. Similar arguments can be applied to situations in which primary increases in HCO3, or decreases in Pco2,

1113

occur. Primary alterations in CO2 are denoted as respiratory acidosis or alkalosis, and primary changes in buffer base as metabolic acidosis or alkalosis. These terms apply regardless of whether or not appropriate compensatory mechanisms have been sufficient to maintain pH within the normal range (compensated metabolic or respiratory acidosis or alkalosis). Respiratory compensation is discussed in Chapter 13, page 610; see also Figure 13.7. 1

TABLE 21.11 Changes in Pco2 and HC03 in acid-base disorders Pco2

PH

Metabolic acidosis Metabolic alkalosis Respiratory acidosis Respiratory alkalosis

N N N N

or or or or

HCO3

II

Slight II

Slight

The primary derangements are denoted by double arrows. N = normal,

INVESTIGATION OF ACID-BASE STATUS BLOOD GAS ANALYSIS Blood gas analysers measure pH and Pco2 directly by means of specific electrodes, and bicarbonate concentrations are automatically calculated using the HendersonHasselbalch equation. Values are usually also given for the so-called 'standard bicarbonate', which represents the theoretical bicarbonate concentrations at a Pco2 of 5.3kPa (40mmHg), and thus purports to show the extent of a given acid-base disturbance attributable to metabolic causes alone. In addition, values of 'base deficit' or 'base excess' indicate the deviation of bicarbonate from normal per litre of blood at a theoretical Pco2 of 5.3 kPa. These data may be misleading because of differences in buffering dynamics between the in vitro and in vivo situations. In practice, however, clinical assessment and measurements of pH, Pco2, Po2 and bicarbonate are sufficient for the accurate classification of pure or mixed (e.g. acute metabolic acidosis and chronic respiratory acidosis) acid-base disturbances (Table 21.11). Metabolic acidosis results in rapid respiratory compensation owing to stimulation of carotid body, aortic and medullary chemoreceptors. Metabolic alkalosis, on the other hand, is less well compensated by respiratory mechanisms, probably because any decrease in ventilation is limited by hypoxic respiratory drive. Chronic respiratory acidosis is partially compensated by a rise in plasma bicarbonate via increased hydrogen ion excretion and renal conservation of bicarbonate, a longterm effect occurring over 2-3 days. Difficulties in interpretation may arise with mixed acid-base disturbances, which are most commonly seen with the superimposition of metabolic acidosis on chronic respiratory acidosis. The combination results in a low pH (by definition), an elevated Pco2 (inability to respond to acidotic respiratory drive), and a fall in previously elevated bicarbonate level. The clinical presentation, history and

1MCQ 21.7

1114

2

MCQ21.8

3

MCQ 21.9

critical evaluation of pH, Pco2 and bicarbonate will usually indicate the dual diagnosis, and a decreased Po2 will provide additional evidence of the respiratory component.

THE ANION GAP Subtraction of the total plasma concentrations of chloride and bicarbonate anions from sodium and potassium cations normally yields a 'gap value' of 10-20 mmol/L, made up of negatively charged proteins, phosphate, sulphate, lactate and small quantities of ketoacids. Calculation of this anion gap in metabolic acidosis is useful for distinguishing cases caused by bicarbonate loss (e.g. pancreatic fistulae, renal tubular acidosis), in which the anion gap is normal, from those due to increases in endogenously produced acid (e.g. ketoacidosis, lactic acidosis and the acidosis of renal failure), in which the gap is increased. In the former, plasma chloride is increased (hyperchloraemic acidosis) to maintain electroneutrality. 2

ACID-BASE DISORDERS METABOLIC ACIDOSIS The common causes of metabolic acidosis are listed in Table 21.12. The increased respiratory drive that results from severe metabolic acidosis is clinically recognizable as deep, sighing respiration (Kussmaul respiration). Respiratory compensation for metabolic acidosis is dependent on adequate respiratory reserve. In many of the conditions listed in Table 21.12, accumulation of more than one acid may occur. If acidosis, from whatever cause, is severe, reduction in cardiac output may result in a superimposed lactic acidosis (type A). This is due to increased peripheral glycolysis, which occurs with tissue anoxia. Similarly, diabetic ketoacidosis is associated with salt and water depletion, and the resulting fall in circulating volume leads to increased peripheral glycolysis and lactic acid accumulation.

The situation is further complicated because acidosis itself partially inhibits the glycolytic pathway in peripheral tissues (Fig. 21.10), which tends to offset the increase in lactic acid production. However, acidosis directly inhibits hepatic gluconeogenic enzymes and, because lactate is an important gluconeogenic substrate, this may result in progressive lactic acid accumulation. Loss of the slight intracellular alkalinizing effect of hepatic lactate metabolism further accentuates the effects of acidosis on hepatic lactate removal (Fig. 21.10). The acidosis of renal failure has traditionally been attributed to decreased ammonia formation (from glutamine) in the diseased kidney, with consequent decreased buffering capacity in the urine. Decreased urinary buffer results in the minimum urinary pH being reached at a lower total

hydrogen ion content, and thus leads to systemic acidosis. However, it has been pointed out that, because the metabolism of glutamine in renal tubular cells yieldsNH+4rather than NH3, this mechanism cannot be responsible for net hydrogen ion excretion by the kidney. The other route of glutamine metabolism is via urea formation in the liver. This mechanism results in net bicarbonate consumption and, as glutamine is diverted to hepatic metabolism when renal metabolism is impaired, it follows that the acidosis of renal failure may be primarily related to the acidgenerating (i.e. bicarbonate-consuming) effect of hepatic ureagenesis (Fig. 21.11). Details of renal tubular acidosis and salicylate poisoning are given in Chapters 20 and 1, respectively.

21

METABOLIC ALKALOSIS TABLE 21.12 Causes of metabolic acidosis Normal anion gap Gut bicarbonate loss (e.g. pancreatic fistula) Renal tubular acidosis (urine pH inappropriately high) Distal type (failure of proton secretion). Primary and secondary Treatment with carbonic anhydrase inhibitors Proximal type (bicarbonate wastage). Primary and secondary Hyperkalaemia Hypoaldosteronism

Increased anion gap Diabetic ketoacidosis Starvation ketoacidosis Lactic acidosis Type A secondary to increased peripheral glycolysis in circulatory failure or hypoxia Type B secondary to failure of lactate metabolism or to net lactate production in liver, e.g. biguanide drugs, ethanol, methanol, ethylene glycol, fructose, liver disease, mitochondrial myopathies Acidosis of renal failure Salicylate poisoning

FIG. 21.10 The metabolic consequences of metabolic acidosis Acidosis tends to decrease hepatic metabolism with resultant lactate and hydrogen ion accumulation. These effects are partially offset by a direct partial inhibition of glycolysis by acidosis and an increase in lactate transport into hepatocytes. (-) and (+) denote the potential changes in plasma lactate.

Metabolic alkalosis results from direct loss of hydrogen ions or ingestion of bicarbonate (Table 21.13). Respiratory compensation is poor because hypoxia would be its direct consequence, and possibly also because intracellular pH may increase relatively less than extracellular pH in some instances, leading to a lesser respiratory drive to compensate. 0

RESPIRATORY ACIDOSIS

Carbon dioxide accumulation may occur as a result of many respiratory disorders (see Table 13.32, p. 670). The

FIG. 21.11 Routes of glutamine metabolism in liver and kidney Renal disease results in diversion of glutamine metabolism to the liver, with urea and hydrogen ion production.

Ill5

CASE STUDY 21.3 HAEMATEMESIS AND HYPOTENSION IN A 66-YEAR-OLD MAN A 66-year-old man presented to his local Accident and Emergency department with a history of several episodes of haematemesis in the preceding 48 hours. On arrival he appeared pale, had cold peripheries and was sweating profusely. Blood pressure was 86 mmHg systolic in the lying position, with a pulse rate of 116 per minute in regular rhythm, and he felt faint on sitting upright. He described a history of mild epigastric discomfort after meals dating over 2 years. There had been no weight loss. He had suffered a myocardial infarction some 18 months prior to this presentation but had not had any chest pain in the interim. He had been started on frusemide and amiloride as a result of symptoms of shortness of breath on exertion 6 months ago. Previous medical history was otherwise unremarkable. Initial investigations demonstrated haemoglobin 7.6g/dL (MCV 78), serum sodium 133mmol/L, potassium 4.9mmol/L, bicarbonate 9mmol/L, chloride 102mmol/L, urea 16.3 mmol/L, serum creatinine 166 umol/L and plasma glucose 6.3 mmol/L. A provisional diagnosis of bleeding peptic ulceration was made; blood was immediately drawn for grouping and cross-matching and arrangements were made for emergency upper gastrointestinal endoscopy. Simultaneously, because of the low serum bicarbonate, arterial blood gases were performed (on air)

and yielded the following results: pH 7.16, Po212.3 kPa, Pco2 2.7 kPa, standard bicarbonate 8 mmol/L. He was unable to pass urine for analysis.

Questions 1. What is the interpretion of the serum urea and creatinine results? 2. What is the most likely explanation for the derangement in acid-base status? Discussion This patient's clinical presentation is consistent with profound circulating volume depletion occurring as a consequence of acute blood loss. The decrease in haemoglobin suggests that he had been losing blood, albeit more slowly, prior to the acute presentation. Both serum creatinine and urea are elevated but the increment in urea is disproportionately greater. This finding is typical of prerenal reduction in glomerular filtration rate, and occurs because of passive reabsorption of urea in renal tubules, in contrast to the active secretion of creatinine. This phenomenon is likely to be a consequence of an acute reduction in circulating volume superimposed on the longer-term effect of diuretic therapy in depleting total body sodium. In addition, the 'protein meal' effect of blood in the gut will tend to further elevate urea

condition may be chronic (e.g. chronic obstructive airways disease) or acute (e.g. neuromuscular problems such as my asthenia). There are marked differences in compensatory responses in the two situations because several days are required for significant renal conservation of bicar-

without increasing serum creatinine. The decrement in serum bicarbonate is consistent with a metabolic acidosis. Serum bicarbonate may also decrease in states of primary hyperventilation, but not to the extent evident in this case, and furthermore there was no apparent precipitant for an increase in ventilation other than the presence of acidosis itself; in particular there was no history of salicylate intake. None the less, a serum salicylate measurement would be a wise additional investigation in this case. Calculation of the 'anion gap', obtained by subtracting the sum of chloride and bicarbonate concentrations from the sum of sodium and potassium, yields an abnormally high value of 26.9 mmol/L. Furthermore, the arterial blood gas analysis indicates a typical picture of metabolic acidosis with partial respiratory compensation. The overall acid-base disturbance is therefore most likely to be due to the accumulation of lactic acid as a result of decreased peripheral perfusion (type A lactic acidosis). His blood lactate concentration was indeed elevated, at 10.9mmol/L (normal <1.5mmol/L). A similar derangement in acid-base measurements may occur in diabetic ketoacidosis, a highly improbable diagnosis in this case given the normal plasma glucose.

bonate to occur. Thus, a new steady state of raised Pco2 and bicarbonate with maintenance of normal pH is frequently seen in chronic lung disease.

RESPIRATORY ALKALOSIS 1 1

1116

Case 21.3

2

MCQ 21.10

An increase in ventilation and a consequent fall in Pco2 usually arises as a primary event, as in hyperventilation due to anxiety or in hypoxic states (Table 21.14). When chronic hypoxia is the precipitating cause, some compensation may

TABLE 21 .13 Causes of metabolic alkalosis

Glycolysis in skin, muscle and RBC

I Cardiac and skeletal muscle contractility

21

Gastric acid loss (esp. pyloric stenosis) +

Potassium dificit leading to renal H loss

Ingestion of alkali or inappropriate intravenous administration

TABLE 21.14 Causes of respiratory alkalosis Stress hyperventilation Hypoxic stimulus to ventilation Alveolar disease Right-to-left shunt

Altitude Liver failure Drug-induced stimulus to ventilation Salicylate poisoning

Plasma [K+]

pH

Bone demineralization

Hepatic gluconeogenesis

FIG. 21.12 The multiple effects of acidosis on heart, skin, red blood cells, liver and bone, and on plasma K+ concentration

occur by means of increased renal bicarbonate excretion. In most instances, however, the fall in Pco2 is acute and pH rises rapidly.

CLINICAL CONSEQUENCES OF ACIDOSIS

The clinical consequences of acidosis are outlined in Figure 21.12. Acidosis is associated with a shift to the right of the oxygen dissociation curve (Fig. 21.13), thus tending to improve oxygen delivery to the periphery (provided pulmonary function is adequate). This effect is reduced to some extent by the fall in 2,3-diphosphoglycerate (2,3DPG) concentration in erythrocytes, which occurs over a period of days. This has important implications for the management of metabolic acidosis, in that overzealous correction of acidosis prior to the restoration of adequate peripheral perfusion may adversely affect oxygen delivery to peripheral tissues (smaller change in oxygen saturation for a given fall in P02). 2

CLINICAL CONSEQUENCES OF ALKALOSIS

In clinical terms the most dramatic result of a rise in pH is a fall in ionized calcium, resulting in tetany (carpopedal spasm). Milder symptoms, also suggesting a decreased ionized calcium, include peripheral and circumoral paraesthesia and are frequently found in patients with hyperventilation associated with stress. Alkalosis has a hypokalaemic effect (p. 1112) and also tends to increase peripheral glycolysis. In practice, however, raised lactic acid levels are not a feature of alkalotic conditions, with the possible exception of respiratory alkalosis accompanying liver failure, in which lactic acid metabolism is impaired.

FIG. 21.13 The effects of (a) acid-base changes and (b) 2,3-DPG concentration on haemoglobin-oxygen dissociation A shift to the right indicates increased oxygen delivery per unit fall in Po2. A shift to the left indicates decreased oxygen delivery per unit fall in Po2.

Management of metabolic acid-base disturbances Metabolic alkalosis rarely requires more than the correction of salt, water and potassium depletion, and treatment of the underlying pathology. However, in severe metabolic acidosis, particularly lactic acidosis, because of the vicious circle of progressive extracellular and intracellular acidosis, large quantities of sodium bicarbonate have been used. One approach is to administer 1.4% sodium bicarbonate by infusion at a rate of 500 mL every 30 minutes until arterial pH is greater than 7.2, and then at a rate of 500mL hourly until the pH is normalized. The sodium load that inevitably accompanies bicarbonate administration may necessitate dialysis, particularly if there is coexisting renal impairment. Much controversy surrounds the use of bicarbonate in lesser degrees of acidosis. It has been suggested that rapid diffusion of CO2 (formed by titration of hydrogen ions by administered bicarbonate) into cells may exacerbate intracellular acidosis. However, these arguments do not take account of the rapid pulmonary elimination of CO2 in this situation, and are probably not clinically

1117

RECENT ADVANCES IN ALKALI THERAPY IN METABOLIC ACIDOSIS The use of bicarbonate therapy in metabolic acidosis may have theoretical adverse effects on oxygen delivery to peripheral tissues by virtue of a shift to the left of the oxygen dissociation curve. In addition, in vitro studies have demonstrated intracellular acidification as a result of bicarbonate reversal of extracellular acidosis, an effect thought to be due to diffusion of CO2 (formed by titration of protons by bicarbonate) into cells. Whether this latter effect is important in vivo remains to be demonstrated, but the accumulating experience to date suggests that use of alkali therapy in severe metabolic acidosis (e.g. type A lactic acidosis) confers little advantage above that of restoring circulating volume. In diabetic ketoacidosis, bicarbonate therapy is rarely required, and in cardiopulmonary arrest, administration of bicarbonate is no longer a first line therapy. Type B lactic acidosis, a condition in which administration of large quantities of bicarbonate might have particular advantages, is sufficiently rare that insufficient data are available to determine the utility of this treatment.

relevant in most circumstances. None the less, it should be recognized that retrospective analyses have failed to demonstrate dramatic effects of bicarbonate administration on survival. Alternative alkalinizing strategies (e.g. equimolar mixtures of sodium bicarbonate and sodium carbonate) which are not associated with intracellular acidification in animal models do not appear to convey any clinical advantage. Mild to moderate diabetic ketoacidosis (pH > 7.1) does not require alkali administration. In fact, such treatment may be potentially hazardous because of the risk of a left-

1118

ward shift of the oxygen dissociation curve (Fig. 21.13) before peripheral perfusion has been improved by salt and water administration. This would exaggerate the adverse effects of lowered erythrocyte 2,3-DPG concentration on oxygen delivery. Restoration of circulating volume, lowering of blood sugar and inhibition of lipolysis by insulin are followed by renal excretion and tissue metabolism of ketoacids (with net hydrogen ion consumption). When administration of intravenous bicarbonate is necessary it should be given in isotonic form (1.4%) if possible. The use of hypertonic solutions of bicarbonate (e.g. 8.4%, containing 1 mmol sodium/mL) is limited to the rapid administration of 50-100mmol boluses in the management of refractory cardiac arrest; immediate administration of bicarbonate does not improve the initial success rate in cardiac resuscitation and is no longer advised. Renal tubular acidoses are treated by oral bicarbonate and/or potassium supplements (Ch. 18).

FURTHER READING Anon 1991 Potassium disorders and cardiac arrhythmias. Drug Ther Bull 29: 73-75. Ayus J C, Arieff A L 1996 Brain damage and postoperative hyponatraemia: the role of gender. Neurology 46: 323-328. Bartter F C, Schwartz W B 1967 The syndrome of inappropriate secretion of antidiuretic hormone. Am J Med 42: 790-806. Berl T 1990 Treating hyponatraemia; damned if we do and damned if we don't. Kidney Int 37:1006-1018. Cohen R D 1991 Roles of the liver and kidney in acid-base regulation and its disorders. Br J Anaesth 67(1): 154-164. Gluck S L 1998 Electrolyte quintet. Acid-base. Lancet 352: 474-479. Halperin M L, Kamel K S 1998 Electrolyte quintet. Potassium. Lancet 352:135-140. Kumar S, Berl T 1998 Electrolyte quintet. Sodium. Lancet 352:220-228. Monson J P 1993 Metformin and lactic acidosis. Prescribers J 33:170-173. Monson J P, Williams D 1992 Osmoregulation in pregnancy and its disorders. J Endocrinol 132: 7-9.

larly on the increasing prevalence of osteoarthritis and osteoporosis.

22

FURTHER READING Mclntosh E 1996 The cost of rheumatoid arthritis. Br J Rheumatol 35:781-790

STRUCTURE AND FUNCTION OF JOINTS

Brian Hazleman

Structure and function of joints 1119

Systemic lupus erythematosus 1172

Clinical assessment 1121

Systemic sclerosis (scleroderma) 1177

Rheumatoid arthritis 1130 Seronegative spondarthritides

1147 Osteoarthritis 1154 Infective arthritis 1158 Childhood arthritis 1162

Dermatomyositis and polymyositis 1180 Vasculitis 1181 Low back pain 1185 Soft tissue rheumatism 1192

Crystal synovitis 1166

In developed countries musculoskeletal disorders are the commonest causes of disability in adults and, including back pain, of time lost from work. In the UK each year, an estimated 20 million people experience some form of rheumatic complaint and eight million seek help from their general practitioner. At least half a million people have rheumatoid arthritis (RA) and around five million are affected by osteoarthritis (OA). There are 500000 patients with gout and about the same number with ankylosing spondylitis, and low back pain and soft tissue rheumatic disorders together account for over 50% of the rheumatic causes of working days lost annually in the UK (in total about 88 million days). These are consequently important causes of morbidity. By recognizing arthritis early, much can be done to help these patients. In 1992, the total economic impact of RA in England was estimated to be £1.3 billion, of which approximately half was due to indirect costs of loss of production. The direct costs were attributed to hospitalization, outpatient care, drugs, residential care and social services provision, with hospitalization consuming the largest proportion of expenditure. The prevalence of musculoskeletal disorders is greatest in the elderly, and as their numbers increase so will the burden on health services. Age has an effect, particu-

Synovial joints have a capsule (Fig. 22.1) which is continuous with the periosteum covering the bone. The nonarticular surfaces within the joint are covered by synovial tissue. Articular cartilage lies on subchondral bone. Additional 'spacers' may be present in the form of fibrocartilage (e.g. knee menisci) or fat pads covered by synovium. Muscles acting across joints have an important function in maintaining joint stability (see also Fig. 22.2).

Joint capsule In most joints the capsule is composed of bundles of collagenous fibres arranged somewhat irregularly, in contrast to their more regular arrangement in tendons and many ligaments. These bundles tend to spiral, thus making them sensitive to tension in most positions that the joint adopts. Change in tension stimulates proprioceptive nerve endings in the capsule and ligaments. Most ligaments have both mechanical and proprioceptive functions. The joint is covered by the 'soft tissues', including tendons, bursae and ligaments. The junction of tendon and bone is called an enthesis; this can become inflamed.

Synovial tissue The synovial membrane is a specialized connective tissue lining the capsule of diarthrodial joints, bursae and tendon sheaths. Its main function is to produce synovial fluid. The normal synovium - glistening, slightly pebbly and with multiple redundant folds in its gross appearance has only three or four cell layers lining its surface. It is customary to divide the synovial lining cells into: • Type A, which are macrophage-like and have a primarily phagocytic function; • Type B, which are secretory and similar to fibroblasts, with a large amount of endoplasmic reticulum. Neither the structure of the synovium nor the composition of the synovial fluid suggests that there is a major barrier to fluid movement between the synovial capillaries and the synovial cavity. Furthermore, fenestrated capillaries have been described in the superficial part of synovium, and this type of capillary is usually found in tissues where there is a relatively high fluid and plasma protein flux between blood and tissues.

1119

FIG. 22.2 MRI scan of knee joint showing patella and tendons and intact posterior cruciate ligament

The functions of synovial fluid are lubrication (in association with articular cartilage) and nutrition of cartilage cells. 1

FIG. 22.1 Schematic cross-section synovia! joint

and X-ray B of normal

Synovial fluid The normal joint contains only a small volume of synovial fluid, essentially a dialysate of blood plasma with the addition of hyaluronic acid, which is secreted by synovial lining cells and imparts to the fluid its stickiness and high viscosity. Both the concentration of hyaluronic acid (normally about 3.5 g/L of fluid) and its molecular weight are reduced in conditions of inflammatory synovitis, particularly rheumatoid arthritis, with a resulting decrease in fluid viscosity. Most of the protein (60-75%) in synovial fluid is albumin; the larger globulin molecules are present in relatively lower concentrations. Plasma proteins of high molecular weight are present in small amounts in normal synovial fluid. When the synovium becomes inflamed, the protein content of the fluid increases and the quantity of large molecular weight proteins is greater than in normal fluid.

1

1120

MCQ 22.1

Articular (hyaline) cartilage Like other connective tissues, hyaline cartilage consists of three components: • Cells. The cells are chondrocytes and they synthesize the other components. • The matrix, which consists of proteoglycans linked to hyaluronate to form large aggregates. • The fibres, consisting of collagen, which binds the cartilage to bone and entraps the proteoglycan aggregates. Because proteoglycans absorb water, they swell to distend the collagen network and give cartilage elastic properties.

Joint sensation Synovial membrane is relatively insensitive to pain, but in contrast, capsule, ligaments and periosteum have a rich sensory supply, and these tissues are probably the main source of pain in arthritis, haemarthrosis and septic joints. With advanced joint damage sensory fibres from bone are also stimulated, owing to the release of chemical mediators. Arthritis tends to produce a 'flexion deformity' because there is an increase in synovial fluid and the joint is held in the position in which the capacity of the synovial cavity is greatest.

TABLE 22.1 Rheumatological terminology Term

Meaning

Arthralgia Arthritis Bursitis Enthesopathy Monoarthritis Oligoarthritis/pauciarticular Polyarthritis Synovitis Tendinitis Tenosynovitis Seropositive arthritis Seronegative arthritis

Pain arising in the joints Objective joint abnormality Inflammation of a bursa Inflammation or abnormality of an enthesis Affects one joint Affects two, three or four joints Affects more than four joints Inflammation of synovial joint Inflammation of tendon Inflammation of tendon sheath Rheumatoid factor present in serum Rheumatoid factor absent in serum

FURTHER READING ON STRUCTURE AND FUNCTION OF JOINTS Clements C D 1980 The joints. In: Gray's Anatomy, 30th American edn. Lea and Febiger, Philadelphia, pp. 329-428 Henderson B, Edwards J C W 1987 The synovial lining in health and disease. Chapman & Hall, London Nordin M, Frankel V H 1989 Basic biomechanics of the musculoskeletal system, 2nd edn. Lea and Febiger, Philadelphia Williams P L (ed) 1995 Skeletal system. In: Gray's Anatomy, 38th edn. Churchill Livingstone, Edinburgh, pp. 425-736

CLINICAL ASSESSMENT In arriving at a specific diagnosis, the information obtained from a detailed history and careful clinical examination must be collated with the radiological and laboratory findings. In addition, it should be remembered that often no single physical sign, laboratory test or radiological appearance is unique for a particular disease. Table 22.1 summarizes the terms commonly used in rheumatology.

HISTORY General Age, sex and race Age and sex are of some diagnostic value. Systemic lupus erythematosus (SLE), RA and Reiter's syndrome predominantly affect the young and middle-aged, whereas polymyalgia rheumatica and giant cell arteritis tend to affect the elderly. RA and SLE are more common in females, whereas ankylosing spondylitis, Reiter's syndrome and polyarteritis nodosa are more common in males. Gout

is more common in men, the sex ratio being 20:1 and the mean age at onset 40 years; in women, the onset of gout is postmenopausal. There is a higher incidence of SLE in female American blacks than in black males and whites of either sex, and familial Mediterranean fever is common in Sephardic Jews.

22

Occupation Repeated minor trauma resulting from occupational factors, unaccustomed exercise, leisure activities or changes in lifestyle may lead to arthropathy or soft tissue inflammation involving tendons, bursae or ligaments. OA may be caused by minor trauma, as in the proximal interphalangeal joints in wicket-keepers' hands. Arthritis may be due to a specific toxic agent, e.g. saturnine gout (lead), acrosteolysis (polyvinyl chloride) or avascular necrosis of the femoral head (nitrogen in deep sea divers). In RA and OA the dominant hand may be preferentially, or more severely, affected. Family history A genetic factor is present in some rheumatic diseases, e.g. ankylosing spondylitis, gout, psoriasis and haemophilia. First-degree relatives of RA patients have an increased incidence of RA, as well as other autoimmune diseases, e.g. myxoedema and pernicious anaemia. There is an association between RA and histocompatibility antigens DR1 and DR4. Most patients with ankylosing spondylitis have the histocompatibility antigen B27. Social history A detailed assessment of the patient's functional capacity, both at home and at work, is important. Practical details of the patient's occupation, mode of transport to work, and leisure pursuits are also important, as is the involvement of friends, family, community and social services. In addition, the patient's cooperation, motivation and goals must be assessed. Drug history The introduction or withdrawal of many drugs may exacerbate or precipitate existing rheumatic conditions. For instance, fluoroquinolone antibiotics can cause tendonitis. Attention must be paid to the dosage and duration of steroid therapy, as this can cause osteoporotic, vertebral crush fractures and, less commonly, avascular necrosis of bone. Exacerbation of symptoms is common if steroids are withdrawn too quickly. Details of previous drug therapy, the response to these agents and any adverse effects should be noted. Gout and SLE may be precipitated by drugs in susceptible individuals (Table 22.2). Previous medical history Inquiry should be made about similar illnesses in the past and their response to treatment (e.g. salicylates in rheumatic fever, colchicine in gout), as well as results of investigations. Previous aches and pains, rashes, venereal

1121

TABLE 22.2 Drugs precipitating gout and lupus syndrome Gout

Lupus syndrome

Thiazide diuretics Aspirin (low dosage) Allopurinol/uricosuric agents (initial therapy)

Hydralazine Procainamide Phenytoin Isoniazid Oral contraceptives (may exacerbate pre-existing SLE) Penicillamine

Cytotoxic therapy for malignancy or polycythaemia

diseases or other recent infections may have a bearing on the present illness. Prodromal illness A recent history of streptococcal sore throat is usual in rheumatic fever, and non-specific rashes or upper respiratory tract infection commonly precede viral arthritis. Previous episodes of diarrhoea, iritis or urethritis may indicate Reiter's syndrome or arthropathy complicating inflammatory bowel disease. Constitutional symptoms Constitutional symptoms are usually non-specific. Lowgrade fever, fatiguability, lethargy and night sweats are common in the connective tissue diseases and inflammatory joint disease, but are absent in OA. These symptoms may be present in acute RA, as well as in patients with an underlying malignancy. A swinging fever characteristically occurs in Still's disease, and in connective tissue diseases such as polyarteritis. A persistent low-grade fever may accompany tuberculous arthritis.

History of presenting complaint

1122

It should be clearly established which joints are the most troublesome and whether the patient is affected by pain, stiffness, impaired function or immobility. Pain is the chief symptom and major cause of disability in most rheumatic diseases. Its site, nature, duration, aggravating and relieving factors, radiation and relation to any specific incident must be determined. Some causes of pain have characteristic features: the pain of malignancy is constant, persists at night and is usually unrelieved by rest; that due to ankylosing spondylitis may be relieved by exercise; pain from the hip may often radiate to the knee. Stiffness may be particularly marked in the mornings, or after immobility. The former is typical of RA and is a useful guide to disease activity. The nature of onset of joint symptoms must be noted: e.g. whether this is acute and abrupt (as in infection or crystal synovitis) or chronic and insidious (as in RA and OA). RA may be of acute onset in the elderly. It should also be determined whether the progression of symptoms is episodic (as in gout) or migratory (as in rheumatic fever);

and the number and order in which joints are involved. Many rheumatic diseases have characteristic patterns of joint involvement, for example: • Mono articular, as in infective and crystal arthritis • Oligo- or pauciarticular, as in juvenile arthritis • Poly articular, as in RA and SLE. Problem identification It is necessary at the beginning to identify the major clinical problems. Once the doctor has established the reason for the consultation, then the site and principal symptoms can be clearly identified. In particular, symptoms arising from the joints should be differentiated from those due to bursitis, tendonitis, myalgia, vascular insufficiency, peripheral neuropathy or radicular or spinal compression. In peripheral arthritis pain is usually maximal over the joint; in soft tissue rheumatism (including low back pain) it is less easy to localize.

PHYSICAL EXAMINATION Many rheumatic complaints are part of a multisystem disorder, and a complete physical examination is necessary. Special attention must be paid to those organs that are most frequently involved in rheumatic conditions, such as the skin and mucous membranes, the eyes, and the gastrointestinal and genitourinary systems. The patient's posture in bed may indicate 'protection' of affected joints from movement or undue pressure. Mouth ulcers may be a manifestation of disease, e.g. Behcet's (painful) or Reiter's syndrome (painless). These conditions are often associated with genital ulcers or circinate balanitis and, in Reiter's syndrome, plaquelike lesions on the glans penis. Ulcers in the mouth and throat may also be caused by infection secondary to the neutropenia of Felty's syndrome or drug therapy, particularly the use of gold and immunosuppressive agents. Leg ulcers are a feature of Felty's syndrome (p. 1137). Dryness of the conjunctiva and mucous membranes, as a result of reduced lacrimal and salivary gland secretions, occurs in the sicca syndrome (p. 1138). Splenomegaly and hepatomegaly are found in Still's disease, Felty's syndrome and SLE. Abnormalities of the skin and its appendages may be associated with joint disease (Table 22.3). The eyes are commonly involved in connective tissue disorders, and symptoms may antedate those due to joint disease (Table 22.4).

Musculoskeletal system Clinical assessment involves inspection, palpation and assessment of function based on the range of joint movement. Most joints and muscle groups are paired and can therefore be compared. Inflamed joints are painful and must be examined gently. The nature of the joint swelling,

TABLE 22.3 Dermatological signs in joint disease

TABLE 22.5 Patterns of polyarticular disease

Rash Localized Butterfly rash and light-sensitive rash in SLE Psoriatic plaques Erythema chronicum migrans in Lyme disease Generalized Macular rash in Still's disease Drug rash Erythema marginatum in rheumatic fever

Peripheral (small joints of hands, feet and wrists) Symmetrical Rheumatoid arthritis Asymmetrical Psoriatic arthritis Osteoarthritis Gout

22

Central (sacroiliac joints, spine, lower limb joints) Ankylosing spondylitis, enteropathic arthritis, Reiter's syndrome etc.

Ulcers Leg ulcers in Felty's syndrome and rheumatoid vasculitis Ischaemic ulcers of fingertips in systemic sclerosis Infarction Nailfold infarcts in RA, SLE and vasculitis Nodules Sited over pressure areas and tendons in RA Tophi in gout

Nails Pitting and onycholysis in psoriasis Hair Alopecia or loss of frontal hair in SLE

TABLE 22.4 Ophthalmic complications of joint disease Disease

Structure(s) affected

Gonococcal arthritis Sicca syndromes (e.g. Sjogren's syndrome) Rheumatoid arthritis Ankylosing spondylitis, Reiter's Behcet's syndrome Vasculitis in SLE Drug treatment of joint disease

Conjunctiva Lacrimal gland and conjunctiva Sclera and episclera Iris, uveal tract Iris Retina Cataract (e.g. due to steroids in children) Retinopathy (e.g. due to chloroquine)

together with the temperature and tenderness of the joint, can be ascertained by palpation: • If the joint swelling is soft, warm and tender, it is usually due to synovitis; • If hard, it is usually due to bony overgrowth; • If fluctuant, it is usually due to an effusion. Type and distribution of joint involvement Many rheumatic diseases have characteristic patterns of joint involvement (Table 22.5). However, clinical variants are not uncommon and the pattern may be atypical in the early stages of disease.

FIG. 22.3 Joints of the hands involved in rheumatoid arthritis and Osteoarthritis Note how OA affects the carpometacarpal joint of the thumb, and RA affects the wrist. 1 OA of the first carpometacarpal joint gives an appearance of a 'square hand' due to enlargement of the joint and adductive deformity of the metacarpal joint. 2 Osteophytes of the terminal interphalangeal joints are called 'Heberden's nodes',

In the hand (Fig. 22.3), RA usually affects the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints, while sparing the distal interphalangeal (DIP) joints. In contrast, primary OA involves the PIP and DIP joints as well as the first carpometacarpal joints, and tends to spare the MCP joints. Joint swelling may be caused by fluid, subcutaneous tissue, synovial or bony overgrowth (e.g. Heberden's nodes in OA). Fluid may result from effusion within either a joint or a bursa. It is often tense but, when present in small amounts, may be squeezed from one side of the joint to the other. Subcutaneous tissue is often warm and tender, indicating acute disease, commonly septic arthritis, gout or tendonitis. Pitting oedema of tissues overlying a joint is also a sign of acute inflammation and may occur in early RA. Synovial or capsular thickening is confined to the anatomical boundaries of the joint. It feels doughy and can best be felt by pinching the soft tissues gently and rolling the synovium over the joint. Deformity is usually a feature of established disease and has many causes (Table 22.6). It may limit both function and movement and should be accurately described. Many conditions are associated with characteristic deformities

1123

TABLE 22.6 Factors contributing to joint deformity

TABLE 22.7 Modified Beighton scoring system

• • • •

Manoeuvre

Score

1. Extend little finger >90° 2. Bring thumb back parallel to or touching forearm 3. Extend elbow >10° 4. Extend knee >10° 5. Touch floor with palms of hands, keeping the legs straight

1 point for each finger 1 point for each thumb

Synovial hypertrophy Bony or cartilaginous overgrowth Urate deposits Joint subluxation/dislocation

• Bone absorption/misalignment • Muscle contracture • Tendon rupture

1 point for each elbow 1 point for each knee 1 point

A score of 6 or more indicates hypermobility.

FIG. 22.4 Types of knee deformities A Varus - due to medial compartment damage; typical of OA. B Valgus - seen when both compartments are damaged; typical of inflammatory arthritis. C Flexion deformity - common in many arthritides.

(e.g. at the knee; Fig. 22.4), but no deformity is pathognomonic of one disease. Tenderness may be localized when caused by meniscal tears, inflamed Heberden's nodes and bony spurs. Synovial inflammation, however, is diffusely tender over the joint surface and its severity is a useful parameter in the assessment of disease activity. Range of movement of an individual joint is determined by its anatomical configuration. Active movement may be limited by damage to the articular surfaces, muscle weakness and tendon involvement. Passive movement may produce pain or discomfort, resulting in reflex spasm or voluntary contraction of muscles, which reduces the actual range of movement. When the active and passive ranges are not equal, the passive is usually the greater and is a more reliable indicator of the actual range of movement. The pattern of pain on movement is of diagnostic significance. Pain absent or minimal in the midrange but increasing towards the extreme of restricted movement is 'stress pain'. Pain in most/all directions is the most sensitive sign of synovitis. Pain in one plane of movement is characteristic of a localized intra- or periarticular lesion. Pain uniformly present throughout a range of movement suggests a mechanical rather than an inflammatory problem. The range of movement may be increased in hypermobility syndromes, such as Ehlers-Danlos and Marfan's

1 1124

MCQ 22.2

(pp. 71-72). Approximately 10% of normal people also fall into the hypermobile spectrum. Although normal, such hypermobility may contribute to locomotor problems, e.g. dislocation, enthesopathy. Generalized hypermobility can be assessed using a modified Beighton score (Table 22.7). During movement, crepitus may be felt. This is a sensation of creaking or grinding, which is a sign of damage to the bearing surfaces. Characteristically, this is coarse in OA and fine in RA. Crepitus may also arise from tendon sheaths. Instability is usually caused by a combination of ligament laxity, rupture or joint displacement. The knee and ankle joints should be tested with the patient bearing weight, as well as on the examination couch. Gait should be observed with the patient wearing shoes. The patient's ability to rise from a chair, bend and undress will provide valuable clues in diagnosis. Muscle power. The muscles should be evaluated for both atrophy and weakness. In patients with joint disease these usually involve muscles adjacent to the affected joints. Muscle tenderness is uncommon, except in patients with inflammatory muscle disease.

INVESTIGATION There are few specific and reliable tests in rheumatology, and so results should not unduly influence clinical judgement. Haematological and immunological investigations Haemoglobin A moderate anaemia is the commonest systemic manifestation of inflammatory joint disease, and its severity reflects disease activity (Table 22.8). Although the anaemia is often hypochromic and sometimes microcytic, it generally reflects the inability of the reticuloendothelial cells to release sequestered iron, and only occasionally a genuine iron deficiency. However, a haemoglobin below l0g/dL usually indicates iron deficiency or a cause other than disease activity.

TABLE 22.8 Anaemia in rheumatoid arthritis Measurement

Typical value in RA

Haemoglobin

Males 12.5g/dL Females 11.0g/dL 28-32.0 g/dL (normal 32-36 g/dL)

Mean corpuscular haemoglobin concentration Serum iron Transferrin Ferritin Serum folate Red blood cell folate Bone marrow

Low Normal or low Lower limit of normal (without iron deficiency); low with iron deficiency Low Occasionally low Normoblastic; very occasionally megaloblastic

TABLE 22.9 Pathogenesis of the anaemia of chronic disease Decreased production of red cells Inadequate iron supply Impaired absorption and transport Failure to release iron stores Erythropoietin Decreased concentrations Increased marrow resistance

trophilia, occurs in infective arthritis, acute gout, juvenile chronic polyarthritis, and in rheumatoid patients receiving corticosteroids. Higher counts of 30 000/mm3 or more, with or without eosinophilia, may be a feature of polyarteritis nodosa (PAN). Eosinophilia also occurs in rheumatoid patients as a result of gold sensitivity and, rarely, in association with nodular, vasculitic, erosive and strongly seropositive disease. RA with splenomegaly and neutropenia is referred to as Felty's syndrome', anaemia and a slight thrombocytopenia are also common. Drug sensitivity, e.g. to gold or penicillamine, may cause a pure agranulocytosis, whereas cytotoxic drugs tend to cause a more general depression of the white cell count. Leukopenia is a feature of SLE, although counts of under 2 x 10-9/L are infrequent, and the response to infection is usually preserved.

22

Platelets Thrombocytosis is found in approximately one-third of patients with RA, and has been observed to correlate directly with disease activity. Most commonly, thrombocytopenia is related to therapy with antirheumatoid drugs, such as penicillamine, gold and cytotoxic agents. Regular platelet counts are necessary when these agents are used. An autoimmune thrombocytopenia occurs in up to 20% of patients with SLE and in patients with the primary antiphospholipid antibody syndrome. In some patients antiplatelet antibodies can be demonstrated.

Ineffective erythropoiesis Abnormal development of erythroid progenitor cells

The avid retention of iron by the reticuloendothelial system and synovial membrane is reflected by a rise in both serum ferritin concentration and normal iron stores within the bone marrow. In this situation, measurement of serum iron and transferrin is often unreliable: the serum iron level may fall, as it is no longer released, and transferrin synthesis by the liver may be depressed, causing a slow fall in the total iron-binding capacity (the anaemia of chronic disease, see Table 22.9). A hypochromic microcytic anaemia with a low serum concentration and a raised total iron-binding capacity may be due to complications of the disease such as oesophagitis, but is usually a complication of treatment with non-steroidal anti-inflammatory drugs. Anaemia can also be autoimmune haemolytic in type, which occurs in up to 10% of patients with systemic lupus erythematosus. Macrocytosis usually reflects folate deficiency, but pernicious anaemia is associated with autoimmune rheumatic diseases, particularly RA. Macrocytosis is a complication of therapy with methotrexate, a folate antagonist, and azathioprine, drugs commonly used in the treatment of rheumatic diseases. 1 White cell count A raised white cell count, of 12 000-20 000/mm3 with a neu-

Erythrocyte sedimentation rate The erythrocyte sedimentation rate (ESR) is a non-specific indicator of inflammation and is rarely of diagnostic value. In RA the ESR is measured to follow the course of disease. However, patients with long-standing disease and hyperglobulinaemia may have persistently raised values. Conversely, patients with progressive erosive disease may have only a mildly elevated ESR. Similarly, in other inflammatory arthritides, normal values do not exclude active disease. In polymyalgia rheumatica (PMR) an ESR of over 50mm in the first hour is usual and alerts the clinician to the possibility of this disease in patients with rheumatic symptoms but minimal joint signs. A normal ESR can occur even in active PMR, particularly if flares occur during treatment. Viscosity Plasma viscosity has replaced the ESR in some laboratories, as the test can be automated and the results are not influenced by age, sex or haematocrit. Both measurements are mainly dependent upon changes in fibrinogen and other globulins. Acute-phase proteins The acute-phase proteins, which include C-reactive proteins (CRP), fibrinogen, haptoglobin, caeruloplasmin and a1-antitrypsin, are raised in 'active' inflammatory joint disease. The term is misleading, as changes may occur in both acute and chronic inflammation. About 35 acute-

1125

TABLE 22,10 Seropositivity and antinuclear antibodies in connective tissue disease Disease

FIG. 22.5 The RA latex test Latex beads passively coated with human IgG are cross-linked by rheumatoid factor to produce visible flocculation.

phase proteins have been described. In RA patients, measurement of both CRP and ESR may be more helpful than either alone in assessing disease activity. As acutephase proteins are single proteins, measurement is less influenced by anaemia, changes in size and shape of red cells, serum immunoglobulins and cholesterol concentrations. Synthesis of acute-phase proteins in the liver is triggered by several cytokines, including interleukin-1, interleukin-6 and tumour necrosis factor. Cytokines derive from macrophages that have been activated at the site of the injury, and also from fibrobasts and endothelial cells. C-reactive protein Measuring C-reactive protein can be a useful test for distinguishing between a lupus flare and infection: it usually remains normal in a flare, unless accompanied by serositis or synovitis but is elevated in infection. The ESR will be elevated in both, and occasionally remains elevated when the disease is clinically quiescent.

1126

Rheumatoid factors Rheumatoid factors (RFs) are autoantibodies directed against antigenic determinants on the Fc fragment of immunoglobulin G (IgG). RF is locally produced in the rheumatoid synovium. Although RF may also belong to immunoglobulin classes IgG and IgA, the standard tests measure IgM RF. The commonly used tests are those in which indicator cells (sheep red cells) or particles (latex), coated with IgG, are agglutinated (Fig. 22.5). The latex test is more widely used and is cheaper than the more specific but time-consuming sheep cell agglutination test (SCAT). Normal ranges vary between laboratories, but titres greater than 1:80 are generally considered to be positive results. Detection of IgG and IgA rheumatoid factors by enzymelinked immunosorbent assay (ELISA) is becoming more widely available. The clinical specificity of IgA rheumatoid factor is not clear, but it has been found early in the course of rheumatoid arthritis. Oligoarticular rheumatoid arthri-

Rheumatoid arthritis Sjogren's syndrome Systemic lupus erythematosus Systemic sclerosis Dermatomyositis Polyarteritis nodosa Juvenile chronic arthritis Other diseases Chronic hepatitis Fibrosing alveolitis Sarcoidosis Cryoglobulinaemia .

IgM rheumatoid factor (%)

Antinuclear antibodies (%)

70 90

20-30 60-80 90-100

30

70 30

10

30

10-20

65

15

30

tis may be associated with a negative test for IgM rheumatoid factor but a positive test for IgG rheumatoid factor. Although RF is found in up to 80% of patients with RA, its presence is by no means diagnostic: it is also present in other connective tissue diseases (Table 22.10), chronic infections, other immunological disorders, and in 4% of the general population. The incidence in the general population increases with age (25% over the age of 75 years) and is higher in relatives of people with positive tests, whether or not they have RA. Recent work suggests that a common factor may be a defect in glycosylation of the IgG molecule, leading to a reduction of terminal galactose and an increase of N-acetyl glucosamine. This has revived interest in the idea that mycobacteria or streptococci (which also express this sugar) may be involved in the aetiology of RA. This defect in galactosylation appears to be related to disease activity, becoming less marked with disease remission. RF may be absent in early RA. Indeed, it commonly takes up to 6 months from the onset of symptoms before RF is detectable. The role of IgM RF is not entirely clear, but evidence suggests that it is capable of fixing complement and it may facilitate the phagocytosis of immune complexes by neutrophils in the synovial fluid. Antinuclear antibodies Antinuclear antibodies are described on page 1172. Table 22.10 shows the incidence of antinuclear antibodies in connective tissue disease. Antinuclear antibodies include antibodies binding to a wide range of structures, including DNA, RNA, histones, etc. It is often possible to characterize an antinuclear antibody, and this is usually helpful in diagnosis in rheumatological disorders. Serum complement The serum complement level (total haemolytic complement, C3 or C4) is a useful investigation in SLE. Low com-

plement levels in the presence of a high DNA-binding titre are diagnostic of active SLE. Serial measurements of complement are useful in following the clinical course of lupus, as the level drops by about 50% before, and remains low during, an exacerbation. Particularly low levels of complement components, especially C3 and C4, are strongly indicative of active lupus nephritis, as a result of complement being continuously consumed by the immune complexes deposited in the glomeruli. Deficiency of a complement component may occasionally be hereditary, and a deficiency of C2 is associated with the development of lupus. These cases are rare, and low concentrations of complement are almost always acquired. As part of the acute-phase response, complement proteins often show a modest rise in many inflammatory rheumatic diseases.

Biochemical investigations Biochemical screening results are frequently abnormal in connective tissue diseases, but apart from a markedly raised serum urate in gout, have little diagnostic value. Tests of renal function are essential, as the kidney is frequently affected by glomerulonephritis in SLE and may be affected by amyloid in RA and ankylosing spondylitis. Abnormalities in liver function may reflect disease activity (e.g. raised alkaline phosphatase in rheumatoid arthritis and raised liver enzymes in polymyositis). Many of the drugs used in treatment may lead to abnormal liver function. Muscle diseases, in particular polymyositis, may be associated with a rise in creatine kinase, and serial measurements reflect activity, but exercise can lead to a temporary but dramatic increase.

Synovial fluid examination Synovial fluid examination is critically important if septic arthritis is a possibility. The appearance, cell count, Gram stain and culture all contribute to the diagnosis. For other rheumatic conditions, results must be interpreted in the light of biochemical and other laboratory features because considerable overlapping of diagnostic groups can occur. Skill in joint aspiration is easily acquired and it is a virtually painless procedure; indeed, removal of fluid often relieves pain. Confidence is gained by studying diagrams, watching clinicians, and finally by using the techniques. The risk of iatrogenic infection is minimal when a careful aseptic or no-touch technique and disposable syringes and needles are used. Single-dose ampoules should be used whenever possible. The patient should be relaxed. Careful palpation of bony margins and surfaces before skin preparation aids success. Fluid for a differential cell count should be placed in anticoagulant, and is best examined within a few hours; fluid for culture and for crystal examination should be placed in a sterile container without anticoagulant or preservative. Examination of the synovial fluid identifies urate and

22

FIG. 22.6 Identification of joint crystals by polarized light microscopy

calcium pyrophosphate crystals by using the effect of polarizing light to demonstrate the differences in crystal lattice structure of the compounds. When viewed under the compensated polarized light microscope, urate crystals show strong negative birefringence and calcium pyrophosphate shows weak positive birefringence (Fig. 22.6).

Synovial biopsy Tissue may be obtained by open surgery, arthroscopy (see Fig. 22.7) or ultrasound-guided needle biopsy. Needle biopsy has the disadvantage of possible sampling error. Synovial biopsy is indicated in monoarthritis, when the diagnosis is in doubt. Specific histological features are found in tuberculosis, amyloid and Whipple's disease.

Radiological investigations X-rays of clinically involved joints are often helpful in the investigation of rheumatic disease. X-rays of the hands and feet are the most valuable, as the bones and joints of the hands and wrist are involved in many types of arthritis, the connective tissue diseases and some metabolic disorders. X-rays may demonstrate diagnostic features despite the absence of symptoms and signs in these joints; this is particularly so in RA, juvenile arthritis and psoriatic arthropathy. Radiological changes in rheumatoid arthritis The radiological changes seen in RA (Fig. 22.8) are: • Soft tissue changes. An increase in soft tissue shadows due to an effusion; • Juxta-articular osteoporosis. Rarefaction of bone, an early sign of inflammation; • Uniform narrowing of joint spaces. This implies loss of cartilage; • Erosions at margins of joints (near origin of synovium and capsule). This is the most definitive radiological change and implies removal of bone substance. In most patients it takes at least 3 months for bone changes to appear (e.g. cartilage thinning or bone erosion). Radiology is helpful in the diagnosis of conditions mimicking RA. In the case of gout, tophi may erode bone outside the joint capsule (unusual in RA), and frequently tophi have a greater density than surrounding soft tissue. In degenerative arthritis reactive bone formation is

1127

FIG. 22.7 Synovial appearances of inflammatory arthritis visualized through an arthroscope, showing inflamed polyps and haemorrhage around small blood vessels

ageing and should not be used indiscriminately to explain musculoskeletal symptoms in the elderly. Chondrocalcinosis (Fig. 22.9) is a radiological finding characteristic of 'pseudogout' or calcium pyrophosphate arthropathy (p. 1171). CT scanning This is particularly helpful in visualizing the spine and intervertebral discs, and can determine spinal cord compression. Images of the small joints are difficult to interpret and expose the patient to large doses of radiation.

FIG. 22.8 Rheumatoid arthritis of the wrist and hands: progressive radiological changes over a 5-year period

prominent and distal interphalangeal joint involvement is common, whereas osteopenia around joints and metacarpophalangeal joint damage are rare. It should be remembered that degenerative changes in joints are a feature of

1

1128

Fig. 22.1

Magnetic resonance imaging (MRI) MRI is now used extensively to image joints and soft tissues. The introduction of more powerful magnets has allowed high definition of soft tissues and the detection of early bone erosions. Enhancement of the images using gadolinium-DPTA allows the early detection of synovitis. MRI is mainly used for imaging the spine and large joints. MRI of the spine allows visualization of disc protrusions and intradural abnormalities such as arachnoiditis. In rheumatoid arthritis it is useful in evaluating cervical spine pathology, and in patients with musculoskeletal problems is used particularly in knee and shoulder pain.

Other investigations An arthrogram, produced by injection of radio-opaque dye into the joint, may show the meniscus or a ruptured joint capsule. A bone scan shows increased uptake in inflammatory arthritis and is useful in demonstrating malignancy.

TABLE 22.11 Diseases that may present as acute polyarthritis

TABLE 22112 Clinical Glues in the differential diagnosis of polyarthritis

• • • • • • • • • • • • • • •

• Family history - of gout and familial Mediterranean fever • Similar episodes in the past, and response to treatment, e.g. salicylates in rheumatic fever and colchicine in gout • Genitourinary symptoms suggest Reiter's syndrome; in homosexual males suspect gonococcal arthritis • Symptoms of inflammatory bowel disease suggest enteropathic arthritis • Immunosuppressive therapy, e.g. corticosteroids may predispose to septic arthritis • A history of photosensitivity, Raynaud's phenomenon or recurrent abortions suggest SLE • Symptoms of infection in Septic arthritis

Rheumatoid arthritis and palindromic rheumatism Adult and childhood Still's disease (juvenile chronic arthritis) Rheumatic fever Systemic lupus erythematosus Infections - viral (rubella), rarely pyogenic and tuberculous Reiter's disease Seronegative arthritides, e.g. psoriatic arthritis Gonococcal arthritis Gout and pyrophosphate arthropathy Serum sickness Acute sarcoidosis with erythema nodosum Familial Mediterranean fever Henoch-Schonlein purpura Type II hyperlipoproteinaemia Leukaemia

22

Technetium pertechnetate in isotope form can be used to measure blood flow and show increased uptake in inflammatory arthritis. Bone-seeking preparations such as diphosphonates labelled with technetium also show increased uptake. White cell scanning, which involves labelling a sample of a patient's white cells with a radiolabel and then reinjecting them into the patient, may be useful in identifying areas of infection. Arthroscopy is useful for demonstration of mechanical lesions, particularly in the knee, where a torn meniscus can be demonstrated and partially removed. It is also used for obtaining synovial biopsies and in the management of septic arthritis (after partial removal). Ultrasonography is sensitive at detecting synovitis of joints and has an impact on the overall clinical diagnosis and management of a number of musculoskeletal conditions. It is likely to become more widely used.

DIFFERENTIAL DIAGNOSIS OF POLYARTHRITIS

FIG. 22.9 Chondrocalcinosis A Common radiological sites for pyrophosphate deposition (knee, symphysis pubis and wrist). B Chondrocalcinosis in the knee joint. Calcification is present the menisci and the joint shows degenerative changes, with loss of joint space, osteophyte formation and cysts. 1

Chronic rheumatic disorders, with their characteristic deformities and clinical, radiological and serological abnormalities, do not usually pose problems in differential diagnosis. However, an acute polyarthritis may be the presenting feature of many rheumatic diseases (Table 22.11) and, at this early stage, diagnosis may be difficult: there is wide variation in the severity of acute attacks and the number of joints involved, and the pattern may change with recurrent attacks of the same illness. It must be stressed that an acute polyarticular presentation is not the only mode of onset in the diseases listed in Table 22.11, and the list itself is by no means exhaustive. A practical approach to differentiate diagnosis is to separate RA from the rest. General points that may help in the differential diagnosis of polyarthritis are given in Table 22.12. Certain types of arthritis tend to be commoner in particular sexes and age groups (Table 22.13). Determining the balance of joint and systemic symptoms may also be helpful in diagnosis (Table 22.14).

1129

TABLE 22.13 Types of arthritis according to age and sex Age/sex

Type of arthritis

Child Adolescent

Juvenile arthritis, viral infection, rheumatic fever Traumatic synovitis, ankylosing spondylitis, infectious mononucleosis Reiter's syndrome, rheumatoid arthritis Degenerative joint disease, pyrophosphate arthropathy (pseudogout) Rheumatoid arthritis, systemic lupus erythematosus Gout, Reiter's syndrome Nodal generalized osteoarthritis

Adult Elderly Female Male Perimenopausal

TABLE 22.14 The balance between joint and systemic symptoms* in acute polyarthritis Conditions in which joint disease predominates Acute-onset RA Rheumatic fever Reiter's syndrome Gonococcal arthritis Gout and pseudogout (pyrophosphate arthritis) Conditions in which systemic disease predominates SLE Still's disease - adult and juvenile systemic types Acute sarcoidosis with erythema nodosum Polyarteritis nodosa * Systemic features include fever, rash, lymphadenopathy and hepatosplenomegaly.

The combination of symptoms in well-recognized clinical syndromes can help in the diagnosis, e.g. Reiter's syndrome presents as a classic triad of acute polyarthritis, urethritis and conjunctivitis. The major clinical features of rheumatic fever are carditis, chorea, arthritis, subcutaneous nodules and erythema marginatum.

Patterns of arthritis and progression In addition to the anatomical distribution (Table 22.5) of joint involvement, the temporal pattern and progression of polyarthritis are helpful in arriving at a probable diagnosis. Temporal patterns Migratory pattern Joints that were initially inflamed remit, whereas other 1

1130

MCQ 22.3

joints simultaneously become acutely inflamed. Although occasionally seen in RA and SLE, this pattern is more common in acute rheumatic fever, postviral arthritis, gonococcal arthritis and meningococcal septicaemia. Additive pattern Here, features tend to accumulate during the disease while the original features persist. This pattern is non-specific and is seen in RA, SLE and post-rubella arthritis. Palindromic or intermittent pattern This describes conditions associated with recurrent attacks of synovitis that remit completely without sequelae. Short episodes (2-3 days) are seen in RA and gout, and may occur in sarcoidosis and familial Mediterranean fever (FMF). Longer episodes (7-10 days) occur in the peripheral synovitis of spondylitis, the arthropathy of inflammatory bowel disease, Behcet's syndrome, and also in FMF Concerning progression, polyarthritis may be transient, e.g. in viral infections; recurrent, as in palindromic rheumatism; or may develop into a chronic disorder, e.g. in RA. Palindromic rheumatism is a descriptive term for acute episodes of joint pain, swelling, redness, tenderness and stiffness recurring at irregular intervals, developing spontaneously and lasting a few hours. Up to one-third of cases subsequently develop RA. 1 FURTHER READING ON CLINICAL ASSESSMENT Doherty M, Hazleman B, Blake D, Maddison P, Perry D 1992 Rheumatology examination and injection techniques. W B Saunders, London Liang M H, Jette A J 1981 Measuring functional ability in chronic arthritis: A critical review. Arthritis Rheum 24:80-86

RHEUMATOID ARTHRITIS

Rheumatoid arthritis is the most common chronic inflammatory disease of joints. Although the brunt of the disease falls on the joints, this is a systemic condition and may affect other organs. The median life expectancy is reduced by 7 years in males and 3 years in females. An increased mortality of around two to three times is seen if only those treated in hospital are considered. Life-table analysis has shown that patients have a worse 5-year survival rate than age-matched cases with Hodgkin's disease or triple-vessel cardiovascular disease. In addition to inflicting disability and increased mortality, RA also has a serious economic toll on health-care systems. Compared to an age- and sex-matched population without the disease, individuals with RA incur three times the cost of medical care, twice the rate of hospitalization and four times the number of visits to a physician. Patients have 10 times the work disability rate of the general population and after 10 years only 50% of RA patients remain employed, and 40% cease work within 2 years.

A Definite cases (%)

Ratio of female to male cases

population was more similar to rates in the western world. The onset appears more common in winter.

22

Aetiology The aetiology of RA remains unknown. A wide range of epidemiological, immunological and clinical observations must be considered in arriving at a unified concept of aetiology and pathogenesis.

B Prevalence in each decade (%)

Prevalence in each decade (%)

FIG. 22.10 Epidemiology of rheumatoid arthritis A Estimates of prevalence of RA (probable and definite) in different countries derived from surveys conducted at similar times. B Prevalences of RA in the UK 1954-62 using American Rheumatism Association criteria. (After Lawrence JS, 1977.)

• The first European descriptions of the disease date from the 19th century, although remains of American Indians show typical RA features dating from centuries earlier. • Genetic factors account for some 60% of the variance noted in epidemiological studies. However, concordance in monozygotic twins is only 12-15%. The presence of the 'shared epitope' of HLA-DR4 is the strongest single factor correlating with progressive disease (rather than the presence of disease), and may be a useful marker in identifying patients for more aggressive treatment. • The contraceptive pill may protect against the development of severe disease. It is also noted that disease may become quiescent during pregnancy, flaring in the puerperium. • A number of infectious agents have been investigated, particularly the herpesvirus family (EBV, CMV) and the retro virus HTLV-1. Antibodies are identified in many patients, but may represent an epiphenomenon of a generalized increase in immune reactivity. Furthermore, there are important differences between reactive arthritis (see below) and RA. • The innate immune system learns tolerance of selfantigens. A number of theories relate to altered expression of these antigens, perhaps in conjunction with the HLA-DR4 (class II MHC), activation of dormant autoreactive T cells by an environmental trigger (infective or otherwise), or release of a normally sequestered self-antigen in damaged joints. Collagen type II is the favoured autoantigen in current theories.

Pathogenesis Epidemiology RA is a condition of unknown aetiology whose distinctive features include a persistent and symmetrical peripheral inflammatory arthritis. RA remains the major disease against which other forms of arthritis are compared, because it is the most common (1-3% of the population) and the most disabling of the inflammatory arthritides. There is a female preponderance of 3:1 and 70% of cases begin between the ages of 25 and 59, although it can begin at any age and the mean age of onset is increasing. (Fig. 22.10). There is some evidence for a declining trend in the incidence. Differences in prevalence rates have been reported for various ethnic populations. In black rural Africans a low prevalence rate of 0.1 % for definite RA was reported, whereas the prevalence rate in an urban black

Both inflammation and joint destruction are the characteristic features of RA. The major events in the pathogenesis of RA are shown in Figure 22.11. Conventional models have described a linear progression of joint inflammation leading to synovial hypertrophy, which then erodes cartilage and bone. More recent observations suggest that inflammation and erosive disease may progress somewhat independently. Furthermore, systemic activation is an early feature of disease, manifest as an acute-phase response, the production of a rheumatoid factor and, in some, other extra-articular manifestations. In others these systemic features appear at a later stage. Histological studies implicate a number of different cell types, their related cytokines and other factors. • Two principal types of synovial cell are found in rheumatoid synovium. Type A cells are macrophage-like and

1131

FIG. 22.11 A schematic representation of the major events thought to be involved in the immunopathogenesis of rheumatoid arthritis

are a key source of cytokines, which mediate many of the pathological processes in addition to perpetuating the inflammation itself. Type B cells are fibroblast-like. There is some evidence that these cells become 'transformed', i.e. manifesting features associated with malignant proliferation. Oncogenic markers are identified, and mutations in the tumour supressor gene p53 support the concept of altered growth potential, explaining the proliferation of these cells leading to the production of the invasive pannus characteristic of RA. The role of T-cells is increasingly recognized. The Thl subclass of CD4+ cells is associated with a proinflammatory cytokine profile (IL-1, interferon [IFN]-y) and with cell-mediated immunity. These cells are almost certainly critical in early RA, though later disease is largely mediated by T cell-independent pathways. Furthermore, specific anti-T cell therapies have had disappointing results. Immunological abnormalities in the serum of patients include hypergammaglobulinaemia and the presence of rheumatoid factors (RF). IgG RF, in particular, readily undergoes self-association through its binding affinity for its own Fc determinants, forming immune complexes. These complexes have been detected in the synovial membrane, synovial fluid, serum and surrounding blood vessels. They are phagocytosed by neutrophils, monocytes and macrophages, with the release of inflammatory mediators and enzymes. In addition, immune complexes containing RF can activate the complement cascade, which generates inflammatory and chemotactic factors

1 1132

MCQ 22.4

with further accumulation of inflammatory cells. High titres of RFs, both IgG and IgM, correlate closely with the presence of severe erosive joint disease, nodules, vasculitis and extra-articular complications of RA. • Cytokines are the immunological signal peptides. Produced by a number of cells in the immunological system, some have a very specific role, whereas others have a number of target cells and/or a range of effects on those target cells. Positive feedback loops ensure the perpetuation of disease. The most important cytokines in RA are TNF-a and IL-1 (from monocytes) and IL-6 from fibroblasts. IL-12 and -15 are important in stimulating further T-cell growth and differentiation from the Thl subtype, whereas IL-17, produced by T cells, stimulates fibroblasts and osteoclasts which erode cartilage and bone. • Matrix metalloproteinases are a group of degradative enzymes, of which collagenase and stromolysin are the most important in RA. These MMPs are produced together with their inhibitory proteins (tissue inhibitors of metalloproteinases, or TIMPs), but the active enzyme exceeds the amount of regulatory protein present. Degradation of bone matrix requires other enzymes, the cathepsins. • Pannus, the proliferative layer of synovial fibroblasts, is oedematous, highly vascular and inflamed. Lymphoid follicles can form and plasma cells are present. Active inflammation of the synovium is also associated with inflammatory changes in the synovial fluid, which contains large numbers of granulocytes (these are not present in the synovium). Pannus first erodes bone at the 'bare area' which is intra-synovial but is not covered by hyaline cartilage. Studies of the erosive front reveal osteoclast precursors, forming functional multi-nucleate osteoclasts at the site of erosion. The stimulation for differentiation and erosion remains obscure, though T-cells and fibroblasts express the osteoclast-regulatory signal RANK-L (receptor activator of nuclear factor kappa-B), and IL-17 stimulates osteoblasts to activate osteoclasts through this same signal (and by downregulation of the inhibitory signal osteoprotegerin). Each of these factors is believed to be important in the overall pathogenesis of RA, and a plausible theory should explain how they interact. One favoured theory implicates CD4+ T cells in a critical initiating event, interacting with antigen-presenting cells in the joint, or perhaps in subchondral bone, which present an altered self-antigen in the context of specific MHC-II markers. This leads to the activation of monocytes which produce large amounts of TNF-a and IL-1, initiating a cascade of cytokines through various positive feedback signals. These activate a wide range of other cells, particularly synovial fibroblasts, which proliferate to produce the pannus, producing cartilagedegrading enzymes and activating the osteoclasts that erode bone. There is also increased expression of intercellular adhesion molecules on endothelial cells, resulting in further influx of inflammatory cells, thereby perpetuating

the inflammatory and destructive process. This increased understanding of the pathogenesis of RA has identified a number of new therapeutic targets. Indeed, it is feasible that increased understanding of genetic factors will define subsets of patients in whom one element dominates, allowing more specific, targeted therapy. Inflammatory mediators Local release of inflammatory mediators leads to increasing exudation of high molecular weight proteins such as fibrinogen. This results in local fibrin deposition, with activation of the fibrinolytic system and the release of further inflammatory and destructive enzymes. Local fibrin deposition may be a further immunological stimulus to the cellular phase of the inflammatory response. Enzymes Local destruction of bone and cartilage is brought about by local enzyme release. The metalloproteinases, in particular collagenase and stromelysin, are present in increased amounts in RA and have been located at the site of cartilage damage. Proteoglycan degradation is an important but reversible step in cartilage degradation, whereas damage to type II collagen appears to be an irreversible step. Collagenase is capable of clearing intact collagen type II at neutral pH, and collagenase inhibitors can prevent collagen loss.

RECENT ADVANCES I THE PATHOGENESIS OF RA Hypotheses implicating one component of the immune system to the exclusion of others in the pathogenesis of RA have been fused into a broad concept of immune dysregulation where T-cell interactions with antigenpresenting cells, the subsequent cytokine cascade, and proliferation of fibroblasts and other cell types; are each recognized as important targets for therapeutic intervention. Aetiology remains obscure, though environmental - particularly infective - triggers are believed to be critical in initiating disease in a genetically predisposed individual. Genetic subtyping may reveal individuals who will develop particular variants of RA, for example erosive disease, extra-articular involvement or vasculitis. Our understanding of the pathogenesis of RA in molecular terms has progressed rapidly. This has provided a number of molecular targets, and therapeutic trials based on these targets have been initiated. The first was of monoclonal anti-CD4, which can produce beneficial but transient effects. Attempts are being made to devise peptide-based therapies that will selectively block the HLA peptide-presenting genomes. Trials of monoclonal antibodies against cytokines TNF-a and IL-1 or soluble receptors are being undertaken and have shown promising results. Inhibitors to metalloproteinases prevent joint destruction in vitro and trials in humans are taking place.

TABLE 22.15 Diagnostic criteria tor rheumatoid arthritis

22

Arthritis of three or more joints (soft tissue swelling or fluid) Arthritis of hand joints (wrist and/or metacarpal) Symmetrical swelling of same joint areas Serum rheumatoid factor Radiographic features of RA Signs must have been present for at least 6 weeks Revised by American Rheumatism Association, 1987.

Diagnosis Diagnostic criteria (Table 22.15) are useful in standardizing groups of patients in comparative studies. However, there is a wide differential diagnosis for new-onset arthritis and the exact diagnosis is not always clear at first. In early-onset rheumatoid arthritis the condition may be mild and affect only the small joints. Blood tests and X-rays may be normal early on; RA may also coexist with other diseases (e.g. OA) and test results may therefore be confusing. Thus there are no radiological or immunological features that are pathognomonic for RA at the time of presentation. For example, up to 60% of patients may not have an acute-phase response, around 50% have normal X-rays, and some 60% have a negative rheumatoid factor. The diagnosis of inflammatory arthritis cannot therefore be based on investigations alone, as this would delay the referral and treatment of many patients. Diagnosis should instead be based on clinical features, including joint swelling, symmetrical symptoms, metacarpal and metatarsophalangeal involvement, significant early-morning stiffness and a good response to NSAIDs.

Predicting the persistence of synovitis Not all patients with RA have a uniform outcome. A disease assessment called PISA (persistent inflammatory symmetrical arthritis) has been developed to assess the risk of persistent disease in early RA. This system requires patients to have had persistent symmetrical arthritis of the metacarpophalangeal joints of at least 12 weeks' duration. PISA aims to differentiate those patients who manage to fulfil ACR criteria for RA but who are likely to have either 'self-limiting' or good-prognosis disease from those with a more serious problem.

Clinical features 1 Disease onset In most cases RA begins insidiously or subacutely, which may be associated with a worse prognosis. In 10-20% of patients the onset is very sudden and may be associated with systemic symptoms, including fever. Many patients describe prodromal symptoms such as aches and pains in a variety of joints. The classical presentation is of a woman

1133

TABLE 22.16 Patterns of presentation of RA • • • • •

Gradual onset - the most common Slow monoarticular presentation Abrupt acute polyarthritis Acute monoarthritis Palindromic onset

in her mid-30s with pain, stiffness and swelling of several weeks' duration in the small joints of her hands, wrists and feet. There may be associated lethargy, weight loss and depression. Gradually more joints are affected, accompanied by morning stiffness. Carpal tunnel syndrome or episodic arthritis (palindromic rheumatism) may antedate acute symptoms by months or years. Overall there is a 3:1 female preponderance, but this is in young people and in the elderly the age-related incidence is equal. 1 Articular features The characteristic pattern of joint involvement at onset occurring in 65% of cases - is symmetrical and peripheral. Large joints are involved in 30% of cases, and both large and small joints in 5%. In a few patients a single joint may be involved, the disease remaining localized to that joint and then spreading slowly (Table 22.16). Joint pain and swelling, and stiffness on waking in the morning and after periods of rest, are the main symptoms. Stiffness may be related to fluid retention in the periarticular tissues; it is a valuable semiquantitative measure of the activity of the inflammatory process. In the early stages of RA the inflammatory changes may not be localized to the joints. Tender swelling of the entire hands or forearms, or swollen feet and ankles may be the earliest findings. As joint destruction progresses, the anatomical changes themselves produce increasing functional disability. The distinctive features of RA are the symmetry, the prominent signs of inflammation and, to a lesser degree, the location. The most commonly affected joints (in order of decreasing frequency) seem to be proximal interphalangeal, metacarpophalangeal, metatarsophalangeal, wrists, knees and ankles, but any joint can be affected. Persistent inflammation leads to destruction of cartilage and bone, stretching and rupture of tendons and, eventually, to subluxation and dislocation of the joints themselves; this results in the characteristic rheumatoid deformities of the peripheral joints (Fig. 22.12). Hands and wrists The typical patient shows fusiform inflammatory swellings, often with a dusky cyanosis over the inflamed joints. Later,

1 1134

MCQ 22.5

0 Fig. 22.2

FIG. 22.12 Rheumatoid arthritis in the hands, illustrating ulnar deviation, metacarpal phalangeal swelling, swan-neck deformity and muscle wasting 0

there may be marked synovial hypertrophy on the dorsum of the wrist with involvement of the extensor tendon sheath, which may cause rupture of the tendons. In the palmar aspect of the wrist, synovial hypertrophy may lead to the carpal tunnel syndrome. The ulnar head may be prominent and extremely tender. Early synovial swelling of the wrist is highly characteristic and is a valuable sign in distinguishing inflammatory from degenerative disease. Wasting of the dorsal interosseous muscles is often marked, and RA is the commonest cause of wasting of the small muscles of the hand. Synovial infiltration of flexor tendon sheaths often causes a trigger finger. Palmar erythema is common. Other mild vasomotor disturbances are frequent in RA. Typical Raynaud's phenomenon may occur, but if it is severe in the presence of only mild arthritis then one should consider the diagnosis of scleroderma. Deformity of the hands takes the form of ulnar deviation of the fingers, the buttonhole or boutonniere deformity and the swan-neck deformity (Fig. 22.12). Involvement of the distal interphalangeal joint is rare. Anterior subluxation of the wrist may occur. Knee joint Involvement of the knee joint accounts for a great deal of disability. Synovial hypertrophy and effusion are often marked, and the bursae in the popliteal fossa may be swollen and may communicate with the joint cavity. These enlarged bursae are called Baker's cysts and may sometimes rupture. Quadriceps wasting is often marked, even in the early stages of the disease. Flexion contractures may develop, and these are especially important because of the disability they produce. Both the cruciate and the lateral ligaments may be destroyed, resulting in gross joint instability and valgus or varus deformity. Rupture of the joint or a Baker's cyst, as a consequence of the high intra-articular pressure developed during

exercise, causes acute pain in the knee, radiating into the calf, which becomes swollen and tender on pressure. This may lead to a misdiagnosis of deep vein thrombosis, but an arthrogram or ultrasound scan will demonstrate the lesion. Cervical spine The upper cervical discs are frequently involved in RA, in contrast to lower cervical involvement in OA (p. 1155). The cervical vertebrae may become subluxed, and this may cause serious neurological involvement. The atlantoaxial articulations and their associated ligaments are frequently involved. This is detected by taking lateral radiographs in both flexion and extension, where separation between the odontoid process and the first cervical vertebra exceeds the normal 2-3 mm. Patients with this involvement often complain of pain radiating along the distribution of the first and second cervical nerves. Pain commences in the cervical spine and radiates upwards over the occiput and vertex to the forehead. Symptomatic relief may be found with a well-fitting cervical collar. Atlantoaxial dislocation may cause vertebrobasilar insufficiency or may produce neurological signs by direct pressure on the cord. However, neurological sequelae are less common than might be expected. The abnormality is present in 25% of patients requiring joint reconstructive surgery, and it is important that anaesthetists are aware of the potential dangers of neck manipulation. Involvement of other joints Pain in the forefoot is commonly due to downward metatarsal head subluxation. The patient complains of a feeling of 'walking on pebbles', and the metatarsal heads are readily palpable on the sole of the foot. Erosive changes in asymptomatic feet often occur early and prior to involvement of the hands. The most common deformities are subluxation of the metatarsophalangeal joints with the toes displaced upwards, together with fixed flexion deformities of the interphalangeal joints. The hip joint is less commonly involved than the knee or metatarsophalangeal joints, but when it occurs it causes serious disability. The femoral head may penetrate the acetabulum (protrusio acetabuli) and the femoral head may collapse. This is often referred to as avascular necrosis and is more common in corticosteroid-treated patients. Extra-articular manifestations RA is a systemic disease: some 75% of patients have two or more extra-articular features at some stage. Systemic involvement occurs in patients with more active disease and warrants a more aggressive therapeutic approach. Systemic features also increase the likelihood that there will be premature death from RA. Active RA is associated with a number of systemic features, including low-grade fever, anorexia, weight loss and malaise. Anaemia Anaemia is the commonest extra-articular manifestation of RA and is present in about two-thirds of patients with

active disease. Usually, it resembles the anaemia of chronic disease (see Table 23.6, p. 1212).

22

Osteoporosis Spontaneous fractures of the long bones, neck of femur and the pelvis are well recognized in patients with RA (whether or not they are receiving corticosteroid therapy). Osteoporosis occurs early in active RA, and rarefaction of the bones in the neighbourhood of an affected joint is one of the first radiological signs of the disease. Lymph node enlargement Generalized lymphadenopathy is a common feature of Still's disease, but is rare in adult arthritis. Some patients, particularly those with seropositive RA, develop marked enlargement of nodes proximal to the inflamed joint. Biopsy shows large germinal centres, and occasionally hyperplasia is so marked as to resemble giant follicular lymphoma. Infection Infections are common in patients with RA. Those with severe chronic seropositive RA, or with Felty's syndrome, are particularly susceptible. Periarticular manifestations Subcutaneous rheumatoid nodules Rheumatoid nodules occur in approximately 25% of patients at some time in the course of their disease (Fig. 22.13). Nodules are found in patients with high titres of RF and indicate severe, potentially more destructive, disease. The nodules are a few centimetres in diameter and are not tender on palpation. Normally, they are subcutaneous, but can be intracutaneous or attached to periosteum. They vary in size and number with the activity of the disease. They are found along the extensor surfaces of the forearms, but also occur over pressure areas or may be related to tendons.

SUMMARY 1 Extra-articular manifestations of rheumatoid arthritis Common

Uncommon

• • • • • • • • • • • • • • • •

• • • • • • • • •

Fever, weight loss, malaise Anaemia Osteoprosis Lymphadenopathy Infection Depression Muscle wasting Peripheral oedema Nodules Tendinitis and bursitis Scleritis Keratoconjunctivitis sicca Carpal tunnel syndrome Nailfold vasculitis Peripheral neuropathy Pleural effusion

Hearing impairment Myositis Episcleritis Systemic vasculitis Pericarditis Pulmonary fibrosis Pulmonary nodules Splenomegaly Amyloidosis

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TABLE 22. 17 Pulmonary complications of rheumatoid arthritis • • • • • • • •

FIG. 22.13 Rheumatoid nodules at the elbow These commonly occur over pressure points 1

They can ulcerate and can be painful over the ischial tuberosities and on the feet. Excision is rarely helpful as they reform. Methotrexate therapy may cause multiple nodules. Nodules are pathognomonic of RA. Palisaded tissue macrophages (histiocytes) surround a central area of hyaline necrosis. Around the histiocytes are scattered lymphocytes and the occasional plasma cell. Tendons and bursae Rheumatoid synovitis can extend to the synovial sheaths of tendons and bursae, particularly in the hands, where pressure from the granulation tissue may contribute to extensor tendon rupture 2. In addition, nodules can form in the tendons and can impact in the flexor tendon sheaths of the fingers to produce triggering. Local steroid injections will often relieve this condition. When the ulnar styloids become unduly prominent, because of erosions and/or dorsal subluxation at the inferior radioulnar joint, there may be progressive rupture of the extensor tendons, starting from the ulnar side. Some bursae become inflamed in almost all cases of RA, and as there are more than 150 bursae, there are numerous ways bursitis can present. The following are common: • Olecranon bursitis is a common problem; rarely it becomes infected. • Prepatella bursitis (housemaid's knee); this is uncommon in RA. • Subacromial bursitis, which is a common cause of shoulder pain. • Trochanteric bursitis; this may cause pain down the anterolateral aspect of the thigh. Myositis Muscle wasting is very common in RA, mainly due to

1 1136

Figs 22.3, 22.4 2

Fig. 22.5

3

Fig. 22.6

Infection Pleural effusion Rheumatoid nodules or granulomata Fibrosing alveolitis Rheumatoid pneumoconiosis (Caplan's syndrome) Pulmonary hypertension Empyema Obliterative bronchiolitis

disuse associated with painful joints. In addition, ischaemic atrophy can result from vasculitis and, very rarely, true polymyositis can occur (p. 1180). Corticosteroid therapy can cause proximal myopathy. Chloroquine can also cause a myopathy associated with characteristic vacuolation of muscle fibres. Rarely, penicillamine therapy may lead to polymyositis. Oedema Recurrent oedema of the lower limbs is commonly found in association with RA. In some cases it develops around an acutely inflamed ankle joint. In many instances there is no clearly defined cause. Organ involvement Heart Cardiac involvement takes the form of pericarditis and effusion, rheumatoid granulomata, myocarditis and coronary arteritis. In patients with RA clinical evidence of pericarditis is not common, but at postmortem it is found to be present in about 40% of cases. Clinical evidence of pericarditis is found in 10% of patients admitted to hospital and, using echocardiography, subclinical pericardial effusions can be detected in one-third. Effusions are usually small and posterior. The pericardial fluid is an exudate characterized by very low levels of glucose and complement. Gammaglobulin and lactate dehydrogenase levels are increased. Rheumatoid granulomata can occur in any layer of the heart or in the valves. They are found in 1-3% of postmortem studies. The valve lesions are usually mild and of no haemodynamic significance. Non-specific interstitial myocarditis and endocarditis occasionally occur, presumably secondary to vasculitis; they can be associated with patchy valvular fibrosis. Coronary arteritis is rare, and is usually part of a generalized vasculitis. Lungs The main syndromes are shown in Table 22.17. Pleural effusion. Typically, pleural effusion is unilateral and occurs in seropositive males over 45 years of age. It may precede the arthritis and, unlike most other extraarticular lesions, can occur early in the disease. The effu-

sion can be chronic and be associated with considerable pleural thickening. Rheumatoid nodules. These are usually symptomless and solitary, and are found by chance on a routine chest X-ray. Like pleural effusions and pericarditis, with which they can be associated, they are commoner in males with seropositive nodular disease. Rarely they can precede the arthritis, but even at that stage the patient is usually seropositive. The nodules are often subpleural and may be multiple and recurrent. The histology resembles subcutaneous nodules. They may disappear, remain unchanged for years or, rarely, cavitate, become infected or even rupture. Biopsy is sometimes necessary to exclude tuberculosis, fungal infection or malignancy. Fibrosing alveolitis. This condition may occur in isolation (Ch. 13, p. 695) or be associated with a variety of disorders, including RA. Obliterative bronchiolitis. An association has been suggested between this condition and rheumatoid disease. The illness is characterized by a rapid onset of breathlessness, which may progress over a few months to complete incapacity or death. Lung function tests show a gross reduction in vital capacity, with severe hyperinflation. The chest radiograph is virtually normal. The condition may also be associated with penicillamine therapy. Nervous system Both the peripheral and central nervous systems (CNS) can be involved in RA. CNS involvement may occur as a result of cervical cord and vertebral artery compression (p. 1380), whereas peripheral neuropathy may be due to entrapment; symmetrical, either sensory or sensory and motor; or due to mononeuritis multiplex. Entrapment neuropathies develop where the nerve is enclosed by a tight soft tissue band, or where a nerve passes over a bony area close to the skin. The usual presentation is an insidious onset of pain and paraesthesiae in the distribution of a peripheral nerve; weakness is sometimes the main problem. The median nerve at the wrist, the ulnar nerve at the elbow, the tibial nerve at the ankle and the lateral popliteal nerve at the head of the fibula are the most common sites. Sensory or mixed motor and sensory peripheral neuropathies present with a glove-and-stocking distribution. The cause is probably a vasculitis of the vasa nervorum. A sensory neuropathy is most common and is benign; a mixed neuropathy occurs with systemic vasculitis. Mononeuritis multiplex is caused by vascular lesions in several different peripheral nerve trunks. The sites of involvement are similar to those of the entrapment neuropathies and may lead to foot drop. Cervical subluxation The neurological consequences of cervical subluxation are unpredictable, but survival tables suggest that they do not, in themselves, significantly shorten life expectancy in rheumatoid disease.

Splenomegaly Splenomegaly occurs in about 5% of patients with RA, but only 1% develop leukopenia as well. Felty's syndrome is the association of RA, lymphadenopathy, splenomegaly, anaemia, thrombocytopenia and neutropenia. Patients have seropositive RA (often with relatively inactive synovitis). Leg ulcers are also common and are associated with severe infections.

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Skin Skin complications are common. The elderly rheumatoid patient has thin fragile skin, often made worse by corticosteroid therapy. Ulceration frequently occurs, particularly on the legs, where it may be due to trauma (often minimal), stasis and poor venous return due to inactivity, Felty's syndrome or vasculitis 3. Rheumatoid nodules can also ulcerate, particularly over pressure points. Sjogren's syndrome Sjogren's syndrome is the association of keratoconjunctivitis sicca and/or xerostomia with RA or another connective tissue disorder. The lacrimal glands are infiltrated by chronic inflammatory cells, producing acinary atrophy and fibrosis, and a reduction of tear and saliva secretion. The same pathological process may affect other exocrine glands, such as bronchial, pancreatic and vaginal glands. Patients may have a high incidence of adverse drug reactions, particularly to antibiotics and gold therapy, and have an increased risk of developing lymphomas. Gastrointestinal tract Most of the gastrointestinal symptoms in RA are related to drug therapy. However, vasculitis can cause ischaemic colitis and infarction, and amyloidosis can result in malabsorption. Apart from amyloidosis, no histological abnormality is found on jejunal biopsy, although malabsorption can be demonstrated in up to one-quarter of patients with active arthritis. Gastrointestinal ulceration and haemorrhage frequently occur from the ingestion of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs). The anti-inflammatory effects of NSAIDs are achieved through the inhibition of COX-2, whereas inhibition of COX-1 is responsible for their gastric and renal side-effects. NSAIDs that are highly selective COX-2 inhibitors are now available. Kidney Although infections are common in patients with RA, the urinary tract is seldom affected. However, structural changes are commonly found in the kidney at autopsy. It is difficult to assess the role of drug therapy in these changes (see Ch. 20, p. 1080). Paracetamol alone is probably not nephrotoxic. NSAIDs can cause an acute or chronic tubulointerstitial nephropathy. All patients receiving drug treatment for RA should have their renal function assessed

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intermittently. With gold, proteinuria may present at any time or with any dose, and a clear association has been described between the presence of HLA-DR3 and/or HLA-B8 and the development of proteinuria. Drug-induced proteinuria may persist or initially increase after stopping therapy, before decreasing gradually and resolving completely in more than 80% of cases by 2 years. In those with persistent proteinuria moderate impairment of renal function may occur, but this has not been shown to progress to chronic renal failure. Proteinuria in RA may also be caused by amyloidosis. Amyloidosis RA is the commonest cause of amyloidosis in the western world. It is found in 20-60% of cases at postmortem, but is rarely evident during life, when it is usually manifested by proteinuria (see Ch. 20, p. 1078). Renal amyloidosis is rarely associated with hypertension. Involvement of the gastrointestinal tract can result in malabsorption or intractable bloody diarrhoea. The liver, spleen or kidney can be infiltrated, but are seldom greatly enlarged. Vasculitis Approximately 25% of patients with RA have been found to have vasculitis at postmortem examination. Vasculitis may conveniently be considered in four categories: 1. Mononeuritis multiplex or acute peripheral neuropathy 2. Peripheral gangrene 3. Biopsy evidence of acute necrotizing arteritis plus systemic illness 4. Deep cutaneous ulcers or active extra-articular disease if associated with typical digital infarcts or biopsy evidence of vasculitis. The size of vessel involved ranges from the aorta to the capillaries. Small-vessel vasculitis can occur in isolation as small nailfold or nail-edge lesions. These are generally considered to be benign but can herald or coexist with major arterial disease. The eye RA and other rheumatic diseases frequently involve the eye. Keratoconjunctivitis sicca, scleritis and uveitis are the commonest manifestations. In RA, 11% of patients have keratoconjunctivitis sicca, and 0.5% develop scleritis with a marked predilection for severe cases with a bad prognosis. Uveitis is a complication of juvenile chronic arthritis. A large number of drugs used for the treatment of the rheumatic diseases can themselves cause eye lesions, including chloroquine, mepacrine, allopurinol, indomethacin and ibuprofen. In summary, although RA is chiefly a disease of joints,

1

1138

MCQ 22.6

there are often major systemic manifestations. Indeed, these features may impose a prognosis far more serious than that of the patient's joint disability. The presence of extra-articular features indicates that aggressive therapy should be started at an early stage. In the vast majority of patients, complete or adequate control of the disease can be achieved.

Principles of management The progressive destructive inflammatory process in RA may cause not only crippling deformity, but also systemic illness and changes outside the joints that may prove fatal. In its early stages, before joint destruction and deformity have occurred, it can be a reversible disease. It is important to remember that drug treatment is just one component in the total management of arthritic patients. Management must also include advice about rest and exercise, splintage, the provision of appliances designed to reduce dependence upon others, and advice about employment. The general principle of drug therapy is to use the fewest agents in the lowest effective dosage. Drug regimens must be tailored to the needs of the individual (Fig. 22.14). RA is often badly treated: patients are kept on antiinflammatory drugs alone for long periods, in the face of obvious deterioration; or corticosteroids are given early, with considerable immediate effect but at the cost of complications later on. There is an understandable tendency to gradually increase the dose of drugs to alleviate the patient's symptoms, but this is dangerous and often unnecessary. The inflammatory process can usually be suppressed, with symptomatic improvement, better function, less stiffness and considerable pain relief, but the disease cannot be cured. Hence, adequate patient education is required from the outset, stressing the importance of controlling the disease, to help give the patient realistic expectations. The aims of treatment are to reduce inflammation, maintain function and prevent deformities. Adequate

Summary 2 Principles of management of RA Pain control Rest Splints, collar Joint aspiration and steroid injection Analgesics NSAIDs Joint replacement Prevention of disability Aids, appliances Domestic adaptation Job retraining Financial support

Preservation of function Ice and exercise Splints Hydrotherapy Joint protection advice

TABLE 22.18 Assessment of disease activity • • • • • •

FIG. 22.14 A flow chart of the treatment regimens for rheumatoid arthritis

suppression of chronic inflammation allows secondary manifestations, such as anaemia, to revert to normal. 1 Improving outcome with early treatment Improved outcome can be achieved in three ways: developing new and better drugs; using current drugs better; or starting therapy with current drugs earlier in the disease. There is now good evidence that early intervention represents the maximum long-term benefit for the minimum risk. The use of suppressive drugs within 6 months of disease onset improves function; at this stage there is inflammation present but little joint destruction. Rheumatoid arthritis at an early stage usually involves the small joints of the hands and feet; large joints such as the knee are less frequently involved. Destructive arthritis is best indicated at the onset of the inflammatory synovitis by the presence of rheumatoid factor, prolonged morning stiffness, rheumatoid nodules, a high ESR and early erosive arthritis. There is little advantage in using HLA typing to predict outcome, although some subtypes, such as DRBP0401, may be more closely related to progression than others. Physiotherapy and occupational therapy The physiotherapist can help in relieving musculoskeletal symptoms of pain and stiffness, improve joint movement and muscle power, and re-educate the function of the joints. Heat, ice, wax baths and other local external applications may relieve symptoms and aid relaxation. Patients are also instructed to exercise at home to maintain joint movement and muscle power in order to pre-

Assessment of pain Assessment of tender joints Measurement of grip strength Measurement of joint size Assessment of joint stiffness Functional evaluation

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• Aspirin or paracetamol consumption • Patient's drug preference • Laboratory correlates (ESR, acute-phase proteins)

vent deformities. Hydrotherapy has an important role, allowing muscles to relax and joints to move freely in a warm environment. It is particularly useful for painful hips and backs. The value of rest cannot be overemphasized. Patients with acute lesions should have complete bed rest; patients with chronic lesions should alter their domestic and work patterns so that they are less stressful. The dangers of short-term rest have been exaggerated: joints do not stiffen in days, and muscles cannot be strengthened if a joint is inflamed. However, as soon as pain and inflammation are controlled, mobility and strength can be restored. Splints may be used to rest joints, to prevent deformity or to aid the power and function of a limb. Splints are useful in active disease as rest is important, but daily exercises to maintain joint motion and muscle bulk are necessary. In chronic disease, wrist splints may aid power when finger movement is impaired by pain and deformity, or by inflammation at the wrist; back splints for the knee may prevent flexion contractures. Orthoses are more permanent appliances used to prevent instability and movement, and require fitting to each patient. They include spinal supports and braces, and T-straps to control ankle instability. A variety of simple aids and appliances may transform the lives of disabled patients, as joint deformity may prevent normal function. Occupational therapists assess the difficulty encountered in daily tasks and advise about aids to daily living, such as toilet seat raisers, long-handled combs and handles for taps. These and similar appliances can often allow independent living. A home visit is often helpful.

Drug therapy Alteration in disease activity in response to a drug treatment can be assessed by a number of subjective and objective parameters (Table 22.18). Pain remains the parameter that correlates best with the overall assessment of a change in disease activity. A standardized Health Assessment Questionnaire (HAQ) assesses a person's overall ability to carry out the activities of daily living. This has become an integral part of standard measures of drug efficacy in trials, and is increasingly being used in the clinical setting to inform treatment decisions. Alternatively, a disease activity score (DAS) may be used, which calculates a single

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value reflecting objective evidence of active disease (number of swollen and tender joints and the ESR) and the patient's own assessment of their overall wellbeing. Analgesics Most patients with RA see pain relief as their most desirable objective. Simple analgesics, such as paracetamol with or without dextropropoxyphene, are usually considered to be best because of their lack of CNS side-effects. Codeine-containing preparations can be associated with constipation, particularly in the elderly. This adverse effect is less common with the opiate analogues meptazinol or tramadol. Non-steroidal anti-inflammatory drugs The NSAIDs encompass both aspirin and its derivative indomethacin, the more recently introduced propionic acid derivatives, oxicams and phenylacetic acids. These drugs have been known for almost 30 years to interfere with prostaglandin synthesis, and two isoenzymes of cyclooxygenase (COX) are now recognized. COX-1 is constitutively expressed and its inhibition results in reduced synthesis of the gastroprotective prostaglandin. COX-2 is induced in inflammatory conditions. The enzyme is inhibited selectively by the most recent additions to the NSAID family, rofecoxib and celecoxib, with a significant reduction in the risks of peptic ulcer disease (PUD) and its lifethreatening complications of perforation and bleeding. Some NSAIDs offer a relatively higher inhibition of COX2 than COX-1, with an associated apparent reduction in GI side-effects. Most recently, it has been shown that COX-2 is active primarily in the dorsal horn, but despite offering analgesia comparable to that from diclofenac or naproxen, COX-2-specific NSAIDs may not be as efficacious in reducing inflammation at the primary site. There is little to choose between the non-steroidal antiinflammatory analgesics in terms of pain relief, nor is it likely that using them in combination will provide any more relief than using them singly. Because of the increasing evidence of pharmacokinetic interaction between these drugs, pain should, whenever possible, be controlled with a single NSAID (though combination with simple analgesia has a role). There is a large variation in an individual's response to NSAIDs, and it is often necessary to try a number of drugs before finding one that provides adequate relief of symptoms. Each drug should be given for 2 weeks to assess its efficacy. The newer NSAIDs can be given in a convenient dosage schedule (many once daily). Guidelines for prescribing an NSAID include: • • • • • • 1140

Use a drug you are familiar with. Prescribe cheaper, established drugs. Prescribe only one drug at a time. Prescribe an adequate dose. Encourage compliance by flexible dosing. Prescribe for 2 weeks and then review.

Aspirin (acetylsalicylic acid) Aspirin has both analgesic and anti-inflammatory proper-

ties, but it requires blood levels of 250-300 mg/L for an adequate anti-inflammatory effect; this requires a daily dose of 3-6 g. As the therapeutic level is near toxic levels, salicylism (tinnitus, deafness, nausea and vomiting) may occur. The content of standard aspirin BP tablets is 300 mg. These are seldom used, however, because they consistently cause gastric mucosal injury. Soluble aspirin is better tolerated, as are enteric-coated preparations. Indometacin (indomethacin) Idometacin (indomethacin) is a potent anti-inflammatory agent. It is particularly useful in reducing morning stiffness when given at a dosage of 50-100 mg at night. The daily dose is up to 150 mg and the main restrictions on the drug are its side-effects, which occur in 10-20% of patients. The two common problems are gastric irritation and ulceration (even when given as a suppository), and cerebral symptoms. These include headaches, muzziness and dizziness, and seem to be dose-related. Other infrequent side-effects include leukopenia, thrombocytopenia, skin rashes, oedema and hypertension. Other non-steroidal drugs The major advantage of these compounds is a reduction in adverse effects. When NSAIDs have been compared in controlled studies, no significant differences have been found in terms of pain relief or the patient's assessment of efficacy. NSAIDs can be divided broadly into those with a short half-life (ibuprofen) and those with a long half-life (piroxicam). Many of the short half-life NSAIDs can be effective in a twice-daily dosing regimen. Long half-life NSAIDs remain in the body for longer once administration has ceased: adverse effects may persist for many days. Also a steady-state level is not reached for 2 weeks and the onset of action is slow. All anti-inflammatory drugs can cause gastrointestinal bleeding, partly by a local action on the stomach and partly by a systemic effect. Therefore, alternative routes of administration (suppository, topical) reduce but do not avoid risks. About 20% of all cases of ulcer haemorrhage and perforation are directly attributable to the use of NSAIDs. The risk is increased in elderly women. If patients develop severe indigestion or peptic ulceration it is best to discontinue the NSAID. If this is not possible, an H2-antagonist or proton-pump inhibitor may allow healing to occur; this is less likely with a gastric ulcer. A prostaglandin analogue, misoprostil, may be used to reduce PUD complications, and is combined with two commonly prescribed NSAIDs (diclofenac and naproxen). However, studies have shown omeprazole to be better tolerated for prophylactic NSAID cover. There are many other side-effects of NSAIDs, and these are listed in Table 22.19. More specific antirheumatic drugs For decades a pyramidal hierarchy of treatment was used,

RECENT ADVANCES IN THE SAFETY OF INDIVIDUAL NSAIDs A recent publication by the Committee on Safety of Medicines has given guidelines to selecting these drugs, which previously have been prescribed more by the class of drug. The committee assessed several years of reports of adverse drug reactions (yellow cards) for the seven most widely used NSAIDs in the UK. Ibuprofen was associated with the lowest risk; naproxen, indomethacin and diclofenac with intermediate risk; and azapropazone had the highest risk of serious adverse upper gastrointestinal complications. In addition, azapropazone had the highest number of yellow card reports for renal, liver, haematological and hypersensitivity reactions. Drugs with low risk should generally be preferred, and these should be started in the lowest recommended dose. Only one NSAID should be used at a time. NSAIDs which specifically target only the COX-2 isoenzyme have a safer gastrointestinal profile, but do not appear to offer lower renal toxicity. These agents are to be preferred in those at significant risks of gastrointestinal toxicity, which will frequently include OA and RA patients. Tiaprofenic acid is also mentioned in the same report as a cause of severe cystitis. Like oral preparations, topical NSAIDs have been implicated as causing renal impairment, although blood levels are usually low.

patients having a trial of combined physical therapy and anti-inflammatory drugs for many months, those who continued to have active disease then taking increasingly potent, but also more toxic, 'second-line' treatments as the disease progressed. A number of studies following such cohorts of patients have demonstrated that this approach was allowing significant joint damage and consequent disability to occur before adequately controlling disease. Some of the 'second-line' therapies were found to reduce radiological progression if introduced earlier in the disease course, and are now called disease-modifying antirheumatic drugs (DMARDs). Their effects are often not apparent for several months, and some authors therefore describe them as slow-acting antirheumatic drugs (SAARDs) (Table 22.20). The pyramidal approach to treatment is now replaced by attempts to identify patients who are likely to have more aggressive disease, and introducing the potent DMARDs as soon as possible with the aim of inducing disease remission and prevent radiological damage. Although specific algorithms differ, in clinical practice such patients are usually readily identified. As mentioned, the HAQ is a useful indicator, as are persistence of inflammation beyond 6 weeks, an elevated acute-phase response (ESR or CRP), positive rheumatoid factor, and female gender. Large-joint involvement at onset is also important. Criteria for 'a good

TABLE 22.19 Main side-effiects of NSAIDs Gastric Indigestion Ulceration Haemorrhage Small bowel perforation Renal Hypertension Renal impairment Fluid retention Hepatic Hepatocellular damage Reye's syndrome

22

Skin Erythema multiforme Photosensitivity Urticaria Pulmonary Bronchospasm CNS

Dizziness Confusion Headache Haematological Thrombocytopenia Neutropenia

TABLE 12.20 Characteristics of slow-acting antirheumatic drugs • Slow action. Begin working after 4-6 weeks and may take 6 months to produce full benefit • Improvement in joint symptoms accompanied by fall in ESR and RF • May retard progression of erosive change seen on X-ray • Patients feel much improved in general health

response' to treatment include the objective and subjective measures referred to above (Table 22.18). Radiographic progression, for which X-rays of hands and feet are the most sensitive, is an indicator of progressive disease and can occur despite apparently satisfactory control of inflammation. An ideal standard of treatment of RA therefore includes early referral and assessment of the need to introduce potent DMARDs, with regular review by rheumatologist, specialist nurse or in primary care to ensure efficacy, and modifying treatment in the face of relapse, radiological progression, or indeed successful remission. Throughout this period, occupational therapists and physiotherapists have an ongoing role in maximizing functional ability and joint protection. A multidisciplinary team would also aim to address social and employment issues. Sulfasalazine Sulfasalazine, an acid azo compound of sulfapyridine and 5-aminosalicylic acid, is an effective antirheumatoid agent. Its mode of action is unknown, but both the sulfapyridine and 5-ASA moieties appear to be active. It is as well tolerated as gold or penicillamine over 2-5-year periods, and has fewer serious adverse effects; its principal problem is the symptom complex of nausea, dyspepsia and depression encountered early in treatment. The dose is increased from the initial 500mg/day to a maintenance dose of 2 g/day over 4 weeks. Serious side-effects are rare, but blood dyscrasias and hepatotoxicity may occur.

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Thrombocytopenia is a common side-effect and occurs early. It is often dose-related and may be severe, but it is usually possible to resume treatment on a lower dosage once the platelet count has recovered. Proteinuria is common but may resolve without interruption of treatment, although progression to kidney damage may occur. Many rheumatologists prefer to stop penicillamine if proteinuria exceeds 1 g in 24 hours.

FIG. 22.15 The traditional treatment pyramid, which is no longer justifiable as it delays the use of effective therapies

It has a quicker onset of action than gold or penicillamine. Some response may be seen by 2 months, with maximum benefit at 6 months. Males should be advised that reversible oligospermia can occur. Gold salts Gold salts have been used in the treatment of RA for over 50 years. In the UK, the gold preparation sodium aurothiomalate has been used for longer than any other. It is given by weekly intramuscular injections of 50mg, after a 10 mg test dose, either until a total dose of 1g has been given or disease remission has occurred. It does not produce a disease-suppressing effect before 2-3 months of treatment. After remission, gold is continued indefinitely with a monthly maintenance regimen. About one in three patients develops toxic adverse effects, which include rashes, stomatitis, thrombocytopenia, leukopenia and, occasionally, bone marrow aplasia, glomerulonephritis and pneumonitis. Regular monitoring of platelet and white cell counts, and of urine for proteinuria, is essential. A FBC and urine examination for proteinuria should be carried out at the time of each injection, and the FBC results must be available before the next. Patients should be asked about the presence of rash or ulceration before each injection. Auranofin is an orally active gold preparation that has a lower incidence of adverse effects than intramuscular gold. The most common reaction is diarrhoea or loose stools. Dosage is 6-9mg/day. Studies have suggested that it is a weaker DMARD, and it is best regarded as obsolete in modern practice.

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D-penicillamine D-penicillamine (375-750 mg/day) is a sulphur-containing amino acid related to cysteine. It has similar indications and incidence of adverse effects to gold therapy. Loss of taste is an early adverse effect, but this usually disappears if the drug is continued. Myasthenia gravis and a druginduced lupus syndrome occur rarely as complications.

Hydroxychloroquine (HCQ) Antimalarial drugs also have antirheumatic properties, and HCQ is used in preference to chloroquine as it has similar efficacy with less risk of adverse effects. Their mechanism of action is unknown, though they are known to interfere with intracellular processes in antigen-presenting cells and neutrophils. Used alone, HCQ is a mild antirheumatic drug and probably does not retard radiological progression. Concerns about retinal toxicity led to ophthalmological review before initiating therapy and regularly thereafter. However, this recommendation was reviewed by the Royal College of Ophthalmologists. Provided visual acuity is normal (with glasses if necessary), the drug may be commenced at a dose not exceeding 6.5mg/kg ideal body weight. Visual acuity, using test types, should be recorded annually. Referral to an ophthalmologist is only required in the event of reported blurred vision or documented reduced visual acuity. Methotrexate Methotrexate (MTX) is an inhibitor of folate metabolism used in high doses in the treatment of malignancy. Its mechanisms of action in RA are believed to include inhibition of trafficking of leukocytes from blood vessels into synovium, and reduced expression of a number of key cytokines. It is being increasingly recognized as the goldstandard DMARD, and is the first choice of the majority of rheumatologists in all but the mildest forms of RA. Usually given orally, absorption is variable and some patients respond to intramuscular therapy when oral therapy has failed. A starting dose of 7.5 mg is given once per week. Increments of 2.5 mg should be made every 8 weeks as tolerated until remission, which occurs at a mean dose of 15-18 mg/week. It is usually well tolerated, more patients remaining on MTX at 5 years than on any other DMARD. Side-effects are usually mild and transient, stopping when the drug is withdrawn. They include nausea, stomatitis, rash and alopecia. Pulmonary hypersensitivity affects up to 3% of patients, and a chest radiograph is normally obtained before initiating MTX therapy; those with pre-existing lung disease are not at increased risk of MTX pneumonitis, but will be more vulnerable if this occurs. Symptoms include cough, fever and dyspnoea, and methotrexate should be stopped if these symptoms develop. Care must be taken to avoid concurrent trimethoprim therapy, as there can be an interaction. It is also teratogenic and should not be given to women of childbearing age unless they are using a reliable contraceptive. Bone

marrow suppression is rare with low-dose treatment given weekly rather than daily, although neutropenia or thrombocytopenia can occur. Hepatotoxicity can also occur. Fortnightly liver enzymes and FBC are required for the first 3 months. Monthly tests are sufficient thereafter, but must be done fortnightly again if the dose is increased. Patients in whom liver function tests exceed three times the normal range should stop methotrexate. Routine liver biopsy after a fixed accumulated dose, still regarded as mandatory in dermatology practice (where the drug is used for psoriasis), is not routinely carried out in the rheumatology setting. Corticosteroids Corticosteroids are the most powerful agents in suppressing the inflammation of arthritis. More than any other intervention in the management of RA, corticosteroid use remains contentious, with significant shifts in recommended treatment. Indications on which there is broad agreement include: • Intra-articular injections of triamcinolone or methylprednisolone are valuable in suppressing active disease in a small number of joints. • Intramuscular methylprednisolone 'depot' injection is used as 'bridging' therapy, to control disease while awaiting the delayed onset of action of the DMARDs, or to treat a generalized flare of disease. • Corticosteroids are also used in intractable iritis, common in juvenile arthritis or in Reiter's syndrome. • A low-dose regimen (7.5mg/day) with DMARDs may have disease-modifying effects for up to 2 years. The main adverse effects are glucocorticoid-induced osteoporosis (GIO), skin fragility and other cushingoid features, and avascular necrosis of bone, particularly after intravenous pulses. Guidelines have been produced for the prevention and management of GIO. Risks are minimized by using the smallest amount, for the shortest time, using the DMARDs and NSAIDs to their maximum potential.

RECENT ADVANCES IN THE TREATMENT OF RA The conventional pyramid of treatment has been replaced by paradigms of early patient assessment for more aggressive DMARD treatment at the earliest opportunity. Disease remission is the aim of treatment, using potent DMARDs individually or in combinations to achieve this goal. Leflunomide is a new DMARD specifically for RA. Biological therapies target key regulatory signals in the inflammatory process, and two anti-TNF-a drugs are now in clinical use. Other biologic therapies are in development. A multidisciplinary approach to care is essential throughout the disease, and prognosis is likely to be better than at any time in the past.

Joint aspiration and steroid injection Corticosteroids can also be given as an intra-articular injection, usually after the aspiration of fluid; 2-30mg of triamcinolone hexacetonide is commonly used, depending on the size of the joint. Its local effect in preventing recurrent effusion and pain may be dramatic. Repeated injections may result in joint destruction, resembling a neuropathic joint, and for this reason it is often recommended that weight-bearing should be reduced immediately after an injection. Stringent aseptic precautions are required. Therapy should only be considered when one or possibly two joints are actively inflamed, while others are under good control from general treatment. The major contraindication to intrasynovial steroid administration is the presence of infection; this procedure should therefore never be performed without a definite diagnosis, including microscopic synovial fluid examination if naked-eye examination is inconclusive. An injection of corticosteroid can relieve the symptoms of carpal tunnel compression and localized areas of tenosynovitis, although injections directly into a tendon can lead to rupture.

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Immunosuppressive drugs Immunosuppressive drugs are reserved for the treatment of severe RA and its complications, such as vasculitis. Cyclophosphamide is the drug most commonly used. The purine analogue azathioprine is effective, and may be safely combined with parenteral gold. Other combinations do not appear to be effective, and azathioprine's other role is as a steroid-sparing agent in those who require long-term prednisolone therapy. Bone marrow toxicity and the induction of lymphoma are rare, whereas nausea and hepatotoxicity are more common. Cyclophosphamide is used in the management of systemic rheumatoid vasculitis (and other vasculitides; see below). Daily treatment with oral cyclophophamide was associated with haemorrhagic cystitis (caused by the drug metabolite acrolein), bladder tumours, and permanent gonadal failure in men and women. Studies of intermittent pulses of intravenous therapy have significantly reduced these risks. Mesna (Uromitexan) is also used to reduce the risk of bladder toxicity, as is pulsed oral therapy. Ciclosporin A First studied in RA in 1979, this drug, which interferes with IL-2 expression by T cells, has moderate efficacy as a true DMARD in RA. Guidelines for its use as monotherapy have been produced by the American College of Rheumatology. Nephrotoxicity is the leading side-effect, requiring monthly monitoring of creatinine and blood pressure. Mild hypertension may be controlled while continuing the drug (preferably with a calcium-channel inhibitor). A rise in serum creatinine of 30% above the pretreatment baseline requires a reduction in dose. A microemulsion fomulation allows lower doses (usually 2.5-3.5 mg/kg/day in two divided doses) to be used. However, the use of ciclosporin A as monotherapy is limited, and it is mainly used in combination therapy with MTX (see below).

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CASE STUDY 22.1 STIFF PAINFUL FINGERS IN A 24-YEAR-OLD WOMAN A 24-year-old woman presents to a rheumatology clinic with a 2-month history of stiff, painful fingers and painful feet on walking. Stiffness is particularly marked for several hours in the morning, when washing and dressing, and preparing breakfast has been a struggle. When walking, she notes sharp pain in the balls of her feet, like having stones in her shoes. She has noticed that her fingers are swollen along their length. She has been well until now, notes no symptoms other than her joints, and is not aware of a family history of rheumatological disorders. Her GP has given her diclofenac, which appeared to be helpful initially but is now ineffective, and she requires coproxamol regularly throughout the day. On examination she is clearly uncomfortable walking but is not limping. The proximal interphalangeal and metacarpophalangeal joints are swollen and tender, and she is unable to make a fist. Her wrists, elbows and shoulders appear normal, as are hips, knees and ankles. She has tenderness when the metatarsophalangeal joints are compressed (between index finger and thumb on the first and fifth metatarsophalangeal joints). Her skin appears normal (including the scalp, navel and natal cleft), and there is no nail pitting. Questions 1 How would you characterize this woman's symptoms? 2. What differential diagnosis should be considered? 3. What investigations will be helpful? This is a typical presentation of a persistent inflammatory symmetrical polyarthritis. Morning stiffness and visible swelling on examination confirm its inflammatory nature, and the 2-month duration is longer than anticipated for self-limiting

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conditions. Symmetry is a useful feature to identify, as is the involvement of small joints. It is important to distinguish between her description of finger swelling (suggesting dactylitis) and the examination findings. The main differential diagnoses are rheumatoid arthritis and a rheumatoid pattern of psoriatic arthritis. The other spondarthropathies are less likely in the absence of other features and with the exclusive involvement of small joints. Postviral arthritis is also unlikely in the absence of any prodromal or coexisting features, and sarcoidosis is commonly associated with erythema nodosum (and hilar lymphadenopathy on chest X-ray), particularly in young women. At present, she has three of the seven American College of Rheumatology criteria for a classification of rheumatoid arthritis (morning stiffness over 1 hour, hand involvement, symmetry), where four are required (the remaining ones being nodules, rheumatoid factor, radiological changes, or one further joint area involved). Key investigations, therefore, are rheumatoid factor and radiographs of the hands and feet. However, it is important to bear in mind that in such early presentations both investigations may be normal, even in those subsequently developing typical seropositive RA. Baseline renal and liver profiles and a full blood count are important before selecting appropriate treatment, and ESR or CRP are useful in determining the appropriate level of treatment and in monitoring treatment. In this case the patient was found to have positive rheumatoid factor and normal radiographs; her ESR was 68 mm/h, with normal renal and liver profiles and FBC. Thus the diagnosis was acute seropositive rheumatoid arthritis.

Question 4, What management plan will you recommend to her?

Rheumatoid arthritis is a chronic and very variable disease, best managed by a multidisciplinary team with the patient's full involvement embarking with this approach will ensure the best support for the patient irrespective of the nature of their disease. Early arthritis clinics typically involve the occupational therapist advising on joint protection, providing splints and facilitating activities of daily living; the physiotherapist advising on exercises and preserving joint function; and a nurse specialist who can provide support and information, and who will usually be the first line of contact regarding drug treatment. The patient should be asked to complete a standardized Health Assessment Questionnaire. The score obtained (ranging from 0 to 3) is included with ESR and the clinical assessment to determine the most appropriate level of treatment. In this woman's case, she was having considerable difficulty with activities of daily living and her work; this, together with the high ESR, positive rheumatoid factor, being female and having persistent symptoms, indicates that aggressive management is appropriate. Methotrexate and salazopyrin are the appropriate first choices of DMARD for this level of treatment, and methotrexate is increasingly preferred. The side-effect profile and blood test monitoring should be discussed, together with explanations about their delayed onset of action and the importance of effective contraception. A baseline chest X-ray is usually obtained in those starting methotrexate to allow for comparison in the event that respiratory symptoms develop. Most rheumatologists would also give

corticosteroid to control RA until the DMARD became effective, either as an intramuscular methylprednisolone injection (120 mg is expected to cover a 6-week period) or a course of oral prednisolone (10 mg daily for 2 weeks, then 7.5 mg for 6-8 weeks). Inflamed large joints should also be aspirated and injected, but this would not apply to this particular case. Review should be arranged within 6-8 weeks, to address any issues of treatment side-effects, ensure effective control of disease (so the patient should be off steroid for a week when seen), or increase the dose of methotrexate if necessary. (The dose of salazopyrin (1 g b.d.) is standard, rarely increasing to 1 g t.d.s. However, it may take 12 weeks for this drug to be effective, so a later review is needed if this DMARD is chosen). Treatment with weekly methotrexate was increased over 4 months until satisfactory control was obtained on 15 mg/week. Oral ulceration and gastrointestinal upset were relieved by taking folic acid

5 mg on alternate days (not on the day of the methotrexate dose). Now, 2 years since her first presentation, the patient wishes to start a family. Question 5. What advice can you offer? Many people are anxious about a 'hereditary' component to RA. She can be assured that the chance of a person with one parent who has RA developing the same condition is only minimally increased. During pregnancy over 70% of women experience an improvement of their RA, and there is no recognized illeffect of RA on pregnancy, even if a flare occurs. It is useful to check for anti-Ro antibodies (associated with congenital heart block). Methotrexate should be stopped 3 months before contraception is relaxed. She has been stable for 18 months and might not suffer any deterioration in her symptoms, but if this occurs, NSAIDs may be used (though best avoided in the first and last 8 weeks of

Leflunomide This is the first new DMARD developed specifically for RA for many years. It is an immunomodulator that inhibits pyrimidine synthesis in T cells, and has DMARD properties comparable to those of MTX or sulfasalazine. It is given as a prodrug which is activated in the liver. The sideeffect profile is similar to that of MTX, with the exception of the latter's lung toxicity. Diarrhoea and nausea are the usual limiting side-effects. Marrow toxicity can occur, and fortnightly FBC is required for the first 6 months of treatment. If toxicity occurs, the clearance of this drug, which has a long half-life, is improved by the administration of cholestyramine. Neither men nor women should try for pregnancy within 6 months of taking the drug. Minocycline This tetracycline has been found to have chondroprotective properties, and in studies of early rheumatoid arthritis has been shown to improve the outcome for patients with seropositive RA treated in the first 3 months compared to placebo. As treatment paradigms are increasingly moving towards early active treatment, the true value of this evidence is debatable and minocycline is not currently an established part of antirheumatic treatment.

pregnancy). Prednisolone is relatively safe throughout pregnancy; it is not necessary to routinely introduce this when DMARD is withdrawn unless significant difficulties are anticipated (frequent disease flares or persisting symptoms). Systemic use can be minimized by injecting individual symptomatic joints where possible. A postpartum flare can occur, particularly in the first 8 weeks. If breastfeeding is not planned, her DMARD can be reintroduced without delay. Most NSAIDs may be used during breastfeeding, but long-acting drugs should be avoided and the dose is best taken just as a feed begins (the drug will be at a low level during feeding, and the level will also be low by the time the next feed is due). This patient may wish to defer the decision to restart methotrexate postpartum as her RA may be in remission. Comparing new radiographs of the hands and feet (the absence of erosions after 2 years being a good prognostic sign) would influence this decision.

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Combinations of DMARDs Recognizing the failure of DMARD monotherapy to completely prevent radiological progression and disability, efforts were made to use these drugs in combination. Whereas earlier studies found increased toxicity, three recent studies have shown the value of this strategy, with improved outcome compared with monotherapy and no increased toxicity. Hydroxychloroquine (400 mg) with sulfasalazine (Ig, half the conventional dose) and methotrexate (increased as tolerated) was found to be significantly superior to MTX alone in patients with established RA who had failed on one or more DMARDs. There are some arguments in favour of prednisolone plus sulfasalazine plus methotrexate in early disease. The combination of MTX and ciclosporin has also been found to be of value, again in patients with established disease. Another useful combination is the addition of MTX to sulfasalazine, where the latter has failed as monotherapy. However, it is currently preferred to aim for remission on monotherapy before resorting to any of these combinations: Biological response modifiers in RA Advances in the recognition of the small signal peptides

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involved in RA, their receptors and natural inhibitors, have allowed the development of highly targeted therapies. The first of these to reach clinical practice are inhibitors of tumour necrosis factor-a (TNF-a), a pivotal cytokine in RA pathogenesis. Two different forms are available, a chimeric monoclonal antibody to TNF-a (infliximab) and a soluble TNF-receptor attached to a human immunoglobulin (etanercept). These are given parenterally, either as infusions at 8-weekly intervals (after an initial loading schedule - infliximab), or as twice-weekly subcutaneous injections (etanecept). This technology is also being exploited to produce inhibitors of IL-1, and a human recombinant IL-1 receptor antagonist is currently undergoing trials. Other potentially relevant interleukins include the anti-inflammatory IL-10, where a recombinant form has shown some benefit in early studies. It is likely that, having been established as monotherapy in resistant RA, these biological agents will be used in combinations with existing DMARDs. Trials with MTX have already been reported as combining MTX and etanercept to good effect, and the reduced immunogenicity of infliximab when used with MTX means that it is now routinely given in this combination. Combined therapy with ciclosporin A also has theoretical advantages which remain to be tested in clinical trials.

Patient support RA is not a disease the patient should contend with alone. Patients with any chronic disease must know something of their disability, how to control it, and how to live with and adapt to it.

Surgery Combined clinics with physicians and orthopaedic surgeons are now common in most rheumatology centres, surgical treatment being an important stage in a patient's continuing therapy and management. This team approach allows surgery to be carried out at the optimum time, rather than only when patients become seriously disabled from joint damage and wasted muscles. Surgery has two main objectives, depending on the stage of the disease: prophylactic, designed to prevent joint damage and deformity; and reconstructive, aimed at restoration of function and stability and the correction of deformity (Table 22.21). Excision of inflamed synovium will often relieve pain and swelling, although, contrary to earlier expectations, it does not halt the progress of the disease. Persistent synovitis of the wrist and extensortendon sheath of the hand commonly leads to rupture of the tendons, which can be prevented by synovectomy and 1

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MCQ 22.7

2

MCQ 22.8

TABLE 22.21 Indications for surgery in rheumatoid arthritis Stage of disease

Surgical procedure

Proliferation of synovium Destruction of tendon Moderate to advanced destruction and deformity

Synovectomy and debridement Tendon reconstruction interposition arthroplasty Total joint replacement or excision arthroplasty

excision of the ulnar head. If the tendons rupture, suture or transfer of a slip of adjacent tendon corrects 'dropped fingers'. The reconstructive surgical procedures used include arthroplasty (provision of a new joint), arthrodesis, osteotomy, tendon repair and transplantation. Joint replacements are most successful in the hip, and usually both acetabular and femoral components are replaced. Prognosis

The course of RA is variable. In general, 25% remain fit for all normal activities, 40% have moderate impairment of function, 25% are qite badly disabled and 10% become wheelchair bound. Although disease parameters correlate best with functional measures (HAQ) in early disease, radiological progression is the most important outcome variable in later stages. A poor prognosis is indicated by a number of factors, as follows: • • • • • •

Extra-articular manifestations Insiduous polyarticular onset High titre of rheumatoid factor Functional disability at 1 year Presence of HLA-DR4 Early appearance of erosions on X-ray.

Patients who have remissions generally do better than those with continuous disease, and explosive onset is often associated with a good outcome. DMARDs are often needed to treat patients with RA, and experience and close monitoring is required to ensure their safe use. Drugs do produce a clinical improvement beyond that achieved by other measures, but withdrawals due to toxicity are common, and improved long-term outcomes do not necessarily follow. Improved understanding of disease pathogenesis, and more aggressive early RA management, will hopefully lead to a much better outlook for patients in the future. 1

FURTHER READING ON RHEUMATOID ARTHRITIS Lipsky P E 1999 Specific Cox-2 inhibitors. In: Emery P (ed) Rheumatology Highlights 1998-99, Health Press, Oxford. Moreland L W 1999 Biological agents for the treatment of RA. In: Emery P (ed) Rheumatology highlights 1998-99. Health Press, Oxford. Resnick D 1989 Rheumatoid arthritis. In: Resnick D (ed) Bone and joint imaging. WB Saunders, Philadelphia, pp. 259-287.

Spector T D 1990 Rheumatoid arthritis. In: Hochberg M C (ed) Epidemiology of rheumatic disease. Rheumatic Disease Clinics of North America 16:513-537. Wolheim F A 1998 Rheumatoid arthritis - the clinical picture. In: Maddison P J, Iseberg D A, Woo P, Glass D (eds) Oxford Textbook of Rheumatology. Oxford University Press, Oxford, pp. 1004-1030. Wordsworth P, Bell J 1992 The immunogenetics of rheumatoid arthritis. Springer Seminars in Immunopathology 14:59-78.

SERONEGATIVE SPONDARTHRITIDES The seronegative spondarthritides (spondyl: joint of the back-bone) are a group of disorders characterized by a consistent absence of RFs in the serum, by involvement of the sacroiliac joints and by peripheral inflammatory arthritis. These conditions are, as a group, clinically distinguishable from RA (Table 22.22). Clinical evidence of overlap exists between the various seronegative spondarthritides. Thus a patient with psoriatic arthropathy may develop uveitis or sacroiliitis, and a patient with inflammatory bowel disease may develop ankylosing spondylitis or mouth ulcers. Pathological changes are concentrated at sites of insertion of ligaments or tendons (enthesopathy) rather than the synovium, and changes may also be seen in the eye, aortic valve and skin. There is a tendency to familial aggregation, and the disorders are linked as a group by association with histocompatibility antigen HLA-B27. This association ranges from 50% for psoriatic and enteropathic spondylitis to over 95% for ankylosing spondylitis.

TABLE 22.22 Comparison of seronegative spondarthritis and seropositive rheumatoid arthritis Feature

Seronegative

Seropositive

Peripheral arthritis Spinal involvement Cartilaginous joints

Asymmetrical Ankylosis Commonly affected (especially SI joints) HLA-B27 Anterior uveitis, conjunctivitis Epidermal dysmaturation (psoriasis keratoderrna blenorrhagica), mucosal ulceration, erythema nodosum Fibrosis of aortic root, aortic regurgitation, conduction defects Chest wall ankylosis

Symmetrical Cervical subluxation Rarely affected

Tissue typing Eye involvement Skin involvement

Heart involvement

Pulmonary involvement Gastrointestinal involvement Genitourinary involvement

Ulceration of small or large intestine Urethritis/prostatitis, genital ulceration

HLA-DR4 Scleritis, keratoconjunctivitis sicca Cutaneous nodules, vasculitis

Pericarditis

Alveolitis, nodules, effusions Drug-induced symptoms

The concept of seronegative spondarthritis is useful in a clinical context for a number of reasons:

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• The prognosis is better than for RA. • A knowledge of the clinical associations can allow an earlier diagnosis to be made. • Physical management differs from that of RA. • Awareness of sacroiliitis in this group can avoid the error of labelling back pain as lumbar disc disease. • Awareness of the frequency of familial associations may help the patient or undiagnosed relative. In the differential diagnosis of arthritis seronegativity is of wider importance than these spondarthritic conditions, and includes all forms of inflammatory polyarthritis in which the RF is absent. For this reason, the term seronegative spondarthritis should only be applied when there is spinal involvement. Radiological examination of the affected joints aids diagnosis because bony ankylosis, marginal periostitis and asymmetrical involvement are found more often in the seronegative group. More detailed assessment using magnetic resonance imaging has further highlighted differences between RA and the seronegative spondarthropathies, implying separate underlying pathological processes between the two groups, although there are also likely to be many similarities in the immunological processes occurring. 2

Pathogenesis The pathogenesis of these disorders is poorly understood. Three characteristic features to be considered are: • A strong association with HLA-B27, particularly in ankylosing spondylitis; • An association with a number of bowel pathogens; • The presence of enthesitis as the initial pathological lesion. Although 95% of those with ankylosing spondylitis have HLA-B27, normal individuals with HLA-B27 (approximately 8% of the population) have only a 1-2% chance of developing disease, and the risk for HLA-B27+ relatives of HLA-B27+ patients with ankylosing spondylitis is about 10%. Concordance in twin studies ranges between 13% in dizygotic twins and 75% in monozygotic pairs. Therefore, it appears that other genetic factors are inherited in addition to the well-recognized HLA-B27 link. Approximately 10-20% of HLA-B27-positive individuals develop Reiter's syndrome after exposure to Shigella or other infectious agents. The explanation for the link between HLA-B27 and the spondarthropathies remains unknown. However, it is recognized that two subtypes, HLA-B2706 and B2709, are not associated with the spondarthropathies. These subtypes differ in the conformation of the antigen-presenting groove, and B27 is therefore believed to have a pathogenic role, rather than simply representing a genetic predisposition or being associated as an epiphenomenon. Theories have included HLA-B27 being itself presented as an

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antigen. Homology has been noted between Klebsiella antigens and parts of the HLA-B27 antigen-presenting groove, but simple antigenic mimicry is unlikely to explain the clinical diversity of the spondarthropathies. The leading current hypothesis has developed from recent advances in the immunogenetics of HLA-B27. It appears that some HLA-B27 subtypes fail to interact with pVmicroglobulin, resulting in low-affinity binding to T cells during thymic selection. Instead of being negatively selected, these autoreactive T cells are released into the periphery. It is debated whether HLA-B27-restricted antigen presentation directly to CD4+ T cells can occur later (remembering that MHC-I class normally interact with CD8+ T cells). Other aspects of this theory note that HLA-B27 may modify the host response to antigen, with persistence of non-replicative forms which continue to stimulate an immune response, perhaps favouring relatively avascular sites such as the enthesis. The association with a number of bowel pathogens (particularly Yersinia, Shigella or Salmonella) or urinary tract infections in Reiter's disease has for a long time prompted a search for a mechanism directly associated with these infections. The association with inflammatory bowel disease, and the finding of subclinical bowel inflammation in up to 30% of patients with ankylosing spondylitis, led to the suggestion that the immune system was triggered by leakage through the bowel of these bacteria, which were usually not immunogenic. It has further been postulated that only bacterial antigens subsequently processed and presented with HLA-B27+ are arthritogenic. However, identical clinical disease is found in the absence of these bacteria or of identifiable bowel pathology. The events occurring at the enthesis in spondarthropathies are poorly understood. However, TNF-a again appears to be a critical cytokine mediator, and it is postulated that this and other cytokines are subsequently released into the joint, causing synovitis as a secondary phenomenon. The proliferative periosteal response is attributed to the release of bone morphogenetic proteins, particularly transforming growth factor-^, though the reason for this is unknown.

ANKYLOSING SPONDYLITIS Epidemiology Ankylosing spondylitis occurs in both sexes, but is usually milder and therefore less frequently diagnosed in women. Recent estimates suggest that it is three times more common in men. Clinical features of ankylosing spondylitis are seen in 0.5% of males. The prevalence in different ethnic groups is related to the frequency of HLA-B27 in O Figs 22.7, 22.8

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SUMMARY 3 Conditions that overlap to torm the seronegative spondarthritides, and their common features The seronegative spondarthritides • Ankylosing spondylitis • Psoriatic arthritis • Enteropathic arthritis (associated with ulcerative colitis, Crohn's disease and Whipple's disease*) • Reiter's syndrome/reactive arthropathy • Behget's syndrome* Common features • Negative tests for rheumatoid factor • Absence of rheumatoid nodules • Inflammatory peripheral arthritis • Radiological sacroiliitis • Evidence of clinical overlap between members of the group • Tendency to familial aggregation *The arthropathy of Whipple's disease and Behget's syndrome may be included, although they are more controversial.

these populations (Fig. 22.16A). Ankylosing spondylitis is uncommon in African blacks and in the Japanese, who have a low frequency of B27, whereas the North American Haida Indians have a high frequency of both HLA-B27 and ankylosing spondylitis. An abnormal response to bacteria, such as Klebsiella, which carry an antigen that mimics B27, has been suggested as the underlying cause of ankylosing spondylitis. Identical twins homozygous for HLAB27 may be discordant for ankylosing spondylitis.

Pathology The early histological changes in the synovial joints resemble RA; however, the most important effects are in the cartilaginous joints. Bony ankylosis is more frequent and the sacroiliac joints often become fused. The apophyseal joints are involved and the discs show replacement of the nucleus pulposus, the annulus fibrosus and parts of the vertebral body by vascular fibrous tissue, with no evidence of marked inflammatory changes. In the spine the lesion is in the ligamentous attachment to bone (the enthesis), and this is characteristic of the disorder. The disease is characterized by bilateral sacroiliitis. The sacroiliac joint is a composition joint with the lower half to two-thirds being a synovial joint and the upper part ligamentous. Early inflammatory changes occur in the synovial joint. As the disease extends up to the intervertebral joints there is 'squaring' of the vertebral bodies radiologically, seen on the lateral view (Fig. 22.16B), and calcification of the annulus fibrosus, giving the characteristic syndesmophytes which fuse to form the classic 'bamboo spine'. This is caused by inflammation of the anterior corners of the

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FIG. 22.16 Ankylosing spondylitis \A\ Prevalence of ankylosing spondylitis and HLA-B27 in different parts of the world. (After Lawrence JS, 1977.) B X-ray of the spine in severe ankylosing spondylitis; there are extensive syndesmophytes ('bamboo spine') and the sacroiliac joints are fused.

vertebrae which extends into the outer layers of the annulus fibrosus. Calcification of the intervertebral ligaments occurs. At this stage there is osteoporosis of the vertebra, and fractures of the spine after minor trauma can occur. Other cartilaginous joints, such as the sternomanubrial joint and symphysis pubis, can be affected with erosions and bony ankylosis.

Clinical features The disease most commonly begins between 16 and 40 years of age. Articular features Back pain is the usual presenting symptom. Its onset is gradual and is often accompanied by constitutional disturbances. The pain usually disturbs sleep and is associated with morning stiffness and stiffness after immobility. In the late stages of the disease there may be a reduction in spinal pain as the axial skeleton becomes ankylosed. Involvement of the costovertebral joints may result in chest pain and, later, decreased chest expansion. Symptoms improve with exercise. Diagnosis is often delayed, symptoms being ascribed to lumbar disc disease. In spondylitis spinal mobility is limited in all directions, in contrast to disc prolapse, when lateral flexion is usually normal. The lumbar spine becomes flat-

SUMMARY 4 Extra-articular features of ankylosing spondylitis • • • • •

Malaise and weight loss Iritis Apical pulmonary fibrosis Amyloidosis Cardiac involvement Aortic regurgitation Conduction defects • Neurological features Spinal fractures Cauda equina syndrome

tened and the normal lordosis is lost. Sacroiliac tenderness may be present. In an advanced case the diagnosis is easy, as posture, gait and limitation of back movement are typical. O However, only a few patients exhibit marked kyphosis and spinal rigidity. Peripheral joints are involved in about a quarter of patients, and involvement of the hip is important because of the functional implications. Sometimes, pain and tenderness at the site of tendinous insertions can be a prominent feature, with the back, pelvic brim and ischial tuberosities being characteristic sites. Several joints are involved, usually the large joints of the lower limb.

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Extra-articular features Although primarily an articular disease of the axial and peripheral skeleton, other organs may be involved. Iritis may be a presenting feature: it occurs in 25% of cases and can cause blindness. Aortitis and myocarditis are causes of death, as is uraemia from amyloidosis. Spinal cord or cauda equina compression may occur because of atlantoaxial subluxation or fracture of a rigid spine. Patients with severe ankylosing spondylitis may exhibit chronic fibrotic changes in the upper lung that resemble tuberculosis. Features suggestive of inflammatory spinal disease are: • • • • •

Insidious onset of discomfort Age at onset of less than 40 years Persistence for more than 3 months Association with morning stiffness Improvement with exercise.

Investigation The ESR is often elevated in active phases of the disease. There is little correlation with disease severity. Tissue typing for HLA-B27 is both expensive and unnecessary, as diagnosis can be made on the clinical findings and X-rays. Raised IgA levels are associated with activity. Anteroposterior views of the sacroiliac joints and lateral X-rays of the lumbar spine should be obtained. Both may be normal in early disease. The earliest changes are of sclerosis and erosions in the sacroiliac joints, usually bilateral. Later, complete fusion may occur. Early changes in the lumbar spine are erosions of the edges of the vertebral bodies with squaring of the vertebrae and syndesmophyte formation (Fig. 22.16B). In the most severe cases, ossification of the anterior longitudinal ligaments and apophyseal joints occurs, with the production of a 'bamboo spine'. The characteristic lesion of entheses - such as of the plantar fascia and Achilles tendon insertion - may appear as radiographic erosions. In the spine MRI is the modality of choice to image any soft tissue structure, and shows pressure on the neural canal by disc, ligament and inflammatory process. It may show changes at sacroiliac joints before sacroiliac X-rays are abnormal. Q

an exacerbation, the patient with ankylosing spondylitis stiffens with bed rest and should be encouraged to remain active. Lumbar supports should not be prescribed. The patient must understand that the purpose of antiinflammatory drugs is to reduce pain and stiffness so that an active exercise programme can be followed. Phenylbutazone can still be prescribed for ankylosing spondylitis, and sulfasalazine can help the peripheral synovitis. Advice should be given about posture. A firm bed with one pillow is appropriate at night. The patient should be taught exercises that can be performed daily at home, and these should include spine extension and breathing exercises. Support groups and group physiotherapy sessions may help by providing advice and support in carrying out exercises. Surgical intervention is most often carried out for hip involvement. Rarely, spinal osteotomy is used for severe spinal curvature. Genetic counselling Most patients with ankylosing spondylitis are HLA-B27positive, and 50% of their offspring will carry this antigen. If HLA-B27-positive, a son or daughter has a 33% chance of developing ankylosing spondylitis. Parents should be advised that if the child develops symptoms such as swollen joints or painful eyes, they should seek medical advice.

Prognosis With suitable treatment the prognosis is excellent and 85 % of patients never lose a day's work. After the early, painful phase, the back may be stiff but disability is minimal unless hip involvement is present. About 5% of patients have an unfavourable course from the outset.

PSORIATIC ARTHRITIS

Psoriasis occurs in about 2% of the population and arthritis occurs in about 10% of patients with psoriasis, particularly in those with nail involvement. It affects the sexes equally. The skin and nail changes involved in psoriatic arthritis are described on pages 410-411.

Clinical features Management A long-term programme of active mobilization combined with anti-inflammatory drug therapy is the mainstay of management. Indomethacin is usually effective. The aim is to ease pain and stiffness, to keep deformity to a minimum, and to maintain spinal mobility as much as possible. In contrast to the patient with RA, who is put to bed during 1

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Fig. 22.9

The onset of arthritis usually follows a long history of psoriasis and can be acute, insidious, monoarticular or polyarticular. Occasionally it precedes the skin lesions. There does not appear to be a correlation between the severity of the skin lesions and the development of the arthropathy, although the joint lesions are usually associated with involvement of the nails (Fig. 22.17). The severity and ultimate deformity caused by the disease is usually less than that due to RA, and remissions are more frequent. There may be some synchrony of activity of joint and skin manifestations. Different types of psoriatic arthropathy are recognized:

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FIG. 22.17 Nail and skin changes of psoriatic arthritis

FIG. 22.18 Psoriatic arthropathy, with extensive involvement of the distal interphalangeal joints

• Asymmetric oligoarthritis, which involves one or two joints of fingers or toes, but can affect large joints; • Symmetrical polyarthritis, which resembles RA; • Arthritis mutilans, the most severe form of destructive arthritis; • Psoriatic spondylitis, in which radiological sacroiliitis occurs in 20% of cases; • Psoriatic nail disease and distal interphalangeal joint involvement.

Management and prognosis

The joints involved and the pattern of destruction suggest the diagnosis. Although any joint can be affected, the most characteristic are the distal interphalangeal joints of the hands and feet. A search for psoriasis should include the scalp, natal cleft and feet. Mucosal psoriatic lesions may affect the genitalia and tongue.

Investigation Radiological features of psoriatic arthritis are erosions in the distal interphalangeal joints, with ankylosis, reabsorption of the terminal phalanges, and marginal bone overgrowths at the tendon insertions. When this last feature is associated with osteolysis of the middle phalanx the radiological 'pencil in cup' deformity appears. If osteolysis progresses to 'telescoping' of the phalanges, the condition is known as arthritis mutilans (Fig. 22.18). Sacroiliitis is found in up to 30% of cases, in which erosions, sclerosis and ankylosis may occur. Unlike ankylosing spondylitis, the involvement is usually asymmetrical. It is particularly common in patients with the severe arthritis mutilans form of disease. Paravertebral calcification and occasional large syndesmophytes may be seen. However, the incidence of typical ankylosing spondylitis is also higher in psoriatics and relatives than might be expected in the general population. Hyperuricaemia can occur in up to 20% of all psoriatics, and the arthropathy should not therefore be confused with gout.

The treatment of the peripheral arthritis is similar to that of RA. Methotrexate therapy may be required for the more severe cases. Spinal disease is treated in the same way as ankylosing spondylitis. In most cases the prognosis is good and joint function is barely impaired, but deformity and disability occur in some patients.

REITER'S SYNDROME AND REACTIVE ARTHRITIS Reiter's syndrome was described several times before 1916, when Hans Reiter described the case of a Prussian cavalry officer serving on the Balkan Front who developed an acute febrile illness characterized by arthritis, urethritis and conjunctivitis. The attack followed an episode of bloody diarrhoea. Although the venereal form of the disease is commoner in the UK, the postdysenteric form predominates in Europe. The incidence in patients with dysentery is approximately 0.2%, and 0.8% of patients with non-specific urethritis develop Reiter's disease. Reactive arthritis refers to non-septic arthritis strongly linked to a recognized episode of infection. Arthritis may be described as reactive if it is associated with bacterial infection at a distant site but viable microorganisms are not present in the affected joint. The term is equally applicable to rheumatic fever, arthritis after meningococcaemia, and Reiter's syndrome after dysentery. The terms sexually acquired reactive arthritis (SARA) and enteric reactive arthritis (ERA) have been introduced to allow accurate categorization of conditions associated with infections at specific sites.

Aetiology Several gut and genitourinary pathogens are thought to trigger reactive arthritis (Table 22.23) on the basis of pre-

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TABLE 22.23 Microo rganisms linked with reactive arthritis Genitourinary

Gastrointestinal

Other

Ch/amydia trachomatis Ureaplasma urealyticum Neisseria gonorrhoeas

Shigella spp. Salmonella spp. Yersinia spp. Campylobacter jejuni Clostridium difficile Giardia lamblia Escherichia coli

Borrelia burgdorferi Chlamydia pneumonias

ceding and concurrent infection, enhanced antibody and cellular immune responses and selection of bacterial antigens in material from inflamed joints. FIG. 22.19 Reiter's disease; X-ray showing plantar spur

Clinical features The diagnostic triad in Reiter's syndrome comprises urethritis, conjunctivitis and arthritis. It has been defined more recently by the American Rheumatism Association as an episode of peripheral arthritis of more than 1 month's duration occurring in association with urethritis or cervicitis, or both. Most cases of Reiter's syndrome occur in the age range 16-35 years, and the male to female ratio is 20:1. However, urethritis is often not clinically apparent in females. Postdysenteric Reiter's syndrome has an equal sex distribution. Urethritis is usually the first feature to appear, and occurs up to 1 month after sexual exposure. It is often mild, but rarely there is a bloodstained discharge. The complaint of dysuria is almost invariable, and there is frequency and suprapubic discomfort owing to bladder involvement and prostatitis. Mucocutaneous lesions in the glans penis are characteristic. Superficial ulcers often coalesce to form circinate patches. Involvement of the mucous membranes of the mouth is found in 10% of patients. The lesions are often painless and subside spontaneously. The typical cutaneous lesion of Reiter's disease is kemtoderma blenorrhagica. Initially a red macular eruption O^ it becomes hyperkeratotic and histologically identical to pustular psoriasis. This can occur anywhere on the body, but is most characteristically seen on the palms of the hands and soles of the feet. The crust is eventually shed, leaving no scar. Sterile conjunctivitis is the most common form of eye involvement and is usually mild. Occasionally, ocular involvement may be very severe, with almost all parts of the eye being involved, although the disease has a predilec-

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Fig. 22.10

2

MCQ 22.9

3

MCQ 22.10

tion for the conjunctiva and anterior uveal tract. Frequently, there are transient abnormalities of cardiac conduction which may progress to complete heart block. Pericarditis and aortic valve lesions also occur. Transient pulmonary shadowing has been described. The arthritis varies in severity from a mild, transient synovitis to a chronic destructive arthritis. It tends to involve large weight-bearing joints, and although it may on occasion be monoarticular, this is uncommon; it is usually asymmetrical, involving fingers and toes. In a typical case arthritis may last for weeks or months, although in a few cases permanent joint damage may result. A feature of the condition is its liability to recurrences. Over 60% of patients have two attacks or more. Symptom-free intervals of 10 years or more are not uncommon, but in a small number no clear-cut remission occurs.

Investigation The ESR is elevated, sometimes markedly so in the acute phase. Radiological examination in the early weeks may reveal no abnormality or only juxta-articular osteoporosis. Periostitis is a characteristic finding, especially in the metatarsals and in the phalanges of the feet. The new bone formation has an exuberant, fluffy appearance. Plantar spurs occur in 20-45% of cases (Fig. 22.19). Unilateral or bilateral changes are seen in the sacroiliac joints, the frequency increasing to 50% after 5 years, and changes of ankylosing spondylitis may be seen in the spine. The skin lesions and the arthropathy may resemble psoriasis. There have been cases when apparently typical Reiter's disease has progressed to typical psoriatic arthropathy. The link is emphasized by family studies, where among the male relatives of patients with Reiter's disease the prevalence of psoriasis is 13%.

Management and prognosis For most patients a NSAID is useful. Methotrexate or azathioprine should be considered for severe intractable disease. Uveitis should be evaluated by an ophthalmologist if it does not respond rapidly to steroid eye-drops. Spouses are often concerned that they may catch the disease from the patient. This does not occur. Most patients with Reiter's syndrome do not seem to have sexually acquired disease. Tetracycline is effective in the treatment of non-specific urethritis, but has no effect on the other manifestations of the disease. Reiter's syndrome was at one time considered to be a self-limiting condition but is now known to be persistent in many patients: about 80% have evidence of disease activity when they are examined after 5 years. ©

WHIPPLE'S DISEASE

22

Whipple's disease is a rare condition. The finding of bacilliform bodies on electron microscopy and the good response to long-term antibiotic therapy suggest that it has an infectious aetiology. An episodic arthritis is a common presentation and may precede the gut symptoms by several years. The pattern of joint disease is similar to that seen in intestinal inflammatory disease, but the absence of overt gut symptoms should alert one to the possibility of Whipple's disease. Prolonged antibiotic therapy leads to improvement. It is usual to give tetracycline 1 g daily for 12 months, following an initial 10 days' treatment with parenteral penicillin and streptomycin.

BEHCET'S SYNDROME ENTEROPATHIC ARTHROPATHIES The term enteropathic arthropathy means arthropathy associated with bowel disease (usually ulcerative colitis and Crohn's disease). There are two main clinical patterns: • An episodic synovitis mainly involving weight-bearing joints • Sacroiliitis. About 50% of individuals with both inflammatory bowel disease and ankylosing spondylitis are HLA-B27 positive. Synovitis occurs in 12% of patients with ulcerative colitis and in 21% of those with Crohn's disease. The synovitis correlates with exacerbations of ulcerative colitis, and is more likely when the bowel disease is extensive or when complications such as perianal suppuration occur. A total proctocolectomy abolishes the synovitis. In Crohn's disease surgery seldom offers a radical cure, but synovitis tends to correlate with bowel activity. In both cases the synovium shows non-specific inflammatory changes and, irrespective of the number of recurrences of the condition, progression to radiological joint destruction does not occur. Radiologically typical ankylosing spondylitis or sacroiliitis occurs in 17% of cases of inflammatory bowel disease. This frequently antedates the bowel symptoms and the progress of the two manifestations is not synchronous. In ulcerative colitis, radical excision of the colon does not provide a cure for the spondylitis. Involvement of the peripheral joints may lead to confusion with enteropathic synovitis; however, the presence of sacroiliac and spinal disease, the lack of association of joint and bowel symptoms, and the presence of radiological changes in the involved joints all help in differentiation. Family studies show an increased evidence of sacroiliitis and ankylosing spondylitis in relatives. This supports the view that the spondylitis is an hereditary accompaniment, rather than a complication, of the disease.

Beh§et's syndrome was first described in Turkey and is common in eastern Mediterranean countries and Japan, though rare in the UK. It is of unknown aetiology and is characterized by the triad of aphthous-type oral and genital ulcers and iritis. Other features that commonly occur include thrombophlebitis, erythema nodosum, pustules and folliculitis. Some patients show the phenomenon of pustule formation where the skin is subjected to trivial injury, e.g. venepuncture. Pathergy describes the excessive subacute inflammatory reaction to non-specific injury that appears to be central to the pathogenesis of Behcet's syndrome. Patients comment that their skin readily becomes inflamed in response to scratches or pricks, and that oral ulcers are induced by dental procedures. Large-vessel thrombosis and bowel disease resembling ulcerative colitis can occur. The CNS can be involved, with meningoencephalitis, cranial nerve palsies, hemiparesis and transient episodes resembling strokes. Vascular involvement of the eye is one of the most serious aspects of Behcet's syndrome, with blindness being a frequent outcome. Arthritis occurs in 60% of cases, affecting mainly the weight-bearing joints, and the course tends to be chronic. The inclusion of Behcet's syndrome in the seronegative group is somewhat speculative. The most typical picture is a self-limiting non-erosive monoarthritis or symmetrical oligoarthritis involving predominantly the knees, ankles, wrists and elbows. Involvement of the spine and sacroiliac joints is uncommon. There is association with HLA-B5 but not HLA-B27, and eye disease is particularly associated with HLA-B51. Acute episodes, especially those involving the eye, usually require high-dose corticosteroid therapy. Colchicine is useful for some aspects of the disease, especially the orogenital ulceration. Ciclosporin A has shown promise, particularly for controlling the eye disease, as has azathioprine. Thalidomide is often effective in reducing the severity and frequency of mucocutaneous disease resistant to colchicine. ©

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FURTHER READING ON SERONEGATIVE SPONDARTHRITIDES Archer J R 1994 HLA-B27 and its role in arthritis. Rheumatology in Europe 23:97-99. Carette S, Graham D, Little H, Rubenstein J, Rosen P 1983 The natural disease course of ankylosing spondylitis. Arthritis and Rheumatism 26:186-190. McGonagle D 1998 Classification of inflammatory arthritis by enthesitis. Lancet 352:1137-1140. Pickering M, Haskard D 2000 Behget's syndrome. J Roy Coll Physicians 34:169-177. Richter M B 1985 Seronegative spondarthropathies. Clinics in Rheumatic Diseases 11(1):147-169. Segundo-Gonzalez 1999 Immunogenetics, HLA-B27 and spondyloarthropathies. Curr Opin Rheumatol 11:257-164. Wright V, Moll J M H 1976 Seronegative polyarthritis. NorthHolland, Amsterdam.

OSTEOARTHRITIS

Osteoarthritis is the commonest condition to affect synovial joints and the single most important cause of locomotor disability. Osteoarthritis (OA) is defined pathologically and radiologically by reduced joint space secondary to loss of cartilage, by sclerosis of subchondral bone and by osteophyte formation (an accompanying reparative process). The term primary OA is used to distinguish cases with no apparent cause from secondary OA, when a number of localized or generalized pre-existing disorders are present (Table 22.24).

Epidemiology Radiographic evidence of OA is found in 35% of people under 30 years of age, and in 85% of 80-year-olds (Fig. 22.20). OA of the hip is more common in men under 35 years of age, but in later years it is more common and more severe in women. Although radiographic evidence of OA appears to have an equal sex ratio, symptoms are three times more common in women. There is a marked familial tendency, particularly in association with Heberden's nodes, and the geographical distribution of joint involvement varies. Certain occupations have a high frequency of OA, e.g. coalminers develop OA of the spine and knees. OA is seen in all cultural groups, though the pattern of involvement varies. Hip disease is uncommon in people

with Down's syndrome and hand disease is seldom seen in Afro-Caribbeans.

Aetiology A number of processes are involved in the development of OA: • • • • •

Failure of bone and cartilage remodelling Inflammation Ageing Abnormal joint loading Deposits of apatite and calcium pyrophosphate are common, but how they affect the joint remains unknown • Alterations of the complex reflex neurological and muscle function around a joint, resulting in an impaired shock-absorbing capacity • Enzymic destruction of cartilage. The development of OA appears to be a 'final common pathway' in joint malfunction, but age and loading patterns appear to be the most important predisposing factors. Once the natural history of the disease has been established, the course varies from rapid progression, through relapsing phasic activity to apparent stabilization.

Pathology Previously considered as a degenerative condition, osteoarthritis is now viewed as a metabolically dynamic reparative process. The early stages of OA include an increase in proteoglycan turnover, a change in proteoglycan composition and an increase of type II collagen production. The relationship of these changes to ageing is uncertain. Cartilage shows thinning, erosions, fibrillation, clefts and loss of joint surface congruity with areas of chondrocyte loss. Subchondral bone becomes sclerotic with increased

TABLE 22.24 Secondary causes of osteoarthritis

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• • • • •

Previous inflammatory arthritis Previous joint infections Avascular necrosis Intra-articular fracture Joint dysplasias

• • • • •

Congenital dislocation of hip Perthe's disease Acromegaly Ochronosis Haemochromatosis

FIG. 22.20 Age and sex distribution of generalized osteoarthritis (GOA) in the UK in patients with and without Heberden's nodes (After Lawrence JS, 1977.)

FE

RECENT ADVANCES IN AETIOLOGY OF OSTEOARTHRITIS Genetic factors are increasingly under investigation. A hereditary component to OA has been noted for decades, particularly in the settings of primary generalized and nodal disease. A positive family history is identified in 20% of those with primary generalized OA, and heredity is estimated to account for 50-65% of the population variance overall. More recent work suggests that Heberden's nodes do not reflect a genetically separate disease, genetic factors being equally predictive in those with knee OA only. The search for putative genetic links has concentrated on the collagen types predominantly found in cartilage. Of these, type II is the most abundant, and a number of mutations have been found in the Col2Al gene. However, these mutations have so far only been detected in rare familial types of OA. Others have examined genes for the collagen link protein (CRTLI} or for other non-collagen matrix proteins (e.g. CRTM) without rinding a convincing association. As with cartilage degradation in RA,TNF-a, IL-1 and inducible nitric oxide synthase are now of interest.

vascularity, and bone distant from the joint undergoes remodelling. Proliferation of the cartilage produces osteophytes, which is usually a late phenomenon. In the later stages, cysts are formed in the underlying subchondral bone, and the articular surface may collapse. A mild synovitis may be seen, and the synovial fluid may contain apatite and pyrophosphate crystals.

Clinical features The main initial symptom of OA is pain made worse by movement and eased by rest. Stiffness may be present after inactivity, but morning stiffness is not a feature. As the joint deteriorates, with loss of movement and instability, the pain becomes more pronounced and is present at rest and in the night. Only about a third of patients with radiological OA have symptoms, and the cause of pain is not understood as there are no pain receptors in cartilage. Pain may also arise from the ligaments or bursae around the joint. Examination shows deformity and bony enlargement of the joint, with occasional synovial thickening and effusion. There is coarse crepitus on movement. The pattern of joint involvement varies, but those most commonly affected include the first metacarpophalangeal, the first metatarsophalangeal, and the distal interphalangeal joint of the hands (Fig. 22.3). The hip and knee are affected less frequently and the shoulder and ankle are seldom involved. In the spine, the apophyseal joints around C5-C7 and L3-L5 are commonly involved (Fig. 22.21). OA is not a single static condition but a family of conditions, with widely different pathogenetic factors. Generalized OA affects several joints and there are usually Heberden's nodes present. 'Inflammatory' OA affects par-

FIG. 22.21 Finger deformities in osteoarthritis

ticularly the interphalangeal joints and is associated with cartilage erosion. Hip arthritis can be confined to one area of the hip, particularly the superior pole or the medial pole, or may involve the entire joint. Similarly, there are different patterns of knee involvement. Lateral compartment changes seldom occur without medial compartment changes. Predominate patellofemoral disease is a feature of pyrophosphate arthropathy (p. 1171).

Investigations OA can only be diagnosed by X-ray, showing bone sclerosis and osteophyte formation. All blood tests are normal in uncomplicated OA.

Management Increasingly, OA is recognized as a dynamic process, and the concepts of 'chondromodulation' and of 'structuremodifying osteoarthritis drugs ('SMOADs')' have been introduced. However, the natural history of OA is poorly documented. There is evidence that the process may stop, or even improve, in some patients, and in those that have progressive disease severe joint failure tends to occur in a weight-bearing joint in a minority of cases. Thus, clinical evaluation of therapy in trials is complex. In vitro cartilage explant research and arthroscopic evaluation of cartilage in vivo have led to some useful developments. • 'Viscosupplementation' describes the intra-articular injection of a high-molecular weight hyaluronan. Hyaluronic acid is believed to be an important factor in the mechanical properties of a joint, acting as a shockabsorber but also important in cartilage nutrition. To date, three to five weekly injections into symptomatic and radiologically advanced OA knees have proven symptomatic benefit over NSAIDs and analgesia alone. However, a 'disease-modifying' effect has only been demonstrated in in vitro studies. • A number of agents have been shown to have potential as SMOADs in in vitro studies, reducing cytokines

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CASE STUDY 22.2 BILATERAL LOWER LEG PAIN IN A 67-YEAR-OLD WOMAN A 67-year-old woman complains of pain in her lower leg. This is present throughout the day, but particularly towards the end of the day and through the night. Described as a deep ache in her bone, it extends from the knee to the middle of the shin anteriorly. Symptoms have been present for about 6 months, gradually becoming worse - at this point she is unable to walk more than 200 yards with any comfort, and is being woken at night with a throbbing ache in her lower leg. She also states that she is afraid of walking without a companion, as she has felt that her leg was about to give way under her on a few occasions. She is not sure if there has been any swelling, but describes feeling stiff when first getting up from a chair if she has been sitting for long. Other than mild hypertension, controlled with hydrochlorothiazide, she is well and has no other joint symptoms.

Question 1. This woman describes a classic history of what condition?

These are the typical features, not all of which would be always present, of osteoarthritis of the knee. Although stiffness is described, early morning predominance was not noted and swelling has not been remarkable, thereby excluding a primarily inflammatory arthropathy. Bone aching could also occur with Paget's disease and with osteomalacia, but neither condition would involve the joint (secondary osteoarthritis can complicate Paget's disease). Diuretic use is the leading cause of gout in women, but presentations are then acute and inflammatory features usually readily identified.

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Question 2. What aspects of examination, are particularly important?

First, one should look for those features at the knee that support the clinical impression of osteoarthritis. These include reduced range of movement in the knee (and fixed flexion in late stages), pain at the end of range, crepitus during movement (not the 'crack' sound that often alarms patients, but a continuous grating sensation throughout movement), and joint-line tenderness. Bony deformity may be noted (most commonly varus in OA, in contrast to valgus in RA), and an effusion should specifically be sought by palpation and ballotting the patella. Ligamentous stability of the knee should also be confirmed. It is important to assess the hip, as pain may be referred distally. The lumbar spine and leg length should be assessed to identify contributory factors.

Question 3. What treatment advice will you give?

Treatment may be divided broadly into symptomatic relief, disease-modifying therapy, and non-pharmacological therapies. Symptomatic relief should concentrate on identifying the least amount of the least toxic medication. Treatment may gradually increase, starting with simple analgesia (paracetemol) and increasing to combinations with codeine-based drugs (coproxamol/codydramol). Opiate analgesia is rarely required. The addition of a non-steroidal antiinflammatory can be helpful,

particularly in those with a significant inflammatory component (stiffness, inflammation); mild NSAIDs such as ibuprofen are usually sufficient. Topical NSAIDs are controversial: although a placebo response is noted, the pharmacological effect appears to rely on systemic absorbtion. Intraarticular injection of corticosteroid (80 mg methylprednisolone or 40 mg triamcinolone) can offer symptomatic relief for up to 3 months. Injection of the knee with hyaluronic acid analogue (Hyalgan or Synvisc) has been shown to offer comparable symptomatic relief, with perhaps a longer duration than steroid injection. Disease-modifying agents have been identified in laboratory studies, but such an effect has failed to be transferred to clinical practice; therefore, agents such as chondroitin, glucosamine and ASU (see text) should only be recommended with the caveat that their value remains unproven. Delaying the progression of OA in the knee and preserving joint function can also be addressed by encouraging exercise in general, and specifically those exercises that strengthen the quadriceps muscles. Non-pharmacological therapies offering analgesia include the application of heat, TENS or acupuncture. Lifestyle factors include weight reduction and cessation of smoking. Ultimately, joint replacement can be undertaken - the degree of disability, pain disturbing sleep and the knee giving way are important factors in the decision to replace the knee, in addition to radiographic assessment. Two years later the patient presented to the A&E department because her knee had become painfully swollen. On examination, the knee was warm, tender to touch, with a large effusion. She was otherwise well, and had not fallen or injured her knee.

Question 4, What are the leading diagnostic possibilities, and how will you make a definite diagnosis? In a person with pre-existing osteoarthritis, a crystal arthropathy is the most likely cause of an acute inflammatory monoarthritis. Calcium pyrophosphate dihydrate (CPPD) crystals are the most commonly identified (the clinical picture is then called pseudogout), although as she is taking a diuretic, the monosodium urate crystals of gout should also be sought. Hydroxyapatite crystals are less frequently identified. Sepsis is invariably considered, but in the absence of a procedure or illness that might introduce infection, this is

unlikely. A definitive diagnosis, in addition to therapeutic relief, is obtained by aspirating the joint and requesting urgent microscopy of the aspirate; crystals are less frequently seen if fluid is left overnight. Radiographs are often obtained in A&E departments; however, with the exception of ruling out a fracture in traumatic cases (which may be difficult clinically in a deformed knee), there are no conclusive diagnostic radiological features. Chondrocalcinosis in the fibrocartilage of the menisci indicates CPPD deposition but does not prove that a specific acute episode is pseudogout. In this case, a cloudy aspirate was obtained (indicating large numbers of inflammatory cells, not necessarily infection), and microscopy confirmed the presence of CPPD crystals.

implicated in cartilage breakdown and increasing proteoglycan synthesis. Chondroitin, glucosamine sulfate, diacerhein and avocado/soybean unsaponifiables (ASU) have each been evaluated in humans. Each has demonstrated symptomatic relief superior to placebo, with some improvements in functional indices and reduced NSAID requirements, particularly in those with more severe radiographic disease. However, no effect on disease progression has been identified to date. • The interaction between matrix-metalloproteinases and their inhibitors has been investigated. Tetracyclines, and particularly the synthetic derivative minocycline, has significant MMP-inhibitory properties and is currently in trials of knee OA. However, although these studies may provide useful interventions in the future, the mainstay of OA management remains symptomatic relief and preservation of function. Patients should be reassured that they do not have a relentlessly progressive disease such as RA. Weight reduction is desirable in obese patients and may reduce the progression of knee osteoarthritis. Pain relief can be achieved with analgesics such as paracetamol, increasing to combinations with codeine-based drugs (e.g. dextropropoxyphene in coproxamol). NSAIDs have more side-effects, but may be necessary when pain is severe or where there is clearly an inflammatory component. The COX-2-specific NSAIDs (see RA above) are an important advance in this group of patients, who are often elderly and have comorbidities increasing their risks of peptic ulcer disease and its complications. Intra-articular steroid injections and joint

Symptomatic relief may be obtained with NSAIDs. Intraarticular corticosteroid can be injected directly after aspiration if one is confident that sepsis can be excluded, on history and by obtaining a clear aspirate. However, one should always err on the side of caution, awaiting microscopy confirmation when there is doubt. A knee effusion may extend posteriorly, producing a Baker's cyst. If this then ruptures, the irritant synovial fluid in the muscular compartment results in a clinical picture often indistinguishable from that of DVT. A previous history of OA and the presence of a residual knee effusion are helpful diagnostically, and aspiration and injection are again the most useful interventions.

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RECENT ADVANCES IN TREATMENT OF OSTEOARTHRITIS There is increasing interest in therapeutic measures aimed at reversing the changes in cartilage in OA ('chondromodulation'). These include intra-articular injection of hyaluronan, oral chondroitin, glucosamine, and inhibition of degradative enzymes (metalloproteinases) with minocycline. Research is ongoing into the cytokines and tissue growth factors in the OA joint. The reimplantation into cartilage defects of chondrocytes grown from a patient's own cartilage, obtained by biopsy of a healthy site, is gaining momentum. The cells are covered by a periosteal patch, holding them in place and providing growth factors, including bone morphogenetic protein-2 (bmp-2) and fibroblast growth factor. Over a 2-year period the cartilage defect is filled, cartilage becomes firm, and a calcified layer appears.

aspiration may help in restoration of function if there are effusions and inflammatory changes. Physical therapy OA in a weight-bearing joint may be helped by physiotherapy. This may restore the function of wasted muscles, improve mobility and compensate for some instability. Heat may provide pain relief. Hydrotherapy helps to reduce the load on the joint, allowing mobilization. Fixed flexion deformity of the knee can be helped by serial splint-

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TABLE 22,25 Some surgical procedures in osteoarthritis • Synovectomy/debridement • Arthroplasty • Osteotomy

• Arthrodesis • Tendon repairs • Nerve decompression

ing. A walking stick is useful for hip or knee involvement. Splints may support unstable joints, and walking aids may be helpful. Cushioned shoes (e.g. trainers) are useful in redistributing stress and reducing impact loading. Surgery Surgery is indicated if pain and loss of function have failed to respond to conservative measures. Surgical procedures include removal of loose bodies, osteotomy to relieve pain and arthrodesis and arthroplasty (joint replacement) (Table 22.25). Proper assessment is the key to a successful outcome, and surgery should only be carried out when there is a clear indication that function will be improved. Joint replacement will continue to develop. There is still much basic research to be done into the biomechanics of joints both under normal conditions and after prosthetic replacement, and on the problems of lubrication. O FURTHER READING ON OSTEQARTHRITIS Altman R 1998 Intra-articular sodium hyaluronate in the treatment of patients with osteoarthritis of the knee: a randomised clinical trial. J Rheumatol 25:2203-2212. Bland J H, Cooper S M 1994 Osteoarthritis: a review of the cell biology involved and evidence for reversibility. Management rationally related to known genesis and pathophysiology. Semin Arthritis Rheum 14(2):106-133. Britberg M 1994 Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med 331:889-895. Felson D T 1990 The epidemiology of knee osteoarthritis: results from the Framingham Osteoarthritis Study. Semin Arthritis Rheum 20(3):42-50 Felson M, Zhang Y 1998 An update of the epidemiology of knee and hip osteoarthritis with a view to prevention. Arthritis Rheum 41:1343-1355. Hall R, Pope F M 1989 Osteoarthritis and the collagen genes. Lancet 11:1337-1338

INFECTIVE ARTHRITIS

Arthritis may arise from direct infection of joints by microorganisms, or as a reaction to a preceding infec-

1

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MCQ 22.11

0 Figs 22.11, 22.12

FIG. 22.22 Septic joint in rheumatoid arthritis

tion. Infection must be considered in all cases of acute arthritis, particularly when only one joint is affected. Delay in treatment may lead to permanent joint damage or septicaemia.

BACTERIAL INFECTIONS

Most cases of bacterial arthritis result from haematogenous spread; much less frequently, infection results from joint aspiration or injection, or spread from osteomyelitis. The most frequent organisms are Staphylococcus aureus, Streptococcus pyogenes, Diplococcus pneumoniae and Neisseria gonorrhoeae. Certain organisms appear to exhibit a tropism for joints: for instance, septic arthritis complicates about 1% of pneumococcal and salmonella infections when treatment is delayed, whereas about 80% of patients with gonococcal septicaemia develop arthritis. The frequency with which different organisms are associated with septic arthritis is partly age-dependent. The organisms that cause septic arthritis in young children are usually not the same as those causing it in adults. Septic arthritis may occur at any age, but is particularly common under the age of 15 years and in the elderly. Other predisposing factors include debilitating disease, hypogammaglobulinaemia, corticosteroid and immunosuppressive therapy, and RA.

Clinical features Usually a single joint is involved and there is marked inflammation, with severe pain, tenderness, erythema and swelling (Fig. 22.22). There may be minimal signs of inflammation in patients receiving corticosteroids or with a debilitating illness. In an infant there may also be little systemic illness, and the child may present with sudden refusal to move a limb. An infected joint is commonly associated with a fever, often accompanied by rigors, and the patient looks ill.

When the organism is the gonococcus, a migratory polyarthritis may precede localization in a single joint. A total of 10-20% of staphylococcal infections and 75-85% of gonococcal infections involve two or more joints. More than one joint may also be involved in immunosuppressed and debilitated patients. The identification of a septic joint in RA can prove difficult, but must be considered whenever there is increase in pain, swelling or other evidence of inflammation in one or a limited number of joints. The development of low-grade infection in prosthetic joints is an increasing problem, and recognition may take several months. Organisms of low virulence, especially Staphylococcus albus, predominate.

Diagnosis Diagnosis of septic arthritis depends on demonstrating the organism in joint fluid or tissue, and synovial fluid and blood should be sent for culture. In addition to routine aerobic and anaerobic cultures, special media are needed for the isolation of N. gonorrhoeae, and additional culture of sputum, urine and cervical mucus may prove helpful in special circumstances. Osteomyelitis should be considered if the site of maximal tenderness extends beyond the joint. If there is any doubt about the bone adjacent to an infected joint, an isotope scan will demonstrate bone involvement. The condition known as transient synovitis of the hip can prove a difficult differential diagnosis. No definite cause has been established for this disorder and it may represent a number of conditions. It affects children between the ages of 2 and 12 years, who present with pain, a low-grade fever and slight elevation of the ESR. It is safest to treat this as an infection until the diagnosis of septic arthritis has been excluded. While MRI techniques are seldom necessary in the evaluation of septic arthritis, clinically important information about joint integrity and the presence of otherwise unapparent para-articular osteomyeltis may be demonstrated. ©

Management Antibiotics should be started as soon as specimens have been sent to the laboratory. Changes in therapy can be made once the sensitivities of the infecting organism are known. Therapy should be administered intravenously for up to 2 weeks and then oral therapy given for at least 6 weeks. Intra-articular therapy is not required. The joint should be splinted in a suitable position to relieve pain until the inflammation has subsided. Synovial fluid should be aspirated when it reaccumulates, as the presence of purulent material may inhibit the action of antibiotics. Gross joint destruction and the presence of contiguous osteomyelitis are indications for surgical drainage, as is failure of response to drug therapy within 72 hours. Once the acute inflammation has subsided, passive and then active exercises can be given. Weight-

bearing can be resumed when signs of inflammation have subsided.

22

Specific bacterial arthritides Gonococcal arthritis Gonococcal arthritis is most common in females and homosexual males, in whom the primary infection is often asymptomatic. Clinical features The most common pattern of joint involvement is a migratory polyarthritis associated with tenosynovitis, with the synovitis localizing in one or two joints. Joint symptoms occur within 3 weeks of infection and are accompanied by fever and rigors. There is a tendency for the small joints of the upper limbs to be involved, rather than larger joints; however, the knee is also frequently affected. A sparse erythematous skin rash, which may be macular, vesicular or pustular, occurs in one-third of cases and is found adjacent to involved joints. It appears before, or within a few days of, the arthritis and may be painful at the outset. Diagnosis The gonococcus is difficult to grow, and repeated blood and synovial fluid cultures may be required to confirm the diagnosis. The organism is identified in joint fluid in only 25% of patients. There should be little difficulty in distinguishing between Reiter's disease and gonococcal arthritis. There is an 80% female preponderance of gonococcal arthritis, compared with a high proportion of males with Reiter's disease. In gonococcal arthritis pyrexia is more common, the upper limb joints are involved more frequently, and the arthritis is less symmetrical than in Reiter's disease. Reiter's disease is associated with the tissue antigen B27; gonococcal arthritis is not. Treatment Benzylpenicillin is given intravenously until there is a clinical response. Penicillinase-producing strains of gonococci are resistant to penicillin and cephaloridine. For such patients spectinomycin or cephoxitin is the treatment of choice. Meningococcal arthritis Meningococcal infection is complicated by arthritis in 5-10% of patients. Characteristically, it affects large joints and sometimes flits from one to another. The onset is a few days after the beginning of the illness. Once treatment has begun, resolution occurs in 1-4 weeks. Infective endocarditis Joint manifestations are present in about half of patients with infective endocarditis. Large joint involvement is usual, and symptoms vary from mild arthralgia to an acute, red, swollen, painful joint. The combination of fever, arthritis and cardiac murmur may initially suggest rheumatic fever.

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Lyme arthritis This was first described in Old Lyme, Connecticut (USA), in 1972. Symptoms include a recurrent asymmetrical arthritis involving a few large joints. The arthritis follows 1-24 weeks after an erythematous rash, erythema chronicum migrans. The causative agent is a tick-borne spirochaete, Borrelia burgdorferi, which is transmitted by Ixodes dammini or related ixodid ticks. Lyme disease usually begins in summer with erythema chronicum migrans; this is the unique clinical marker, which begins as a red macule or papule that expands to form a large annular lesion. Skin involvement is often accompanied by fever, headache and regional lymphadenopathy, and migratory musculoskeletal pain and arthritis. Meningeal irritation and cardiac involvement may follow. Diagnosis is made by a serological test for Borrelia antibodies. Penicillin or tetracycline therapy given at the time of the rash may shorten the early illness and prevent arthritis. Later stages respond to high-dose intravenous penicillin. Tuberculous arthritis Tuberculosis should be considered in the differential diagnosis of chronic joint disease. It is most common in immigrant children and in the middle-aged or elderly. Only about 1% of all patients with tuberculosis have skeletal involvement; of these, approximately 50% have spinal disease, 30% infection of the hips or knees, and 20% arthritis of other joints, particularly the sacroiliac joints. Involvement of the knee is more common in adults, and of the spine and hips in children. About half the patients do not have pulmonary disease. It is assumed that haematogenous dissemination infects subchondral bone adjacent to a joint or a spinal intervertebral disc. The resulting osteomyelitis may remain dormant for years before there is reactivation. Alcoholism and chronic debilitating disease may predispose to reactivation. When the vertebral column is involved, dissection along fascial planes may cause a psoas abscess. Spread of infection to involve adjacent vertebrae may lead to wedging and kyphosis. The anterior portions of the vertebrae between the sixth thoracic and fifth lumbar levels are usually involved. Bone biopsy may be necessary to confirm the diagnosis. Peripheral joint involvement is usually monoarticular and destruction of cartilage occurs later than in pyogenic arthritis. The usual organism is Mycobacterium tuberculosis, but atypical organisms (e.g. M. kansasii, M. trivale) have been isolated from infected joints, and the bovine strain has been implicated in carpal tunnel infection. Diagnosis and treatment The diagnosis is made by biopsy and culture of the syn-

O MCQ 22.12

1160

ovium, as the bacilli are rarely grown from synovial fluid. Treatment is with antituberculous therapy (p. 645). Syphilitic arthritis Direct invasion of the synovium by Treponum pallidum is uncommon. A migratory polyarthritis occurs infrequently during the secondary stage of acquired syphilis and may resemble rheumatic fever. Congenital syphilis may cause: • Acute epiphysitis or osteochondritis, most commonly of the humerus and usually in the first weeks of life • 'Glutton's joints', painless bilateral swelling of the knees between the ages of 8 and 16 years • Rarely, a neuropathic arthropathy secondary to tabes dorsalis (Charcot's joint).

FUNGAL INFECTIONS Fungal infections of joints are rare. Culture of pus, synovial fluid or biopsy material permits diagnosis. Surgical drainage and excision of necrotic tissue may facilitate recovery. Actinomycosis commonly affects the mandible, but involvement of vertebrae occasionally occurs from local spread. Bone abscesses develop. Blastomycosis, coccidiomycosis, histoplasmosis and sporotrichosis can all affect the joints.

ARTHRITIS IN VIRAL DISEASE Several viral infections may be accompanied or followed by an arthropathy. Joint symptoms may coincide with, follow, or even precede the onset of other signs and symptoms; they are usually mild and tend to resolve spontaneously in a few weeks. In contrast to bacterial infections, viral arthropathies are usually polyarticular. It is thought that the synovitis results from immune complex deposition. Only in rubella arthritis has the virus been isolated from an affected joint. A viral arthritis should be suspected if the patient has a low white count with a relative lymphocytosis. Rubella In rubella (see p. 294) the arthritis involves the metacarpophalangeal or proximal interphalangeal joints (85%), elbows, wrists and knees, in a symmetrical fashion. Morning stiffness, painful tenosynovitis, the occasional occurrence of carpal tunnel syndrome and a positive latex test for RF may make the resemblance to RA even more striking, and differentiation between the two conditions in the early stages is not always possible on clinical grounds alone. The ESR is usually normal or slightly elevated. Rubella antibodies may be demonstrable in high litre.

Complete resolution of the arthritis occurs within a few weeks to a few months. Only in rare cases are symptoms so severe that a short course of corticosteroids is required. Arthralgia may persist for several months. Rubella vaccination Rubella vaccination produces musculoskeletal symptoms in up to 20% of cases. An arthritis similar to that associated with the natural infection occurs 2-4 weeks after vaccination and lasts for a few days, although it can persist for several weeks. Occasionally, synovitis continues for months. Joint pain affecting the arms or legs 2-10 weeks after rubella vaccination is caused by radiculoneuritis, and may be associated with paraesthesia. Infectious hepatitis During the early incubation period of viral hepatitis some patients may experience joint symptoms; these may be mild and transient (usually type A infections) or acute and prolonged (usually type B). It is rare before adolescence. Acute onset polyarthritis in a rheumatoid distribution, including the small joints of the hand, may occur in acute infections due to hepatitis C. Hepatitis C virus is often associated with Type 2 cryoglobulinaemia. It may be present as essential mixed cryoglobulinaemia, a traid of arthritis, palpable purpura and cryoglobulinaemia. There is bilateral and symmetrical involvement of the proximal interphalangeal joints and the spine is occasionally involved. Other symptoms are a rapid onset of morning stiffness, and warm, red and tender joints with slight effusions, associated with fever, anorexia, malaise and an occasional urticarial rash. The arthritis usually resolves with the appearance of jaundice. Joint disturbances can also be prominent in anicteric cases. A/lumps

Arthritis caused by mumps is most common in teenage males. Overall, less than 1% of those affected by mumps develop arthritis, usually 1-4 weeks after the start of the illness. It is usually migratory and asymmetrical, involving large joints. When the pattern of joint movement is accompanied by pericarditis, it can resemble rheumatic fever. During an epidemic, children may have an arthritis but no parotitis. Chickenpox Chickenpox may be complicated by bacterial arthritis, with spread from infectious scabs. A transient, acute arthritis may occur at the time of the rash. Adenoviral arthritis The arthritis associated with adenovirus infections usually occurs in children. It begins with fever, coryza and pharyngitis, followed by a macular erythematous rash and symmetrical arthritis. Infectious mononucleosis In infectious mononucleosis, widespread lymphadenopathy, splenomegaly, rash, fever and transient arthritis or

SUMMARY 5 Viral causes of arthritis • • • •

Rubella and rubella vaccination Infectious hepatitis Mumps Infectious mononucleosis

22

• Adenovirus infections • Arbovirus infections • Chickenpox • Parvovirus infections • HIV

arthralgia may mimic both rheumatic fever and systemic juvenile chronic arthritis. However, the skin lesions tend to be larger and raised, and do not recur as often as those of juvenile arthritis. This is a disorder of adolescents. In children, cytomegalovirus can cause a similar picture. Arboviruses Viral infections endemic to certain parts of the world can give rise to illnesses with prominent musculoarticular symptoms. The Ross River virus, a group A arbovirus found in Australia, causes a macular rash and fever, and a polyarthritis usually involving the small joints of the hands. Dengue fever, of south and southeast Asia, can cause a haemorrhagic rash, fever, and severe joint and muscle pains. The joint symptoms are self-limiting. Arboviruses are discussed further in Chapter 9, page 295. Parvoviruses In adults, joint involvement (transient arthralgia and arthritis) is common (80-90%) but this is less so in children (<10%) (see Ch. 9, p. 289). An acute self-limiting symmetrical polyarthritis occurs typically in young women and can last for up to 1 year. Rheumatic manifestations of HIV infections Increasingly, HIV-infected individuals are presenting to rheumatologists, and in some rheumatic symptoms are the first manifestation of infection. Patients may present with Reiter's syndrome or an acute oligoarthritis, which predominantly affects the lower limb joints, in the absence of clinical features of Reiter's syndrome. Other rheumatic syndromes which have been associated with HIV infection include myositis, vasculitis and lupuslike illness with low-titre antinuclear antibodies. It is difficult to attribute these clinical features exclusively to HIV infection, as many patients are likely to be exposed to other infections. However, septic bone and joint lesions do occur more commonly in patients with AIDS as their CD4 cell count falls. 1

FURTHER READING ON INFECTIVE ARTHRITIS Calabrese L H, Kelley D M, Myers A, O'Connell M, Easley K 1991 Rheumatic symptoms and human immunodeficiency virus infection. Arthritis Rheum 34:257-263. Cooper J D, Schoen R T 1992 Epidemiology, clinical features and diagnosis of Lyme disease. Curr Opin Rheumatol 4:520-528. Ryan M J, Kavanagh R, Wall P G, Hazleman B L 1997 Bacterial joint infections in England and Wales: analysis of bacterial isolates over a 4-year period. Br J Rheumatol 36: 370-373.

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TABLE 22.26 Differential diagnosis of arthritis in children • • • • • • • • • • • •

Joint infections (bacterial, tuberculous) Virus infections (rubella and mumps in particular) Juvenile idiopathic arthritis (JIA) Reactive arthritis Rheumatic fever Henoch-Schb'nlein purpura Leukaemia and haemorrhagic disease Neuroblastoma and lymphoma Connective tissue' disease Trauma and synovitis Idiopathic localized or diffuse pain syndrome Perthes' disease

Siegel L B, Cohn L, Nashel D 1993 Rheumatic manifestations of hepatitis C infection (Review). Semin Arthtitis Rheum 23:149-154. Smith C A, Petty R E, Tingle A J 1987 Rubella virus and arthritis. Rheum Dis Clin North Am 13:265-274. Van Dam A P Kuiper H, Vos K et al 1993 Different genospecies of Borrelia burgdorferi are associated with distinct clinical manifestations of Lyme borreliosis. Clin Inf Dis 17:705-717.

FIG. 22.23 Skin rash in systemic arthritis

Diagnosis of juvenile idiopathic arthritis All three of the following criteria must be met: • Arthritis persisting for more than 6 weeks • Onset of arthritis before 16 years • Exclusion of other diseases that may cause arthritis. The International League Against Rheumatism devised a classification of JIA in 1995.

CHILDHOOD ARTHRITIS There are a number of causes of arthritis in children (Table 22.26) and the diagnosis can be difficult. The commonest cause used to be rheumatic fever, but there has been a marked reduction in its incidence in the past 40 years. Children seem to suffer less discomfort from arthritis than adults. Arthritis may be first suggested by joint swelling, or by a limp or by guarding of the joints.

JUVENILE IDIOPATHIC ARTHRITIS Juvenile idiopathic arthritis (JIA) is a generic term covering several overlapping patterns of disease (Table 22.26). Common mistakes in diagnosis include diagnosis in the absence of persistent joint swelling and a failure to exclude differential diagnoses. About one child in every 1000 has JIA; each year one new case would be expected in every 10000 children. The diagnosis of juvenile idiopathic arthritis is often difficult initially because swelling of joints may be subtle or absent and complaints of pain may be difficult to elicit.

1

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MCQ 22.13

Classification of JIA • • • • •

Systemic arthritis Polyarticular rheumatoid factor-negative arthritis Polyarticular rheumatoid factor-positive arthritis Persistent oligoarthritis Extended oligoarthritis - presents as oligoarthritis but extends to involve >4 joints • Enthesitis-related arthritis • Psoriatic arthritis - diagnosis requires a history of psoriasis in the child or a first-degree relative • Other - includes overlaps, e.g. psoriatic arthritis with enthesitis.

Systemic arthritis The most common age of onset of systemic JIA is under 5 years, when boys are affected as frequently as girls; but the disease can present later in childhood, and even in adult life. With later presentation, girls are affected more commonly than boys. This is the rarest form of juvenile idiopathic arthritis.

Clinical features Fever and rash are the main clinical features (Fig. 22.23). The fever is characteristic. It differs from that of rheumatic fever in that the temperature may be normal or subnormal in the morning, and the child may then appear to be reasonably well. By the late afternoon, however, a temperature of up to 40°C may be recorded and the child looks ill.

Salicylates or paracetamol usually control the fever. When high fever precedes arthritis, diagnosis can prove difficult and is often aided by the appearance of the rash. About 40% of children develop a rash, which is evanescent, often appearing when the temperature is high. It is usually pink, macular, discrete and non-pruritic, and affects the trunk and limbs, although it can be widespread and involve the face, palms and soles. Generalized lymph node enlargement may be marked, so that the clinician may suspect leukaemia or lymphoma, but histology shows reactive hyperplasia and the nodes regress as the disease subsides. Enlargement of the mesenteric glands may cause abdominal pain. Splenomegaly is moderate. If it persists, the complications of amyloidosis should be considered. Initially there may be no joint symptoms, minor arthralgia or definite arthritis. Ultimately, however, most patients develop arthritis affecting the knees, wrists and ankles. Flexor tendon involvement of the hands is common. Involvement of the cervical spine occurs and leads to pain and limitation of movement. Pericarditis is detected in 7% of patients, but is found in approximately 45% of necropsies. Myocarditis may also occur. Subcutaneous nodules are less common in children than in adults. Interestingly, their histology resembles that of the nodules of rheumatic fever. Differential diagnosis The diagnosis is a clinical one. Infective causes of fever and arthritis must be excluded. In the first few days it can be difficult to distinguish systemic JIA from a viral infection, but the persistent spiking fever and recurrent maculopapular eruptions, together with a rising white blood count, are helpful. In the past, the most difficult differential diagnosis was rheumatic fever, but this is now unusual. O

Oligoarthritis This is the most common subtype of juvenile idiopathic arthritis, accounting for more than half of cases. It usually affects preschool girls. The knee, ankle and elbow are most commonly affected, although involvement of a single finger or toe is also common. There are probably several different patterns of illness, the most common being that seen in younger children. Here, the most serious complication is chronic uveitis, which is either present at onset or develops within the next year. The uveitis affects both sexes and is associated with antinuclear antibody in the serum. The danger to these children is therefore not from joint involvement, which is usually mild, but from serious eye involvement. Slit-lamp examination is therefore important in all children diagnosed as having JIA. In the subtype 'persistent oligoarthritis' the articular prognosis is good, symptoms persisting for a few years only. After the first 6 months a third of patients develop 'extended oligoarthritis', involving more than four joints, which is difficult to control.

The diagnosis of monoarticular arthritis can be difficult. Infection, trauma and foreign bodies in the joints are possible causes which may not be readily apparent at onset.

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Polyarticular-onset JIA Polyarthritis (defined as involvement of five or more joints) can develop at any time in childhood and is found in 30-40% of children with JIA. Females and older children are predominantly affected. Patients are usually seronegative; however, 10% have persistent IgM RF, tend to be older (over 10 years), and have a different prognosis and distribution of joint involvement. Both groups have a poorer articular prognosis than those with persistent oligoarthritis; at least 30% develop bony erosions and active arthritis that persists into adulthood. Clinical features The disease may begin acutely or insidiously. The most commonly involved joints are the knees, the wrists and the ankles, with relative sparing of the metatarsophalangeal joints. There is flexor tenosynovitis of the hands, neck involvement is seen early, and lymphadenopathy may be present. Although there may be an occasional spike of fever, the marked spiking of systemic illness is absent. When IgM RF is present, joint involvement has a clinical appearance and course indistinguishable from that of adult RA, i.e. polyarticular, peripheral and symmetrical. Large joints may be involved, but usually in association with small joint involvement. Systemic features are similar to those of the adult disease: nodules occur and the prognosis is poor.

Psoriatic arthritis Arthritis may predate the onset of psoriasis by many years. Clues in the absence of a typical rash are a family history of psoriasis, pitting or oncholysis of nails, and dactylitis. The prognosis is poorer than that of persistent oligoarthritis.

Enthesis-related arthritis Children who are predisposed to ankylosing spondylitis are usually boys, who develop a predominantly lower-limb arthritis during late childhood or adolescence. They have enthesitis, inflammation and tenderness at the sites of insertion of tendons, ligaments or fasciae into bone, usually around the foot. There is usually a family history of back pain, inflammatory bowel disease or uveitis. More than half will eventually develop ankylosing spondylitis.

Management of JIA As with adults, the child is managed by a multidisciplinary team. Early referral to an ophthalmologist to screen for uveitis is essential. Treatment usually includes education about the disease for the parents, physical therapy, NSAIDs and intra-articular corticosteroids. Methotrexate should be considered for any form of arthritis not controlled by NSAIDs. It helps up to 70%

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of patients with polyarthritis and a smaller proportion of those with systemic arthritis. The starting dose is 0.5 mg/kg per week orally, and this is increased until clinical benefit is noted or adverse effects intervene (up to a maximum of Img/kg/week). Immunizations with live vaccines such as rubella should be avoided in children receiving methotrexate or other immunosuppressive drugs. Children with JIA can experience exacerbations of arthritis with viral infections. Around 80% of patients with JIA are able to lead useful independent lives, although one-third may require antiinflammatory drugs to control pain, and up to 10% die from infection or chronic renal disease secondary to amyloidosis. The aim of treatment is to achieve a state in which the child lives at home with minimal residual joint deformity. A successful outcome depends on two main factors: support from the child's family, who must understand the aims of treatment; and liaison between the GP and hospital, social and educational services. Drugs form only part of the treatment. Daily exercises are important. Bed rest is indicated only in children with severe systemic features because it can result in muscle wasting and joint ankylosis. Weightbearing is restricted only if there is severe pain or a flexion deformity that requires serial splinting. Hip and knee flexion is discouraged by daily periods of lying prone. Night splints are used during the acute phase, to rest the joints in a good position. In view of the association with aspirin therapy and Reye's syndrome, an NSAID such as naprosyn, ibuprofen or piroxicam is used. In children reluctant to take tablets or suspensions, sublingual piroxicam (Feldene Melt) is available. If the disease progresses, methotrexate is being increasingly prescribed, helping up to 70% of patients. Sulfasalazine (50mg/kg/day) in divided doses appears to be effective in children with persistent oligoarthritis, enthesistis-related arthritis and polyarthritis. There are few indications for using corticosteroids; they do not influence the ultimate prognosis or prevent complications, and can cause side-effects, including growth retardation. They are, however, indicated in severe systemic disease, chronic iridocyclitis that does not respond to local steroids, and progressive disease that is resistant to other drugs. Alternate-day dosage is preferred; this allows for some skeletal growth and does not suppress growth spurts, sexual maturation or reaction to stress. Intra-articular corticosteroids can be helpful for arthritis that is not controlled by NSAIDs. Surgery is restricted to synovectomy in children old enough to cooperate with postoperative physiotherapy. Correction of joint deformities, or joint replacement, is carried out in adolescence or adult life after growth has ceased.

ADULT STILL'S DISEASE Adult Still's disease is a distinct entity. Characteristically, it is a flitting polyarthritis with a similar distribution to that encountered in the childhood variety. Systemic features are also similar. The fever, which usually responds to salicylates, may sometimes be prolonged, requiring treatment with corticosteroids. A meticulous search for sources of sepsis must be made before embarking on steroid therapy. Recurrences are frequent.

RHEUMATIC FEVER Rheumatic fever was at one time the commonest cause of acute polyarthritis in childhood, but it is now rare in the developed world, although recent outbreaks have been reported. It is seldom seen before 4 years of age; the peak age for first attacks is around 6 years and they are rare after 15 years. The sexes are equally affected. Rheumatic fever starts 1-5 weeks after a throat infection with a group A (3haemolytic streptococcus.

Clinical features Articular symptoms Arthritis is the most common major manifestation and is usually the presenting symptom. Joint involvement may vary from arthralgia, where the patient has acutely painful and tender joints with little objective signs of inflammation, to an acute arthritis with effusion and involvement of pericapsular structures. The overlying skin is hot and red. Carditis is frequent and severe in the younger child, whereas arthritis is frequent and severe in the adolescent and adult. The onset of arthritis is typically acute and polyarticular, affecting mainly the knees (75%) and ankles (50%), and occasionally the wrists and elbows. In contrast to RA, involvement of the small joints of the hands (8%) and feet (15%) is uncommon. Historically, the arthritis of rheumatic fever was described as 'migratory' or 'flitting', conveying the erroneous impression that, as the inflammation flits from one joint to another, the joint involved earlier may revert to normal. In practice, particularly if untreated, many joints may remain actively involved at the same time, and give the appearance of a symmetrical polyarthritis. Symptoms of a throat infection may be so mild as to have passed unnoticed. A preceding streptococcal infection can be demonstrated by a rising antistreptolysin O titre (>250 units for adults; >333 for children), and lack of evidence of recent streptococcal infection makes the diagnosis less likely. A leukocytosis is common and a raised ESR is invariable unless cardiac failure is present.

Q Fig. 22.13

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Systemic symptoms Systemic symptoms are prominent but non-specific. Fever

usually starts at the onset of joint involvement, and is usually high (up to 40°C) and sustained. It is accompanied by sweating, anorexia, malaise and vomiting, all of which could also result from salicylate therapy. When abdominal pain occurs with nausea and vomiting, it is usually caused by mesenteric adenitis and may simulate an acute abdomen. The subcutaneous nodules of rheumatic fever, like those of RA, occur at pressure points - elbows, knees and the soles of the feet - but (unlike RA) they occur early in the course of the disease, are smaller and more numerous, and tend to last for a shorter period. Histologically they are distinguishable from those of seropositive RA by the lack of necrosis and palisade layer. Erythema marginatum (Fig. 22.24) Erythema marginatum is strongly suggestive of, but not entirely specific for, rheumatic fever and occurs in only a small proportion of patients. It is a fleeting, non-pruritic, pink or red, macular or papular rash which extends centrifugally (in contrast to fixed drug eruptions) to become circinate or leaf-like while fading at the centre. It occurs most frequently in children, in association with carditis and subcutaneous nodules, and is most apparent at the height of the fever. It mainly affects the trunk, and less frequently the proximal parts of the limbs, but never the face. (Note that in SLE and adult Still's disease the face is involved.) OThe appearance of signs and symptoms and ECG evidence suggestive of carditis (p. 581) in the presence of a rash and fever are strongly suggestive of rheumatic fever. The difficulty of establishing a diagnosis has led to the development of diagnostic criteria (Table 22.27).

Management Complete bed rest is important to minimize cardiac work and rest painful joints. Penicillin should be given to eradicate any streptococci. Fever and joint pain can be controlled with salicylates. Although the initial response to salicylates (in adequate dosage) and corticosteroids can be equally dramatic in RA and Still's disease, the response to salicylate in rheumatic fever seems to be more complete and longer lasting. With clinical improvement, all but penicillin should be withdrawn slowly and activities gradually increased. In severe carditis steroids will often prevent or resolve cardiac failure. Neither steroids nor salicylates have any other effect on the disease, on the likelihood of recurrences, or on the final cardiac state.

ANAPHYLACTOID (HENOCH-SCHONLEIN)

22

FIG. 22.24 Rash of erythema marginatum

TABLE 22.27 Criteria for diagnosis of rheumatic fever* Major manifestations • Carditis • Polyarthritis • Chorea • Erythema marginatum • Subcutaneous nodules

Minor manifestations • Fever • Arthralgia • Previous rheumatic fever or rheumatic heart disease * Elevated ESR or CRP • Prolonged PR interval

* These criteria are a revised version of the Jones criteria. Diagnosis is based on one major and two minor criteria plus supporting evidence of preceding streptococcal infection.

ial papules occur on the buttocks and the extensor aspects of the limbs. These become flat, purpuric, and may coalesce or even ulcerate. Localized oedema of the face, scalp, hands and feet occurs; in young children it can mimic arthritis. Haemorrhage into the gut wall can cause colic, melaena or haematemesis. Usually the joint involvement is mild, consisting of transient, non-migratory synovitis that typically affects more than one joint. The ankles, knees, hips, wrists and elbows are usually affected, with a tendency to lower limb involvement. The synovial fluid is inflammatory in character. Joint destruction does not occur. A mild focal glomerulonephritis, producing proteinuria and microscopic haematuria, occurs in 50% of cases. Occasionally it progresses to the nephrotic syndrome and, very rarely, to renal failure. The disease usually settles in 4-6 weeks without sequelae, but may recur.

PURPURA FURTHER READING ON CHILDHOOD ARTHRITIS Anaphylactoid purpura is due to a widespread vasculitis involving arterioles and small capillaries. It can occur at any age, but primarily in children, especially boys. The disease occurs most often in the spring, and usually follows an upper respiratory tract infection. The onset is acute, with fever, headache and rash. Initially, macules or urticar-

David J, Vouyiouka O, Ansell B, Hall A, Woo P 1994 Amyloidosis in juvenile chronic arthritis: a morbidity and mortality study. Clin Exp Rheumatol 11: 85-90 Davies V M, Rooney M, Preece M, Ansell B, Woo P 1994 Treatment of growth retardation in juvenile chronic arthritis with recombinant human growth hormone. J Rheumatol 21:153-158

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Elkon K B 1982 Adult-onset Still's disease: twenty years follow-up and further studies of patients with active disease. Arthritis Rheuma 25:647-654 Lang B A, Shore A 1990 A review of current concepts on the pathogenesis of juvenile rheumatoid arthritis. In: Laxer R M, Shore A, Silverman E D (eds) Perspective in paediatric rheumatology. J Rheumatol 17:1-15 Woo P, White P, Ansell B (eds) 1990 Paediatric rheumatology update. Oxford: Oxford University Press

CRYSTAL SYNOVITIS

GOUT Gout is the principal clinical manifestation of sustained hyperuricaemia. Clinical features include acute arthritis (tenosynovitis, bursitis), tophaceous deposits, renal disease and urolithiasis.

Epidemiology Gout occurs mainly in developed countries, with a prevalence in the UK and USA of 0.3%. The prevalence of hyperuricaemia is about 5%. Men are 10 times more likely to have gout than women. At puberty, male blood uric acid levels rise and remain higher than those of females until the menopause, when female uric acid levels also rise. Gout is very uncommon before puberty, when it usually suggests an enzyme defect. Serum uric acid concentrations are related to several demographic factors, the most important being age, sex, body bulk and genetic constitution (Fig. 22.25). Values are higher in urban than in rural communities and correlate positively with social class, weight and a high-protein diet. Values are distributed in a population as a continuous variable, with a skew towards the higher values. Hyperuricaemia can be defined as the mean plus two standard deviations, which gives values of above 0.42mmol/L (7mg/100mL) in adult males and above 0.36mmol/L (6mg/100mL) in adult females.

Uric acid production and disposal

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Uric acid is derived from the breakdown of purine bases (Fig. 22.26). These are the products of essential nucleotides which are synthesized in the liver. Adenine and guanine are reutilized. About 60% of uric acid is replaced daily; the quantity produced is directly proportional to body size. Less than 10% comes from preformed dietary nucleotides. Seventy-five per cent of uric acid is excreted in the kidneys and the remainder is lost in the gut. The uric acid is freely filtered at the glomerulus and 90% is then resorbed. Renal handling of uric acid involves glomerular filtration, proximal tubular reabsorption, tubular secretion and postsecretory reabsorption. The paradoxical effects of high- and low-dose aspirin on uric acid excretion can be explained by differential effects on active secretion and reabsorption.

FIG. 22.25 Age and sex distribution of serum uric acid levels ffl Distribution of serum uric acid levels by age in males and females after the age of 6. IT] The mean serum uric acid levels in males and females for different age groups.

Uric acid circulates as monosodium urate, but is found mainly as the free acid in the urine. In hyperuricaemia, urate is usually present in the blood as a supersaturated solution. Lowering of the pH lessens the solubility and increases the likelihood of crystal formation.

Causes of hyperuricaemia Diuretic drugs are the main cause of hyperuricaemia, accounting for some 60% of cases, but clinical gout is an uncommon association. Hyperuricaemia occurs with renal failure, but here too gout is surprisingly rare. Other genetic and environmental factors lead to hyperuricaemia by decreasing the excretion, or increasing the production, of uric acid (Table 22.28). In most patients, although there is often a family history, no definite cause can be found. Dietary purines have only a modest effect on plasma urate levels, and avoidance will lead to a fall of uric acid of some Img/lOOmL. Only in 10-15% of patients is gout due to overproduction of uric acid. These patients can be detected by mea-

FIG. 22.26 A simplified diagram of some of the metabolic pathways involved in the formation of uric acid PRPP = phosphoribosyl pyrophosphate. HGPRTase = hypoxanthine-guanine phosphoribosyl transferase.

obesity, type IV hyperlipoproteinaemia, impaired glucose tolerance, hypertension and ischaemic heart disease. Hyperuricaemia may occur when large quantities of nucleoprotein are broken down during treatment of leukaemia or lymphoma, and prophylactic therapy is sometimes given to avoid the risk of urate nephropathy (Ch. 20, p. 1079). Enzyme defects may rarely cause overproduction of uric acid. Hypoxanthine-guanine phosphoribosyl transferase deficiency is associated with accelerated purine synthesis, childhood gout and renal stones. Complete deficiency is a rare, X-linked, inborn error of metabolism in which gout is associated with spasticity, a variable degree of mental deficiency and compulsive self-mutilation (the Lesch-Nyhan syndrome). Phosphoribosyl pyrophosphate synthetase overactivity is another X-linked inborn error of metabolism associated with gout and increased purine synthesis. Many drugs affect renal elimination of uric acid. For example, aspirin reduces clearance at low doses but is uricosuric at high doses. Other drugs reducing clearance include diuretics (except amiloride and spironolactone), pyrazinamide and ethambutol. Lead also reduces clearance (saturnine gout).

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Pathology TABLE 22.28 Causes of hyperuricaemia Increased production of uric acid Increased purine synthesis Hypoxanthine guanine phosphoribosyl transferase deficiency Phosphoribosyl pyrophosphate synthetase overactivity Increased turnover of preformed purines Lymphoproliferative and myeloprol iterative disorders Secondary polycythaemia Chronic haemolytic anaemia Severe psoriasis Carcinomatosis Decreased renal excretion of uric acid Chronic renal disease Drug administration Diuretics Salicylates (low dosage) Pyrazinamide Reduction in fractional urate clearance Increased levels of organic acids (exercise, starvation, alcohol, ketoacidosis) Hypertension Hyperparathyroidism Hypothyroidism

suring the excretion of uric acid on a 70 g protein, purinefree diet. Overproducers excrete more than 3.6mmol/24h (600mg/24h). Gout and hyperuricaemia are often associated with

Prolonged hyperuricaemia leads to the formation of small crystal aggregates. These accumulate in the synovium and at external sites, such as the ear cartilage, and olecranon, and may eventually become visible tophi. Crystal deposition may proceed over several years without symptoms. Uric acid and urate deposition in the kidney can lead to a variety of pathological effects, including interstitial nephritis, renal stones and acute tubular damage (Ch. 20, p. 1079). Joint inflammation is the result of uptake of crystals by polymorphonuclear leukocytes. When crystals are phagocytosed they enter an endocyte vacuole (phagosome). Fusion with lysosomes occurs and these contain hydrolytic digestive enzymes. There is interaction between the crystals and the phospholipid of the lysosomal membrane, possibly owing to the weak acidic groups on the surface of the crystal-forming hydrogen bonds. Disruption of the membrane follows, with release of lysosomal enzymes and the crystal. Phagocytosis of urates leads to increased production of lactic acid, which causes further precipitation of crystals. Crystal ingestion stimulates the production of a chemotactic factor, producing further recruitment of leukocytes. Hageman factor is activated, and this leads to a series of further reactions, releasing chemical mediators of inflammation, including kinins. Colchicine has been shown in vitro to stabilize the lysosomal membrane, block the release of chemotactic factor and hinder the assembly of intracellular microtubules involved in lysosomal release. These factors are less pronounced in pyrophosphate arthropathy; this is consistent with the relative ineffectiveness of colchicine in this condition.

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TABLE 22.29 Factors provoking an acute attack of gout • • • • • •

Joint trauma Unusual physical exercise Alcohol High-protein diet or starvation Surgery Drugs Diuretics Initiation ot uricosuric or allopurinol therapy • Severe incidental illness

Clinical features Classic gout is easily diagnosed. The typical patient is young or middle-aged, male, and wakes in the early hours of the morning with severe pain, usually in the big toe. On average, three out of four attacks affect the big toe and one in 10 affects more than one joint. Several factors may provoke an attack (Table 22.29). The affected joint is usually red, swollen and warm. The overlying skin is often shiny, with periarticular oedema, and there is often fever. The joint is extremely painful and tender. Untreated, the attack lasts days or weeks before subsiding spontaneously. Patients may have just one attack, or may have recurrences at monthly or yearly intervals. Recurrent attacks may merge into each other, leading to destruction of cartilage, bony erosion (Fig. 22.27) and disability. No synovial joint is immune from gout, but feet, ankles, knees, wrists and fingers are the most susceptible. Bursitis, especially of the elbow, may occur. Polyarthritis as an initial manifestation of gout is unusual, but when it occurs it can mimic RA. Similarly, about 5% of patients with pyrophosphate arthropathy have multiple joint involvement, with subacute attacks lasting from 4 weeks to several months. The diagnosis of crystal synovitis should be considered in patients whose joints are inflamed sequentially (rather than together, as in RA), and when osteophytes are present; diagnosis is proved by the demonstration of crystals in the joint fluid. Tophi Recurrent acute attacks of gout lead to asymmetrical, hard swellings, and tophaceous deposits may also occur in periarticular tissues, the cartilage of the ear (Fig. 22.28), bursae and tendon sheaths. Tophi may occur at atypical sites (e.g. the fingertips), especially in elderly patients receiving diuretics. O Renal calculi A history suggestive of renal calculi is present in up to 10%

FIG. 22.27 Gout; X-ray of proximal interphalangeal joint showing erosion with no surrounding osteoporosis

FIG. 22.28 Gouty tophi in the ear

of gout patients; this is higher in hot climates. Uric acid calculi may be radiolucent (composed of uric acid alone) or radio-opaque (combined with calcium salts). They are produced by dehydration and excessive purine ingestion, or may be associated with defects in tubular reabsorption of uric acid, or the use of uricosuric drugs. All patients should be instructed in the necessity for a high fluid intake.

Diagnosis and investigation 1

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Figs 22.14, 22.15

A number of conditions should be considered in the differential diagnosis of acute and chronic gouty arthritis (Table 22.30).

CASE STUDY 22.3 A PAINFUL SWOLLEN WRIST, FOLLOWING A PROLONGED PERIOD OF GARDENING, IN A 45-YEAR-OLD MAN A 45-year-old Caucasian man had spent the weekend gardening. He was awoken early next morning by a painfully swollen right wrist. He was not aware of any other joint symptoms, and had no previous joint complaints. He had had a mild diarrhoeal illness for 2 days about 10 days previously, but otherwise was in good health. He was right-handed. He had no recollection of injury to his wrist; he had been pruning roses, among other activities, but only had minor skin abrasions and no penetrating injury. On examination he appeared generally well, was afebrile, and had a swollen, erythematous, tender wrist which would not allow any movement, either active or passive. The remaining joints of the hand were normal, as was the remainder of the musculoskeletal examination. Questions 1. What are the three leading differential diagnoses for this presentation? 2. What further investigations are appropriate? Discussion An acute monoarthritis presenting in a middle-aged man, previously well, appearing 1 week after a diarrhoeal illness and developing acutely after physical activity, raises the possibilities of a reactive arthritis, a crystal arthropathy and, in the context of gardening work, a more unusual monoarthritis caused by thorn synovitis. Reactive arthritis may present as a monoarthropathy, usually involving the larger joints, and is particularly associated with diarrhoeal or genitourinary infections. The other manifestations of Reiter's syndrome (keratoderma blenorrhagica, urethritis, conjunctivitis) may or may not be present. HLA-B27 positivity confers an increased risk of

developing Reiter's, but its presence is not diagnostically useful. Identifying the bacterial pathogen is useful if signs of the original infection persist, as antibiotic therapy can curtail the arthritis. Thorn synovitis, though uncommon, produces an acute inflammatory synovitis, typically followed by a latent period and later a chronic inflammatory arthritis. The acute injury is often overlooked in these chronic presentations. The blackthorn is the most common cause in the UK, but roses and other foreign bodies produce an identical reaction. Aspiration of synovial fluid may identify fragments of the foreign body, appearing as intensely birefringent material on polarized light microscopy. Treatment requires removal of the thorn fragment; the synovitis will then resolve with NSAID treatment or intra-articular steroids. A crystal arthropathy may be precipitated by trauma, increased physical activity, or by changes in the metabolism of uric acid. Although 70% of gout episodes involve the first metatarsophalangeal joint, the first episode can present in any joint. The attack typically occurs in the early hours of the morning, possibly owing to changes in temperature leading to the precipitation of monosodium urate crystals in the joint. Calcium pyrophosphate dihydrate (CPPD) crystals may be deposited in fibrocartilage, i.e. the knee menisci, or the triangular fibrocartilage complex in the wrist. This may be recognized on radiography, which can be useful, despite not conclusively proving that a particular episode is due to CPPD crystal arthropathy. Septic arthritis is invariably considered in the differential of an acute monoarthritis. However, it is extremely uncommon in a person previously well with no predisposing risk factor in a joint, and should not lead to empirical antibiotic therapy,

[22

thereby delaying correct diagnosis and more appropriate treatment. Aspiration of the joint is the most effective single test for definitive diagnosis, offers symptomatic relief in many instances, and allows intraarticular injection when appropriate. Technique varies for each joint, requiring familiarity with the relevant anatomy. However, the knee, wrist and shoulder present more commonly than other joints, and the skill can be quickly acquired. An aseptic approach is essential, but the practice of ensuring a large sterile field or bringing a patient to theatre is unnecessary. The number of white cells, and the differential of polymorphonuclear cells and lymphocytes, overlap considerably and are rarely diagnostic. Gram stain, and later culture, is critical where infection is suspected. Polarized light microscopy allows recognition of CPPD and MSU (monosodium urate) crystals, although the experience of the examining person significantly improves detection. In this case, MSU crystals were identified, with no evidence of infection. Question 3. What treatment would you propose? The acute episode should be treated with a potent NSAID. As the COX-2 inhibitors appear to act centrally, a conventional NSAID should be chosen, indomethacin being the traditional drug of choice. Gastroprotection should be considered in those at risk, though acute attacks are expected to resolve in a week or so. Colchicine is an alternative: give 500 jig 4-6-houiiy until the attack subsides. However, effective doses are often complicated by diarrhoea and other GI sideeffects. The dose can be reduced in some without losing efficacy. Failure

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CASE STUDY 22.3 CONTINUED to improve with these measures may be treated with intra-articular corticosteroid injection. The decision to start prophylactic therapy depends on an assessment of individual risk, taking account of serum urate, precipitating causes, and whether these are reversible (e.g. diuretic use for hypertension) or

permanent (e.g. the progression of renal failure); 30% of patients will not have a further attack in the absence of a precipitant. If allopurinol is used, an acute attack may be caused if not adequately covered with NSAID or colchicine (SOOugbd) for at least the first 3 months. The drug should not be

TABLE 22.30 Differential diagnosis of gout Acute arthritis Infective arthritis Another crystal arthritis, e.g. pseudogout due to pyrophosphate crystals, or apatite arthritis Traumatic arthritis Rheumatoid arthritis Seronegative arthritis Chronic arthritis Nodular rheumatoid arthritis Osteoarthritis with Heberden's and Bouchard's nodes Xanthomatosis

In all cases of suspected gout, details of previous rheumatic symptoms and those of urinary tract calculi should be elicited. The patient's family history should be recorded and serum uric acid measurements made. Synovial fluid should be examined under polarizing light for monosodium urate crystals, and possible causes of secondary hyperuricaemia should be investigated. Serum uric acid measurements A high serum level of uric acid with a typical history is almost diagnostic of gout. However, a raised serum uric acid alone does not justify the diagnosis of gout, because of the many factors which raise the serum level. Polarized light microscopy Diagnosis can only be made with certainty by demonstrating crystals in joint fluid taken during an attack. In gout the synovial fluid is turbid, and although other inflammatory joint conditions and sepsis can have similar appearances, the diagnosis is made by the presence of monosodium urate crystals. Urate crystals show strong negative birefringence and calcium pyrophosphate shows 1

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MCQ 22.14

2

MCQ 22.15

started until 6 weeks after an acute episode has resolved. The dose of allopurinol may be increased if a further episode occurs, and the drug should not be withheld during an attack in a person already taking the drug. Alternatives to allopurinol include the uricosurics probenicid or benzbromarone.

weak positive birefringence, when viewed under the compensated polarized light microscope (see Fig. 22.6).

Management There are three main aims: • Reduce acute synovitis • Prevent further crystal formation • Identify associated disease. Reduction of acute synovitis The first line of treatment of acute synovitis is with an NSAID. Indomethacin is the drug of choice, at a dose of 50 mg 4-hourly until the attack subsides. Other antiinflammatory drugs can be used: azapropazone (standard dose 600 mg twice daily) is both uricosuric and antiinflammatory. Colchicine is effective, but has to be taken every 2 hours until control is achieved. Main side-effects include nausea, vomiting, intestinal colic and diarrhoea. These develop at the time of clinical improvement. Intravenous colchicine is effective, but is not generally used because of the small risk of serious toxicity. If long-term management is to be instituted, then allopurinol or uricosuric drugs should not be started for several weeks, as they may prolong the acute attack or trigger further episodes. Salicylates and diuretics should also be avoided. Prevention of crystal formation A single attack of gout does not justify preventive drug treatment. Obese patients should lose weight, alcohol should be reduced and the need for diuretics causing hyperuricaemia should be reconsidered. Indications for long-term therapy include recurrent attacks, tophaceous gout and renal disease. During the reduction of plasma urate, there is a risk of provoking acute gouty arthritis (presumably because of a gradient between blood and tissue stores). Therefore prophylactic anti-inflammatory drugs or colchicine should be prescribed concomitantly for the first 3 months. Successful lowering of plasma urate abolishes the risk of gout, and tophi will eventually disappear. If the underlying cause of hyperuricaemia cannot be modified,

indefinite hypouricaemic therapy is required. Treatment is aimed at keeping the serum uric acid level below the solubility level (0.45mmol/L or 7.5mg/100mL). Uricosuric drugs (probenecid and sulfinpyrazone) act by blocking the renal tubular transport of uric acid which allows the filtered load to be excreted. Side-effects are uncommon, but include nephrotic syndrome and skin rashes. These drugs are less effective than allopurinol in severe disease, and often ineffective in patients with renal failure. They are best avoided in patients with urolithiasis or purine overproduction, because they do not reduce the risk of nephropathy or stone, and are best reserved for underexcretors of uric acid. Allopurinol, a xanthine oxidase inhibitor, reduces the oxidation of hypoxanthine to xanthine, and of xanthine to uric acid (Fig. 22.23). The more soluble xanthine is excreted. Indications for this drug include extensive tophaceous gout, renal impairment, hyperuricaemia due to antimitotic drug therapy, and intolerance or failure of response to uricosuric therapy. Side-effects are few, and include dyspepsia and skin rash. Therapy is usually for life. Asymptomatic hyperuricaemia Provided blood pressure, weight and renal function remain normal no therapy is required for asymptomatic hyperuricaemia. This is because the likeliest risk of a raised urate concentration is gout; the formation of kidney stones and renal damage depend on other factors. 1

PSEUDOGOUT AND PYROPHOSPHATE ARTHROPATHY (CALCIUM PYROPHOSPHATE DIHYDRATE DEPOSITION DISEASE)

Pyrophosphate arthropathy is the term used to describe the clinical presentation of acute and chronic arthritis, whereas chondrocalcinosis refers to the radiological appearance caused by the deposition of calcium pyrophosphate crystals in cartilage. Fibrocartilage is most commonly involved, especially the menisci of the knee, but articular hyaline cartilage also calcifies, as do other articular structures, including ligaments and joint capsules. This leads to a degenerative arthropathy which usually affects old people, but can occur earlier in life if there is a strong family history. Up to 7% of the elderly have radiological change of chondrocalcinosis.

Aetiology The pathogenesis of both the chronic crystal deposition and acute arthritis (pseudogout) is poorly understood. Acute attacks of arthritis are precipitated by shedding of crystals from preformed deposits in cartilage into the joint cavity. The mechanism leading to the formation of these deposits is unknown. Current evidence suggests a local articular, rather than a systemic metabolic, disturbance of pyrophosphate metabolism.

A large number of other conditions have been associated with calcium pyrophosphate deposition, including diabetes mellitus, hypertension and hypothyroidism. Not all are necessarily of aetiological significance, because patients are often elderly and multiple diseases might be expected to be present. However, 7% of patients prove to have hyperparathyroidism, and pyrophosphate deposition also occurs in haemochromatosis and Wilson's disease.

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Clinical features and diagnosis Pyrophosphate arthropathy may present as an acute arthritis affecting particularly the knees and wrists, which resolves within 1-4 weeks. Trauma, surgery or medical illnesses may precipitate an attack. Less frequently RA may be mimicked, as there may be multiple joint involvement and associated joint inflammation. Pyrophosphate deposition may present as asymptomatic chondrocalcinosis and is a common finding in the elderly. Common sites of chondrocalcinosis include the pubic symphysis, the triangular ligament of the wrist, and knee menisci. Deposition may also be seen with severe generalized OA. There may or may not be inflammatory exacerbations. The knees are most frequently affected, and hips, shoulders, elbows, ankles and wrists may also be involved. The diagnosis is made on the basis of clinical features, chondrocalcinosis on X-ray and demonstration of crystals by polarizing microscopy of synovial fluid from an involved joint (Fig. 22.6).

Management Primary metabolic disorders should be identified and treated appropriately. Treatment of an acute attack of pyrophosphate arthropathy is similar to that for acute gout, although drugs are less effective; joint aspiration together with the injection of corticosteroid gives relief. Unfortunately, there is no effective means of preventing further attacks of pyrophosphate arthropathy, although colchicine may sometimes prove helpful. Management is that of OA, with analgesics, physiotherapy and local measures when appropriate. 2

FURTHER READING ON CRYSTAL SYNOVITIS Dieppe P A, Calvert P 1983 Crystals and joint disease. London: Chapman & Hall. Doherty M, Dieppe P A 1986 Crystal deposition disease in the elderly. Clin Rheum Dis 12:97-116. Jones A C, Chuck A J, Arie E A, Green D J, Doherty M 1992 Diseases associated with calcium pyrophosphate deposition disease. Semin Arthritis Rheum 22:188-202. McCarty D J (ed) 1988 Crystalline deposition disease. Rheuma Dis Clin North Am 14:2. Puig J E et al 1994 Purine metabolism in women with primary gout. Am J Med 97:332-338.

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Epidemiology The prevalence of SLE appears to vary from country to country; in the UK it is about one per 10000 of the population. Females are affected six to nine times more frequently than males, and the disease is especially common during the childbearing years. Blacks and Chinese are particularly susceptible; in the USA, one in 250 black women of childbearing age may be affected. There is an increased prevalence of SLE in the families of patients with the disease, and the incidence of ANAs, hypergammaglobulinaemia and false positive serological tests for syphilis is also increased in healthy members of these families. There may therefore be a genetically determined susceptibility to the development of SLE in appropriate environmental circumstances in some individuals. A null or absent allele for C4 on the sixth chromosome has been noted in family studies, and twin studies show a greater than 60% concordance of SLE in monozygotic twins.

Pathology Many of the histological changes are non-specific. Two findings suggestive of SLE are the periarteriolar or onion skin fibrosis in the spleen, and the haematoxylin body - the tissue counterpart of the LE cell. There is usually widespread small and medium vessel vasculitis, portions of the walls of which may become necrotic and be found to contain fibrinoid deposits. These deposits contain immune complexes consisting chiefly of DNA, anti-DNA antibody and complement components.

FIG. 22.29 Butterfly rash Typical facial appearance of SLE O

SYSTEMIC LUPUS ERYTHEMATOSUS

Systemic lupus erythematosus (SLE) is a disease of unknown aetiology; it affects predominantly young women and has a marked tendency to exacerbation and remission. The diverse clinical features reflect the multisystem involvement that is characteristic of the disease (Fig. 22.29). Currently there is much interest in the possibility that the disease may arise from an interaction of genetic factors and viral infection. The high prevalence of SLE in women of reproductive age suggests that female hormones may modify the immune response. There are a number of haematological and serological abnormalities, of which the key one is the formation of antinuclear antibodies (ANAs). The use of DNA-antibody and complement estimations has improved the clinical management of SLE patients and led to a greater understanding of their role in immune complex-mediated tissue damage.

O Figs 22.16, 22.17

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© MCQ 22.16, 22.17

Immunological features of SLE Antinuclear antibodies ANAs are a constant feature of SLE and are directed at different antigenic components. The demonstration of ANAs, by immunofluorescence, is the most widely used screening test for SLE. The test is very sensitive but is negative in about 5% of patients (uraemia may render an ANA result negative). However, positive tests are found in many other conditions. A frozen tissue section is incubated with the test serum to allow antibodies to fix, washed thoroughly to remove any unfixed antibodies, and then stained with a fluorescent antibody to human globulin. This will bind to any fixed antibody. The tissue is then examined using an ultraviolet microscope. The value of the ANA test has been enhanced with the use of human cell lines such as the HEp~2 cell line. Sometimes the pattern of nuclear staining gives a clue to the antigen involved (e.g. chromatin pattern staining is associated with antibody to nucleoprotein) and carries some diagnostic significance: for example, the rim (or ring) staining patterns represent antibodies to double-stranded DNA and are thus more specific for SLE. Antibodies to DNA Anti-DNA antibodies are usually detected by the Farr

assay (a precipitation test) or by ELISA. Other tests, particularly the immunofluorescence test with Crithidia luciliae, are also available. Crithidia also contains doublestranded DNA, and the test is rarely positive in patients who do not suffer from SLE. DNA antibodies are found in high titre in lupus, especially those with renal disease, and they often reflect disease activity. RNA antibodies Antibodies to both single- and double-stranded RNA can be detected in SLE by a variety of techniques. The occurrence of antibodies to double-stranded RNA is interesting, as human RNA is single-stranded with the exception of small helical regions on transfer RNA. Some viral RNA, on the other hand, is double-stranded, and this finding has stimulated speculation on the possibility of a viral aetiology in this disorder. Serological tests for syphilis False positive tests for syphilis are found in up to one-third of SLE patients. Rarely, a positive TPHA test occurs; this is probably caused by antibody reacting against the DNA in the treponeme. Other autoantibodies in SLE Table 22.31 demonstrates the wide variety of antibodies that occur, the pattern varying from patient to patient. They appear to reflect a general immunological disturbance, which results in an exaggerated production of humoral antibodies. Sometimes the antibodies precede the clinical manifestations of SLE by years. They only rarely

TABLE 22.31 Autoantibodies in SLE Antinuclear antibodies Anti-DNA histone (LE cell) Anti-DNA (double-stranded) Anti-DNA (single-stranded) Anti-RNA Antinucleoprotein (soluble or particulate) Antinuclear glycoprotein (Sm antigen) Antiextractable nuclear antigen (ENA) - Ro (SSA), La (SSB) Other antibodies Anticytoplasmic antibodies (mitochondrial and microsomal) Rheumatoid factors (IgG and IgM - 33% of cases) Cryoglobulins Lymphocytotoxic antibodies Antiphospholipid antibodies (cardiolipin, lupus anticoagulant) Organ-specific autoantibodies Elevated litres of antiviral antibodies (e.g. measles) Antibodies against: red cells lymphocytes leukocytes platelets

give rise to clinical abnormalities, although antibodies to platelets, red cells, leukocytes and clotting factors may cause haematological disorders. Patients may also have serum antibodies which are apparently lymphocytotoxic. Clinical subsets of SLE have been defined by antibody typing, as certain antibodies appear to be associated with specific clinical features. Anti-Ro antibodies are associated with the development of congenital heart block in the offspring of SLE patients. Antibodies to Ro and La (also known as SSA and SSB) are found in lupus and Sjogren's syndrome. Antibodies to Sm are almost always restricted to lupus (particularly in the black population). There is, however, considerable overlap between the expression of clinical disease and that of particular antibodies.

22

Antiphospholipid antibodies Antiphospholipid antibodies bind chiefly to negatively charged phospholipids such as cardiolipin. They are usually tested for by an ELISA test, or by a coagulation assay based on the partial thromboplastin time. The VDRL test (used in the diagnosis of syphilis) can also detect antibodies. Raised concentrations of antiphospholipid antibodies are associated with several clinical features, including thrombosis (arterial and venous), recurrent fetal loss, thrombocytopenia and various neurological disorders. The antiphospholipid syndrome may occur in isolation or in the presence of connective tissue disease. Serum complement The serum complement level (either total haemolytic complement, or C3 or C4) is a useful investigation in SLE. Low complement levels in the presence of a high DNA binding titre are diagnostic of active SLE. Serial measurements of complement are useful in following the clinical course, as the level drops about 50% before, and remains low during, an exacerbation. Particularly low levels of complement components, especially C3 and C4, are strongly indicative of active lupus nephritis, during which complement is continuously consumed by the immune complexes deposited in the glomeruli. Individuals with a genetic deficiency of C2 appear to have an increased incidence of SLE. SLE is not associated with any particular HLA antigen, but associations have been described with HLA-B8, DR2 and DR3. 0

Aetiology The cause of SLE is unknown but there is some evidence for a viral aetiology. A strain of mice known as New Zealand Black/New Zealand White Fj hybrid develop a lupus-like disease. Immune complexes in the kidney can be shown to contain DNA and various oncorna virus antigens. These findings suggest a viral aetiology, but no oncorna virus has been isolated in human SLE. The disease is more severe in females, and can be partially reversed by testosterone. Immunosuppression selective for T cells (such as with ciclosporin A) also reduces severity.

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TABLE 22.32 Relative incidence of the major clinical manifestations of SLE* Manifestations

Incidence (%)

Musculoarticular Cutaneous Fever Neuropsychiatric Renal Pulmonary Cardiac

95 81 77 59 53 48 38

* After Estes D and Christian CL1971 Medicine 50: 85.

Pathogenesis There is considerable evidence that the lesions of SLE are due to immune complexes causing local damage. Immune complexes can be detected free in the serum, and precipitated in the kidneys on the mesangium and glomerular basement membrane. These would be expected to fix complement, and complement breakdown products (e.g. C3d) are present in the serum. Patients possessing anti-DNA antibodies and entering a relapse will have free circulating DNA, and must therefore go through a stage where immune complexes form. At this stage, the serum complement levels fall. DNA itself will bind to glomerular basement membrane, and this membrane-bound DNA can react with antibody and complement to give a nephrotoxic type of damage.

Clinical features The clinical features of SLE are extremely variable in both nature and severity (Table 22.32). An exacerbation may be precipitated by exposure to sunlight, infection, drugs or pregnancy. Common initial features are general malaise, with fever, fatigue and loss of weight. SLE presents in the majority of patients with articular or cutaneous features. Because many of the symptoms are non-specific, differentiating SLE from similar disorders can be difficult. Musculoskeletal features The commonest musculoskeletal complaint is of joint or muscle pains, occasionally presenting years before other features become obvious; the pain often appears out of proportion to the degree of synovitis. The small joints are most commonly involved and the arthritis is symmetrical. Erosions are rare. Occasionally a patient develops a deforming arthritis, as a result of capsular and ligamentous

1

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Case 22.1

2

Fig- 22.18

3

MCQ 22.17

laxity, Jaccoud-type arthropathy. Tendon involvement may be prominent, leading in some cases to flexion contractures at the forearm and wrist. A proximal myopathy occurs in 5% of patients; this differs from steroid myopathy in that the shoulder girdle is more commonly involved and the serum muscle enzymes are usually elevated. Aseptic necrosis affecting the weight-bearing joints occurs in patients who have been receiving high doses of corticosteroids for long-standing SLE. Skin manifestations The skin lesions appear most often on sun-exposed areas. The classic eruption is the 'butterfly' rash, an erythematous eruption over the nose, spreading to the cheeks. It occurs in less than half of all patients. The scalp is frequently involved in patients with cutaneous LE, producing patches of permanent alopecia. Photosensitivity is particularly common in patients with anti-Ro. Livedo reticularis, a reticular blotchy pattern especially common on the lower extremities, is often associated with anticardiolipin antibodies. Diffuse alopecia occurs in about 60% of patients and is an important sign of active systemic disease. The hair tends to regrow when the disease enters a remission. Erythema, telangiectasia and capillary infarcts in the proximal nailfolds are often seen. Chilblain-like purplish-red swellings on the digits, and vasculitic lesions which can ulcerate, also reflect involvement of the cutaneous vasculature. Skin biopsy can be helpful in diagnosis; immunoglobulin and complement are demonstrated at the dermalepidermal junction both in discoid lesions and generally in SLE, including unaffected skin. Purpura may occur, usually associated with thrombocytopenia. Mucosal ulcers, affecting the mouth and genitalia, occur in active SLE but settle in remission, unlike skin lesions, which may persist. Cardiovascular features Pericarditis frequently occurs during acute exacerbations of the disease. Myocardial disease is common in SLE, and may lead to arrhythmias and, uncommonly, to cardiac failure. Hypertension occurs following severe renal involvement. A non-infective endocarditis occurs (Libman-Sacks endocarditis); this most commonly affects the mitral valve and is usually clinically insignificant. Murmurs are frequently heard in SLE, often in the absence of any anatomical proof of endocarditis, and are an unreliable guide to its diagnosis. A vasculitis may produce scleritis, myocardial infarction, Raynaud's phenomenon, digital ulceration and atrophic skin changes, bowel perforation and chronic leg ulceration. Thrombophlebitis also occurs, and may be recurrent or migratory. Respiratory system Pleurisy is common and usually bilateral, and pleuritic pain may remain a problem long after all other evidence of disease activity has regressed. LE cells may be present in

pleural fluid and complement levels decreased. Recurrent pneumonitis may occur, with patchy, plate-like atelectasis or diffuse basal infiltration. Loss of lung volume from vascular damage leads to gradual elevation of both hemidiaphragms and restrictive lung defects. The diaphragm may also be affected by a myopathy. Acute pulmonary lesions are responsive to steroid therapy. Bacterial pneumonia is common. Renal system Sixty per cent of patients have renal involvement, and its extent and severity significantly affect the prognosis. According to current concepts of immune complex disease, renal involvement probably occurs transiently in the majority of cases. Mesangial deposition of immunoglobulin may be a reversible change. Diffuse proliferative glomerulonephritis often leads to nephrotic syndrome, hypertension and uraemia, and the mortality is greater than 60% at 3 years. Patients with the membranous form of nephritis almost all develop the nephrotic syndrome, but hypertension and uraemia are less frequent. Nervous system The importance of neuropsychiatric involvement in SLE has recently become apparent, because of both its prevalence and its association with a poorer prognosis than renal disease. The commonest abnormalities are disorders of mental function and seizures; other manifestations include cranial nerve palsies, chorea, tremor and headache. CNS involvement is most frequent in well-established cases of lupus, and 50% of patients with renal involvement also have some CNS abnormality. The CNS symptoms are likely to be the result of small-vessel vasculitis in the CNS. Peripheral neuropathy may occur and is probably due to vasculitis. Haematological features Neutropenia and/or absolute lymphocytopenia is a frequent finding. An autoimmune haemolytic anaemia may antedate the other manifestations of the disease by many years. This responds well to corticosteroids but not to splenectomy. The normochromic anaemia of chronic disease, and the hypochromic anaemia that may accompany drug therapy or bleeding from vasculitic lesions, are more frequent causes of anaemia in SLE than are immune mechanisms. A low platelet count, with or without demonstrable platelet antibodies, is common and may be sufficiently low to cause all the signs and symptoms of idiopathic thrombocytopenic purpura. Response to splenectomy is good. Lymphadenopathy is common; the pathological changes are those of reactive hyperplasia. Splenomegaly is rarely gross. Bacterial infection occurs frequently in SLE, and infections with opportunistic organisms are more common in patients on suppressive therapy. Differentiating between a lupus fever and infection can be difficult. Measuring Creactive protein can be useful for distinguishing between a

lupus flare and infection: it usually remains normal in a flare, unless accompanied by serositis or synovitis, but is elevated in infection. Sulphonamides should be avoided as they can cause neutropenia. 1

22

Syndromes related to SLE Discoid lupus erythematosus Discoid lupus erythematosus is a chronic skin disease characterized by erythema, scaling, plugging of the sebaceous glands and scarring, often on the cheeks and bridge of the nose. There may be marked alopecia. It is generally benign, but a small proportion of patients do develop systemic disease. A variety of serological abnormalities may be found in otherwise healthy discoid patients, e.g. ANA may be positive. Mixed connective tissue disease 0 In a small group of patients the features of SLE, myositis and systemic sclerosis occur either in sequence or concurrently. The original description was of a good prognosis and a low incidence of renal disease. The term 'mixed connective tissue disease' has been proposed for this group. The sera of these patients do not have anti-DNA antibodies, but show both a strongly positive 'speckled' pattern of ANA tests and antibodies to extractable nuclear antigen, an RNA protein. Whether or not it is clinically useful to so define a group of patients remains a subject of debate. The clinical picture evolves over time and the prognosis depends on the rate of progression and severity of the specific organ involvement. Antiphospholipid syndrome High titres of IgG antiphospholipid antibodies identify a population at risk of recurrent arterial and venous thromboses and recurrent abortions, and lupus anticoagulant may or may not be present. Antiphospholipid syndromes may be primary (not associated with a known underlying disease) or secondary (associated with SLE or another connective tissue disease). Thrombotic events, when accompanied by persisting antiphospholipid antibodies, require treatment with oral anticoagulants. Recurrent fetal loss may require subcutaneous heparin during pregnancy. Drug-induced lupus A large number of drugs may, in certain individuals, give rise to a syndrome closely resembling SLE, with rashes, fever, arthritis, polyserositis and pulmonary manifestations (see Table 22.2, p. 1122). Steroids are occasionally required to suppress symptoms, even after discontinuing the drug. Circulating ANAs develop in the majority. In drug-induced lupus, anti-DNA antibodies are usually present in low litre, and renal disease is absent in most cases. Furthermore, the disease is usually reversible on stopping the drugs, though up to 70% of patients with hydralazine-induced lupus have a more prolonged course. Antihistone antibodies are seen with hydralazine-induced lupus and perhaps with other drugs. 3

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TABLE 22.33 Treatment for systemic lupus erythematosus Non-steroidal anti-inflammatory drugs For symptomatic relief Antimalarial drugs For rashes, arthritis and malaria Corticosteroids For severe flare For maintenance treatment (low doses) Immunosuppressive drugs For severe flare (in conjunction with corticosteroids) Additional treatment For infection For thrombosis For hypertension For cerebral lupus (anticonvulsants)

Management The high incidence of emotional and neuropsychiatric problems, together with the unpredictability of the disease, calls for particularly sympathetic care of patients with SLE. Both patients and relatives need explanation and reassurance. There is no evidence that treatment during periods of remission alters the long-term prognosis, and it is usual not to treat patients in remission with normal complement levels. Most patients have a near-normal life span.

Drug therapy (Table 22.33) Hydroxychloroquine salts should be considered before corticosteroids in patients in whom the skin and joint manifestations predominate, although many of the joint symptoms respond to salicylates alone. The possibility of retinal damage by chloroquine must be borne in mind. Local application of steroids can be helpful for rashes. Effective sunscreens should be used routinely on light-exposed skin. Measures designed to help prevent a relapse include the avoidance of sunlight and all non-essential drugs, and prompt treatment of infections. Sunscreens with a high protective factor should be applied; long-sleeved clothes and sun hats should be worn. Regular measurement of anti-DNA antibodies will often show a rise preceding clinical relapse. Oral contraceptive pills containing low doses of oestrogen are probably safe with mild lupus, but should be used with caution in active lupus as they may cause a flare. They are contraindicated in patients with

1

1176

Fig. 22.19

migraine, hypertension, a history of thrombosis, or high litres of cardiolipin antibodies. Progesterone-only pills are safe. The safety of hormone replacement therapy is still uncertain. In the management of active SLE, prednisone dosage should be the lowest sufficient to control symptoms and signs. Some features, such as pericarditis or haemolytic anaemia, respond well to corticosteroids. Others, particularly CNS manifestations, are difficult to manage. It is now realized that the steroid dose may be fairly rapidly reduced once the acute episode is over, and most patients are maintained on dosages of 10 mg daily or less. There is evidence that immunosuppressive drugs, e.g. azathioprine and cyclophosphamide, are of value. Most controlled studies have been of patients with renal lupus, where it appears that the combination of prednisone with an immunosuppressive drug is superior to the use of either drug alone. Landmark studies carried out at the National Institute of Health showed improved renal survival with regimens that included cyclophosphamide.

Prognosis Unless there is severe renal or CNS involvement, the outlook in SLE is now much improved. The estimated 5-year survival is over 90% and 10-year survival is 80-90%. For those with renal disease, however, the prognosis is less good; the outlook for diffuse proliferative nephritis is poor, with a 5-year survival of around 50% without dialysis or transplantation. Infection remains the terminal event in many instances. There is an increased mortality from the complications of atherosclerosis in later years; corticosteroids probably predispose to atheroma. Patients who are non-white, male, or at the extremes of the age range far worse.

Pregnancy in SLE Fertility is normal, except when there is severe renal involvement or when high-dose steroid therapy causes amenorrhoea. Recurrent abortion can occur before or during the clinical course of SLE; this may be due to the presence of antiphospholipid antibodies. Although remission of the disease occurs in 30% of patients, an exacerbation may occur at any time during pregnancy. A postpartum deterioration is common, and may occur very early after delivery. Patients with active renal disease have a much worse prognosis: they seldom become pregnant and the fetal mortality is around 30%. Increasing proteinuria and hypertension may mimic pre-eclamptic toxaemia. Treatment with low-dose prednisolone, chloroquine and azathioprine can continue if indicated during pregnancy. Neonatal SLE is uncommon; it may be associated with a lupus rash, anaemia, thrombocytopenia, splenomegaly and cardiac conduction abnormalities. The complication occurs almost exclusively in the offspring of women with anti-Ro antibodies.

FURTHER READING ON SYSTEMIC LUPUS ERYTHEMATOSUS Goulet J, Mackenzie T, Lewinton C, Hayslett J, Campi A, Esdaile J 1993 The long-term prognosis of lupus nephritis: the impact of disease activity. J Rheumatol 20:59-65. Isenberg D A, Horsfall A 1993 Systemic lupus erythematosus. In: Maddison P, Isenberg D, Glass D, Woo P (eds) Oxford Textbook of Rheumatology. Oxford: Oxford University Press, pp. 733-755. Triplett D A 1993 Antiphospholipid antibodies and thrombosis: a consequence, coincidence or cause. Arch Pathol Lab Med 117:78-88. Urowitz M B, Gladman D, Fasewell V, Stewart J, McDonald J 1993 Lupus and pregnancy studies. Arthritis Rheum 36:1392-1397. Worrall J G, Snaith M L, Batchelor R, Isenberg D A 1990 SLE - a rheumatological view. Q J Med 275:319-330.

SYSTEMIC SCLEROSIS (SCLERODERMA)

Systemic sclerosis is an uncommon multisystem disorder caused by fibrosis of connective tissue throughout the body. It is three times more common in women than in men, and its peak age of onset is between the third and fifth decades. Scleroderma is the name used for the fibrosis and hardening of the skin, but occasionally patients have limited or absent skin involvement.

Aetiology and pathology There are familial cases reported, suggesting that genetic and environmental factors may be important in the aetiology of systemic sclerosis. Chromosomal abnormalities have been reported, and there are weak associations with HLA antigens DR3 and DR5. There is extensive deposition of collagen in the skin, internal organs and blood vessels. The sequential changes of inflammation, fibrosis and atrophy are most frequent in the skin, but occur to a lesser extent in the gut, heart, lungs and kidneys. The widespread vascular changes involve both small and medium-sized arteries as well as arterioles and capillaries, and the relationship between the fibrosis and vascular abnormalities remains to be determined. The characteristic changes include concentric proliferation and thickening of the intima, with fibrosis of the adventitia. The capillary abnormalities can be seen at the nailfold. Raynaud's phenomenon occurs in up to 90% of patients.

Classification of scleroderma Scleroderma-like changes occur in diseases other than systemic sclerosis, e.g. carcinoid syndrome, and systemic sclerosis varies from a mild, limited disease with a good prognosis to a severe disease with diffuse skin involvement and a high risk of renal disease. There are two main subsets of scleroderma, diffuse and limited. This is a classification based on the extent of skin involvement, plus certain organ and serological associations.

TABLE 22.34 Classification of scleroderma Classification

Example

Localized

Morphoea Linear scleroderma

Limited cutaneous scleroderma Diffuse cutaneous scleroderma scleroderma sine scleroderma Chemical or drug-induced scleroderma Diseases with skin changes mimicking scleroderma Eosinophilic fasciitis

22

Polyvinychloride Bleomycin Sclerodema

Limited cutaneous scleroderma (previously called CRST) 1 is a benign variant associated with calcinosis (C), Raynaud's phenomenon (R), sclerodactyly of the fingers (S), telangiectasiae (T) and sometimes also oesophageal involvement. There are few if any constitutional symptoms, but in later stages vascular lesions worsen and pulmonary hypertension may develop at 10-15 years, with or without interstitial lung disease. The anticentromere antibody is seen more commonly in this subset (70-80%). Diffuse cutaneous scleroderma has an abrupt onset of Raynaud's associated with oedematous and itchy skin. Arthritis, myositis and tendon involvement are common. Rapid progression of skin disease is accompanied by increased risks of renal failure (often presenting as hypertensive renal crisis) and of pulmonary interstitial, early cardiac and gastrointestinal disease. Scleroderma sine scleroderma. Some patients have Raynaud's plus internal organ involvement, such as restrictive pulmonary disease, cardiac failure and hypertensive renal crisis without their skin being affected. Localized forms of scleroderma include morphoea where there are discrete cutaneous plaques of induration, sometimes yellowish in colour and often with violaceous borders; and linear scleroderma, where a band of fibrosis may involve subcutaneous tissue, muscle and even bone (Table 22.34). These localized forms are rarely associated with systemic disease and are usually self-limiting: • Sclerodema is a painless self-limiting oedema of the face, neck and upper trunk that occurs in children. • Eosinophilic fasciitis is a rare disorder associated with acute swelling and thickening of the forearms and legs, often following trauma or unaccustomed exercise. There is eosinophilia, a high ESR associated with a typical histological appearance. This condition responds to corticosteroids.

Clinical features Skin involvement There are three stages in evolution of the skin disease in diffuse cutaneous scleroderma. First, there is an oedema-

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FIG. 22.30 Systemic sclerosis A Facial appearance (photograph reproduced with permission). B Hands of a patient with systemic sclerosis showing thickening of skin and flexor deformities.

tous phase associated with bilateral painless oedema of the hands, legs and face. This is followed by thickening and tightening of the skin, affecting the fingers, face and hands, and sometimes spreading to involve the limbs and trunk. Finally, atrophy occurs and limb contractures can occur, often with areas of hyperpigmentation, vitiligo and alopecia. The face becomes pinched, microstomia develops, and telangiectasiae are seen on the face, lips, mouth, palms and nailfolds (Fig. 22.30). There is intracutaneous and subcutaneous calcification which affects the fingertips and may also affect the forearm; this may ulcerate. Raynaud's phenomenon may precede cutaneous changes by many years. It occurs in many connective tissue disorders, and the risk of patients with Raynaud's developing systemic sclerosis is less than 2% in females and about 6% in males. In severe disease there may be ischaemic changes of the fingertips 1 and gangrene may develop. In the absence of Raynaud's phenomenon the diagnosis of scleroderma should be doubted. Musculoskeletal involvement Tendon involvement leads to friction rubs and flexion contractures. Arthralgia and arthritis are often early features 1

1178

Fig. 22.20

2

MCQ 22.18

of systemic sclerosis; the arthritis can be erosive and progressive. Muscle weakness and wasting are common, and muscle biopsy shows deposition of collagen and myofibrillar degeneration; florid inflammation is uncommon. Gastrointestinal involvement After the skin, the gut is the most common organ to be involved. The oesophagus is frequently affected, and a barium swallow shows decreased or absent peristalsis with oesophageal dilatation (Fig. 22.31). The commonest clinical complaint is of dysphagia for solid foods and heartburn, but the patient can be asymptomatic. The small bowel is involved in about 50% of patients, causing symptoms from intestinal stasis or malabsorption. Large bowel involvement is fairly common but usually asymptomatic; wide-mouthed colonic diverticulae are characteristic of the condition. Other clinical features Cardiac abnormalities include conduction defects, pericarditis and cardiomyopathy; these are often asymptomatic. Renal involvement is the major cause of death in systemic sclerosis, the onset being acute or chronic. Chronic renal failure is associated with proteinuria and hypertension. Acute renal disease presents with malignant hypertension, rapid renal failure and microangiopathic haemolytic anaemia. Pulmonary complications, which

TABLE 22.35 Management of scleroderma • • • •

22

Explanation and support for patient and family Treat individual symptoms (such as oesophagitis and hypertensive renal crisis) Treat Raynaud's syndrome In early phase of diffuse scleroderma, use immunosuppressive drugs

blesome. Patients should be told to avoid both smoking and exposure to cold. Nifedipine can be helpful, as can thymoxamine. Prostacyclin infusions can improve peripheral blood supply in severe Raynaud's and when there is critical ischaemia, as can digital sympathectomy. If the diffuse form of the disease is identified in its early oedematous stage, immunosuppressive drugs such as cyclophosphamide, methotrexate and antithymocyte globulin are probably appropriate. Cyclophosphamide is also of use in interstitial lung disease. Treatment of fibrosis is more difficult as studies have shown that neither o-penicillamine nor a-interferon has a positive effect. ©

FURTHER READING ON SYSTEMIC SCLEROSIS

FIG. 22.31 Barium swallow in a patient with systemic sclerosis, showing loss of peristalsis and stricture formation

occur in 50% of patients, include interstitial fibrosis, pleurisy and pulmonary hypertension. Antinuclear antibodies are positive in about 70% of patients; a nucleolar or speckled pattern of fluorescence is characteristic. Anticentromere antibodies occur in patients with the CRST syndrome. Anti-Scl-70 antibodies are present in 20% of scleroderma patients. The antigen has recently been identified as a topoisomerase enzyme. They mark out those at risk of interstitial lung disease. Antibodies to RNA polymerases I and III occur in a small percentage of patients with diffuse disease and predispose to hypertensive renal crises.

Management (Table 22.35) No treatment has been shown to alter the long-term progression of systemic sclerosis. The natural tendency of the disease is towards skin softening, which complicates the assessment of new treatments. Management tailored to the stage and subset of the disease can improve quality and length of life. Oesophagitis caused by oesophageal involvement responds to omeprazole. Strictures of the gastrooesophageal junction may require surgery or dilatation. In patients with hypertension, control of blood pressure with angiotensin-converting enzyme inhibitors may improve survival. Raynaud's phenomenon may be particularly trou-

Black C M, Denton C P 1995 The management of systemic sclerosis. Br J Rheumatol 34:3-7. Hochenberg M 1994 Silicone breast implants and rheumatic disease. Br J Rheumatol 33:601-602. Jayson M I V, Black C M (eds) 1988 Systemic sclerosis, scleroderma. New York: John Wiley.

RECENT ADVANCES IN SYSTEMIC SCLEROSIS

Renal and pulmonary involvement continue to be the leading causes of morbidity and mortality in this disease. Increased understanding includes the recognition that anticentromere antibodies and telangiectasia identify those at increased risk of pulmonary hypertension, whereas pulmonary fibrosis is more common in patients with Scl-70 antibodies and more diffuse disease. The term CREST syndrome has been replaced by limited systemic sclerosis. Early recognition of alveolitis using pulmonary function tests and highresolution computed tomography is important, as immunosuppression with cyclophosphamide improves survival. Infusion of prostacyclin analogues has significantly improved the outlook in those with pulmonary hypertension. Another important therapeutic advance is the use of angiotensin-converting enzyme inhibitors, or the more recent angiotensin-II receptor antagonists, to delay the progression of renal disease in those at risk - those with early renal involvement, diffuse disease and rapid progression in skin scores. Avoidance of high-dose steroid therapy (>20mg) is recognized as critical to avert the development of 'scleroderma renal (hypertensive) crisis'.

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LeRoy E C 1992 Raynaud's phenomenon, scleroderma, overlap syndromes, and other fibrosing syndromes: editorial overview. Curr Opin Rheumatol 4(6):821-878. Maddison P J 1991 Mixed connective tissue disease, overlap syndromes and eosinophilic fasciitis. Ann Rheum Dis 50:887-893. Silman A J 1995 Scleroderma. Baillieres Clin Rheumatol 9: 471-478.

DERMATOMYOSITIS AND POLYMYOSITIS Polymyositis is an inflammatory disease of muscle which may occur either alone or in association with another connective tissue disease. It is characterized by symmetrical proximal muscle weakness; when it is associated with a rash, the term dermatomyositis is used. Polymyositis is less common than SLE, and similar in frequency to systemic sclerosis. Both dermatomyositis and polymyositis may occur in childhood, and there is an association with underlying malignancy in a minority of cases. Peak ages of onset are in childhood and in the fifth and sixth decades.

Aetiology The aetiology of polymyositis is unknown. Several viruses, including rubella, influenza and Coxsackie, can cause acute myositis, and cellular immunological mechanisms are also implicated. Cytotoxic lymphocytes from patients have been shown to kill muscle cells. There is a weak association with HLA-B8 and DR3. A number of autoantibodies have been detected, including Jo-1; sera with anti-Jo1 activity bind histidyl-t-RNA and block its aminoacylation. Jo-1 is associated with myositis and pulmonary involvement.

Clinical features The hallmark of polymyositis is progressive proximal muscle weakness, often insidious in onset. In severe acute forms there is muscle pain and tenderness, but usually there is little pain. Typical presenting features are difficulty in climbing stairs and weakness of the neck muscles. There may be dysphagia and weakness of the respiratory muscles and, with progressive disease, muscle wasting and muscle contractures. Arthralgia occurs in about 25% of patients but is usually mild. Fever may be present. Cutaneous features include oedema and erythema and a characteristic rash causing a lilac (heliotrope) discoloration of the eyelids and periorbital oedema. A scaly erythematous rash involves the dorsum of the hands and knuckles and the extensor surfaces of other joints. Longstanding disease is associated with skin deposits of calcium, which can present as nodules that may ulcerate. Calcinosis

1 1180

MCQ 22.19

0 Case 22.2

of subcutaneous tissue and fascial planes between muscles can occur, particularly in children. Vasculitis may involve the skin and internal organs, especially the gastrointestinal tract. Involvement of cardiac muscle can cause arrythmias and congestive cardiac failure. Pulmonary problems can be severe. Weakness of the respiratory muscles may result in breathlessness and ventilatory failure. Weakness of the upper airway musculature, combined with disordered swallowing, predisposes to aspiration, and impaired cough predisposes to pneumonia. Fibrosing alveolitis may also occur. An underlying malignancy is present in up to 20% of adults, particularly with dermatomyositis, and treatment can lead to resolution of the skin and muscle changes. The commonest neoplasms are carcinoma of the bronchus, breast, stomach and ovary. 1

Investigation The most important investigations are serum muscle enzyme measurements, electromyography (EMG) and muscle biopsy. Any one of these investigations may be normal, even during active disease. The creatine phosphokinase (CPK) is usually the most sensitive muscle enzyme to measure, and may be used in following the course of the disease. Serial measurements of muscle strength can also be useful in assessing progress, and vital capacity measurements are valuable in assessing respiratory muscle involvement. EMG abnormalities are well described and are useful in establishing the diagnosis and in distinguishing between myositis and steroid myopathy. Muscle biopsy changes include necrosis, muscle fibre regeneration and lymphocytic infiltration. A search for underlying cancer should be made in adults over the age of 50 with dermatomyositis. The skin and muscle disease may, however, appear 1-2 years before the cancer is apparent.

Management Corticosteroids usually control the disease, and are given initially in dosages of 40-60 mg of prednisolone daily. Immunosuppressive therapy with azathioprine, methotrexate or cyclophosphamide is frequently used, particularly if the disease is difficult to control with steroids. Treatment may be required for years. Plasma exchange has been used but without clear evidence of benefit. 2

FURTHER READING ON DERMATOMYOSITIS AND POLYMYOSITIS Askanas V, Engel W, Mirabella M 1994 Idiopathic inflammatory myopathies: inclusion body myositis, polymyositis and dermatomyositis. Curr Opin Neurol 7:448-456. Callen J P 1994 Myositis and malignancy. Curr Opin Rheumatol 6:590-594. Engel A G, Emslie-Smith A M 1989 Inflammatory myopathies. Curr Opin Neurol Neurosurg 2:695-699.

Mastaglia F L, Walton J N 1992 Inflammatory myopathies. In: Mastaglia F L, Walton J N (eds) Skeletal muscle pathology, 2nd edn. Edinburgh: Churchill Livingstone, pp. 453-491.

VASCULITIS The vasculitides are characterized by inflammation of blood vessels. Excluding giant cell arteritis and cutaneous vasculitis, the annual incidence of vasculitis is approximately 38 cases per million, ranging from 1 per million for Churg-Strauss or classic polyarteritis nodosa, to 10 per million for Wegener's granulomatosis. There are over 20 cases per million population of cutaneous and hypersensitivity vasculitides, whereas the incidence of giant cell arteritis is estimated at around 200 per million over 50 years of age and appears to be increasing compared with statistics from the 1950s (Fig. 22.32). Vasculitic syndromes are commonly classified on the basis of vessel size, which reflects treatment strategies. They may also be separated into primary vasculitic syndromes and those where vasculitis is occurring as a secondary feature (Table 22.36). Antineutrophil cytoplasmic antibodies bind to antigens in the cytoplasm of neutrophils. Usually, one of two patterns is seen on indirect immunofluorescence: a diffuse 'cytoplasmic' staining (cANCA) or a 'perinuclear' staining pattern (pANCA). The antibodies bind to several proteins, the most common being serine proteinase III (PR3, corresponding to the cANCA pattern) and myeloperoxidase (MPO, in the pANCA pattern). Other antigens less commonly identified, again with the pANCA pattern on immunofluorescence, include lactoferrin, and bacterial permeability-increasing protein (BPI). Antibodies to PR3 are found in about 80% of patients with Wegener's granulomatosis. Those against MPO are found in polyarteritis nodosa and more commonly in microscopic polyangiitis, and also in rheumatoid and lupus vasculitis. A pANCA pattern with other antigen specificities in low titre occurs

RECENT ADVANCES IN THE TREATMENT OF SYSTEMIC VASCULITIS

[22

Systemic vasculitis (including that associated with rheumatoid arthritis) may have a high death rate. Combinations of high-dose corticosteroids and cyclophosphamide have been shown to be very effective in improving morbidity and mortality. Vasculitis complicating rheumatoid arthritis may not be recognized because the usual signs - skin infarction, neuropathy and scleritis - may be lacking. The only indications of this potentially treatable complication of the disease may be a rapid weight loss, fever, malaise and a persistently raised ESR. in a variety of disorders, including septicaemia. To date, the presence or specific type of ANCA has not been included in the classification of the vasculitides, although in clinical practice they are commonly used as a corroborative test. Systemic vasculitis can be life-threatening, so early diagnosis is important, as improved treatment has dramatically increased survival. The severity and clinical presentation are related to the size and site of the vessels affected. Biopsy is central to the diagnosis, in addition to searching for associated factors such as cryoglobulins or hepatitis viruses (see below).

POLYARTERITIS NODOSA (PAN) AND

MICROSCOPIC POLYANGIITIS (MPA) PAN is a systemic necrotizing arteritis of medium-sized vessels which may be associated with cutaneous as well as systemic features (p. 409). The disease affects men more frequently than women. MPA is now considered a separate

TABLE 22.36 Classification of vasculitis Size of vessel involved

Primary vasculitis

Secondary vasculitis

Large arteries

Giant cell arteritis Takayasu's arteritis

Aortitis in RA or infection

Medium arteries

Classic PAN Kawasaki disease

Hepatitis B infection

Medium arteries and small vessels

Wegener's granulomatosis* Churg-Strauss* Microscopic polyangiitis*

Systemic rheumatoid vasculitis, SLE, Sjd'gren's Drugs Infection

Henoch-Schonlein Cryoglobulinaemia

Drugs, infections, particularly HCV

Leukocytoclastic (smallest)

FIG. 22.32 Skin and nails in vasculitis

* Denotes those conditions particularly responsive to cyclophosphamide immunosuppression

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TABLE 22.37 Relative incidence of features of polyarteritis Clinical feature

Incidence (%)

Systemic symptoms (fever, weight loss) Renal Arthritis/myalgia Cutaneous Neurological Abdominal

80 75 60 55 50 45

entity on the basis of its clinical presentation, the involvement of smaller vessels and ANCA positivity.

Pathology Muscular arteries throughout the body are affected, particularly in the kidneys, heart, gastrointestinal tract and peripheral nervous system. Orchitis is particularly associated with PAN. All layers of the vessel wall are affected, and acute vasculitis is associated with fibrinoid necrosis and an inflammatory infiltrate of predominantly polymorphonuclear leukocytes. Multiple aneurysm formation is common. Chronicity of the lesion leads to fibrosis and narrowing of the vessel lumen with thrombosis. The vascular lesions may be due to local deposition of immune complexes, and a similar disorder can be produced in animals by intravenous immunization. Some cases may be associated with hepatitis B infection.

Clinical features and diagnosis Systemic features include fever, myalgia and weight loss (Table 22.37), and these may be the presenting complaint. Cutaneous features include peripheral gangrene, rashes and livedo reticularis. The commonest neurological manifestation is mononeuritis multiplex. Renal involvement is common; the clinical features include haematuria, loin pain, acute and chronic renal failure and hypertension. However, glomerulonephritis, implying the involvement of small vessels, should raise the possibility of microscopic polyangiitis (MPA). Abdominal pain is a common presenting symptom and may reflect severe arteritic involvement. Articular features are usually mild. The diagnosis is made on the basis of typical multisystem disease features. There is frequently anaemia, leukocytosis and a raised ESR. Angiography may demonstrate microaneurysms, especially in renal arteries and the coeliac axis. Arteritis can also be detected in about 50% of renal biopsies, and rectal or sural nerve biopsies may also be diagnostic. ANCA (against MPO) is more frequently negative

1 1182

MCQ 22.20

in classic PAN than is MPA, which may have a similar clinical presentation. In the differential diagnosis, exclude: • subacute bacterial endocarditis • atrial myxoma • antiphospholipid syndrome. 1

KAWASAKI'S DISEASE Kawasaki's disease (mucocutaneous lymph node syndrome; see also Ch. 12) is a rare acute systemic illness of infants and children, characterized by fever, exanthematous rash, mucous membrane involvement, conjunctival congestion and cervical lymphadenopathy. There is a necrotizing arteritis, and coronary arteritis can be detected angiographically in up to 60% of cases. Epidemics occur, implying an infective aetiology. The disease is usually selflimiting, although sudden death may be caused by acute myocardial ischaemia resulting from coronary artery occlusion, myocarditis or aneurysm rupture.

CHURG-STRAUSS DISEASE Churg and Strauss described a vasculitic syndrome that differed from PAN in that pulmonary vessels were frequently affected. Patients have a history of allergy, and asthma develops in adult life. The high frequency of pulmonary symptoms, peripheral eosinophilia and the absence or mildness of the renal disease help to distinguish the disease from PAN (p. 675).

WEGENER'S GRANULOMATOSIS Wegener's granulomatosis is the most common of the primary vasculitic syndromes involving small vessels. First described as a disease of necrotizing granulomata of the respiratory tract and of focal glomerulonephritis, a limited form is recognized that involves the upper respiratory tract only. Although the 'ELK' classification (E: ear, nose and throat; L: lung; K: kidney) is useful to recall the organs most commonly involved, disease does not necessarily progress in this pattern. Renal and pulmonary involvement are discussed in detail in Chapters 13 and 20, respectively.

Management of vasculitis (Table 22.38) The use of intravenous pulse therapy with cyclophosphamide and methylprednisolone has led to a dramatic improvement in the prognosis of Wegener's granulomatosis, Churg-Strauss and MPA. Corticosteroid may be used alone for large vessel arteritis, and of course is standard therapy for giant cell arteritis (GCA) and polymyalgia rheumatica (PMR).

TABLE 22.38 Aims of management of vasculitis • • • •

Induction of remission Maintenance of remission Recognition and early treatment of relapse Avoidance of drug toxicity

Various regimens of pulse therapy are used. This strategy has the advantage over continuous oral treatment of significantly reducing the risks of haemorrhagic cystitis, bladder tumour, and gonadal failure. Prophylaxis against Pneumocystis carinii should be considered if treatment is prolonged. In addition to its immunosuppressive effects, methylprednisolone has important antiemetic properties. None the less, corticosteroid adverse effects are not uncommon, and some regimens use cyclophosphamide alone after the induction phase of treatment (for example, six fortnightly pulses). Maintenance is continued with increasing intervals between pulses for up to 2 years before changing to azathioprine or methotrexate for long-term treatment. Relapse of Wegener's may be prevented by administration of cotrimoxazole. This drug may also be sufficient in Wegener's limited to upper respiratory tract involvement without requiring full immunosuppressive therapy.

SMALL VESSEL OR LEUKOCYTOCLASTIC VASCULITIS Small vessel vasculitis is a feature of a number of different disorders, including the connective tissue diseases. A number of distinct clinical syndromes are characterized by small vessel vasculitis, including Henoch-Schonlein purpura and cryoglobulinaemic vasculitis. Cryoglobulins are immune complexes that precipitate spontaneously at low temperatures. It is now recognized that over 90% of individuals with mixed essential cryoglobulinaemia have serological evidence of hepatitis C virus (HCV) infection, whereas other types are associated with occult malignancy. Precipitation leads to complement activation and vasculitis in small vessels. Complete vascular occlusion is less common. A purpuric rash, often most prominent on the flexor aspect of the lower limbs, is a characteristic feature of small vessel vasculitis. This purpura can be differentiated from that of platelet disorders because it is palpable, indicating inflammation of small cutaneous capillaries. Larger vessels are implicated if fresh lesions are irregular in outline. However, smaller lesions often coalesce with time, producing large purpuric areas which may ulcerate. A classic triad of a palpable purpuric rash on the extremities, arthralgia and muscle weakness is described in cryoglobulinaemia. Inflammatory arthritis is uncommon and radiological changes do not occur. Other skin presentations include petechiae, urticaria and aerocyanosis. Other organ involvement is frequently seen in

addition to this triad, particularly glomerulonephritis and peripheral neuropathy. Henoch-Schonlein purpura is usually a disease of children, although a similar presentation can occur in adults of any age. Diagnosis of cryoglobulinaemia requires meticulous attention to phlebotomy and laboratory technique. A positive rheumatoid factor and raised ESR are supportive features, and urinalysis and microscopy for an 'active sediment' should always be carried out in patients presenting with purpura and arthralgia. A thorough search is required for underlying malignancy and for associated HCV. NSAIDs, corticosteroids and steroid-sparing drugs, particularly azathioprine, are used to relieve arthralgia and to prevent the progression of purpura to ulceration. Neurological or renal involvement requires more aggressive therapy, for which cyclophosphamide (oral or intravenous pulses) or chlorambucil are used. Plasmapharesis is of value in rapidly progressive glomerulonephritis, but requires particular care to avoid blood cooling in the extracorporeal circuit.

[22

GIANT CELL ARTERITIS AND POLYMYALGIA RHEUMATICA Giant cell arteritis predominantly affects elderly patients. Although almost any large artery may be involved, with granulomatous inflammation of the internal elastic lamina the majority of clinical signs and symptoms result from involvement of the carotid artery or its extracranial branches. Definitive diagnosis can be made on examination of a temporal artery biopsy. In recent years giant cell arteritis and polymyalgia rheumatica have been increasingly considered as closely related conditions. The two syndromes form a spectrum of disease and affect the same age of patient. Polymyalgia rheumatica (PMR) is a clinical syndrome of middle-aged and elderly patients and is characterized by: • Pain and stiffness, bilateral and symmetrical, typically in proximal muscle groups; • Systemic features such as low-grade fever, fatigue and weight loss; • An elevated ESR; • A dramatic response to small doses of corticosteroids. About 50% of patients with giant cell arteritis have symptoms of PMR, whereas 15-50% of patients with PMR have giant cell arteritis. Problems with case definition and ascertainment complicate epidemiological observations. Both polymyalgia rheumatica and giant cell arteritis are more common in the elderly and in women. Giant cell arteritis and polymyalgia are well recognized in the UK and in Scandinavia. In the USA, most reports derive from northern states; few cases are reported from southern states or in blacks, but the diseases are recognizable worldwide.

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Aetiology and pathology 1 The aetiology of polymyalgia and temporal arteritis is unknown. The constitutional features suggest a viral infection, and many patients notice a distinct prodromal illness resembling influenza. There is little evidence of primary muscle disease in polymyalgia. Muscle biopsy shows only mild atrophic changes and the EMG is normal. Muscle enzymes are not elevated. Giant cell arteritis affects large and medium-sized arteries and involvement is patchy, 'skip lesions' often being found. The arteritis is a panarteritis with giant cell granuloma formation, often in close relationship to a disrupted internal elastic lamina. The gross features are not characteristic. The vessels are enlarged and nodular, having little or no lumen owing to marked intimal proliferation. There may be widespread vasculitis, with involvement of the aorta and its branches, the abdominal vessels and the heart. The pulmonary and renal vessels and the small arterioles are generally not involved, and this may be useful in differentiating between this condition and PAN.

Clinical features Giant cell arteritis Headache is common, and may be either a non-specific tension type or well localized, severe, continuous and with associated scalp tenderness. There can be pain in the face on chewing, caused by claudication from facial artery involvement. Tingling in the tongue, and loss of taste and pain in the mouth and throat can also occur, presumably owing to vascular insufficiency. Infarction of the skin can rarely occur. The great danger, particularly but not exclusively in patients with symptoms of arteritis, is sudden irreversible blindness. This may be preceded by transient visual disturbances, e.g. field defects. Blindness results from ischaemic optic neuritis caused by arteritis of the posterior ciliary and branches of the ophthalmic arteries. The ocular complications usually occur within weeks or months of the onset of systemic manifestations of the disease. If temporal arteritis is suspected, steroid therapy, in adequate dosage, should be started immediately before further investigation of the patient in order to protect sight. The blindness is irreversible and often bilateral, and loss of sight in the second eye may follow within hours of the first. Arteritis can involve the carotid, vertebral, meningeal and, rarely, the intracerebral vessels, leading to hemiplegia, epilepsy or focal vertebral or occipital lobe lesions. Aortic involvement can lead to an aortic arch syndrome; aortic aneurysm is rare.

1

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Fig. 22.21

0 MCQ 22.21

The amount of constitutional upset is variable, but lassitude, arthralgia, anorexia, weight loss, a low-grade fever and depression are all common. A transient synovitis can occur, particularly in the knee and often with an effusion. The systemic features can be vague and easily overlooked; conversely, they can be striking. Polymyalgia rheumatica The initial symptoms of polymyalgia rheumatica may be sudden, with pain and severe stiffness of proximal muscles and periarticular tissues. Stiffness is usually the predominant feature; this is particularly severe after rest, and may prevent the patient getting out of bed in the morning. The muscular pain is often diffuse, and worse after resting. The musculoskeletal symptoms are almost always bilateral and there is tenderness of muscle and periarticular structures. There is often little to find on examination of patients with polymyalgia rheumatica, although anaemia and obvious weight loss are quite frequent. The muscles may be tender, but there is no muscle weakness. Classically, when the temporal artery is involved the vessel is thickened and tender, with absent pulsation, but usually the signs are limited to diminished or absent pulsation, perhaps with tenderness of the scalp. Tenderness in areas distant from arteries may be present even when the vessels are clinically normal. Bruits are often present over large arteries and there may be tenderness, particularly over the subclavian; these are presumably due to arteritis as they disappear with treatment.

Investigation Investigations in polymyalgia and giant cell arteritis are essentially normal apart from a high ESR and increases in the acute-phase proteins. The ESR is usually at least 70mm/h and is often over lOOmm/h, particularly if arteritis is present: this provides a useful means of monitoring treatment. A normal ESR does not exclude the diagnosis. Anaemia, usually of a mild hypochromic type, is common and resolves without specific treatment, but a marked normocytic anaemia occasionally occurs and may be responsible for the presenting symptoms. Abnormalities of thyroid and liver function have been described. Hypothyroidism or hyperthyroidism can occur. Raised serum values for alkaline phosphatase are found in 20% of patients. Liver biopsy specimens may show portal and intralobular inflammation, with focal liver cell necrosis and small epithelioid cell granulomas. Temporal artery biopsy is the most important diagnostic procedure, but in view of the patchy nature of the arteritis a negative biopsy does not exclude the disease. Steroids reduce the inflammatory infiltrate within days, although a healing vasculitis may be recognizable for up to 1 week. Ideally, a temporal artery biopsy should be carried out before treatment is started if possible, but if there is any delay then steroids should be started immediately, in order

TABLE 22.39 Differential diagnosis of polymyalgia rheumatica • • • •

Neoplasm Connective tissue disease Multiple myeloma Leukaemia

• • • •

Lymphoma Polymyositis Dermatomyositis Myopathy

to prevent visual complications. Ultrasound and MRI have been studied as alternatives to biopsy but cannot at present be recommended as being sufficiently sensitive to replace it.

Diagnosis The diagnosis of polymyalgia rheumatica is initially one of exclusion. The differential diagnosis (Table 22.39) in elderly patients with muscle pain, stiffness and a raised ESR is wide because the prodromal phases of several serious conditions can mimic it. In practice, non-specific clinical features and the frequent absence of physical signs make diagnosis difficult.

Management The aims of treatment are to relieve pain and symptoms and to reduce the incidence of complications. Many of the symptoms of polymyalgia rheumatica are improved with NSAIDs. However, these drugs do not control the underlying arteritis or stop the development of vascular complications. Corticosteroids dramatically relieve myalgic symptoms and suppress the arteritis, and are used in almost every case of polymyalgia. It is rarely necessary to exceed 20 mg of prednisolone to control the myalgic symptoms, the ESR being used to titrate the dosage. In proven arteritis, doses of 40 mg of prednisolone usually suppress the disease. The dramatic response to steroid therapy supports the diagnosis. Patients must be reviewed regularly for exacerbations of the disease or for the development of arteritis, and the steroid dosage adjusted accordingly. Once there is no clinical evidence of disease activity the steroids can be gradually discontinued, but recurrences are common, sometimes many years later. However, the majority of patients should be able to discontinue treatment after 5 years, and between one-third and half can do so after 2 years. Relapse is more common if treatment is discontinued within 18 months of onset, and within the first year after completion. Resistance to steroid therapy should prompt a search for underlying malignancy. Those requiring prolonged treatment must be evaluated for glucocorticoid-induced osteoporosis prophylaxis. Azathioprine or methotrexate may be used as steroid-sparing drugs. A regimen of intramuscular injections of methylprednisone with gradually increasing intervals between injections has been used effectively with reduced total steroid requirement.

Prognosis Untreated patients have prolonged ill-health, and up to 20% of those with giant cell arteritis go blind or develop vascular complications. Of treated patients, between one-third and one-half can discontinue treatment after 2 years. ©

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TAKAYASU'S ARTERITIS Takayasu's arteritis is a large vessel granulomatous panarteritis. It is a rare disease, predominantly of young women. Age of onset (under 40 years) is an important discriminating factor between Takayasu's and giant cell arteritis. Features include systemic symptoms, with weight loss and fever. The arteritis involves the aortic arch and its branches, and the inflammation results in stenosis, which may be demonstrated angiographically. Features of arterial stenosis include dizziness, fainting, exertional dyspnoea and reduced or absent peripheral pulses. The acute symptoms may respond to steroid therapy, but vascular reconstruction may be helpful in later stages of the disease.

FURTHER READING ON VASCULITIS Hazleman B, Bengtsson B A, 1991 Giant cell arteritis. Clinical Rheumatology. London: Bailliere Tindall. Hoffman G S, Kerr G S, Leavitt R Y 1992 Wegener's granulomatosis, an analysis of 158 patients. Ann Intern Med 116:488^198. Jerrousse B et al 1995 Polyarteritis nodosa related to hepatitis B virus - a prospective study with long-term observation of 41 patients. Medicine (Baltimore) 74:238-253. Kerr G S 1994 Takayasu's arteritis. Ann Intern Med 120: 919-929. Luqmani R, Watts R, Scott D, Bacon P 1994 Treatment of vasculitis in rheumatoid arthritis. Ann Med Interne 145:566-576. Savage C O S , Lockwood C M 1993 Systemic vasculitides. In: Peters D K, Lachmann P J (eds) Clinical aspects of immunology. Oxford: Blackwell, pp. 1205-1216. Scott D G I, Watts R A 1994 Classification and epidemiology of systemic vasculitis. Br J Rheumatol 33:897-900.

LOW BACK PAIN Although back pain results in the loss of millions of working days each year, most individuals recover without medical attention. Of those who consult a general practitioner, only a very small proportion ultimately undergo surgery.

Anatomy and biomechanics The spine is a weight-bearing structure. Movement occurs at the apophyseal joints, which are synovial, and at the intervertebral discs. These structures are closely related, and disease or deformity of one often affects the other. In the lumbar spine the apophyseal joints resemble a

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mortise and tenon arrangement, which provides strength at the expense of mobility. There is very little rotation, and flexion is 45° (Fig. 22.33). Lumbar disc lesions usually cause root syndromes, because the spinal cord ends at L2. The lumbar nerve root exits high in its foramen and is usually above a prolapsing disc, which compresses the nerve root passing to the interspace immediately below. Pain fibres are present within the spinal ligaments, in the apophyseal joint capsules, in the periosteum at the fascial and tendon attachments and in blood vessels, but only in the outer layers of the intervertebral discs. Pain is produced by pressure on these structures from disc protrusions, osteophytes or trauma. The healthy nucleus pulposus behaves like a gel and distributes pressure equally in all directions. With age, this property declines and localized points of high pressure develop. The pressures within the discs are increased most by lifting while bending forward or sitting.

posterior longitudinal ligament. Occasionally, pain is produced when there is a tear in the annulus but no protrusion. Disc lesions heal by fibrosis, but there is always a risk of recurrence. Degenerative changes are present in the intervertebral discs of all subjects by middle age. These are more marked, and occur earlier, after disc prolapse. There is a direct relationship between the degree of disc degeneration, osteophyte formation on the margins of vertebral bodies and apophyseal joint changes, suggesting that disc degeneration is the primary event leading to degenerative spondylosis.

Aetiology

Pathology

The mechanical and non-mechanical causes of backache are listed in Table 22.40. A detailed history and examination, with the appropriate laboratory studies, usually identifies non-mechanical causes (Table 22.41). The age groups at particular risk are listed in Table 22.42. In general practice, it is people between the ages of 50 and 60 that attend most commonly with low back pain.

Disc protrusions usually occur posterolaterally, because here the annulus fibrosus is no longer reinforced by the

Clinical features History Mechanical and inflammatory back pain must be differentiated: the former is exacerbated by movement and

TABLE 22.40 Causes of backache

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FIG. 22.33 Diagram showing the position of the nerve roots and spinal nerves in relation to skeletal structures A Lateral aspect of the lumbar spine. B Superior aspect of a cervical vertebra. The precise position of the union of the ventral and dorsal nerve roots, to form the spinal nerve, in the intervertebral foramen is a little variable. Dashed lines indicate the usual sites of disc herniation.

Cause

Example

Mechanical

Prolapsed intervertebral disc Apophyseal osteoarthritis Ankylosing hyperostosis Spinal stenosis Spondylolisthesis and other congenital abnormalities Scheuermann's osteochondritis Fractures Non-specific

Inflammatory

Ankylosing spondylitis and related seronegative spondylarthritides Rheumatoid arthritis Infection

Neoplastic

Bone - primary or secondary Spinal tumours

Metabolic

Osteoporotic fractures Osteomalacia Ochronosis Chondrocalcinosis

Paget's disease Referred Depression

Pelvic/abdominal disease Posture

improved by rest, whereas the latter is associated with stiffness after rest. These distinctions are not absolute, as inflammation involves some local swelling (i.e. mechanical change) and trauma generates some inflammation. Back pain also occurs when bone is affected by tumour, infection or metabolic disease. The patient experiences unremitting pain, which is worse at night and exacerbated by movement.

TABLE 22.41 Clinical features of low back pain Feature

History

Examination

Mechanical

Precipitating strain Previous episodes Unilateral leg/buttock pain Worse on movement and coughing Eased by rest

Asymmetrical restriction of movement and of straight leg raise Uniradicular signs

Systemic disease

Constant or progressive Worse on rest or at night Morning stiffness Bilateral or alternating pain

Features of ill health Rigid lumbar spine Symmetrical restriction of movement and straight leg raise Multiradicular signs Other neurological signs Wasting of paraspinal muscles High ESR

Systemic illness Diffuse pain and tenderness

Non-specific

Postural factors Depression Gynaecological symptoms Diffuse pain

Normal movement Local tenderness

Examination The way in which a patient moves should be noted. Painful conditions can cause scoliosis through a protective muscle spasm. Sometimes this is only present on forward flexion, whereas secondary scoliosis (e.g. that caused by unequal leg length) disappears on flexion. Inflammatory conditions cause flattening of the lumbar lordosis. Patients with degenerative disease and disc lesions typically have restricted back movement, but with limitation of lateral flexion to one side; whereas in ankylosing spondylitis there is bilateral limitation of lateral flexion. Neurological examination identifies nerve root irritation. Straight-leg raising is performed with the patient supine. The sciatic nerve is stretched by raising the straight leg until this becomes painful; a restriction to 45° or less indicates significant root irritation. The femoral stretch test is often misinterpreted. Root irritation is present if pain is produced in the anterior thigh on flexing the knee, with the patient prone.

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Investigation Radiology Plain radiographs of the lumbar spine are of little diagnostic help. Radiographs are normal in 25% of patients with disc prolapse confirmed at operation, in early ankylosing spondylitis and early metastases. Bone density appears unchanged until 50% of the mineral has disappeared. In contrast, marked degenerative and disc-space changes can be present in the absence of any symptoms, or can easily be falsely interpreted as the cause of symptoms. In localized bone disease, isotope scanning is often helpful. CT and MRI (Fig. 22.34) are increasingly used as the investigations of choice. The accuracy that can be obtained with MRI and CT scans is such that radiculography is

TABLE 22.42 Caus BS of low back pain related to specific age groups Age group (years)

Cause of pain

Children

Osteochondritis (Scheuermann's disease) Scoliosis - primary or secondary

15-30

Ankylosing spondylitis Prolapsed intervertebral disc and fractures Spondylolisthesis Postural pain from pregnancy

30-50

Degenerative joint disease Prolapsed intervertebral disc Malignancy

50 and over

Degenerative joint disease Osteoporosis Paget's disease Malignancy

FIG. 22.34 Disc protrusion at L5/S1 level The disc has lost hydration (it is darker than the other discs visible) and disc material has extended into the spinal canal (arrow),

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TABLE 22.43 Radiological and laboratory findings in back pain Cause of back pain

Radiological features

ESR

Calcium

Phosphate

Alk. Phos.

Mechanical Inflammatory

Normal or degenerative changes Sacroiliitis Osteomyelitis Psoas abscess Osteolytic or sclerotic deposits Vertebral collapse Reduced bone density Vertebral collapse

N T

N N

N

N

N

N

T

N or

N

N

N

N

Osteoid seams Reduced bone density Sclerosis and expansion of bone

N

Neoplastic Osteoporosis Osteomalacia Paget's disease

N

N

or N N

N

N = normal.

seldom necessary. Intravenous gadolinium can enhance the contrast, allowing differentiation between residual disc material and granulation tissue resulting from a previous surgical procedure. Laboratory investigations Only simple screening tests are usually required (Table 22.43). The ESR is the most useful.

Prolapsed intervertebral disc Only a few patients with back pain have a disc prolapse and the condition is often diagnosed erroneously. The diagnosis is unlikely if there is: • • • • •

No evidence of nerve root compression More than one root involved Bilateral and symmetrical nerve involvement Diffuse pain and tenderness Unremitting pain, worse on resting at night.

The leg symptoms and signs are the result of pressure on the dura mater and nerve roots. Straining or sneezing exacerbates disc pain by raising pressure within the spinal canal. A central protrusion may cause cauda equina compression, with saddle-shaped sacral anaesthesia, flaccid paralysis of the legs and sphincter involvement (usually urinary retention). This constitutes a surgical emergency. The presenting symptoms may be no more than impairment of urethral sensation. Early surgical exploration is indicated to preserve sphincter control (p. 1385). Back pain or sciatica is very occasionally caused by a

1 1188

MCQ 22.22

cauda equina tumour. Diagnosis is difficult, but bladder or bowel symptoms, impotence and wasting of the legs require urgent investigation. 1

Management The causes of back pain are not well understood and treatment is largely empirical. Prophylactic exercises, advice on future activities and general back care should form the basis of management. However, for more severe back pain, treatment may include bed rest, traction, manipulation, the wearing of a surgical corset and surgery. Mechanical back pain Complete prolonged bed rest, usually for no more than 1 week, and analgesics are successful in most cases of mechanical back pain. The mattress should be firm (boards can be placed underneath), and muscle relaxants may help. After a period of immobilization, exercises are started gradually. Isometric exercises (sometimes combined with traction) give better results than active mobilizing exercises (which increase the load on the lumbar spine). A surgical corset may be useful if there is residual pain. Traction Although symptoms are often relieved during traction, there is no evidence that it improves the rate of recovery. Patients with root pain, who find that it is relieved by lying down, benefit most. Traction is seldom effective in chronic back pain or severe sciatica with neurological signs. Manipulation Manipulation can help in both acute and chronic low back pain. Unfortunately, one cannot identify in advance those patients who will respond. Trials suggest that manipulation gives significant immediate benefit, but after 1-2 weeks both manipulated and non-manipulated patients show

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CASE STUDY 22.4 ACUTE BACK PAIN IN A 50-YEAR-OLD WOMAN A 50-year-old woman has come to the emergency department with severe back pain. Since a visit to the dentist 1 week previously she has had backache, but this has increased considerably in the past 48 hours. She recalls having had to sit forward with a twisting motion from a semireclined position to clear her mouth, and noting a 'twinge' at that time. Her work as a driving instructor involves frequent jarring of her back, but she has no past history of an episode such as this. She notes that the pain is increased by sneezing, and is referred into the left buttock. She has no paraesthesiae, but describes a vague sensation 'like cold water poured on my leg' on the anterior aspect of the left thigh. There has been no change in bladder function, but she has noted constipation, which has been attributed to the dihydrocodeine prescribed for the pain. Her mother has been diagnosed with osteoporosis, but family and personal medical histories are otherwise unremarkable. On examination her temperature is 37.5°C. She is able to rise from a chair, limping to minimize weightbearing on the left leg. Inspection of the spine is unremarkable. When standing, movements in all directions are painfully restricted, though this is particularly noted on side flexion to the left and in forward flexion. She has considerable difficulty and pain when attempting to lie on the examination couch. Straight-leg raising (SLR) on the right produces back pain at 60° without referral to the right leg. On the left, SLR is painful at 30°, referred into the buttock, exacerbated by ankle dorsiflexion and relieved by knee flexion. Neurological examination is normal on the right; reflexes and sensation are also normal on the left, but tests of power are equivocal as effort is reduced because of pain. Lying semiprone on the right side, a left femoral stretch test is positive. (The knee is flexed to 90°, the hip then extended; in a positive test pain

is felt in the anterior thigh. It is important to flex the knee first, otherwise pain may occur as a result of excessive hip extension before producing sufficient stretch of the femoral nerve.) Questions 1. Whit differential diagnosis is suggested by the history*? 2. How do the physical findings distinguish between these? 3. Is a plain X-ray of the spine indicated? By far the most common cause of acute back pain in young or middleaged people is acute intervertebral disc prolapse. Although most episodes are self-limiting, about 10% experience prolonged or severe symptoms for which analgesia and relative rest fail to give adequate relief. A history of strain during a lumbar flexion-rotation movement, with pain radiating to a variable extent down one leg, exacerbated by sudden increases in intra-abdominal pressure, supports this diagnosis. Neurological symptoms are often poorly defined. An episode may occur with no preceding history or on a background of repetitive minor injury to the back (lifting, sporting injuries, or as in this patient). Infection of the disc space (discitis) or, less commonly, of bone or paraspinal musculature, is uncommon, but it is critical that such a diagnosis is not overlooked as significant vertebral destruction can occur, with resulting long-term disability. Transient bacteraemia can follow dental or endoscopic procedures, and bacteria may then infect a degenerate disc. A vertebral fracture may occur with minimal increased loading of the spine and is the most common fracture complicating osteoporosis. A family history is one of strongest predictors of reduced bone mineral density. However, the majority of

fractures result in a wedging deformity, with comparatively greater loss of height anteriorly, and nerve root compression is fortunately uncommon. Pathological fractures typically involve the pedicle and may cause dural root compression. The two important distinctions to be made during an examination are, first, between disc and other pathology, and second, to determine whether or not there is neurological impairment. As the annular ring of the disc is weakest in its posterolateral portion, prolapse of the nucleus pulposus typically occurs in a posterolateral direction, producing asymmetrical findings on examination. Impingement upon the emerging nerve root will produce pain, usually in an extradermatomal (i.e. more than one dermatome) pattern. If the nerve root is further compromised, localizing neurological signs will be evident. Impaired reflexes are the most reliable signs, though a well-demarcated area of reduced sensation can be detected in some, again allowing accurate localization of the nerve root involved. When a disc has protruded in a very lateral position there may only be distal signs, without central back pain. Stretching of a peripheral nerve (typically the femoral (L2^4) and sciatic (L3-S1)) is believed to produce pain only in inflamed nerve roots. If pain is not relieved by relaxation of the nerve stretch, then it is due to pathology at another site, prompting consideration of fractures, pelvic inflammatory pain or sacroiliac involvement. An exception is discitis, where the typical pattern of disc signs is distorted by the absence of nerve root impingement. A low-grade pyrexia is not uncommon in the setting of severe pain and is unhelpful. Localized tenderness may be particularly marked if there is fracture or infection. A plain X-ray will identify bone abnormalities. Therefore, as the majority of back pain presentations

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CASE STUDY 22.4 CONTINUED are due to a prolapsed intervertebral disc, such imaging is unhelpful in the majority of cases. Where the history and physical examination give a high suspicion of fracture or a malignancy (e.g. an older male with prostatic symptoms), plain radiography may be helpful without resort to more intensive investigations - discussion with a radiologist with some understanding of the differential diagnosis is invaluable. This woman's history is entirely consistent with a disc prolapse, and the physical findings give no reason to suspect otherwise. Her condition failed to resolve with conservative therapy, and an MRI scan was therefore obtained. This confirmed a

posterolateral disc protrusion at L3/4 compressing the nerve root. Questions 4. What other investigations are important? Unless there is a high index of suspicion of a diagnosis other than disc prolapse, investigation is not required. It is important to ensure adequate analgesia, incorporating NSAIDs, codeine-based drugs and relief of muscle spasm (diazepam, methacarbamol or baclofen are used), and to involve a physiotherapist early. MRI is the investigation of choice if

equal improvement. Manipulation should be restricted to mechanical back pain without neurological involvement or any spinal instability.

an epidural injection can give immediate relief. The benefit may result from the anti-inflammatory action of the steroid, or by the large volume of fluid freeing adhesions around nerve roots.

Lumbar supports Lumbar supports probably act not so much by immobilizing the spine as by raising the intra-abdominal pressure, so that some body load is transmitted through the abdomen, rather than through the spine. They can be helpful if:

Chemonucleolysis An injection of chymopapain into the nucleus pulposus leads to a reduction in disc size and results in improvement in 80% of selected patients.

• • • • •

Surgical treatment Surgical treatment is seldom necessary, unless severe pain either persists in spite of adequate treatment or recurs often, or if neurological signs are progressing. Laminectomy is successful in 80% of selected patients.

The patient remains ambulant Heat and intermittent traction are ineffective Manipulation is contraindicated Bed rest has not relieved pain Back pain recurs in spite of prophylactic exercises and back care.

The spinal support should be worn continuously during the acute episode, and then during the day for several weeks. However, it is important to avoid dependence, and trunk muscle bulk must be maintained during immobilization by static and then active exercises. Prophylactic use during hard physical work and long car journeys is recommended. Epidural injections Epidural injections of local anaesthetic and steroid may reduce pain and allow a patient to return to work earlier. The main indications are chronic sciatica, and sciatica with root interruption. This presents as severe pain unrelieved by rest. It improves spontaneously after several days, but

O Fig. 22.22

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chemonucleolysis or surgical intervention is anticipated, most commonly for pain that fails to improve with conservative measures, where significant nerve root impairment is evident, and of course where cauda equina compression is suspected. If discitis is suspected (an elevated ESR and WCC, end-plate changes on plain radiography), positive identification of the causitive organism is essential. Blood cultures should be taken before empirical antibiotics are started; if these are negative, CTguided biopsy of the disc should be considered. MRI may often demonstrate the lesion. 12

2

Case 22.3

General rehabilitation Patients should be encouraged to resume normal activities, and advised on lifting and bending, exercises, weight control, posture, beds, chairs and the correct height for work surfaces. Prolonged sitting without lumbar support (e.g. from a small cushion or bedrest), stooping and carrying should be avoided. Patients with recurrent pain may have to accept some limitations on their previous activities. Chronic low back pain Despite treatment, less than 50% of patients with low back pain of over 6 months' duration ever return to full employment. A rehabilitation unit may be beneficial; confidence may be increased through a progressive exercise regimen and advice given on employment. Caution and restraint are required when contemplating back surgery. Other causes of bock pain Degenerative disease of the lumbar spine is accompanied by central low back pain and buttock or thigh pain. Neu-

rological signs are uncommon. Many patients respond to heat and mobilizing exercises, whereas others benefit from gentle manipulation. Surgery is rarely required. Paget's disease Paget's disease is a common radiographic finding, but not always the cause of symptoms (p. 974). Metabolic bone disease (Ch. 18) In osteoporosis and osteomalacia, sudden pain may result from compression fractures of the vertebral bodies or from microfractures not visible on the radiograph. Nerve root and cord compression are uncommon, even when there is gross deformity of the spine. Chondrocalcinosis and ochronosis also cause premature disc degeneration and back pain. Patients with any of these conditions should be encouraged to be mobile, as immobility aggravates bone loss. Short leg syndrome Differences in leg length of more than 12.5mm may lead to the gradual onset of backache (usually in middle age), which may be initiated by minor trauma. Provided there are no structural changes, correction of discrepancies of greater than 12.5 mm should relieve or prevent pain. Infections of the spine Infections of the spine are uncommon. Early diagnosis can be difficult, as backache may develop insidiously with few signs of systemic illness. Tuberculosis of the spine is an important cause. Both tuberculosis and brucellosis may produce unilateral sacroiliitis. Discitis occurs much more frequently than vertebral osteomyelitis. Patients are usually symptomatic for several weeks before the diagnosis is made. Presentation is with a painful, tender and stiff back. In the early stages X-rays are normal and then show a narrowing of the intervertebral disc and erosion of the adjacent vertebrae. Congenital abnormalities Congenital abnormalities are usually identified radiologically. Common abnormalities include spondylolisthesis, spondylolysis, transitional vertebrae, spina bifida and abnormalities of the posterior articular facets. Spondylolisthesis, in which there is forward subluxation of the body of one vertebra on to the one below, usually occurs at L5-S1 in athletic adolescent boys. It is usually secondary to spondylolysis (a bony defect of the neural arch), which by itself is symptomless. Approximately 70% of patients with spondylolisthesis have back pain, but only 10% have sciatica. Pain usually responds to conservative treatment, including the use of a corset. Sprung back Tears in ligaments or paraspinal muscles cause acute localized pain and tenderness. Pain is often exacerbated by lifting or by a period of inactivity, and may radiate to the buttocks. There are no articular or dural signs. Neoplastic disease Persistent pain, particularly at night, with associated tenderness should always be investigated. A bone scan

may confirm the presence of metastases before there are any radiological changes. Vertebral collapse may precipitate root pain, and intraspinal tumours may mimic prolapsed disc. However, there are a number of distinguishing features: no response to treatment, progressing neurological signs, sphincter disturbance, multiple root involvement, nocturnal pain and pain unrelated to exercise, the presence of an upper motor neuron lesion and signs of ill health. Bony metastases are much commoner than primary intraspinal tumours of the vertebral column, particularly from carcinomas of the breast, bronchus, kidney and thyroid (all osteolytic), or of the prostate (osteosclerotic). Primary bone tumours are rare.

22

Spinal stenosis Variations in the size and shape of the spinal canal are common. Narrowing can result in pressure on the spinal cord or on nerve roots, or can leave less space to accommodate a prolapse or osteophytes. Spinal stenosis commonly presents in older patients with an annular bulge of the disc and facet joint arthritis, together with hypertrophy of the ligamentum flavum. Spinal stenosis is a symptom complex of root pain and sensory or motor symptoms that comes on during walking and passes off after a few minutes of sitting down or flexing the spine. Scheuermann's osteochondritis Scheuermann's osteochondritis occurs in adolescent males and causes a dull ache in the lower thoracic region. Radiographs are diagnostic. They show fragmentation of the vertebral epiphysial end-plates and, later on, narrowing of the disc space and wedging of the vertebrae, producing a smooth kyphosis. The cause is unknown. Ankylosing hyperostosis In this syndrome, bony spurs usually form on the anterolateral aspect of several dorsolumbar vertebral bodies and fuse to form bridges. There is progressive stiffening of the spine but little pain or disability. Psychological factors Psychological factors are important in chronic back pain, which is common in patients who are unhappy at work or at home. In many of these patients no overt psychiatric symptoms are present, and they may prove very difficult to treat. Compensation neurosis Some patients develop symptoms following an accident that are totally resistant to treatment, and which may remain even after the claim has been settled.

FURTHER READING ON LOW BACK PAIN Deyo R D, Diehl A K 1988 Psychosocial predictors of disability in patients with low back pain. J Rheumatol 15:1557-1563. Jayson M I V (ed) 1992 The lumbar spine and back pain, 4th edn. London: Churchill Livingstone. Kors B, Van Tulder M, van der Windt D, Bouter L 1994 The efficacy of back schools: a review of randomised clinical trials. J Clin Epidemiol 47:851-862.

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Lahad A, Malter A D, Berg A O, Deyo R A 1994 The effectiveness of four interventions for the prevention of low back pain. JAMA 272:1286-1291. Porter R 1992 Spinal stenosis of the central and root canal. In: Jayson MIV, ed., The lumbar spine and back pain, 4th edn. Churchill Livingstone, Edinburgh. Waddell G 1987 Clinical assessment of lumbar impairment. Clin Orthop Rel Res 221:110-120.

SOFT TISSUE RHEUMATISM

Lesions of tendons and their sheaths, fasciae, bursae, joint capsules and the tenoperiosteal junction (the enthesis) cause much morbidity and loss of productivity. They constitute a significant proportion of the workload of general practices and hospital accident, orthopaedic and rheumatology departments. As biopsy and surgery are rarely employed in their diagnosis and treatment, histological data are scanty and their pathologies are poorly understood. Although there are adequate anatomical and clinical features to allow the identification of individual conditions, diagnosis is often imprecise and management remains largely empirical. Any or all of these lesions may occur in association with overt systemic disease, as, for example, in inflammatory arthritis or infection. A large proportion, however, occur in the absence of systemic disease. In these circumstances, local causes, such as chronic repetitive low-grade trauma, or excessive and unaccustomed use either at work or at play, may be responsible. These factors may also cause partial interruption of the blood supply, resulting in incomplete attempts at healing and degeneration; this renders these structures more vulnerable in the middle-aged and elderly, in whom these lesions predominate.

TABLE 22.44 Generalized soft tissue lesions With evidence of inflammation Polymyalgia rheumatica and giant cell arteritis Prodrome of inflammatory arthropathies and connective tissue diseases Viral and bacterial infections Without inflammation Fibromyalgia Hypothyroidism Drug-related painful states associated with steroid withdrawal, chronic barbiturate abuse and the contraceptive pill Dyskinetic phase of Parkinson's disease Chronic brucellosis, Bornholm's disease Associated with malignancy, e.g. myeloma, carcinoma Osteomalacia Fibrositis Associated with weakness Prodrome of polymyositis or dermatomyositis Carcinomatous neuromyopathy (some forms) Hypokalaemic states Psychogenic rheumatism

TABLE 22.45 Localized soft tissue lesions Structure

Lesion

Tendons and tendon sheaths Bursae Tenoperiosteal junction Fasciae Ligaments

Rupture, degenerative tendinitis, peritendinitis, tenosynovitis, ganglia Bursitis - acute or chronic Enthesopathies, apophysitis Fasciitis, Dupuytren's contracture Sprain, strain, tear 1

Classification

Conditions can be divided into generalized and localized. Generalized soft tissue lesions Generalized soft tissue lesions (Table 22.44) may result from underlying disease, and most of the primary conditions can be diagnosed by careful clinical and laboratory assessment. Polymyalgia rheumatica is considered on page 1183. The diagnosis of psychogenic rheumatism must be made with caution and after excluding other disease. Chronic pain may itself lead to psychological problems. Several features suggest a psychological illness, including written lists of symptoms, inconsistent or negative physical findings on repeated examinations, and inappropriate concern with serious future disability.

1

1192

Fig. 22.23

2

Case 22.4

Localized soft tissue lesions The major structures involved in localized soft tissue lesions and the associated lesions are listed in Table 22.45. Examination should permit accurate localization of the anatomical structure involved. Figure 22.35 shows common sites of soft tissue lesions.

The painful shoulder 2 More than 90% of lesions causing a painful shoulder result from extracapsular soft tissue lesions. Trauma is often slight or unnoticed. Night pain and inability to lie on the affected shoulder are common to all the lesions, but careful clinical assessment with particular attention to the presence of a painful arc, location of tenderness and manoeuvres that increase pain (Table 22.46) usually permit an accurate diagnosis. Bony crepitus, when present, is of limited diagnostic value. Examination should include an assessment of those areas of the body where a source of referred pain is sus-

TABLE 22.46 Clinical features of some extracapsular shoulder lesions

FIG. 22.35 Common sites of soft tissue lesions

pected, such as the neck, axilla and chest wall. Both shoulders should be examined and any difference between the two sides noted, in terms of power, stability and range of movement. Weakness rather than pain is usually the predominant symptom if there is a neurological disorder. Painful shoulders often follow or coexist with stiff, painful necks, so that finding musculoskeletal signs in the neck and neurological signs in the arm does not rule out a treatable lesion in the shoulder. Summary of shoulder examination • Inspection at rest: skin changes, swelling, warmth, wasting, deformity; • Inspection of movement: look for painful arc (ask patient to put hands behind head and back) • Palpation: examine sternoclavicular, acromioclavicular and glenohumeral joints, looking for tenderness, swelling, crepitus; • Muscle testing and range of movement: active, passive and resisted; • Assess stability. Rotator cuff tendinitis Although any of the tendons of the rotator cuff may be affected by tendinitis, it most commonly affects the supraspinatus portion of the cuff close to its insertion to the humeral head. Overuse, with resultant wear and tear and relative avascularity, may be important in inducing tendon degeneration. The lesion often remains asymptomatic, but can manifest itself as pain and limitation of active (and sometimes passive) movement, especially abduction. A painful arc on abduction and tenderness over the tendon insertion may be noted. Testing for instability should be undertaken in the younger

Lesion

Painful arc

Pain increased by

Supraspinatus tendinitis, calcific deposit or incomplete tear Infraspinatus tendinitis Acromioclavicular joint disease

Yes

Resisted abduction

Yes

Resisted external rotation Local palpation Resisted abduction

Subscapularis

Yes. Pain begins later in abduction (not below 90°) and increases as full elevation is reached No

Bicipital tendinitis

No

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Resisted internal rotation Resisted flexion and supination of the elbow Tender bicipital groove

and sporting patient as this may be the cause of the tendinitis. Calcific supraspinatus tendinitis Some cases of supraspinatus tendinitis are associated with calcific deposits visible on X-ray (Fig. 22.36). The exact

SUMMARY 6 Common causes of shoulder pain Referred pain Cervical pathology (e.g. degenerative disc disease) Chest wall pathologies, e.g. costochondritis of upper ribs Myocardial ischaemia Diaphragmatic pathology (shoulder-tip pain in intra-abdominal sepsis) Apical lung cancers Capsular pain Anterior/general/rotator cuff capsulitis without adhesions Supraspinatus tendinitis Adhesive capsulitis (frozen shoulder) Rotator cuff tears (traumatic in young, atraumatic in elderly or where occurring in association with an inflammatory joint problem) Articular pain Primary shoulder osteoarthritis is relatively rare, even in the elderly Secondary osteoarthritis, e.g. following rheumatoid etc. Inflammatory arthritis, i.e. rheumatoid arthritis etc. Paget's disease Polymyalgia rheumatica Gives characteristic shoulder and general symptoms Malignant pain A variety of cancers metastasize to the humeral head, including breast, lung, stomach and kidney Myeloma can infiltrate the humeral head

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be a history of injury. Partial tears may be difficult to differentiate from tendinitis, and local anaesthetic infiltration and contrast arthrography may be necessary. Atrophy of supra- and infraspinatus muscles often follows. Bicipital syndromes Tendinitis of the long head of the biceps is less common than are rotator cuff lesions, but may lead to rupture of the tendon. Subacromial bursitis Subacromial bursitis is almost always secondary to tendinitis or another adjacent lesion.

FIG. 22.36 X-ray of shoulder showing calcification of supraspinatus tendon

mechanism responsible for the deposition of the calcium hydroxyapatite crystals in the tendon is unclear. The deposits may remain asymptomatic, or produce chronic symptoms with nagging discomfort in the region of the affected tendon. The crystal may also be extravasated into the subacromial bursa, causing acute bursitis with intense shoulder pain, loss of movement, severe tenderness, swelling and muscle spasm. Fever, sweating and other systemic symptoms may be present, mimicking gout or septic arthritis. Infraspinatus and subscapularis lesions Infraspinatus and subscapularis lesions are less common and seldom calcify. Although the symptoms are usually similar to those of supraspinatus tendinitis, pain induced by resisted external or internal rotation (Table 22.46) usually allows the correct diagnosis to be made. Rupture of the rotator cuff Rupture of the rotator cuff is most common in patients over the age of 50, and almost always begins in the supraspinatus tendon. It probably follows long-standing tendon degeneration. Partial tears are more usual and are a cause of the painful arc syndrome, although they may also be asymptomatic. Complete tears are associated with marked weakness and inability to initiate active abduction; passive movement is full. Pain can be severe and there may

1

1194

MCQ 22.23

2

Fig. 22.24

Frozen shoulder (adhesive capsulitis) Frozen shoulder may occur spontaneously but can follow other rotator cuff lesions or trauma. In addition, conditions that produce pain (e.g. the referred pain of myocardial infarction) or immobility (e.g. stroke or polymyalgia rheumatica) of the shoulder or arm can predispose to the development of a frozen shoulder. Severe night pain and pain on all movement develops and lasts for 4-12 weeks. Severe restriction of all active and passive movements is noted, lasting 6-18 months, before improving to near normal. Early arthrography may reveal a small, shrunken, thickened capsule. Patients with even minor degrees of frozen shoulder may develop a secondary reflex sympathetic dystrophy syndrome - the shoulder-hand syndrome. The symptom complex is characterized by an immobile painful shoulder associated with a swollen, painful, cold and dystrophiclooking hand. The lesion may progress until the patient is left with a painful, tender and useless hand. Fibromyalgia syndrome This is a syndrome of widespread pain characterized by: • Poor sleep pattern • Multiple painful sites at discrete anatomical locations affecting both sides of the body and upper and lower segments • Fatiguability and lethargy • Hypersensitivity of tender sites. • Absense of inflammatory or structural musculoskeletal abnormality. The role of sleep, psychological factors, repetitive trauma, physical and emotional stress and physical inactivity all seem important in the initiation and perpetuation of symptoms. Fibromyalgia has been found to be present in 2-5% of the population, affecting predominantly women in their 40s, and is recognized as the second most common disorder seen in American rheumatological practice. In some, the syndrome complicates the illness of patients with established rheumatic disease. Whether we label patients as having fibromyalgia or not, there is no doubt that many patients have diffuse pain, sleep disturbances, fatigue and tender points. There is no

specific treatment and the prognosis is variable, but individual patients may be helped, by an adequate explanation of the condition, to learn to live with it and avoid further unnecessary investigations and drug treatments. At present, antidepressant therapy and aerobic exercise are the treatments that have been extensively studied. Both have a moderate degree of benefit. Cognitive behavioural approaches and multidisciplinary treatment programmes have also been used to help patients gain control over their symptoms. Both are time-consuming and require further study. Treatment of fibromyalgia • Educate patient. • Educate patient's family. • Keep investigations to a minimum and stop ineffective drug therapy. • Use interventions to improve sleep disturbance. • Improve aerobic fitness. Encourage frequent but small amounts and continuation despite pain. 1

The painful elbow Pain round the elbow is commonly caused by soft tissue lesions, but care must be taken to exclude referred pain from the cervical spine, brachial plexus, shoulder and wrist. Humeral epicondylitis In humeral epicondylitis, lateral involvement (tennis elbow) is much more common than medial involvement (golfer's elbow). In spite of their sporting connotations, both occur more frequently in those performing repetitive movements with their arms, such as operating machinery, using a screwdriver or doing housework. In tennis elbow there is pain over the lateral aspect of the elbow with localized tenderness near the lateral epicondyle. Resisted dorsiflexion of the wrist exacerbates the pain and there is a reduction in grip strength. Thermography usually shows a discrete 'hot spot' on the side of the elbow. In golfer's elbow there is a tender spot at the medial epicondyle and pain is induced by flexing the wrist against resistance, with the elbow fully extended. An enthesopathy has recently been suggested as a unifying pathological

SUMMARY 7 The painful elbow

basis for humeral epicondylitis and shoulder tendinitis, but many other histological changes have also been reported.

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Olecranon bursitis (miner's elbow) The superficial bursa over the olecranon process is commonly involved in RA (with nodule formation) or gout, but can also be affected by trauma or infection. In the acute stage it distends with fluid, with prominent signs of acute inflammation. If it becomes chronic, the wall can be greatly thickened. As the posterior wall of the bursa is so close to the periosteum of the olecranon, pain can be felt down the border of the ulna.

The painful wrist and hand Both seropositive and seronegative arthritides have a predilection for inflammatory involvement of the synovial structures of the tendons and joints in the wrist and hand. Tenosynovitis denotes an inflammation of the synovial lining of the tendon sheath, usually accompanied by inflammation of the contained tendon. The clinical manifestations are pain, tenderness and swelling, with 'crepitus' that is palpable when the tendon moves within the inflamed sheath. 2 Stenosing tenosynovitis Stenosing tenosynovitis is primarily a disorder of fibrosis of the tendon sheaths with intrathecal narrowing of the lumen, especially involving sites near bony prominences where tendons pass through fibrous rings. This more commonly affects the flexor than the extensor tendons of the hand. If a fibrous nodule develops in the flexor tendons a 'trigger finger' can result, which further limits function. The finger often locks in flexion. Extension can be forced with difficulty and is often painful. Palpation during muscle action may reveal a mobile nodule within a tendon sheath of a finger or palm. De Quervain's tenosynovitis De Quervain's tenosynovitis is a common lesion. It is caused by repeated minor trauma, and results from involvement of the tendon sheaths of the abductor pollicis longus and extensor pollicis brevis. The patient complains of pain on using the thumb or wrist. Tenderness is maximal in the 'snuffbox' area between the two tendons, and there is often a visible tender swelling about the radial styloid. Pain can be elicited by forced ulnar

Humeral epicondylitis Lateral - tennis elbow Medial - golfer's elbow Olecranon bursitis Traumatic - student's elbow Secondary to inflammatory joint disease Friction neuritis of ulnar nerve

SUMMARY 8 The painful wrist and hand • • • • • •

Stenosing digital tenosynovitis Tenosynovitis - De Quervain's and others Dupuytren's contracture Rupture of tendons Ganglion Median nerve compression - carpal tunnel syndrome

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deviation after placing the patient's thumb in the palm (Finkelstein's sign).

TABLE 22.47 Repetitive strain syndrome

Acute frictional tenosynovitis Acute frictional tenosynovitis occurs after unusually active use of the wrist over a period of days or weeks. Pain is felt at the back of the wrist and lower forearm, and affects the extensor tendons of the wrist and thumb. A characteristic fine crepitation, caused by the fibrincovered tendon gliding within the inflamed paratendon, is felt if the examiner's hand is placed over the swollen wrist while the patient extends and flexes the affected wrist and digits.

Defined as: • A chronic pain syndrome • Affects one or both neck-arm regions • Occurs in activities requiring controlled posture, often of a repetitive nature • Psychological factors contribute Clinical features include: • Chronic pain in neck, chest wall, arm and hand • Inability to perform previous work performance or carry out leisure activities • Variable hand/arm/forearm swelling with poor grip strength • Poor sleep patterns, often with mood changes

Dupuytren's contracture The condition of Dupuytren's contracture, of unknown aetiology, produces progressive thickening of the palmar fascia and causes flexion contracture predominantly affecting the ring and little fingers. It is commonly bilateral and can also involve the plantar fascia. The palm of the hand becomes indurated, and lines of fibrosis, with nodules and skin puckering, run along the tendons, causing progressive fixed flexion of the metacarpophalangeal and proximal interphalangeal joints. The rate of progression is variable. Surgical fasciectomy should be performed when disability is severe, and should be considered before amputation becomes the only alternative. Repetitive strain Occupational repetitive strain injuries have become a significant source of disability at work, particularly in recent years. There is considerable confusion in diagnostic terminology and a wide variation in reported incidence between countries, perhaps reflecting the contrasting medical, and more particularly legal, attitudes to these conditions. Repetitive strain syndrome (Table 22.47) can be denned as a chronic pain syndrome that usually affects the whole of one or both neck-arm regions, and which normally occurs in the context of activities requiring a controlled posture, usually of a repetitive nature. Psychological factors contribute to the syndrome. The condition affects predominantly female employees engaged in low-paid, monotonous, low-prestige occupations. Symptoms include chronic pain in the neck, arm and hand and are associated with weakness of grip and tight proximal muscles. There may be dysaesthesiae and variable hand and forearm swelling. These symptoms lead to an inability to perform previous work tasks or leisure activities that relate to repetitive movement. Management is similar to that of chronic pain syndromes. Prevention and early diagnosis are important.

Ganglia Ganglia are tense uni- or multilocular cystic swellings that develop in relation to a joint capsule or tendon sheath, and contain a clear jelly-like substance. They vary in size and can be so tense that they may be mistaken for a bony swelling. They are sometimes provoked by injury or arthritis, but often occur spontaneously. Entrapment neuropathy (carpal tunnel syndrome) Nerve compression can occur at any site where a peripheral nerve passes though an opening in fibrous tissue or an osseofibrous canal. If the clinical diagnosis is in doubt, it may be confirmed by EMG. Entrapment of the median nerve in the carpal tunnel at the wrist is the commonest entrapment lesion. It is more common in females. Most cases are idiopathic or caused by unaccustomed repetitive use, but carpal tunnel compression may be associated with RA, myxoedema, acromegaly, pregnancy and the contraceptive pill. Fracture, deformity or dislocation of the carpal bones can cause similar problems. Early symptoms include painful tingling in the wrist and hands, mainly affecting the thumb, index and middle fingers, but often symptoms are poorly localized. The pain may occasionally extend up the arm well above the wrist, and often interferes with sleep. Patients try to obtain relief by hanging the affected limb out of the bed. Later, weakness (first in the abductor pollicis brevis) develops. Diminution of sensation to touch and pinprick, usually over the palmar aspects of the distal phalanges of the index and middle fingers, may be found. Untreated, wasting of the muscles of the thenar eminence develops. EMG is helpful where the clinical diagnosis is in doubt. A delay in motor or sensory conduction velocity across the wrist confirms the diagnosis, although no electrical abnormality may be detected in early cases. 1

The painful knee 1

1196

MCQ 22.24

Tendons, ligaments and bursae are the soft tissue structures around the knee from which pain may originate. When assessing the knee, the clinical history is more valuable than the findings of clinical examination. The patient's

account of the symptoms and their onset will usually make it possible to decide which structures in the knee have been damaged and how seriously. Patellar tendinitis The ligamentum patellae may become painful and tender at its attachment to the upper or lower pole of the patella or at its distal attachment to the tibia. Prolonged and heavy exercise, such as jogging, predisposes to this condition, which usually occurs in adults. Steroid injections may be effective but should be used cautiously; surgical exploration is occasionally necessary. Osgood-Schlatter disease Apophysitis of the tibial tubercle at the insertion of the patellar tendon occurs predominantly in adolescent children and is another common cause of pain in front of the knee. The condition is more common in boys, and symptoms include localized tenderness and swelling at this site. Pain can be reproduced by resisted knee extension, and radiographs may be abnormal and show an isolated spicule of bone at the site of the swelling. Most patients improve spontaneously, but sometimes the pain may persist for several years, and injection, plaster immobilization or even excision of the bony spicule may then be required. A similar, but rare, condition can occur at the lower pole of the patella (Sinding-Larsen disease). Bursitis Some bursae are in direct contact with the knee joint, whereas others are separate. Like bursae elsewhere, acute or chronic inflammation, infection and involvement in systemic diseases, such as gout and arthritis, can occur. Acute bursitis is characterized by classic signs of acute inflammation, with intense localized tenderness and marked restriction of movement. Chronic bursitis may follow acute episodes but is much more commonly associated with repeated trauma. The bursal lining becomes thickened and cells degenerate; adhesions, villi and calcaneous deposits eventually develop. The degree of inflammation, muscle weakness and wasting and limitation of movement can vary widely, making diagnosis difficult. Prepatellar bursitis (housemaid's knee) Here, the bursa is subcutaneous and inflammation usually results from repeated kneeling, but can follow a fall on to the patella. Infection of the prepatellar bursa gives a characteristic red, shiny appearance over the knee, and is often mistaken for an infected joint. When chronic, fibrous bodies and fibrous bands form in the thickened enlarged bursa. Infrapatellar bursitis This small, deep bursa occupies the space between the upper part of the tibial tuberosity and the ligamentum patellae, separated from the synovium by a fat pad. When inflamed, the fluid obliterates the depression on each side of the ligament, the fluctuant swelling being most marked when the knee is actively extended.

Popliteal cysts (Baker's cysts) Synovial cysts in the popliteal fossa are usually referred to as Baker's cysts. They may arise from the semimembranous bursa when they communicate with the knee joint, or from a posterior rupture of the knee joint capsule. Cysts are common in children and are of no serious significance, although in young adults there may be quite severe pain after exercise. The most common course is gradual resolution. If the cyst does not resolve, it may extend into the calf or burst, with fluid tracking down the fascial planes of the calf, mimicking an acute deep venous thrombosis. Arthrography of the knee joint establishes the diagnosis but must be performed early after the onset of symptoms, as the leak may seal off after a few days.

22

Anserine bursitis The tendons of sartorius, gracilis and semitendinosus all cross the lower medial side of the femur and attach by a common tendon to the tibia. The anserine bursa lies beneath this tendon. Pain is felt diffusely on the medial aspect of the knee, but tenderness can usually be localized to the area of the bursa. Knee range is normal, but contracting the hamstrings induces pain. The bursa is often inflamed in elderly obese women with a valgus deformity, and is also a common source of pain in inexperienced joggers, often being mistaken for joint injury. Ligament injuries If a patient has injured the knee in such a way that the structures on the medial side have been stressed, damage to the medial ligament must be suspected. Clinical examination may reveal tenderness localized to the attachment of the ligament to the femur or tibia. The diagnosis can be confirmed by stressing the medial ligament; this will reproduce the pain or demonstrate ligament laxity. Tendinitis The popliteus tendon runs through the knee joint from the lateral femoral condyle, between the lateral meniscus and the capsule, to the back of the tibia. Inflammation may cause lateral knee pain.

SUMMARY 9 The painful knee • • • •

• • • •

Patellar tendinitis Rupture of quadriceps apparatus Apophysitis of tibial tubercle - Osgood-Schlatter disease Bursitis Prepatellar Intrapatellar Popliteal cysts - semimembranous - Baker's cyst Anserine Infrapatellar fat pad lesions Medial and lateral ligament injuries Tendon lesions Anterior tibial syndrome

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The biceps tendon is attached to the head of the fibula, and inflammation will cause pain around the tendon insertion, felt particularly when the knee is flexed against resistance and the area firmly pressed. Pain in the back of the knee may arise from a hamstring injury. The pain usually develops acutely after sudden activity without an adequate warm-up. Anterior tibial syndrome The anterior tibial syndrome consists of severe pain in the anterior aspect of the leg, associated with foot drop, occurring after exercise and relieved by rest. It is thought to be the result of a tight fascia compressing the muscles in the anterior tibial compartment of the leg. There are many predisposing factors, of which exercise is the most common. Surgery gives relief.

The painful heel

Bursitis Subachilles (retrocalcaneal) bursitis may also cause pain at the lower end of the Achilles tendon. Physical examination reveals the bulging tender bursa on either side of the tendon, with normal ankle joint movement. Dorsiflexion of the foot aggravates the pain by compressing the bursa. Frequently, the patient can recall a traumatic incident. Subcutaneous (postcalcaneal) bursitis A more superficial bursitis can develop over the tendon attachment as a result of poorly fitting shoes; here, the swelling is lower down, large and fluctuant. Inflammatory changes in the overlying skin are common.

Pain can arise from either the posterior or the plantar aspects of the heel. Most lesions occur in people who walk or stand a great deal, and are particularly common in athletes. Whatever the cause, the pain tends to be aggravated by walking and relieved by rest. Accurate localization of tenderness is important in diagnosis.

Retrocalcaneal apophysitis (Sever's disease) The insertion of the Achilles tendon into the calcaneum can become inflamed, resulting in symptoms of pain and tenderness behind the heel. This usually occurs in boys aged between 9 and 15 years.

Pain behind the heel

Pain under the heel

Tendon rupture Complete or partial tendon rupture may occur after vigorous activity. In the young the musculotendinous junction tends to be the site of rupture, whereas in the old the tendon itself is at risk. Complete rupture is easily recognized by loss of anatomical continuity and function. Partial rupture is more difficult to diagnose. Initially, swelling and marked tenderness are noted just above the tendon insertion, with exquisite pain on movement. Later, a more irregular swelling due to fibrous tissue develops, with continuing pain on movement.

Plantar fasciitis In weight-bearing, stress is placed on the long plantar ligament and fascia which support the longitudinal arch of the foot. An enthesopathy can develop at the point of attachment of the ligament to the heel. Pain and tenderness may be confined to the point of attachment, but can be much more widespread; they are always aggravated on walking. The presence of a calcaneal spur on the X-ray is not necessarily significant, as it is also commonly seen on films of asymptomatic heels. Plantar fasciitis may be associated with the seronegative arthritides, such as Reiter's syndrome and ankylosing spondylitis.

Central core degeneration of the Achilles tendon Central core degeneration of the Achilles tendon must be differentiated from the more common peritendinous lesion, as tendon rupture is much more likely and local steroid injections are contraindicated. Onset is less dramatic than partial rupture, but other clinical findings can be similar. Pain gradually increases as the day progresses. Careful examination also reveals a localized tender nodule or thickening, 3-6 cm above the insertion to the calcaneum.

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guishing the condition from rupture of the tendon, and occasionally the tendon may calcify. Inflammation of the peroneal tendons behind the lateral malleolus causes pain when the muscle is contracted, as when walking over rough ground. If this tendinitis is chronic, RA should be considered.

Peritendinitis (Achilles tendinitis) Peritendinitis is the common cause of chronic, persistent and often annoying pain at the back of the heel. It occurs most commonly, but by no means exclusively, in athletes, especially long-distance runners. In the acute stage there is diffuse swelling and tenderness on both sides of the tendon, sometimes accompanied by crepitus. Later, signs become less obvious, but pain and tenderness recur with exercise. The symptoms usually develop gradually, distin-

SUMMARY 10 The painful heel Pain behind the heel

Pain under the heel

Achilles tendon lesions Plantar fasciitis Calcaneal apophysitis and spurs Rupture - partial/total Central core degeneration Tender heel pad Ossification Peritendinitis (Achilles tendinitis) Bursitis Subachilles (retrocalcaneal) Subcutaneous (postcalcaneal) Retrocalcaneal apophysitis (Sever's disease)

Tender heel pad The condition of tender heel pad causes pain in the hind part of the heel on standing or walking. The tough fibrofatty pad beneath the prominent weight-bearing part of the calcaneus is tender to finger palpation. The area of tenderness is well localized and may be a result of simple contusion; in most cases there is no history of trauma, and in these patients the tenderness may result from obesity combined with excessive walking in unsatisfactory footwear, or from mild inflammation of uncertain origin.

SUMMARY 11 The painful foot • • • • • • •

22

Anterior flat foot - dropped transverse arch Injuries to the spring ligament Plantar digital neuritis - Morton's metatarsalgia Tarsal tunnel syndrome Plantar warts and callosities Hallux valgus (bunion) Dorsal exostoses with bursae

The painful foot 'Flat feet' 'Flat feet' rarely cause symptoms in the young. In adolescents they may be part of a general postural defect. At this age, especially in boys, spasmodic flat foot is caused by peroneo-extensor spasm. The foot is rigid and painful and symptoms are worse on walking. Flat foot usually leads to osteoarthritis of the midtarsal joint in later life. 'Spring' ligament The 'spring' or plantar calcaneonavicular ligament supports the talonavicular joint from below; it may be strained, leading to deep-seated pain on weight-bearing. Metatarsalgio Patients with anatomical abnormalities of the feet, such as claw toes or equinus deformity, are liable to develop pain in the metatarsal heads on walking. Metatarsalgia, or pain around the metatarsal heads, is not itself a diagnosis. Between the metatarsal heads and the skin lie the flexor tendons and their sheaths and, in the case of the great toe, the sesamoids in the flexor hallucis brevis. Inflammatory joint disease can cause inflammation of the tendon sheaths and causes generalized pain. Hallux valgus Hallux valgus (bunion) is an example of an adventitious bursa resulting from prolonged pressure over a bony prominence as a result of valgus deformity of the hallux. It is frequently inflamed. Initially, treatment consists of padding to reduce pressure and advice on suitable footwear. If these measures prove unhelpful, surgical treatment may be necessary. Tibialis anterior and posterior Pain in the mid-foot may arise around the insertion of the tibialis anterior after strenuous walking. Pain on the medial side of the foot, at the point of insertion of the tibialis posterior tendon on the navicular, is more common; it is particularly severe if the patient has an accessory navicular bone. Dorsal exostoses Some patients develop a bony prominence on the dorsum of the foot at the joint between the navicular and the cuneiform bone. Excessive friction may lead to the formation of a bursa.

Entrapment syndromes in the foot Tarsal tunnel syndrome Compression of the posterior tibial nerve under the flexor retinaculum below the medial malleolus can lead to burning pain under the medial side of the longitudinal arch of the foot. Morton's metatarsalgia (plantar digital neuritis) In this condition, patients complain of a sharp pain in the forefoot shooting through to the toes, usually the third and fourth. There may be tingling, or even numbness, in the adjacent sides of the third and fourth toes. The pain is localized between the metatarsal heads, and the transverse metatarsal compression may produce a palpable click. The condition is caused by interstitial fibrosis compressing the digital nerve just before it divides into its two terminal branches. In the early stages, well-fitting shoes, with or without a metatarsal bar, give relief. Excision of the thickened tissue effects a cure.

Other common entrapment syndromes in the lower limb Lateral popliteal nerve lesions The lateral popliteal branch of the sciatic nerve lies superficially against the head and neck of the fibula, where it is susceptible to compression, especially when sitting with the legs crossed, kneeling or wearing knee pads. Anaesthesia and periods of unconsciousness present particular risks. The symptoms are pain and tingling in the lateral aspect of the leg and dorsum of the foot, associated with weakness of dorsiflexion and eversion of the foot. Wasting of the tibialis anterior, peroneal and extensor digitorum brevis can occur. The high-stepping gait is typical. EMG can confirm the diagnosis. Lateral femoral cutaneous nerve entrapment (meralgia paraesthetica) The lateral cutaneous branch of the femoral nerve traverses a tunnel formed by the lateral attachment of the inguinal ligament as it runs towards the anterior superior iliac spine. Entrapment produces paraesthesia and burning pain over the lateral thigh with reduced sensation. Local trauma, obesity, or pressure from tight garments are known predisposing factors.

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Management of patients with soft tissue rheumatism One feature common to all of the soft tissue rheumatism syndromes is a tendency to spontaneous remission. Many of the syndromes take weeks to improve, and few persist with significant symptoms beyond 6 months. A clear diagnosis therefore allows the physician to reassure the patient that arthritis is not present and that the prognosis is good. Failure to resolve is often due to further injury. Few of the conditions require complete rest; most respond to selective rest of the involved region. Immobilization Tenosynovitis around the wrist may respond to immobilization in a light forearm splint maintaining the wrist in a position of optimum function (10-15° extension), and median nerve compression may respond to night-splinting alone. The acutely painful shoulder also benefits from rest, mobility being maintained by pendular exercises. Physiotherapy in the acute stages only exacerbates the condition. Rest is essential for the painful heel and foot. Raising the heel of the shoe reduces tension on the Achilles tendon, and Elastoplast strapping will help immobilize the ankle. If there is flattening of the medial arch of the foot, then physiotherapy and an arch support may be helpful. Drug therapy The short-term use of NSAIDs may be necessary. Their

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immediate use is beneficial in limiting the pain and swelling of soft tissue trauma. Many soft tissue lesions respond to a local injection with steroid and anaesthetic. Some experience in the various techniques is necessary before reasonable success can be obtained. The choice of steroid and local anaesthetic varies between physicians, but for most purposes the shorteracting hydrocortisone acetate is suitable. After injection there may be an increase in symptoms for up to 48 hours, and patients should be warned of this possibility. About 80% of patients gain symptomatic benefit from these injections. It is important not to inject the Achilles tendon itself, as this may predispose to rupture. In spite of decades of use of ultrasound in treating a wide spectrum of musculoskeletal disorders, its effectiveness remains unproven. Persistent lesions may require further injections, and if conservative measures fail, surgery may be required.

FURTHER READING ON SOFT TISSUE RHEUMATISM Dixon A St J, Gruber J 1989 Local injection therapy in rheumatic disease, 3rd edn. Basle: EULAR. Hadler N M 1987 Clinical concepts in regional muculoskeletal illness. Orlando: Grune and Stratton. Hazleman B L, Dieppe P A (eds) 1990 The shoulder joint. Bailliere's Clinical Rheumatology 3(3). Speed C, Dalton S, Hazleman B 2000 Fast facts: soft tissue rheumatology. Nuffield Press.

Ontogeny of haemopoiesis

23 Haematological Disorders David C Linch

Haemopoiesis 1201 Function of haemopoietic cells 1203 Classification and causes of anaemia 1205

Immune haemolytic disease of the newborn 1232 Non-malignant leukocyte abnormalities 1234 Haematological malignancy 1235

Iron deficiency anaemia 1206

Myeloproliferative disorders 1238

Sideroblastic anaemia 1208

Primary myelofibrosis 1243

The megaloblastic anaemias 1209

Acute leukaemia 1243

The hypoplastic anaemias 1211

Myelodysplasia 1249

Haemolytic anaemias 1214

Malignant lymphoproliferative disorders 1249

Defects of haemoglobin synthesis and structure i: the thalassaemias 1214

Amyloidosis 1262

Defects of haemoglobin synthesis and structure ii: sickling disorders 1217

Diagnosis of disordered haemostasis 1267

Other haemoglobinopathies causing haemolysis 1220 Congenital red cell membrane defects 1220 Congenital red cell enzyme defects 1221 Autoimmune haemolytic anaemias 1223 Acquired non-immune haemolytic anaemias 1224 Anaemia of chronic disease 1226

Normal haemostasis 1264

Platelet disorders i: thrombocytopenia 1268 Platelet disorders ii: thrombocytosis 1272

In the human embryo, nucleated erythrocytes develop in the extraembryonic membranes and the aortogonadmesonephros region, and synthesize specific embryonic haemoglobins. In the 6th week of gestation erythropoiesis transfers to the fetal liver and the embryonic haemoglobins (a2£2, ^£2, ^272) are replaced by fetal haemoglobin (a2y2). Bone marrow haemopoiesis is established between the llth and 22nd weeks of gestation. Hepatic haemopoiesis declines in the third trimester and ceases soon after birth. Finally, at about the time of birth, fetal haemoglobin is replaced by adult haemoglobin (HbA, a2B2). These sequential changes in haemoglobin synthesis during development represent the orderly activation of the globin genes from the 5' to the 3' end of the globin gene clusters (Fig. 23.1). The 8 gene is never fully expressed and HbA2 (a2^2) represents only 2% of adult haemoglobins. The molecular mechanism of Hb gene switching is incompletely understood. Optimal expression of a particular globin gene depends on the binding of proteins to that gene and a 5' locus control region. The changing preference for these proteins to bind more 3' genes may be due to changes in tertiary structure of the chromosome or to changes in the degree of methylation of these genes (methylation in general prevents gene expression). The highly expressed globin genes are hypomethylated. At birth, most of the bone marrow cavity is haemopoietically active, but during the first decade much of the active red marrow is replaced by inactive, fatty yellow marrow. In adults, red marrow and hence haemopoiesis is restricted to the upper ends of the femora and humeri, the vertebrae, ribs, sternum, clavicles, scapulae, skull and pelvis. There is very limited granulocyte and monocyte production until the end of gestation. Lymphoid cells first appear during the first trimester, and by the second trimester leukocytes in the blood are phenotypically mature T and B lymphocytes. However, full functional integrity of the immune system is not achieved until after birth.

Hereditary coagulation disorders 1272 Acquired coagulation disorders 1274 Anticoagulants and antithrombotic drugs 1275 Hypercoagulable states 1279

Blood transfusion 1227

HAEMOPOIESIS Haemopoiesis is the process by which blood cells are derived from multipotential stem cells.

Haemopoietic differentiation The mature elements of the blood probably all arise from multipotent haemopoietic stem cells, which in adult life reside predominantly in the bone marrow. Such cells may self-replicate (and so replenish the stem cell pool) or, alternatively, may proliferate and enter the differentiation pathway (Fig. 23.2) With each division of the haemopoietic stem cell there is increasing loss of multipotentiality, and the stem cells thus become committed to one or more haemopoietic lineages. Monocyte and neutrophil (though not eosinophil) lineages appear to be closely related, as are red cells and megakaryocytes. Committed myeloid progenitor cells do not self-replicate, but divide to produce the later precursor cells. Progenitor cells appear as undifferentiated blast cells, but in the final five or six divisions of the differentiation pathway the cells pro-

1201

gressively acquire the morphological features and functional attributes of the mature cell. These recognizable precursor and end cells account for more than 95% of normal marrow cells.

Myeloid end cells have a limited lifespan. The steady state is maintained by a continuous influx of stem cells and progenitor cells into the precursor cell pool. Mature lymphoid cells, on the other hand, are capable of clonal expansion or, alternatively, of transition to a resting 'memory cell', which is able to divide at a later date when appropriately stimulated. Recent studies suggest there is greater plasticity of stem cells than had been previously appreciated. Experimentally, haemopoietic stem cells can be derived from other cell types, such as endothelial cells and neuronal tissue. Similarly, the haemopoietic stem cell may be able to contribute to the formation of nonhaemopoietic tissues such as liver cells. Regulation of haemopoiesis Haemopoiesis is regulated, at least in part, by a series of glycoproteins referred to as haemopoietic growth factors (HGF). Erythropoietin, produced in response to hypoxia by the peritubular adventitial cells of the kidney, is a true hormone, whereas many of the other HGFs probably act in a paracrine manner. The HGFs can be grouped into three broad categories (Fig. 23.3).

FIG. 23.1 Diagrammatic representation of the cc-like globin gene cluster and p-like globin gene cluster on chromosomes 16 and 11 respectively Hb switching during ontogeny represents the orderly expression of the globin genes from the 5' to 3' end of the globin gene clusters.

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• The late-acting factors are relatively lineage restricted and stimulate the terminal divisions of the maturation pathway, with associated differentiation to mature cells. These include erythropoietin, granulocyte colony-stimulating factor (G-CSF), monocyte colony-stimulating factor (M-CSF), eosinophil colony-stimulating factor, known as IL-5, and thrombopoietin (TPO). • Proliferation of more primitive cells in the pathway is regulated by the multi-CSFs, IL-3 and granulocytemacrophage colony-stimulating factor (GM-CSF),

FIG. 23.2 Diagrammatic representation of the differentiation of haemopoietic stem cells

TABLE 23.1 Selected growth factors ill clinical use Growth factor

Indications

G-CSF

Severe congenital neutropenia Stem cell mobilization Myelosuppressive chemotherapy with a high risk of sepsis

GM-CSF

Stem cell mobilization Myelosuppressive chemotherapy with a high risk of sepsis

SCF

Stem cell mobilization (with G-CSF) in selected patients who are, or are predicted to be, poor mobilizers (precise indications unclear)

TPO

Myelosuppressive therapy with anticipated protracted thrombocytopenia (precise indications unclear)

IL-11

Myelosuppressive therapy with anticipated protracted thrombocytopenia (precise indications unclear)

EPO

Anaemia of chronic renal failure Anaemia of malignant disease (precise indications debatable) Anaemia secondary to chemotherapy (precise indications debatable)

FIG. 23.3 Haemopoietic growth factors

which stimulate the early divisions of several cell lineages, including granulocytes, monocytes, eosinophils, megakaryocytes and red cells. IL-3 also stimulates mast cell progenitors and some early lymphoid cells. • Stem cell factor (SCF) is produced by bone marrow stromal cells and stimulates the proliferation of primitive haemopoietic cells in synergy with other later-acting factors. IL-6 is extremely promiscuous in its target cell reactivity, but appears to act on the most primitive stem cells. Flt-3 ligand is another such early-acting factor, and its levels in the blood tend to vary inversely with the size of the stem cell pool. The categorization of the HGFs into three groups is undoubtedly an oversimplification, and G-CSF and MCSF may have some effects on primitive progenitor cells. Administration of G-CSF and GM-CSF not only stimulates progenitor cell proliferation but also 'mobilizes' primitive cells into the circulation, a phenomenon that is exploited for the harvesting of 'peripheral blood stem cells' to be used for transplantation (see page 1213). SCF can augment the G-CSF- and GM-CSF-induced progenitor cell mobilization and may have a clinical role in patients who are poor mobilizers. The specialized environment provided by bone marrow stromal tissue is essential for effective haemopoiesis, particularly for the survival, self-renewal and proliferation of stem cells. Factors such as stomal-derived factor-1 (SDF-1) produced in the bone marrow also have chemokinetic and chemotactic properties on stem cells, and regulate their migration and homing from the bloodstream to the haemopoietically active marrow. As well as positive factors regulating haemopoiesis there are a number of 'negative regulatory factors', including transforming growth factor (3 (TGF-B) and macrophage inflammatory protein la (MlP-la). These molecules might have the potential for protecting normal haemopoietic stem cells from the effects of chemotherapy, but this has not yet been realized clinically. The activity of the HGFs is not restricted to immature cells. G-CSF enhances many of the functional activities of mature neutrophils, GM-CSF enhances neutrophil, monocyte and eosinophil function, and M-CSF and IL-3 prime some monocyte functions, the latter also modulating eosinophil and mast cell function. The HGFs are produced by a wide range of cell types, including activated T cells, monocytes, endothelial cells and

[23

fibroblasts. Many such cells are found in inflammatory sites, and several of the HGFs probably serve as inflammatory mediators. GM-CSF produced at local inflammatory sites might increase phagocyte expression of cellular adhesion molecules, promote adhesion to the local vascular endothelium, induce migration into the inflammatory site, and increase phagocytic activity. Several of the HGFs are now used in the clinic and others are under development (Table 23.1). Some indications for their use are given in Table 23.2.

FURTHER READING ON HAEMOPOIESIS Metcalf D 1997 The molecular control of granulocytes and macrophages. Ciba Foundation Symposium 204: 40-50 van der Kooy D, Weiss S 2000 Why stem cells? Science 287:1439-1441 Weissman I L 2000 Translating stem and progenitor cell biology to the clinic: barriers and opportunities Science 287: 1442-1446

FUNCTION OF HAEMOPOIETIC CELLS RED CELLS AND HAEMOGLOBIN Erythrocytes (red cells) package haemoglobin for the delivery of oxygen from the lungs to the tissues and carry carbon dioxide in the reverse direction. Haemoglobins have a molecular weight of approximately 65kDa. Each molecule consists of two oc-like and two B-like polypeptide chains, with a haem group attached to each chain within a hydrophobic pocket.

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TABLE 23.2 Indications for the use of G-CSF • Treatment of severe congenital neutropenia • Following very high-dose chemotherapy and stem cell transplantation • Prophylactic use with conventional chemotherapy if risk of sepsis is thought to be greater than 30% • Treatment of severe sepsis when prolonged neutropenia is anticipated • Mobilization of stem cells for use in future transplants

The tetramer is held together predominantly by bonds between the oc and the (3 chains. Because these bonds are not irreversible, the molecule exists in equilibrium between two configurations, one with a low and one with a high affinity for oxygen. Binding of oxygen to a haem group destabilizes the low-affinity form, thereby increasing the oxygen affinity of the molecule. Because of this cooperative binding, a sigmoid oxygen dissociation curve is produced (Fig. 23.4). In the lungs, Po2 is approximately 14kPa and the haemoglobin is nearly fully saturated. In the tissues, where the Po2 is about 5.4 kPa, haemoglobin saturation is about 70%. If tissue oxygen consumption rises, a small fall in tissue Po2 will bring about a large further release of oxygen, because these values of Po2 correspond to the steep part of the oxygen dissociation curve. Various other factors also influence oxygen dissociation. A fall in pH or a rise in Pco2 decreases the oxygen affinity (moves dissociation curve to right). This tends to increase oxygen delivery to tissues where the pH is lower and the Pco2 higher than in the lungs. A rise in temperature, e.g. during heavy exercise, also decreases the oxygen affinity. Haemoglobin's affinity for oxygen is also modulated by 2,3-diphosphoglycerate (2,3-DPG). The mechanism is shown in Figure 23.5. 2,3-DPG is an intermediate on the glycolytic pathway (Fig. 23.6) and is present in relatively high concentrations within the red cell. Hypoxia within the red cell tends to increase 2,3-DPG levels in two ways. First, the increased quantity of deoxygenated haemoglobin means that more 2,3-DPG is bound, thereby reducing product inhibition of DPG mutase. Second, deoxyhaemoglobin is a weaker acid than its oxygenated form, and so red cell pH rises. This increases 2,3-DPG levels, both by stimulating glycolysis in general and by inhibiting DPG phosphatase. With an anaemia of 7.5g/dL the tissue hypoxia causes a rise in 2,3DPG levels sufficient to increase oxygen delivery by about 25%. However, if the hypoxia is sufficiently severe to cause acidosis within the red cell, 2,3-DPG levels will be depressed. Fortunately, this effect on oxygen affinity is balanced by the direct effect of H+ on oxygen affinity (Bohr shift). This is of considerable importance in patients with a severe acidosis treated with bicarbonate. Sudden correc-

1

1204

MCQ 23.1

FIG. 23.4 The sigmoid nature of the oxygen dissociation curve A represents the normal steady state. B represents the shift of the curve to the right seen with decreased pH, increased Pco2 or increased 2,3-DPG. At a given venous Po2 this results in a larger amount of oxygen (marked [3) being given to the tissues.

FIG. 23.5 Diagrammatic representation of the change in configuration of the haemoglobin molecule associated with oxygenation Oxygenation is accompanied by a rotation of the a1-B1 dimer about the contact point between a1 and B2, thus closing up the pocket in which 2,3-DPG binds. Insertion of 2,3-DPG into this pocket prevents this rotation and stabilizes the deoxy configuration, which reduces the oxygen affinity.

tion will immediately negate the Bohr shift and move the dissociation curve to the left, whereas the compensatory rise in 2,3-DPG will take many hours to occur. During this interim period, tissue oxygenation will be further impaired. Some of the CO2 released from the tissues diffuses into the red cells and is rapidly hydrated to carbonic acid (H2CO3) because of the high levels of carbonic anhydrase. The H2CO3 dissociates to H+ and HCO3" and the H+ is buffered predominantly by deoxyhaemoglobin, while the HCCV re-enters the plasma. In the lungs this process is reversed, with the resultant CO2 being released into the alveoli. The normal red cell mass is 25-35 mL/kg in men and 20-30 mL/kg in women. The more readily measured haemoglobin concentration has a wide normal range, which changes with age and sexual development (Table 23.3). 1

Monocytes Monocytes are phagocytic cells that remove microorganisms, damaged cells and cell fragments. They also have a central role in the generation of the immune response, through the presentation of antigen to lymphocytes, regulation of many T- and B-cell functions, and cytotoxic activity towards antibody-coated cells. Monocytes are the precursors of at least a proportion of dendritic cells, the antigen-presenting cells which have the ability to stimulate naive T cells. The monocyte count can be relatively high in the neonate (up to 4 x 109/L) but falls rapidly during early childhood. By 4 years of age the normal adult values of 0.2-0.8 x 109/L are attained.

FIG. 23.6 The production of 2,3-diphosphoglycerate

TABLE 23.3 Changes in haemoglobin concentration with age Age

Haemoglobin concentration (g/dL)

First 3 days of life First month thereafter 1-12 months 1-12 years Adult males Adult females

13-21 10-18 10-13.5 11.5-15.5 13.0-18.0 12.0-16.0

Leukocytes Neutrophils Neutrophils are mobile phagocytic cells able to recognize, phagocytose and then kill microorganisms opsonized by IgG or C3b. They also migrate to non-infective sites of tissue damage, where they contribute to the inflammatory process. The neutrophil count is high in the first weeks of life, but thereafter the normal range is between 2.0 and 7.5 x 109/L. Eosinophils Eosinophils are phagocytes that are particularly effective in the elimination of parasites. They also participate in hypersensitivity reactions, especially in the skin, lungs and gut. The normal eosinophil count is less than 0.4 x 109/L. Basophils Basophils are involved in the pathogenesis of immediate hypersensitivity. When IgE is bound to their surface they release histamine, which causes increased vascular permeability and smooth muscle contraction. The normal count is less than 0.1 x 109/L.

23

Lymphocytes Neonates and young children have a high lymphocyte count, but at puberty this falls to the normal adult range of 1.5-4.0 x 109/L. Thymus-dependent T cells are the major population of lymphocytes in the blood, accounting for approximately 70% of all lymphocytes. Two-thirds of T cells express the CD4 antigen on the cell surface and one-third the CDS antigen. CD4+ cells are predominantly involved in interactions with other cells in association with class II HLA antigens, and serve to initiate and regulate the immune response (helper/inducer cells). The CD8+ population includes cells with cytotoxic activity, which is usually specific for antigen recognized in association with class I HLA antigens, and also cells that suppress the immune response. B cells account for 5-10% of peripheral blood lymphocytes. They have the potential to synthesize and secrete antibody and express surface immunoglobulin. Several heavy-chain isotypes may be expressed, but only one light chain is expressed by a single cell. The remaining 10-25% of peripheral blood lymphocytes are non-T, non-B lymphocytes. Some of these cells have a large granular appearance and non-MHC-restricted cytotoxic activity (natural killer cells).

CLASSIFICATION AND CAUSES OF ANAEMIA Anaemia occurs when the haemoglobin concentration [Hb] falls below the normal range for the age and sex of the individual. [Hb] may be altered when living at high altitudes (which elevates the normal range), and in states such as pregnancy and splenomegaly, which lead to an increased plasma volume, so that a normal red cell mass is maintained at lower haemoglobin concentrations. True anaemia arises when there is an imbalance between red cell production and red cell destruction (Fig. 23.7). Increased cell destruction can be compensated for in part by increased marrow production, so that chronic anaemia

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TABLE 23.4 Classification of anaemia according to the MCV Type of anaemia

Cause

Features on blood film

Microcytic

Iron deficiency

Marked anisocytosis and poikilocytosis Pencil cells

Thalassaemia

Target cells Nucleated red cells Reticulocytes

Chronic disease

May be neutrophilia Target cells-liver disease Burr cells-renal failure

Sideroblastic anaemia

Red cells often dimorphic

Acute haemorrhage

Reticulocytosis

FIG. 23.7 The aetiology of anaemia

Normocytic

only occurs when red cell survival is less than half normal. Many causes of anaemia have multiple mechanisms. In thalassaemia, for example, both ineffective erythropoiesis and haemolysis occur. From the practical standpoint, the classification of anaemia is based on routine haematological investigation - namely, automated cell counter analysis - considered in the context of the clinical history and examination. The automated counters measure the haemoglobin concentration, red cell count and mean cell size (MCV). The mean cell haemoglobin (MCH) and mean cell haemoglobin concentration (MCHC) are derived from these parameters and provide limited additional information. The counters also produce a white cell count (nucleated red cells, which may be prevalent in some haemolytic states, are counted as white cells) and an automatic platelet count. Most machines also perform a white cell differential count. The anaemias are initially characterized in terms of red cell size (Table 23.4). The precise cause of the anaemia can often be surmised from the combination of automated counter analysis and clinical situation, and examination of the blood film provides further clues as to aetiology. Further specific investigations are individually planned, depending on the results of these screening tests.

IRON DEFICIENCY ANAEMIA PATHOPHYSIOLOGY Iron deficiency is the commonest form of anaemia and is particularly prevalent in underprivileged communities. The

1 Fig. 23.1 1206

2

MCQ 23.2

Haemolysis

Reticulocytosis

Marrow hypoproduction

Pancytopenia May be abnormal cells, e.g. leukaemia

Chronic disease

Macrocytic

Combined iron and folate deficiency

Microcytes and oval macrocytes

Megaloblastic change

Prominent oval macrocytes Pancytopenia Multisegmented polymorphs

Reticulocytosis (haemorrhage, haemolysis)

Polychromasia and reticulocytosis

Alcohol Liver disease

Target cells

Myxoedema (rare) Aplastic anaemia (rare)

Pancytopenia

Leukaemia and related disorders (rare)

Abnormal cells Normoblasts and myeloid precursor cells in blood

daily intake of iron is closely related to the calorific value of the diet, so that individuals with poor diets (especially menstruating women) are particularly at risk. Even in western societies, over 5 % of such women have iron deficiency anemia. Others at risk include premature babies, as they have low iron stores and a milk diet which is relatively low in iron content; children during rapid growth periods; and women during pregnancy and lactation, when iron requirements are high. The average Western diet contains 10-15 mg of iron per day and about 10% of this is absorbed. In iron deficiency, absorption is increased and may be as high as 30% of the total ingested. Iron enters the mucosal cells of the upper small intestine and is bound to aproferritin for transport

across to the inner membrane of the mucosal cell, where it is given up to plasma transferrin. The level of transferrin saturation thus regulates absorption. Transferrin transports iron to the bone marrow where it is incorporated into haemoglobin. Iron is taken up by the reticulo-endothelial (RE) system and other tissues, where some is bound to enzymes and myoglobin but most is stored as ferritin and haemosiderin. Iron is lost from the body in sweat, urine, desquamated cells and breast milk, but most of the iron released from effete red cells is recycled. Any bleeding is a major source of iron loss; menstruating women, for example, are only in marginal iron balance. Low levels of iron within a cell result in upregulation of an iron-responsive element-binding protein (IRE-BP). This binds to a 5' sequence in the ferritin mRNA, which inhibits its translation. The IRE-BP also binds to a 3' region of the transferrin receptor mRNA, which stabilizes the mRNA and increases transferrin receptor expression. In this way, more iron is taken up into the cell and less is sequestered as ferritin. When iron loss exceeds iron absorption, the iron stores become depleted and the transferrin saturation in the blood then falls. When this drops to below around 10%, abnormal, iron-deficient erythropoiesis occurs. The MCV falls, with signs of abnormal erythropoiesis on the blood film, such as variation in size (poikilocytosis) and shape (anisocytosis). As the iron deficiency progresses, microcytic anaemia develops, the anisocytosis and poikilocytosis become more marked, and very narrow elliptocytes known as pencil cells may be seen. In more severe cases target cells appear. The red cells are hypochromic in appearance, but this is more a reflection of their small size than poor haemoglobinization, as the MCHC only falls below the normal range when the anaemia is severe.

Clinical features There is a gradual onset of the symptoms of anaemia, with lethargy, weakness, dizziness and palpitations, particularly on exertion. In addition, the hair and nails may become brittle and the nails spoon-shaped (koilonychia). 1 Pruritus vulvae may occur and, in severe cases, cerebral irritability and even cerebral oedema may arise. Very rarely, a postcricoid web develops, which initially causes dysphagia for solids but not liquids.

Aetiology and investigation The aetiology of iron deficiency is illustrated in Figure 23.8. Nearly half of patients who have had a partial gastrectomy develop iron deficiency if not given iron supplements, owing primarily to rapid gastrojejunal transit. Achlorhydria may also contribute to iron deficiency, as hydrochloric acid is important for the absorption of iron contained in foodstuffs. The cause of iron deficiency must always be established and particular attention paid to possible gastrointestinal bleeding. Malignancies of the gastrointestinal

Malabsorption Postgastrectomy Achlorhydria Coeliac disease

Nutritional deficiency

Blood loss Menorrhagia Gl bleeding (Renal tract bleeding)

IRON INTAKE

Rare causes Intravascular haemolysis Pulmonary siderosis

23

IRON LOSS

IRONDEFICIENCY FIG. 23.8 The aetiology of iron deficiency

tract may present with iron deficiency anaemia in the absence of any other symptoms.

Diagnosis This is suggested by microcytosis on the automated counter printout and associated changes on the blood film, and is confirmed by finding a low serum iron and high/normal total iron-binding capacity (TIBC). The percentage TIBC saturation is less than 10%. In the anaemia of chronic disease (p. 1226), which may also be microcytic, the serum iron is also low but the TIBC is reduced and the percentage saturation is thus usually above 10%. As an alternative to the percentage saturation of the TIBC, the serum ferritin can be measured. This is usually below 15mg/L in iron deficiency (normal range 15-300 mg/L) but within the normal range or raised in chronic disease. Discrimination can be difficult if there is iron deficiency and coexistent inflammatory disease. A bone marrow examination gives definitive evidence of the status of the iron stores, as there is no Prussian bluestainable iron in marrow fragments in iron deficiency anaemia. In thalassaemia the percentage saturation is high owing to ineffective erythropoiesis, haemolysis and transfusion.

Management The treatment of iron deficiency requires identification and correction of its cause where possible. The anaemia itself is usually correctable with oral iron supplements. Ferrous sulphate (200 mg t.d.s.) is cheap and usually well tolerated. If gastric intolerance occurs, reduction of the dosage to 200 mg once or twice per day will usually be acceptable and provide sufficient iron. Therapy should be continued until the anaemia has resolved, and then for a further 3 months to replete the iron stores. Parenteral iron is only necessary if oral preparations cannot be tolerated, or if inadequate iron is absorbed by that route. The response to parenteral iron is no faster than that to oral iron. Intramuscular iron is usually given as an iron-sorbitol-citric acid complex (Jectofer). Iron dextran can be given intravenously to correct the iron deficiency in a single infusion, but this therapy can be hazardous and is not generally advisable. ©

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CASE STUDY 23.1 IRON DEFICIENCY A 65-year-old previously fit man presented to his GP with progressive tiredness over the preceding 4 months. He offered no other relevant history, past or present, and was taking no medications. On examination he was pale, but no other abnormalities were detected. A full blood count showed the following: Hb 8.4g/dL (13.5-17 g/dL); MCV 68fl (80-99fl); WBC 6.1 x 109/L (3.5-11.0 x 109/L); platelets 410 x 109/L (150-400 x 109/L). Examination of the blood film showed microcytosis, hypochromasia, anisocytosis, poikilocytosis and pencil cells.

Questions 1. What is the most likely diagnosis? 2. What investigations would you perform to confirm this diagnosis? 3. What other investigations would you carry out?

Discussion This man has an acquired microcytic anaemia and the differential diagnosis is between iron deficiency, the anaemia of chronic disease and, rarely, sideroblastic anaemia. This presentation in the absence of signs and symptoms of chronic disease is most likely to be due to iron deficiency. This is confirmed by

SIDEROBLASTIC ANAEMIA Sideroblastic anaemia is characterized by anaemia in which ring sideroblasts are found in the bone marrow. Ring sideroblasts are normoblasts with an interrupted ring of iron around the nucleus, revealed by a Perl's iron stain. There is a disorder of haem synthesis, with accumulation of iron within the mitochondria.

Aetiology Sideroblastic anaemia may be inherited or acquired (Table 23.5). The inherited form is usually X-linked. Sideroblasts are a frequent finding in clonal disorders of the myeloid stem cell. The presence of anaemia and ring sideroblasts is classified as a form of myelodysplasia (see p. 1249), but if there are no other abnormalities the prognosis is relatively good, with many patients surviving many years without transformation to acute leukaemia.

measuring the serum iron (low), iron-binding capacity (high normal) and/or serum ferritin level (low). The most likely cause of iron deficiency in a 65-year-old man is blood loss from the gut, and investigation of a specific cause is mandatory. At this age there is no role for measurement of faecal occult bloods, because endoscopy and/or barium studies will be required regardless of the result. The serum iron was found to be 5 mmol/L (normal range 12-32 mmol/L) and the TIBC was 69 mmol/L (normal range 45-72 mmol/L), giving a saturation of 7%. A normal upper GI endoscopy was carried out and this was followed by a barium enema, which revealed a caecal carcinoma.

TABLE 23.5 Causes of sideroblastic anaemia Congenital Acquired Myeloid stem cell disorder Myelodysplasia Acute myeloid leukaemia Myeloproliterative disorder Drugs and toxins Isoniazid Alcohol Lead Miscellaneous Connective tissue disorders Widespread carcinoma

Haematological features

1

1208

Fig. 23.2

There is typically a dimorphic blood film, with both normal and microcytic red cells being apparent. The bone marrow shows ring sideroblasts and often other features of dyserythropoiesis. Other haematological findings depend on the cause of sideroblastosis: in myelodysplasia/leukaemia, disorders of the white cell lineage, including an increase in

blast cells, may be apparent in blood and bone marrow; in lead poisoning, punctuate basophilia may be seen in the red cells.

Management Any cause must be identified and, if possible, treated. Pyridoxine is always worth trying. It helps in occasional cases of both congenital and acquired disease. Blood transfusion may be necessary, and consideration must be given to iron chelation therapy.

THE MEGALOBLASTIC ANAEMIAS The megaloblastic anaemias are caused by impaired DNA synthesis and are almost always due to a deficiency of either B12 or folate. These anaemias are characterized by the abnormal morphology (megaloblastosis) of all cell lines within the bone marrow and blood. Although the precise biochemical mechanism of megaloblastic change is unknown, it is clear that DNA replication is blocked, while synthesis of cytoplasmic RNA and protein continues. The production of mature end cells is thus reduced, and many precursor cells die within the marrow (ineffective haemopoiesis).

Clinical features The onset of megaloblastic anaemia is usually insidious and the disease can be very advanced before presentation. The patients have symptoms and signs of anaemia and a slight yellow tinge, owing to the haemolytic component of the ineffective erythropoiesis. The tongue may be red and sore, and slight splenomegaly may be present. In severe cases there may also be a low-grade pyrexia, together with infections and purpura secondary to pancytopenia. In the elderly, the gradual onset of anaemia may produce heart failure. In megaloblastic anaemia secondary to B12 deficiency there may be neurological symptoms and other signs, including optic atrophy, peripheral neuropathy, subacute combined degeneration of the cord and dementia. Because of considerable individual variation in the susceptibility of the nervous system to B!2 deficiency, severe neurological sequelae can occur even with relatively minor anaemia.

Haematological features There is a macrocytic anaemia with a subpopulation of very large, oval macrocytes usually visible on the film. Excessive alcohol intake and liver disease are also frequently associated with a macrocytic anaemia, as is a reticulocytosis, but the blood film will often resolve any diagnostic difficulties. In megaloblastic anaemia the white cells and platelets are also affected and the counts may be

low. This may also be the case in liver disease with hypersplenism, but in megaloblastic change the neutrophils are typically multisegmented. In very severe anaemia, nucleated red cells may appear in the blood and have the appearance of megaloblasts. The definitive diagnosis of megaloblastic anaemia is made by examination of the bone marrow. In the red cell series the nucleus looks 'open', with delayed maturation relative to the haemoglobinizing cytoplasm; the white cell series is also abnormal, with giant metamyelocytes present. It is not essential to examine the bone marrow in all cases of macrocytic anaemia.

23

Aetiology and investigation Megaloblastic change may be due to either B12 or folate deficiency and very rarely to other inherited and acquired anaemias. In patients with macrocytic anaemia, samples for serum B]2 and red cell folate (which is less affected by recent diet than is serum folate) should be taken immediately; liver function tests and plasma thyroxine should also be measured. If an examination and blood film suggest megaloblastic change, therapy with B12 and folate should be started immediately, as delay could result in the development of neurological problems. Bone marrow examination can usually be restricted to those patients where there is considerable initial uncertainty about the diagnosis, or where a rapid response to therapy is not achieved. Further investigation will then depend on whether the cause of the megaloblastic anaemia is a deficiency of B12 or folate.

B12 DEFICIENCY Animal products are the main source of B12 in the diet. Ingested B12 binds to intrinsic factor (IF) secreted by the gastric parietal cells, and the B12-IF complex is then absorbed in the terminal ileum. Large stores of Bi2 are contained in the liver, so that B12 deficiency takes 3 or 4 years to develop in the face of reduced intake and normal requirements. The normal serum B!2 level is 150-950 pg/mL and may be measured by bioassay or radioimmunoassay. The major function of B12 is as a cofactor to the production of formate, which is used in purine synthesis, the conversion of deoxyuridine to thymidine, and in the formation of folate polyglutamate (the major red cell form of folate). In B12 deficiency red cell folate levels are also low, although serum folate is normal or high.

Aetiology The causes of B12 deficiency are shown in Figure 23.9. Nutritional deficiency occurs predominantly in vegans and chronic alcoholics. IF deficiency occurs following gastric surgery and in pernicious anaemia 1 - a relatively

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FIG. 23.10 The Schilling test The urinary excretion of orally administered radioactively labelled vitamin B12 is measured. Low levels are excreted if there is malabsorption of B12 for any reason. If malabsorption is due to pernicious anaemia (IF deficiency), there is correction with simultaneous oral administration of IF. This correction does not occur when the cause of malabsorption is terminal ileal disease or competitive gut microflora. FIG. 23.9 The aetiology of vitamin B12 deficiency

common condition (6000 cases/year in the UK) which occurs mainly in the elderly. In pernicious anaemia there is an autoimmune-mediated atrophic gastritis, resulting in achlorhydria and an inability to produce IF. It may be associated with other autoimmune diseases, such as myxoedema, diabetes mellitus and vitiligo. There may be a family history of other autoimmune disorders and sometimes a history of premature greying of the hair. The disease is more common in individuals with blood group A. Malabsorption of B12 due to terminal ileal disease occurs most commonly in Crohn's disease, when there is often concomitant iron and folate deficiency. Pancreatic failure may also cause B12 malabsorption, probably by reducing the pH and Ca2+ concentration of the terminal ileal fluid to below the optimum for absorption. A variety of drugs have been reported as inhibiting B12 absorption, including the biguanides and high-dose potassium supplements. Bacterial overgrowth, such as occurs with intestinal 'blind loops' (p. 791), may consume ingested B12. The Scandinavian fish tapeworm is a more exotic cause of such intestinal competition.

Diagnosis The diagnosis of the cause of B12 deficiency is made by the Schilling test, in which the fasting patient is given a loading dose of parenteral vitamin B12 to saturate both plasma and liver binding sites, and is then given oral radioactive B12. The possible results of the test are shown in Figure 23.10.

1 1210

Case 23.1

2

MCQ 23.3

Parts I and II of the Schilling test can be done simultaneously if two different cobalamin isotopes are used, one to label free B12 and one to label B12 complexed to IF. The diagnosis of pernicious anaemia is confirmed by the presence in the serum of autoantibodies to both parietal cells (in over 90% of patients with pernicious anaemia, but also in 15-20% of normal elderly people) and IF (in over 50% of patients). Histamine-fast achlorhydria and a raised serum gastrin are also present, but rarely need to be measured.

Management B12 deficiency is treated with hydroxycobalamin supplements. These may be given orally in patients with a dietary deficiency (5-10mg/day), but must be given intramuscularly when malabsorption is present. It is usual to give five or six loading doses of 1000 mg over a period of 1-2 weeks, followed by 1000 mg every 3 months. A brisk reticulocyte response is usually seen after 1 week, although this may be delayed if the patient has other coexistent disease, such as alcoholism. Hypokalaemia and gout may develop during the treatment of severe megaloblastic anaemia. Therapy with B12 may also disclose and exacerbate incipient iron deficiency. Blood transfusion is rarely necessary and is best avoided121

FOLK ACID DEFICIENCY Folic acid is the parent compound of the folates, which facilitate the transfer of one-carbon units necessary in the synthesis of purine and pyrimidine bases. Folates are found in fresh fruit and vegetables, liver and kidney, and are destroyed by thorough cooking. Folate is absorbed in the upper small intestine and stored in a number of tissues, but particularly the liver. These stores provide about 4 months' supply of folate in the absence of further intake.

supplements (5-15 mg/day), which is usually adequate even in malabsorption states. Folic acid is also given prophylactically to pregnant women, premature babies, patients receiving dialysis, and in severe chronic haemolytic states. Folic acid should not be given alone in megaloblastic anaemia until B12 deficiency has been excluded, as it may precipitate neurological changes in B12 deficiency.

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THE HYPOPLASTIC ANAEMIAS The hypoplastic or aplastic anaemias are a group of disorders in which there is anaemia due to a decrease in erythropoietic marrow. Although there is usually pancytopenia, with reduction of all marrow elements, selective cytopenias do occur.

CONGENITAL/INHERITED HYPOPLASTIC ANAEMIAS

FIG. 23.11 Aetiology of folate deficiency

Aetiology The aetiology of folate deficiency is illustrated in Figure 23.11. Dietary deficiency is seen particularly in milk-fed premature babies, the elderly (especially if living alone), and chronic alcoholics. As coeliac disease and tropical sprue primarily affect the jejunum, folate deficiency is also very common in these diseases. They are also often associated with iron deficiency, and the combined deficiency may result in normocytic indices on the automated printout. Examination of the blood film may reveal evidence of both iron deficiency and macrocytosis (dimorphic picture). Megaloblastic change is still apparent on bone marrow examination, and pancytopenia and multisegmented polymorphs may be seen in the blood. Folate deficiency is also common (though less so than B12 deficiency) after gastrectomy; both decreased dietary intake and rapid gastrojejunal transit may contribute to its development. Drugs such as phenytoin may inhibit folate absorption, probably through a direct effect on the enterocyte brush border. Other drugs may interfere with folate utilization, giving rise to megaloblastic anaemia in the presence of normal folate levels. These include the antifolate cytotoxic drugs (e.g. methotrexate), trimethoprim and anticonvulsants (e.g. phenytoin and phenobarbital). Alcohol may also interfere with folate utilization, and this may account in part for the macrocytosis seen with excess consumption.

Management The underlying cause of folate deficiency must be found and treated. The deficiency is treated with oral folic acid

Congenital forms of hypoplastic anaemia occur in childhood. Fanconi's anaemia is an autosomal recessive disorder characterized by chromosomal fragility. At least eight genetic variants (known as complementation groups A-H) have been described and the affected genes cloned for at least three of them, although the cellular function of these genes is poorly understood. Abnormalities of the A gene (FANCA) account for over 60% of cases, and abnormalities of FANCC are the next most frequent. It has been shown that FANCA and FANCC interact to form a nuclear complex. Pancytopenia usually develops between 5 and 10 years of age. Many of these children also suffer from other congenital abnormalities, including skeletal malformations (especially affecting the radii and thumbs), renal anomalies, microcephaly and congenital heart disease. This type of aplastic anaemia is characterized by a high red cell MCV, increased levels of HbF, a high ESR and a high incidence (5-10%) of transformation to acute leukaemia. Without successful bone marrow transplantation, the disease is invariably fatal. Congenital pure red cell aplasia (Diamond-Blackfan syndrome) may be familial but often appears to be sporadic. However, there is variable penetrance and probably over half the cases are in fact inherited, but the affected parent is asymptomatic and has escaped diagnosis. In approximately 25 % of cases there are mutations involving a small ribosomal protein situated on chromosome 19. In other cases the genetic lesion has not yet been identified. Various congenital abnormalities may be present and growth retardation may occur, but not as commonly as in Fanconi's anaemia. A macrocytic anaemia usually appears in the first few weeks of life, although the diagnosis may be made considerably later. Steroids induce remission in many patients, but the majority become transfusion dependent. Other familial and congenital hypoplastic states have also been described but are far less common.

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TABLE 23.6 Aetiology of chronic acquired aplastic anaemia

TABLE 23.7 Differential diagnosis of pancytopenia

• Idiopathic

• Aplastic anaemia • Bone marrow replacement Leukaemias, lymphomas and myeloma Non-haematological malignancies Fibrosis Osteopetrosis (rare) Gaucher's disease (rare) • Hypersplenism

• Drugs Cytotoxic drugs Idiosyncratic reaction to drugs (including choramphenicol, phenylbutazone and thiouracils) • Irradiation • • • •

Chemicals, e.g. benzene Associated with infections, particularly viral hepatitis Associated with autoimmune disease Associated with pregnancy

• Paroxysmal nocturnal haemoglobinuria

ACQUIRED HYPOPLASTIC ANAEMIAS Aetiology The causes of the chronic acquired aplastic anaemias are shown in Table 23.6. Most cases are idiopathic in origin. It has been suggested that in many such cases there is an immunological suppression of haemopoiesis, but definite proof is lacking. Transient episodes of marrow hypoplasia also occur, particularly following infections and idiosyncratic drug reactions. For example, very transient selective erythroid hypoplasia accompanies parvovirus infections. In normal individuals this results in a transient reticulocytopenia, but in patients with haemolytic disease there can be a dramatic fall in haemoglobin level. Chronic pure red cell aplasia also occurs in adults, associated in nearly half the cases with a benign thymoma.

Clinical features Patients with chronic aplastic anaemia present with insidious onset of the symptoms of anaemia, infections secondary to the granulocytopenia, and bleeding due to thrombocytopenia. Examination may reveal signs of the above, but is otherwise usually normal. Splenomegaly, which occurs in less than 10% of cases, always suggests that the pancytopenia may be due to another cause. The differential diagnosis of pancytopenia is shown in Table 23.7. In the marrow replacement states the anaemia is often leukoerythroblastic, i.e. with nucleated red cells and granulocyte precursor cells in the blood.

Laboratory features

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The anaemia of aplastic anaemia is usually normocytic but may be slightly macrocytic. There is an absolute reticulocytopenia. HbF levels may be modestly increased. Granulocytopenia and monocytopenia are present, but the lymphocyte count may initially be near normal. The

platelets are generally reduced. In a patient with a hypocellular marrow, severe aplastic anaemia is indicated by two of the following: reticulocytes <1%, neutrophils <0.5 x 109/L, platelets <20 x 109/L. The diagnosis of aplastic anaemia is made by examination of a large bone marrow biopsy (preferably from two sites). Fat spaces predominate and there is markedly reduced haemopoiesis. Islands of haemopoiesis may be found, and can be particularly confusing on a small biopsy specimen.

Management Support The successful management of aplastic anaemia depends on aggressive supportive care. Infections must be actively sought, recognized early and treated with intravenous antibiotics. In patients with a neutrophil count below 0.5 x 109/L it is usual to give prophylactic oral antifungal agents, such as nystatin or amphotericin B. Some centres also give prophylactic oral co-trimoxazole or ciprofloxacin. Isolation facilities are advisable for severely neutropenic inpatients, but severe neutropenia alone is not an indication for hospitalization. Therapy should be started empirically in patients with significant fever (above 38°C) sustained for 2 hours (less if clinical signs or symptoms are present). If there is a fever, the antibiotics must be broad-spectrum and cover Gram-negative organisms, including the coliforms and Pseudomonas. A third-generation cephalosporin or a combination of an antipseudomonal penicillin and an aminoglycoside are usually used. Ciprofloxacin is also of value but is not adequate for monotherapy. Before initiating such therapy, a throat swab, sputum (if available), midstream specimen of urine, swabs from intravenous catheter sites, and blood taken from both a peripheral site and any central intravenous lines, should be sent to microbiology for culture. The antibiotics can be rationalized later, if and when an organism is isolated and the sensitivities determined. A serum sample should be saved for possible viral antibody litres at a later date. A chest X-ray should be performed. In patients who fail to respond to broad-spectrum antibiotics within 3 days, an opportunistic infection with fungus or Pneumocystis should be suspected. If the chest X-ray

shows pulmonary infiltration, bronchoscopy and alveolar lavage may help in diagnosis. Intravenous amphotericin B therapy is the recommended standard treatment for suspected fungal infection, but it is very nephrotoxic and for this reason liposomal forms of amphotericin are increasingly used, at great expense. Pneumocystis infection may respond to high-dose co-trimoxazole therapy, often given with high-dose steroids when there is severe respiratory embarrassment. Filtered (leukocyte-depleted) red cell transfusions should be given, and although repeated transfusions do increase the risks of graft rejection in patients who are later treated by bone marrow transplantation, it is more important to keep the patient in a good general condition. CMVnegative blood products should be given to CMV-negative individuals if a transplant is to be considered. Platelet transfusions are given to all patients with thrombocytopenia and evidence of bleeding. The prophylactic use of platelets in aplastic anaemia is limited by the chronic nature of the disease and the sensitization to HLA and platelet-specific antigens that may occur. Granulocyte transfusions are not given prophylactically, and their use is limited to the treatment of life-threatening infections in severely neutropenic patients who are not responding to broad-spectrum antibiotic therapy. Even in this situation, their value is unproven. Specific therapy The traditional therapy for aplastic anaemia has been androgen therapy, continued for at least 3-6 months. Oxymethalone is used, as it is less virilizing than the testosterone derivatives. Proof of efficacy is lacking, however, and in severe cases androgens are not used alone. Haemopoietic growth factors (G-CSF, GM-CSF) may raise the neutrophil count in mild aplasia but are rarely effective in severe aplasia. Intensive immunosuppression usually consists of highdose methylprednisone, cyclosporin A and/or a course of antilymphocyte serum. In some series up to half the patients show a significant response, although there may

SUMMARY 1 Management of hypoplastic anaemia Supportive Early treatment of infection with intravenous antibiotics (initially broad-spectrum, rationalized later) Prophylactic oral antifungal agents (Isolation facilities, if severely neutropenic) Red cell transfusion Platelet transfusion Specific therapy Androgen therapy (oxymethalone) Haemopoietic growth factors Intensive immunosuppression Bone marrow transplantation

be variations in the response to different batches of antilymphocyte globulin. This type of therapy is intensive and requires inpatient support similar to that required for transplantation. In the patients who do not respond, the response is usually only partial and completely normal haemopoiesis is not re-established. Bone marrow transplantation is usually limited to individuals under 50 years of age with an HLA-identical sibling. Patients are usually prepared for transplantation with cyclophosphamide (50 mg/kg) on 4 successive days. In multiply transfused patients some centres use total nodal irradiation to reduce the risk of graft rejection, but similar results can be achieved with cyclosporin A. The marrow inoculum required for transplantation in aplastic anaemia is probably higher than that for acute leukaemia, and at least 2 x 108 cells/kg should be given. The development of graft-versus-host disease (GVHD) can be minimized by the administration of cyclosporin A and/or methotrexate. The removal of mature T cells from the marrow inoculum has been shown to be very effective in reducing GVHD, but there is increased graft rejection, particularly in multiply transfused aplastic patients. Complications of bone marrow transplantation GVHD is an ill-understood immunological reaction of mature donor lymphoid cells against host tissue. The severity of the acute form of the disease is increased by the cytokine storm associated with the intensive pretransplant cytotoxic treatment used for immunosuppression. The acute form arises coincident with, or shortly after, haemopoietic regeneration, and manifests as a maculopapular rash involving the hands and feet, hepatocellular liver toxicity and diarrhoea. In its severest forms there can be erythroderma (p. 409), widespread bullae, and then desquamation and torrential diarrhoea. Acute GVHD is treated with a course of high-dose methylprednisone. Severe cases may respond, but the mortality is appreciable. Antilymphocyte globulin is usually used in patients not respond-ing to steroids. Chronic GVHD develops several months after transplantation and is not necessarily preceded by the acute form. It takes the form of sclerodermatous skin changes and obstructive liver disease, which can be debilitating and refractory to treatment. Immunosuppressive agents, such as azathioprine, are usually tried in this situation. Immediately following preparative chemo/radiotherapy the patient with aplastic anaemia becomes even more pancytopenic. The risks of bacterial and fungal infection are thus very high in the 2-3-week period before graft regeneration occurs. Following engraftment the patient remains immunosuppressed for a variable time and opportunistic infections may still occur. Pneumocystis infection typically arises between 4 and 12 weeks, and cytomegalovirus (CMV) infection between 6 weeks and 6 months. Many centres give prophylactic septrin for Pneumocystis following transplantation until there is adequate immunological recovery. Some centres also administer ganciclovir as prophylaxis against CMV, but the availability of serial

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monitoring for CMV by the polymerase chain reaction (PCR) means that prophylactic use is being replaced by treatment when the PCR test becomes positive. Ganciclovir can suppress the neutrophil and platelet counts, and under these circumstances foscarnet is used to treat CMV. This unfortunately has renal toxicity, which can be a major problem when cyclosporin A or nephrotoxic antimicrobial agents are also being used. Despite these problems, over half the patients survive transplantation for aplastic anaemia and obtain haematological normality. In some centres the success rate is in excess of 70%12.1

TABLE 23.8 Aetiology of haemolysis Congenital Defects of haemoglobin synthesis and structure Thalassaemia Sickle cell disease Unstable haemoglobins (rare)

Acquired (non-immune) (seep. 1225, Table 23.11) Acquired (immune) (seep. 1224, Summary 5)

Membrane defects Hereditary spherocytosis Hereditary elliptocytosis Red cell enzyme defects G6PD deficiency Pyruvate kinase deficiency (rare)

HAEMOLYTIC ANAEMIAS The aetiology of haemolysis (excessive destruction of red cells) is given in Table 23.8.

Clinical and laboratory features Patients with acute haemolysis develop profound symptoms of anaemia. However, in the chronic haemolytic states quite severe anaemia can be tolerated, with symptoms only arising on exercise. The patient is jaundiced, but this is often mild and easily missed. The urine is dark (especially after standing), owing to the oxidation of urobilinogen to urobilin. The spleen tends to be enlarged to a degree dependent on the underlying cause of the haemolysis. Leg ulcers, usually over the lateral malleolus, occur in the congenital haemolytic anaemias, particularly sickle cell disease. The presence of haemolysis is usually established in the laboratory by a raised level of unconjugated bilirubin and reticulocytosis. Examination for urine haemosiderinuria is particularly useful in low-grade chronic intravascular haemolysis. Haptoglobin levels are also reduced. Red cell survival studies with 51Cr-labelled red cells are rarely required, but may be useful when combined with surface counting to estimate the role of the spleen in the haemolysis. The normal half-life of 51Cr-labelled red cells is 25-35 days. The marrow can compensate for a half-life reduced to about 15 days, but below this anaemia occurs.

Investigation The history will often indicate whether a haemolytic anaemia is familial or congenital. Particular attention must be paid to coexistent systemic disease and drug ingestion, both of which may be associated with haemolytic anaemia. Examination of the peripheral blood film may show red

1

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MCQ 23.4, 23.5

2

Case 23.2

3 Fig. 23.3

cell changes indicative of the underlying cause. White cell abnormalities, such as the atypical mononuclear cells of infectious mononucleosis or the lymphocytosis of chronic lymphocytic leukaemia, may also indicate the cause of haemolysis. If an acquired haemolysis is suspected, the initial investigation is the direct antiglobulin test to determine whether this has an immune aetiology.

DEFECTS OF HAEMOGLOBIN SYNTHESIS AND STRUCTURE I: THE THALASSAEMIAS Defects of haemoglobin synthesis and structure are one of the major congenital causes of haemolysis. The major examples are the thalassaemias and sickle cell disease. The thalassaemias are inherited disorders in which there is a reduced synthesis of one or more globin chains. This results in unbalanced globin chain synthesis, globin precipitation, ineffective haemopoiesis and haemolysis. The oc-thalassaemias are mainly found in the Far East, Middle East and Africa, whereas the p-thalassaemias are particularly prevalent in the Mediterranean. Thalassaemic genes are found in all racial groups. The primary defect occurs either in the DNA sequences coding for the globin chains or in the intervening sequences between these coding regions. Chromosome 16 contains two genes coding for a chains, and there is a single gene coding for the B-globin chain on chromosome 11 (Fig. 23.1, p. 1202). In the a-thalassaemias the a genes are usually deleted, but such whole gene deletions are rare in the p-thalassaemias. In these cases small aberrations in the gene may lead to decreased or absent transcription of the gene and intervening sequences, or they may prevent processing of the nuclear RNA to cytoplasmic RNA (during which the intervening sequences are removed). Rarely, cytoplasmic RNA is produced but cannot be translated into protein, e.g. where point mutations have introduced a

stop sequence. A thalassaemic (3 gene may thus produce no B-globin B° gene) or low levels of B-globin B+ gene).

(3-THALASSAEMIAS Clinical features Clinically, the B-thalassaemias fall into three broad categories, thalassaemia minor (trait), intermedia and major. Individuals with thalassaemia trait are heterozygous for the thalassaemic gene and are usually fit and well; however, anaemia may develop during pregnancy, or in association with infections. In thalassaemia major both P genes are abnormal, so that the a: (3 chain synthesis imbalance is sufficient to cause a severe anaemia several months after birth. At birth, most of the haemoglobin is HbF (oc2y2) and haemoglobin levels are normal. After birth a-chain production continues, y-chain synthesis diminishes, but there is little or no (3-chain production (which would normally replace synthesis of y). The result is a gradual onset of severe anaemia. Infants with thalassaemia major become listless, have a poor appetite and fail to thrive. Mental development is normal but walking is frequently delayed, and untreated children are grossly incapacitated and fail to develop. Expansion of the marrow cavities of the skull and facial bones results in a typical mongoloid fades, with frontal bossing of the skull and a 'hair-on-end' appearance on skull X-ray. Hepatomegaly and marked splenomegaly occur, and leg ulcers are frequent. Without transfusions these children die in childhood or adolescence, usually from high-output cardiac failure. Sexual maturity is not attained. In thalassaemia intermedia both (3 genes are affected but the clinical course is less severe, with haemoglobin levels typically in the range 6-9g/dL. The molecular basis of (3thalassaemia intermedia is varied and includes:

• Homozygotes with B-thalassaemia in whom there is a genetic predisposition to high HbF production • The combination of (3-thalassaemia with a-thalassaemia trait, which also results in less chain imbalance and decreased severity of the disease.

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Growth is not retarded and diagnosis is frequently delayed for several years until an intercurrent infection precipitates an acute fall in haemoglobin. These patients frequently survive into adulthood without transfusion and achieve normal sexual maturity, but pigment gallstones and leg ulceration are often a major problem.

Laboratory features The thumbprint of thalassaemic genes is the appearance of microcytic red cells in the peripheral blood. In the (3thalassaemia traits the haemoglobin concentration is normal or slightly reduced. The diagnosis is made by exclusion of iron deficiency and the anaemia of chronic disease, and the demonstration of a raised HbA2 in a blood haemolysate. Levels of HbA2 (a2 82) are typically in the range 4-6% (normal is 1.5-3%). In patients with homozygous (3-thalassaemia there is marked anaemia to a degree dependent on the nature of the underlying genetic defect. Poikilocytes and target cells are seen in the blood as well as polychromasia, and nucleated red blood cells are also present in the most severe cases. 0 Haemoglobin electrophoresis usually shows HbF to be the major component. The level of HbA2 is very variable. HbA is present in (3+ cases (Fig. 23.12). In very difficult diagnostic cases - usually (3-thalassaemia traits with microcytosis but a normal HbA2 - the thalassaemic defect can be demonstrated by showing imbalance of a- and (3-globin synthesis in reticulocytes, following in

• Homozygosity for mild B+ thalassaemic genes • Combinations of B+ thalassaemia genes and 8B thalassaemia genes, in which there is decreased 8- and |3-globin production but raised production of y chains

SUMMARY 2 Clinical features of thalassaemia major Features of severe anaemia (if not transfused) • Failure to thrive and growth retardation • Thalassaemic facies • Hepatosplenomegaly • Leg ulcers • High-output cardiac failure Features of iron overload (if transfused) • Growth arrest • Endocrine failure • Liver damage • Cardiac failure

FIG. 23.12 Diagrammatic representation of haemoglobin electrophoresis at pH 8.9 HbD migrates in the same position as HbS, and HbC and HbE in the same position as HbA2.

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vitro pulse labelling with radioactive leucine. Alternatively, molecular analyses can be carried out, particularly in those racial groups where it is possible to hazard a guess at the most likely genetic abnormality.

Management Patients with thalassaemia minor require no specific therapy, but the nature of the genetic defect should be thoroughly explained. In thalassaemia major, blood transfusion is administered once every 4-6 weeks from the time of diagnosis, to maintain a normal [Hb]. This enables a young child to grow satisfactorily and live a relatively normal life. Unfortunately, repeated blood transfusions result in iron overload, and iron accumulates in many tissues. Although much remains within the RE system, some enters and damages other tissues and multiple organ failure develops, most notably in the liver, the endocrine glands and the heart. The iron overload leads to slowing of growth and failure to attain sexual maturity. Death may occur in adolescence as a result of cardiomyopathy secondary to iron toxicity. Serum ferritin levels provide information about the kinetics of iron accumulation, but the absolute levels do not correlate closely with tissue toxicity. Iron overload can be reduced by regular administration of an iron chelator - generally desferrioxamine given subcutaneously (approximately 60mg/kg/day) by infusion pump over 8 hours, 5 or 6 days a week. Ideally, the individual dose should be adjusted in accordance with iron balance studies. Oral vitamin C is also sometimes given to improve iron excretion. Children given desferrioxamine from the age of 2-3 years have grown well and developed sexually, but their ultimate life expectancy is not yet known. There is, moreover, the major problem with subcutaneous desferrioxamine of being attached to a pump for a quarter of one's life. Compliance is often poor and constant encouragement for the patient and family is required. Oral iron chelators are now available in many parts of the world, but there is still concern about their long-term safety. In patients who have developed cardiac failure from iron overload very high-dose intravenous desferrioxamine may cause some 'unloading' of stored iron. Hypersplenism frequently exacerbates the anaemia of thalassaemia, and splenectomy is therefore indicated if the transfusion requirements progressively increase or other cytopenias develop. Antipneumococcal vaccine and antihaemophilus influenza vaccine may be of value if given before splenectomy, and oral penicillin V should be given as prophylaxis against infections with encapsulated organisms such as pneumococcus. In recent years the results of allogeneic bone marrow transplantation from matched sibling donors have been encouraging, but this needs to be carried out before extensive organ damage has occurred.

Antenatal diagnosis 1216

Antenatal diagnosis of thalassaemia and the abortion of affected fetuses is acceptable in some communities, and

appropriate facilities are available in specialist centres. Prenatal diagnosis begins with screening of all pregnant women attending their first antenatal clinic. In thalassaemia trait the MCV is low and the MCHC is normal; the MCH is a product of these measurements and is therefore a useful screening index. Patients with MCH values below 27 pg should have haemoglobin electrophoresis performed to look for a raised HbA2. The iron status should also be determined, as patients with (3-thalassaemia trait and iron deficiency may have a normal HbA2. If the mother is found to have thalassaemia trait, the father should also be screened. Where both parents have the trait and the fetus is therefore at risk, prenatal diagnosis can be offered after full discussion of the implications of the disease and consideration of the ethical issues involved. Prenatal diagnosis can be performed in the second trimester of pregnancy through globin-chain-synthesis studies on fetal blood obtained by fetoscopy, but is now usually made by DNA analysis of first-trimester chorionic biopsy specimens taken at approximately 10-12 weeks' gestation. This has the great advantage of being possible earlier in gestation, at a time when termination of pregnancy is less traumatic.

a-THALASSAEMIAS The a-thalassaemias have a wide spectrum of clinical manifestations, partly because there are four genes coding for a-globin. The commonest genetic abnormality is a complete deletion of one or more genes. • Where only one gene is defective the condition is often clinically silent, with a normal [Hb] and only a slight reduction in the MCV. • In oc-thalassaemia trait there are usually two genes involved. Here, the [Hb] tends to be in the low/normal range, and microcytosis, poikilocytosis and some target cells are present in the blood. Supravital staining of the red cells may reveal inclusion bodies, which are precipitates of (3-chain tetramers known as HbH. HbA2 levels are not raised. In newborn infants with a-thalassaemia trait approximately 5% of the haemoglobin is in the form of y-chain tetramers known as Hb Barts. • The more severe form of this disorder (haemoglobin H disease) is frequently due to the presence of three abnormal a genes. The patient usually has a mild anaemia, which may worsen rapidly with intercurrent infections or during pregnancy. The blood film shows the typical changes of thalassaemia, and 5-20% of the total Hb is HbH. HbA2 is not raised. Patients with HbH disease tend to become folate deficient and should be given prophylactic supplements. Intercurrent infections should be treated vigorously. • If all four a chains are deficient, there is no a-chain synthesis and no production of HbF, HbA or HbA2. The fetus dies in utero of hydrops fetalis, and examination of the blood shows that about 80% of the haemoglobin

is Hb Barts (y4), with small amounts of HbH ((34) and small amounts of the embryonic haemoglobin Hb Portland (£272)There is an association between some of the a-thalassaemia genes and mental retardation, but the very large majority of individuals with an a-thalassaemia gene are intellectually normal.

OTHER FORMS OF THALASSAEMIA Haemoglobin Constant Spring is a variant of the normal a-globin in which there is elongation of the a chain. Synthesis of this globin is reduced, resulting in an octhalassaemic syndrome. a-Thalassaemic genes may be associated with (3thalassaemic genes or abnormal chain variants. In general, this results in a reduction in severity of the underlying p-thalassaemic disease because there are fewer free a chains to precipitate and cause ineffective erythropoiesis. Thus, a combination of P-thalassaemic genes that might otherwise be expected to cause thalassaemia major may give rise to thalassaemia intermedia if there is concomitant a-thalassaemia. The (3-thalassaemic syndromes sometimes involve 5chain production, in which case no increase in HbA2 occurs. In Hb Lepore there is low production of a hybrid formed from a part of the 8 and part of the P chain, giving another form of thalassaemic syndrome with an abnormal haemoglobin on electrophoresis. When there is a major deletion in both the P- and 5-chain genes, y-gene expression remains high, presumably because there is no competition for binding of transcription factors between the locus control region and the specific p-globin gene. This therefore gives rise to one of the forms of hereditary persistence of fetal haemoglobin (HPFH). The heterozygous form of this disorder should be distinguished from the variety of conditions in which reactivation of HbF production occurs (Table 23.9). In the marrow expansion

states the [HbF] is usually less than 3% and is often only detected as a rise in the number of red cells containing HbF (F cells).

23

FURTHER READING ON THE THALASSAEMIAS Higgs D R, Weatherall D J (eds) 1993 The haemoglobinopathies. Bailliere's Clin Haematol 6:1. Olivieri N F, Brittenham G M 1997 Iron chelating therapy and the treatment of thalassaemia. Blood 89: 739-761.

DEFECTS OF HAEMOGLOBIN SYNTHESIS AND STRUCTURE II: SICKLING DISORDERS The sickle cell gene has a single base substitution which results in a change of valine for glutamine in the sixth amino acid position of the P chain. In the deoxygenated form HbS forms non-hydrophobic bonds with adjacent HbS molecules, resulting in fibril formation and the appearance of distorted sickle-shaped cells. Initially, this process is reversible when the haemoglobin becomes oxygenated, but eventually the red cell membrane becomes damaged and leads to the formation of irreversibly sickled cells. The sickle gene originates primarily in areas where the malarial parasite Plasmodium falciparum is endemic, and owes its prevalence to the selective advantage conferred by the sickle cell trait on young children infected with this organism (Fig. 23.13).

SICKLE CELL TRAIT In sickle cell trait (heterozygous state) at least 50% of the haemoglobin is HbA. The concentration of HbS is relatively low, so that sickling only occurs under anoxic condi-

TABLE 23,9 Causes of a raised [HbF] • p-thalassaemia major • Hereditary persistence of HbF • Marrow expansion states Pregnancy Recovery from hypoplasia • Abnormal erythroid clone Chronic myeloproliferative diseases, especially juvenile chronic myeloid leukaemia Acute leukaemia (Paroxysmal nocturnal haemoglobinuria) • Other Some cases of acquired aplastic anaemia

FIG. 23.13 Geographical incidence of the sickle cell gene

1217

tions such as occur with non-pressurized air travel, poor anaesthetics, or (rarely) in conditions of marked acidosis and dehydration, as may occur with severe infections. Individuals with sickle cell trait are not anaemic and are usually asymptomatic. However, the sickle cell screening test - in which an HbS haemolysate precipitates and becomes cloudy at pH 7.1 - is positive. Haemoglobin electrophoresis reveals 35-50% HbS, which runs as a slow band at alkaline pH (Fig. 23.12), with the remainder nearly all HbA. [HbA2] and [HbF] are not raised.

SICKLE CELL DISEASE

SUMMARY 3 Clinical features of sickle cell disease • • • • • • • • • • • • •

Painful 'crises' Sickle lung syndrome Symptoms of anaemia Asepfic necrosis of the femoral head Retinopathy Renal tubular damage Priapism Leg ulcers Gallstones Increased risk of pneumococcal and Salmonella infections Dactylitis (infants) 'Hypoplastic' anaemic crises 'Sequestration' anaemic crises

Clinical features Symptoms occur from the second half of the first year of life onwards, as the HbF levels fall. The major problems caused by sickling in young infants are haemolytic anaemias and dactylitis. Later, the main problem is the occurrence of painful vaso-occlusive crises caused by the sickled cells. These crises are frequently provoked by minor infections or dehydration. The pain may be mild or so agonizing as to require large doses of opiate analgesics. Fever and malaise are common, making it difficult to determine whether there is an underlying infection. Pain may arise in the limbs, back, abdomen or trunk. In childhood, splenic infarcts are frequent, leading to splenic atrophy and functional hyposplenism. Aseptic necrosis of the femoral head is a common and disabling complication. Small vessel occlusions in the retinae lead to ischaemia and vascular proliferation, with visual impairment and a high risk of vitreous haemorrhage and retinal detachment. Retinopathy is particularly common in sickling disorders with a high [Hb], such as HbS/C disease. Haematuria occurs frequently as a result of papillary necrosis, but even in patients without such overt renal episodes there is an acquired tubular reabsorption defect, with inability to produce a concentrated urine. Priapism may occur due to sickling in the corpora cavernosa. This is extremely painful and, unless it resolves rapidly, results in impotence. The anaemia of sickle cell disease may be exacerbated by episodes of erythroid hypoplasia (aplastic crises) precipitated by parvovirus infections, acute splenic and, rarely, hepatic sequestration of red cells, or folate deficiency. The chronic haemolytic anaemia frequently leads to ankle ulceration and the development of gallstones. Patients with sickle cell disease also have an increased risk of infection, which is only partly explained by splenic atrophy. Fulminating pneumococcal infections may occur, and there is an unusually high incidence of Salmonella 1

1218

Fig. 23.4

osteomyelitis, which, initially, can be difficult to differentiate from a vaso-occlusive infarction. Acute pulmonary episodes are the most common, and also potentially the most dangerous, complications of sickle cell disease. The pulmonary lesions may be infective, ischaemic, or a combination of the two. Minor lung changes can progress rapidly, with the development of widespread intra-alveolar consolidation and respiratory failure within hours. It must be emphasized that the clinical course of sickle cell disease is extremely variable. Some individuals have a poor quality of life and spend a large amount of time in hospital, whereas others have few problems.

Laboratory features Haematological investigations reveal a mild to moderate normocytic anaemia. Anisocytosis, poikilocytosis and sickled cells can be seen on the blood film, 1 and in older children and adults, target cells and Howell-Jolly bodies are also seen, as a result of the hyposplenic state. The sickle screening test is positive and haemoglobin electrophoresis shows most of the haemoglobin to be HbS. HbA2 levels are normal. HbF levels are raised in a minority of patients (Fig. 23.12).

Management Appropriate measures should be taken to prevent sickling crises. Patients should avoid severe cold and dehydration, and infections must be treated early and aggressively. Prophylactic penicillin V should be given to all children in view of the hyposplenism, and probably continued throughout life. Hypoxia with anaesthesia or unpressurized air travel must be avoided. In patients with very frequent and severe sickling episodes, a hypertransfusion regimen can be instituted to replace HbS with HbA. This is particularly valuable as a relatively short-term measure prior to surgery (particularly ophthalmic surgery), and in the management of major complications. It is essential to keep the patient undergoing a sickle

RECENT ADVANCES IN SICKLE CELL DISEASE The long-term administration of the dihydrofolate reductase inhibitor, hydroxyurea, has been shown to elevate the HbF level in sickle cell disease and to reduce the incidence of crises and time spent in hospital. The long-term effects of hydroxyurea are not yet known and its use should therefore be restricted to the most severely affected individuals.

crisis warm, hydrated and well oxygenated. Large quantities of opiate analgesics are often required. It is preferable to give these by an infusion pump rather than by bolus injections. Possible infections must be investigated and treated appropriately. It is common practice to give all patients with sickle crises a course of antibiotics after appropriate cultures have been taken, though proof of beneficial effect is lacking. Where a pulmonary infection is suspected, broad-spectrum cover should be given. If a sickle lung syndrome develops, regular blood gases should be performed and the patient ventilated early if hypoxia develops. The long-term administration of the dihydrofolate reductase inhibitor hydroxyurea has been shown to elevate the HbF level in sickle cell disease and to reduce the incidence of crises and time spent in hospital. The longterm effects of hydroxyurea are not fully known, and its

use should therefore be restricted to the most severely affected. Bone marrow transplantation can cure this disease but it is difficult to predict which young patients will have a sufficiently severe phenotype to justify such a drastic procedure. If a decision is delayed until severe pathology (e.g. stroke) has occurred, there is the problem that the lesions may be irreversible and the risks of the transplant greater.

23

Contraception Double-barrier techniques, such as the cap and a spermicidal foam and pessaries, are safe and effective if used correctly. The intrauterine contraceptive device (IUCD) and low-dose contraceptive pill are used in some circumstances, but there are few firm data on their safety in sickle cell disease. Management of pregnancy Folate supplements should be given, but there is otherwise little agreement as to the correct management of sickle cell disease during pregnancy. Many centres institute a 3-4-weekly transfusion regimen during the last trimester, with the aim of achieving normal haemoglobin levels with 70-80% HbA at the expected time of delivery. If there is a history of first- or second-trimester abortions, transfusion is started as soon as possible in the pregnancy. Other specialists feel that transfusion during pregnancy is unnecessary.

CASE STUDY 23.2 SICKLE CELL DISEASE

A 17-year-old student of AfroCaribbean descent developed severe back, chest, leg and arm pains after running a half marathon and was admitted to A & E. He had never had a previous episode of similar pains and had previously been well. He was on no medications. There was no relevant family history. Examination revealed BP100/70, evidence of salt and water depletion, and generalized abdominal tenderness with some rigidity but with normal bowel sounds. The patient was very distressed. A full blood count showed the following: Hb 11.8g/dL (13-17 g/dL); MCV 89fl (80-99 fl); WBC 13.8 x 109/L (3.5-11.0 x 109/L); neutrophils 10.2 x 109/L (2.0-7.5 x 109/L); monocytes 0.4 x 109/L (0.2-0.8 x 109/L); lymphocytes 3.1 x 109/L (1.5-4.0 x 109/L);

platelets 417 x 109/L (150-400 x 109/L). Question 1. What three other investigations would you request in the first instance? Discussion

The patient has a normochromic anaemia and is clinically salt and water depleted, which would tend to raise the haemoglobin above baseline values. In a young man of AfroCaribbean origin with anaemia and diffuse musculoskeletal pains the possibility of sickle cell disease should be considered. Although most affected individuals present at an earlier age, occasional patients with a mild phenotype present much later.

Severe salt and water depletion after running long distances on a hot day could be a precipitating cause. A sickle cell crisis could account for the abdominal pain and the more diffuse trunk and limb pains. In the first instance a blood film should be examined carefully for the presence of sickled red cells. A sickle screening test should also be requested. Although a negative result would exclude the possibility of a sickle crisis, a positive result would not differentiate between sickle cell trait and sickle cell disease. This would require haemoglobin electrophoresis, which would probably not be available as an emergency investigation. Thirdly, an abdominal X-ray (both erect and supine) would be essential to rule out a perforation, despite the absence of definite signs of peritonitis. 1219

SICKLE CELL GENES IN ASSOCIATION WITH OTHER ABNORMAL Hb GENES Sickle cell genes frequently interact with thalassaemic genes. In a-thalassaemia the severity of sickle cell disease in ps (sickle gene) homozygotes is often reduced, possibly as a result of the slightly decreased concentration of HbS in the red cells. If a heterozygote (3s interacts with a (3-thalassaemia gene, the HbS level is higher than in a usual HbS trait, leading to clinical symptoms. If the thalassaemia gene is a (3° gene, a severe sickle cell syndrome may arise. Interaction of (3s with an HPFH (Table 23.9) results in virtually no normal (3-chain production. However, although the level of HbS may be as high as 80%, the high levels of HbF present reduce the risks of sickling. Other forms of 'high F gene' exist and may also reduce the sickling tendency. The sickle gene may also interact with other (3-gene haemoglobinopathies. Thus, HbS/C disease, for example, results in a moderate or reasonably mild anaemia. The blood film shows sickle cells and many target cells, and haemoglobin electrophoresis shows that approximately half is HbS and half HbC, the latter running behind HbS in the same position as HbA2 (Fig. 23.12). The clinical picture is very varied, but ocular complications are particularly common. In contrast to adult sickle cell disease, splenomegaly is often present.

FURTHER READING ON SICKLE CELL DISORDERS Charache S et al. 1995 Effect of hydroxyurea on the frequency of painful crisis in sickle cell anaemia. N Engl J Med 332:1317-1320. Noonan S S 1999 Sickle cell patients find a brand new world. N Engl J Med 96: 23-25.

OTHER HAEMOGLOBINOPATHIES CAUSING HAEMOLYSIS HbC HbC is very common in west Africa, particularly Ghana. The heterozygous state is symptomless and the [Hb] normal. In the homozygous state, however, the [Hb] may be slightly reduced, the spleen is usually large, gallstones may develop and ocular lesions are frequent.

HbD

1220

HbD is found in many ethnic groups. It migrates with HbS on standard agar gels at pH 8.6, but not at acid pH. The heterozygous state is asymptomatic, with a mild anaemia occurring in the homozygous state. An asymptomatic patient with apparent homozygosity for HbS may in fact be HbS/D.

HbE HbE is found predominantly in southeast Asia. It migrates on standard agar gels with HbC and HbA2. The trait (heterozygous state) is symptomless, with a mild microcytic haemolytic anaemia in the homozygous state.

Unstable haemoglobins and methaemoglobinaemia A variety of unstable haemoglobins have been described which tend to precipitate and cause a haemolytic anaemia. Heinz bodies are seen within erythrocytes on a reticulocyte stain. Some forms of autosomal dominant congenital methaemoglobinaemia are due to amino acid substitutions in the region of the haem pocket of globin. The patient is cyanosed and may have a mild haemolytic state.

CONGENITAL RED CELL MEMBRANE DEFECTS Haemolysis can be due to congenital red cell membrane defects, the commonest of which are hereditary spherocytosis and hereditary elliptocytosis.

Hereditary spherocytosis The commonest membrane defect is hereditary spherocytosis, an autosomal condition, usually dominant, that affects 1 in 5000 individuals. The abnormality usually resides in the spectrin molecule of the cytoskeleton. Clinically, the disease is very varied. Haemolysis may be well compensated with no anaemia, or anaemia may be severe. There may also be acute exacerbations of anaemia, such as haemolytic crises associated with intercurrent infections, and aplastic crises associated with parvovirus infections or foliate deficiency. The spleen is usually palpable and not tender, but may become so during haemolytic crises. There is usually mild jaundice, but in the neonate it may be sufficiently severe to cause kernicterus. Gallstones may arise in late childhood and adult life. There is usually a mild normocytic anaemia, but during crises the [Hb] may fall below 8g/dL. The blood film reveals spherocytes and a reticulocytosis. The diagnosis is confirmed by demonstration of increased red cell osmotic fragility (Fig. 23.14) and by exclusion of other causes of spherocytosis, such as autoimmune haemolysis. Family studies may also prove useful. Children, non-splenectomized adults and pregnant women should receive folate supplements. Transfusion may be required for aplastic crises. Splenectomy reduces the haemolysis, prevents acute haemolytic crises and reduces the incidence of pigment gallstone formation, but this is usually delayed until adolescence because of the risks of post-splenectomy infections. If splenectomy is to be performed, gallstones should first be looked for using ultrasound and a simultaneous cholecystectomy con-

23

FIG. 23.14 Osmotic fragility curves showing lysis of red cells at low salt concentrations (A) represents the normal curve and (C) represents normal cells pre-incubated for 24 hours at 37°C. (B) and (D) represent fresh and pre-incubated hereditary spherocytic cells respectively.

sidered. Following splenectomy, prophylactic penicillin should be given.

FIG. 23.15 Simplified scheme of glycolysis and the hexose monophosphate shunt

Hereditary elliptocytosis is an autosomal dominant condition in which an abnormality of the cytoskeleton results in oval red blood cells. A number of genetic defects have been defined that result in defective spectrin oligomer formation, defective association of spectrin with other membrane components, and abnormalities of the membrane proteins 4.1 and glycophorin C. The osmotic fragility is normal. Most patients are asymptomatic but a small proportion have the signs and symptoms of chronic haemolysis, which may necessitate splenectomy.

23.15). ATP is required for transmembrane iron transport and for the maintenance of the shape and flexibility of the red cell. NADH is also produced by the glycolytic pathway and is required for the maintenance of haem iron in the ferrous state. NADPH, produced by the hexose monophosphate shunt, is necessary for the reduction of glutathione, which protects the red cell from oxidant stress. 2,3-DPG is derived as an offshoot of the glycolytic pathway and is important for its modulating effects on haemoglobin-oxygen affinity. The tricarboxylic cycle, protein synthesis and nucleic acid synthesis do not occur in the erythrocyte.

Other hereditary red cell membrane defects

Glucose-6-phosphate dehydrogenase deficiency

These include hereditary stomatocytosis, in which the red cells have a slit-like central pallor resembling a mouth; hereditary pyropoikilocytosis, in which there is marked haemolysis and in vitro fragmentation of red cells upon gentle heating; and hereditary acanthocytosis. This last condition is inherited in an autosomal recessive manner and is associated with abetalipoproteinaemia, malabsorption, retinitis pigmentosa and diffuse nervous system abnormalities.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common inherited disease in the world. G6PD is the first enzyme in the hexose monophosphate shunt, so a deficiency leads to a fall in NADPH and increased sensitivity of the erythrocytes to oxidant stress. The G6PD enzyme is coded on the X chromosome, so that disease due to deficiency of this enzyme mainly affects males. Female heterozygotes (carriers) have on average about 50% of normal levels overall, but owing to the process of Lyonization within individual red cells the G6PD levels are either completely normal or grossly deficient, so that clinical disease may also occasionally occur in females. Furthermore, some females have a 'skewed' Lyonization pattern, so that considerably more than 50% of cells can be deficient. Many isoenzymes of G6PD have been described. The predominant isoenzyme - found in

Hereditary elliptocytosis

CONGENITAL RED CELL ENZYME DEFECTS The glycolytic enzymes in the erythrocyte generate two moles of ATP for each mole of glucose metabolized (Fig.

1221

TABLE 23.10 Drugs which may precipitate acute haemolysis in G6PD deficiency

SUMMARY 4 Clinical presentations of G6PD deficiency

Type of drug

Example

Analgesics

Aspirin

Antibiotics

Sulphonamides Nitrofurantoin Chloramphenicol Quinolones

• • • • •

Para-aminosalicylic acid Antimalarials

Quinine Chloroquine Primaquine

Antiieprotics

Dapsone

Miscellaneous

Vitamin K Vitamin C

Caucasians and 60% of blacks - is designated B+. A normal African variant found in 25% is designated A+. Other isoenzymes, however, lead to G6PD deficiency. In the African A- variant, G6PD is produced in normal quantities and initially has full functional activity. However, the enzyme is unstable, so that the G6PD activity of an erythrocyte declines with time. In Mediterranean-Orientaltype G6PD deficiency the enzyme usually has low or absent functional activity from the beginning. Clinical features The clinical spectrum of G6PD deficiency is wide. The commonest presentation is that of an acute haemolytic episode, precipitated by infection, acute illness or drugs. Many drugs have been implicated in causing acute haemolysis in G6PD deficiency, but only a few commonly used drugs consistently have this effect (Table 23.10). In the Africantype G6PD deficiency (A-), the haemolysis leads to a brisk reticulocytosis and, as the reticulocytes have adequate levels of G6PD, is thus self-limiting. However, in G6PD deficiency variants where reticulocyte G6PD levels are low, the intravascular haemolysis may be sufficiently severe to cause collapse and death. Favism is the condition when acute haemolysis is precipitated in G6PD deficiency following exposure to broad beans, either as lightly cooked food or as pollen. It is mostly confined to the Mediterranean variants of G6PD deficiency and mainly affects young children. The chronic haemolytic anaemia of G6PD deficiency is rare, but has been described with

1 1222

MCQ 23.6, 23.7

Stress-induced acute haemolysis Drug-induced acute haemolysis Favism Chronic congenital haemolytic anaemia Neonatal jaundice

many different variants. The anaemia is usually mild. Neonatal haemolysis occurs mainly in Mediterranean and Oriental variants, and is an important differential diagnosis of immune haemolysis of the newborn in these areas. The administration of vitamin K may precipitate or exacerbate some cases. Laboratory features During haemolytic episodes there is a non-spherocytic anaemia with anisocytosis. Vital staining of the blood film reveals a reticulocytosis and many Heinz bodies (precipitated haemoglobin). Erythrocyte G6PD levels can be measured by a commercially available enzyme kit, but it must be borne in mind that in the African type of G6PD deficiency the level may rise into the female heterozygote range during acute episodes with a reticulocytosis. In these circumstances, definitive assays should be delayed until the convalescent period. Management Patients with G6PD deficiency should receive prompt therapy of all infections and avoid drugs known to precipitate haemolysis. Blood transfusion is occasionally required for severe episodes of haemolysis, and exchange transfusion may be needed in cases of neonatal jaundice.

Pyruvate kinase deficiency Pyruvate kinase (PK) deficiency is rare compared with G6PD deficiency. It is generally an autosomal recessive condition (although occasionally heterozygotes may have minor haemolysis), and is most common in Caucasians. PK deficiency results in the reduced generation of ATP and NADH and inability of the cells to maintain electrolyte balance. Haemolysis is extravascular, with removal of defective cells by the RE system. Clinical and laboratory features There is a congenital non-spherocytic anaemia of very variable severity. Severe anaemia is partially ameliorated by the high 2,3-DPG levels present (distal block), which help maintain tissue oxygenation (p. 1205, Fig. 23.6). The anaemia is often exacerbated by infections. Splenomegaly is common and severe cases may require regular transfusions. Examination of the blood film reveals poikilocytosis and reticulocytosis. The diagnosis is confirmed by measurement of erythrocyte PK enzyme activity.

stances are polyclonal, do not originate from the malignant clone, and are indicative of the overall immune dysregulation that occurs in these conditions. However, when cold antibodies are produced in lymphoma they are frequently monoclonal. AIHA can occur in association with all the autoimmune diseases but is most common in systemic lupus erythematosus, when it may occasionally be the presenting feature. Viral infections frequently predate warm antibody AIHA in children and young adults. Infectious mononucleosis may lead to production of cold antibodies with / blood group specificity, and mycoplasma pneumoniae with / specificity. Drugs may cause AIHA by several mechanisms:

FIG. 23.16 Diagrammatic representation of the direct and indirect antiglobulin test Human anti-immunoglobulin is shown in blue.

General approach to erythrocyte enzymopathies When haemolysis due to an enzyme defect is suspected the G6PD level should be measured first, as this is the commonest enzymopathy. If this is normal, PK activity should be measured. Many other enzyme deficiencies have been reported, but these are extremely rare. The family and clinical history may provide clues, and measurement of 2,3-DPG levels may help localize a defect in the Emden-Myerhof pathway. 1

AUTOIMMUNE HAEMOLYTIC ANAEMIAS Autoimmune haemolytic anaemias (AIHA) are generally categorized according to whether the anti-red-cell antibody is cold or warm. Warm antibodies react with red cells at 37°C, tend to be IgG, and usually destroy red cells by means of opsonization and extravascular clearance in the RE system. IgG antibodies are 'incomplete' antibodies and thus do not agglutinate cells in saline; hence, the addition of albumin or antihuman y-globulin (direct antiglobulin test, DAT; Fig. 23.16) is required. Cold antibodies are usually IgM complete antibodies, which agglutinate cells in saline at room temperature. The thermal amplitude of such antibodies is very variable.

Aetiology AIHA is most commonly idiopathic in origin. Cold antibodies are most common, although they frequently cause few problems. Anti-red-cell antibodies may occur secondary to malignancies, especially the low-grade lymphoproliferative disorders such as chronic lymphocytic leukaemia. The warm antibodies produced in such circum-

23

• Certain drugs, such as methyldopa, L-dopa and mefanamic acid, induce the production of autoantibodies directed against red cell antigens through an unknown mechanism. With chronic methyldopa use, up to 20% of patients acquire a positive direct antiglobulin test, although haemolytic anaemia occurs in less than 1%. If haemolysis does occur it usually ceases within 2 weeks of stopping the drug, although the DAT may remain positive for several years. In this case, the antibody is usually a warm IgG reactive with the rhesus antigen system. • Some drugs cause haemolysis by acting as a hapten. This occurs most frequently with high-dose parenteral penicillin. It is adsorbed on to the red cell and in that form stimulates antibody production. IgM antibodies are frequently produced without clinical effect, but if IgG antibodies are produced haemolysis may be severe. • Immune complex-mediated haemolysis is rare but has been reported with a wide range of drugs. In these cases the patient has usually received the drug before and has become sensitized to it. On rechallenge, immune complexes containing the drug are formed, bind to the red cells and precipitate complement-mediated intravascular haemolysis. Immune haemolysis may complicate blood transfusion, and this and haemolytic disease of the newborn is discussed on pages 1232-1234.

Clinical features Warm antibodies do not generally cause complement activation and intravascular haemolysis. Instead, the red cells are opsonized and removed in the RE system, resulting in anaemia, which may be either acute and severe or a mild chronic disorder. Occasionally, AIHA may be complicated by immune thrombocytopenia, and in these cases bruising and petechial haemorrhages may occur. Cold antibodies may be asymptomatic or, alternatively, give rise to cold haemagglutinin disease (CHAD). The idiopathic form occurs mainly in the elderly. On exposure to the cold, acute episodes of haemolysis may occur and peripheral cyanosis and Raynaud's phenomenon are also frequent. In between episodes the haemoglobin may be

1223

SUMMARY 5 Aetiology of autoimmune haemolytic anaemia • Idiopathic • Secondary Neoplasms, especially lymphoproliferative disorders Autoimmune disorders Infections Drugs - Induction of 'true autoantibodies' - Drugs acting as haptens on red cell surface - Passive absorption of drug-antibody complex onto erythrocyte • Complication of blood transfusion (transient) • Immune haemolytic disease of the newborn

normal or only slightly reduced. Rarely, there is a chronic severe anaemia which is refractory to treatment. Infectioninduced cold haemolysis is usually characterized by an acute onset of anaemia, jaundice and haemoglobinuria, which subsides after several weeks. Paroxysmal cold haemoglobinuria (PCH) is a very rare form of cold antibody haemolysis, in which the antibody is a cold IgG specific for the P blood group system. It may be idiopathic or postinfective, particularly following syphilis. The degree of cold exposure required to precipitate attacks is very variable.

Management Warm antibody haemolysis In primary (idiopathic) cases remission induction is attempted with a course of high-dose steroids (prednisone Img/kg/day), which is then tailed off gradually according to the response. Blood transfusion may be necessary, and this causes considerable difficulties with the crossmatch. Splenectomy is usually tried if steroids fail, and immunosuppression with azathioprine, chlorambucil or cyclophosphamide may prove effective in splenectomyresistant cases. In cases of chronic haemolysis, folic acid supplements should be given. In secondary AIHA, appropriate treatment of the underlying disease will often terminate the haemolytic process. Drugs suspected of causing haemolysis should be withdrawn. Spontaneous remissions may occur, particularly in postinfective AIHA in children. Cold antibody haemolysis If the haemolysis is mild and well compensated no specific therapy is required, but the patient must avoid exposure to cold. During acute episodes (especially following infections) confinement to a very warm room may be necessary, and if transfusion is required washed cells should be given (reduced complement) through a blood warmer. Steroids and splenectomy rarely help in cold haemagglutinin disease; if the haemolysis is chronic and severe, chlorambucil or cyclophosphamide should be tried. 1

Laboratory features The anaemia is usually slightly macrocytic owing to the reticulocytosis. If haemolysis is severe, nucleated red cells may be seen in the blood. Spherocytes are frequently seen and the osmotic fragility may be increased, although usually to a lesser extent than in hereditary spherocytosis. Red cell aggregates are commonly found on the blood film, particularly with cold antibodies. The ESR is usually markedly raised. Hyperbilirubinaemia is present and reflects in part the severity of the haemolysis. Haemoglobinuria occurs with acute intravascular haemolysis, and haemosiderinuria with chronic intravascular haemolysis (p. 1225). The diagnosis of AIHA is made by demonstrating the presence of a red cell autoantibody. With warm antibodies (active at 37°C in DAT) this is usually IgG, and only occasionally IgA or IgM. Cold antibodies are usually IgM and agglutinate at room temperature (less so at 37°C). The DAT is usually positive with anti-C3d, and in some cases only C3d can be demonstrated on the cell surface.

1 1224

MCQ 23.8

ACQUIRED NON-IMMUNE HAEMOLYTIC ANAEMIAS The aetiology of acquired non-immune haemolytic anaemias is shown in Table 23.11.

Hypersplenism Hypersplenism is defined as a peripheral blood cytopenia that can be cured by splenectomy. The spleen is usually enlarged (splenomegaly), the causes of which are shown in Table 23.12. The mechanism of hypersplenism is multifactorial and includes both pooling of cells within the spleen and rapid destruction of cells within the spleen. The plasma volume is usually increased in splenomegaly, and a dilutional factor contributes to any anaemia. Assessment of hypersplenism can be difficult. The diagnosis is usually suggested by the finding of a peripheral blood cytopenia, an active cellular marrow and splenomegaly. However, if there is an underlying haematological disease, such as a haemolytic anaemia, it can be difficult to separate the effects of this from the hypersplenism. In some cases radioactive isotope studies may be of value. Using 51Cr-labelled red cells, a shortened red cell survival can be demonstrated, and surface counting can then be performed over the spleen.

TABLE 23.11 Aetiology of acquired non-immune haemolytic anaemias Hypersplenism Toxic states Infections, e.g. malaria Uraemia Drugs Chemicals, e.g. lead poisoning Venoms, e.g. cobra bites Microangiopathic haemolytic anaemias Disseminated intravascular coagulation (DIG) Haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) Malignant hypertension Trauma to red cells Cardiac prostheses March haemoglobinura Burns Acquired red cell membrane defects Paroxysmal nocturnal haemoglobinura (PNH) Liver disease Vitamin E deficiency, especially in premature babies

In extravascular haemolytic anaemias the role of the spleen in red cell destruction can be partly assessed by comparison of the spleen and liver uptake of 51Cr-labelled red cells over a period of 10 days. A ratio greater than 4 suggests that considerable splenic destruction is occurring and that splenectomy may be beneficial. Blood changes following splenectomy If hypersplenism was present, the cytopenias should resolve following splenectomy. A number of other changes in the blood also occur (Table 23.13). It must be noted that these changes also occur in other hyposplenic states (Table 23.14).

TABLE 23.12 Causes of splenomegaly

23

Primary haematological disorders Haemolytic anaemias, especially if severe and chronic Lymphoproliterative disorders Myeloproliferative disorders Non-haematological disorders Congestive splenomegaly Portal hypertension Hepatic or portal vein thrombosis Chronic congestive cardiac failure Infections Bacterial, e.g. septicaemia, typhoid, tuberculosis Viral, e.g. hepatitis, infectious mononucleosis Tropical, e.g. malaria, kala-azar Collagen vascular diseases Metabolic 'storage disease' Sarcoidosis

TABLE 23.13 Blood changes post splenectomy Blood cell type

Change

Red cells

Howell-Jolly bodies (nuclear remnants) Siderocytes Target cells Normoblasts

Leukocytes

Neutrophil leukocytosis (usually transient) Myelocytes appear in the blood during infections

Platelets

Thrombocytosis (usually transient)

TABLE 23.14 Causes of hyposplenism • Splenectomy • Sickle cell disease • Coeliac disease

• Congenital absence (rare) • Systemic lupus erythematosus (rare) • Senile atrophy (rare)

Microangiopathic haemolytic anaemias The microangiopathic haemolytic anaemias include disseminated intravascular coagulation, haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura. These are discussed on pages 1269-1270.

SUMMARY 6 Clinical features of PNH • • • • • •

Paroxysmal nocturnal haemoglobinuria Chronic haemolysis Mild cytopenias Severe aplastic anaemia Thromboses Leukaemic transformation

Trauma to red cells Trauma to red cells may occur in a number of situations, including cardiac prostheses, march haemoglobinuria and burns. Cardiac prostheses Trauma to red cells due to cardiac prostheses occurs predominantly with prostheses on the left side of the heart, where systolic pressures are high. It is particularly common with faulty valves through which there is regurgitation. The anaemia is usually mild and red cell fragments (schistocytes) are seen on the blood film. The platelet count may also be low.

1225

March haemoglobinuria In march haemoglobinuria, red cells are ruptured in the small vessels of the feet in some otherwise healthy individuals when they engage in long marches or runs. It may be sufficiently severe to cause frank haemoglobinuria, nausea and abdominal cramps. Low-grade march haemoglobinuria may contribute to the anaemia seen in some professional athletes. Haemorrhage from the gut due to repetitive jolting (running) and poor iron utilization may be other contributory factors.

Paroxysmal nocturnal haemoglobinuria Paroxysmal nocturnal haemoglobinuria (PNH) is a rare disorder of multipotential stem cells, in which an affected clone gives rise to abnormal red cells, leukocytes and platelets. It is caused by a mutation in the X-linked PIGA gene involved in the formation of membrane phosphatidyl inositol anchors. It is not known why the PNH clone should obtain a selective advantage over normal haemopoietic cells. The membranes of these cells are deficient in those proteins normally anchored to the cell membrane through a phosphatidyl inositol linkage. As these include complement-deactivating factors, the cells are very sensitive to complement lysis activated by the alternative pathway. There is a high incidence of aplastic anaemia and acute leukaemia, reflecting the aberrant nature of the stem cell. Clinical features This disorder usually presents in adults, and is more common in women. The clinical manifestations are wide. Paroxysmal haemolysis and haemoglobinuria during sleep is reported in only 25% of patients. Severe bouts may be associated with jaundice and low back pain. Chronic low-grade, intravascular haemolysis is more common than the severe form and usually leads to iron deficiency. Mild neutropenia and thrombocytopenia are also common, and occasionally severe aplastic anaemia may arise or be the presenting feature. The thromboses that occur are usually venous, but are occasionally arterial. The sites of thromboses are often atypical and include the hepatic veins and cerebral sinuses. Diagnosis and management Non-immune intravascular haemolysis should always raise the suspicion of PNH, but haemosiderinuria may be the only evidence of haemolysis. Iron deficiency and cytopenias are frequent. The neutrophil alkaline phosphatase score is usually low in PNH (unless aplastic anaemia occurs) and is a useful diagnostic indicator. The standard diagnostic test has been the Ham's test, in which PNH (but not normal) red cells lyse during a 1-hour 37°C incubation 1

1226

MCQ 23.9

with normal sera, but do not lyse if complement is first removed from the sera by inactivation at 56°C. Diagnosis can also be made by immunophenotype analysis for deficient antigen expression (CD59 for red cells and platelets, CD67 for granulocytes, CD14 for monocytes and CD24 for B cells). There is no specific therapy for PNH. Many patients become iron deficient, but giving iron therapy in the presence of anaemia can cause a temporary exacerbation of the haemolytic process, and so careful observation is necessary. Occasionally blood transfusion is required, particularly when there is marrow hypoplasia. Transfusion should be with washed cells to prevent complement infusion, which could trigger further haemolysis. During haemolytic episodes it is important to maintain adequate hydration to prevent renal damage. Anticoagulation is sometimes recommended because of the risk of venous thrombosis, but it is not usual practice unless there has been a previous thrombotic event. Indeed, heparin can also sometimes trigger an acute haemolytic event. Prednisolone has been used to treat both haemolytic episodes and symptomatic hypoplasia. In steroid-resistant hypoplasia a trial of androgen therapy is warranted, and bone marrow transplantation is performed for some patients. The median survival in PNH is approximately 10 years from diagnosis. 1

ANAEMIA OF CHRONIC DISEASE The anaemia of chronic disease is multifactorial. Haematinic deficiency, poor iron utilization, relative erythroid hypoplasia and a slightly decreased red cell survival may all contribute to the anaemia, and other factors may also contribute in specific diseases. The anaemia is usually mild or moderate, and may be microcytic or normocytic. The serum iron is usually low, but the total iron-binding capacity is also reduced, giving a percentage saturation greater than 10%. Marrow iron is present and the serum ferritin is normal or raised. There may be a leukocytosis and the blood film may show features specific to the underlying disease process. Several chronic diseases merit special attention.

Renal failure The anaemia may be severe in chronic renal failure. Retained toxic metabolites may directly suppress erythropoiesis, but the major cause of anaemia is decreased production of erythropoietin. This is due largely to the destruction of erythropoietin-producing tissue, but is also a result of the acidosis and raised phosphate levels (including 2,3-DPG) that occur in renal failure. Red cell survival is often shortened, and in severe renal failure there may be a microangiopathic haemolysis. Examination of the blood in renal failure reveals a normocytic anaemia with crenated cells, and often also red cell fragments.

23

FIG. 23.17 Development of anaemia in carcinoma of the bronchus showing the multiple mechanisms involved

Despite the multifactorial nature of the anaemia of chronic renal failure, a normal haemoglobin can be obtained in most patients by the administration of erythropoietin.

Liver disease In liver disease there is a mild anaemia, which may be normocytic but is frequently macrocytic. Target cells are usually seen on the blood film. There may be a slight reticulocytosis, as mild haemolysis occurs as well as decreased erythropoiesis. Excessive bouts of alcohol intake in patients with chronic liver disease can produce frank haemolysis associated with abdominal pain, jaundice and hyperlipidaemia (Zieve's syndrome). The anaemia may be exacerbated by the complications of cirrhosis, i.e. hypersplenism and blood loss.

TABLE 23.15 Criteria for the acceptability of blood donors

in the UK • Aged 18-65 years • Good general health and 'feeling well' • [Hb] greater than 13.1 g/dL (men) greater than 12.5 g/dL (women) • Not pregnant at present or in the last year • Never suffered from:

Cancer

•

•

Malignant disease The anaemia of non-haematological malignancy is multifactorial, and that which may occur in carcinoma of the bronchus is shown as an example in Figure 23.17.

• •

Syphilis Brucellosis No recent: Malaria infectious mononucleosis Hepatitis/jaundice Not had (in last 6 months): Blood or blood products Surgery, tattoos, ears pierced Contact with hepatitis Not in high-risk group for AIDS Not in tropics in the previous 3 months

BLOOD TRANSFUSION Donors All blood products should ideally be obtained from volunteer donors to reduce both the expense and the risks of infection transmission. The risks to the donor are very small, consisting mainly of bruising at venepuncture (and, rarely, arterial puncture) sites. The commonly used criteria for the acceptability of donors are shown in Table 23.15. Blood from all donors is screened for syphilis serology, HIV and hepatitis C antibodies, and hepatitis B surface antigen. In many countries donors are also screened for

hepatitis B core antigen, because there is a period after infection when the core antigen is positive and the surface antigen is negative. In some countries blood is also tested for HTLV-1. Selected units are screened for anti-CMV antibodies, as only CMV-negative blood is given to neonates and CMV-negative immunosuppressed individuals.

Red cell antigens and antibodies All blood is classified according to its ABO and rhesus antigen phenotype.

1227

ABO system There are three alternative genes that act on the product of the H gene to produce the O (H), A and B antigens (Fig. 23.18). The approximate incidence of the ABO antigens in various racial groups is shown in Table 23.16. At approximately 6 months of age, so-called naturally occurring antibodies arise to the ABO system, as shown in Table 23.17, probably as cross-reactions to antigens on gut flora. They are IgM antibodies, which will agglutinate red cells in the cold in saline (complete antibodies). Subgroups of A are recognized. Approximately 80% of Caucasians are Al and 20% are A2. Rhesus system The rhesus system is composed of three closely linked allelic genes, one group of three being inherited from each parent. The D antigen is clinically most important, and approximately 85% of Caucasians are D+. In Chinese populations nearly 100% are D+, and in black people the incidence is approximately 95%. For general blood transfusion purposes a recipient is called Rh-negative if he or she is d/d, but a Rh-negative donor is defined as cde/cde. Some patients have an abnormal D antigen (Du), which may type very weakly or even as d. Naturally occurring antibodies to the rhesus system do not occur. However, antibody formation occurs following sensitization during pregnancy, or after mismatched transfusion. The antibodies formed are warm-reacting IgG antibodies, which do not agglutinate in saline (incomplete antibodies). They can be detected on the addition of albumin or by using anti-immunoglobulin as a crosslinking reagent. Anti-Rh antibodies are most important in the context of immune haemolytic disease of the newborn (p. 1232). 1 Other antigen systems Many other red cell antigen systems have been described but are not routinely typed. However, preformed antibodies to these antigens will be detected in a cross-match and can then be identified with panels of typing cells.

TABLE 23.16 Incidence (%) of ABO blood groups in various racial groups Blood group

Caucasians

Asians & Indians

African Blacks

A

36 14

24 24

21

3 47

9

5

33

43

B AB 0

TABLE 23.17 ABO genotype, phenotype and naturally occurring antibodies Genotype

Phenotype

Antibodies

AA

A

AO BB

A

BO

B

00

0

Anti-B Anti-B Anti-A Anti-A Anti-A + anti-B

B

O gene No change

H gene

H antigen

+N-acetyl-

A antigen

galactosamine

Bagene

+D-galactose FIG. 23.18 The ABO antigen system

ABO typing is performed by adding known anti-A and anti-B sera to a red cell suspension at room temperature, and then looking for agglutination (Fig. 23.19). The serum is also typed against known red cells as a back-check. Rhesus typing with anti-D cannot be performed in saline at room temperature, but must be carried out at 37°C

1228

0 antigen (H)

A gene

Blood grouping and cross-matching

1

29

MCQ 23.10

FIG. 23.19 ABO grouping

Bantigen

in the presence of albumin or antihuman globulin in an indirect antiglobulin test (Fig. 23.16). At least two anti-D reagents should be used. When the patient's ABO and rhesus group have been determined, a cross-match between the potential donor cells and the recipient serum can be performed. A control is also performed using the recipient's own cells and serum to check for autoagglutinins. The cross-match should be performed both in saline at room temperature to detect cold complete antibodies, and in albumin at 37°C to detect warm incomplete antibodies. An indirect antiglobulin test at 37°C is also performed, and is generally the most sensitive test available. To speed up compatibility testing, an antibody screen on the serum of all potential recipients can be carried out using two batches of carefully selected target cells which express nearly all of the clinically important antigens. If any antibodies are found, they must be identified, appropriate antigen-negative blood found and a full cross-match performed. If no antibodies are found, cross-matching is only performed in surgical cases, such as cardiac surgery or a Wertheim's hysterectomy, in which there is a very high chance of blood being used. Blood is not cross-matched in surgical cases where blood is not usually required. If blood is then required urgently, group-matched blood is issued after a 5-10-minute rapid (spun) cross-match.

Washed red cells Red cells washed three times in saline contain few white cells and platelets, and reactions to platelet and leukocyte antigens in patients with preformed antibodies are thus reduced. In general, the use of washed cells for this purpose has now been replaced by the use of filtered blood. As the plasma is removed from washed red cells, reactions to plasma products, especially IgA, are avoided. Washed blood must be used within 12 hours of washing.

Use of blood, blood products and substitutes

Red cell substitutes Emulsions of perfluorocarbons can be used to transport oxygen and carbon dioxide in the blood. However, they have a short half-life in the circulation and require the patient to inhale 50% oxygen to be effective. Their use is therefore limited to the management of individuals with religious objections to blood products, and perhaps also as a reserve for the treatment of large numbers of casualties after a major disaster.

Whole blood Whole blood should only be used in circumstances such as acute haemorrhage, where there is a need to restore the intravascular volume as well as the oxygen-carrying capacity of the blood (Table 23.18). For exchange transfusions in neonates, the blood should be less than 48 hours old and CMV negative. Red cell concentrates Packed cells are advisable for patients with anaemia but without hypovolaemia. It should also be noted that the majority of patients with anaemia due to haematinic deficiency do not require transfusion unless they are very ill, pregnant, or are being prepared for surgery.

TABLE 23.18 Indications for the use of whole blood • Acute blood loss • Exchange transfusions Sickle cell disease Haemolytic disease of the newborn • Priming extracorporeal circulations Heart-lung machines Some dialysis equipment

23

Filtered blood Filtration removes over 95% of leukocytes, and has recently been introduced as standard practice in the UK to minimize the theoretical risk of prion transmission from potentially 'infected' lymphocytes. This strategy is extremely expensive. Previously, filtered blood was largely reserved for those patients with antileukocyte antibodies causing febrile reactions, and those in whom it was desirable to avoid sensitization to HLA antigens (e.g. potential transplant recipients). Frozen red cells Frozen red cells (after thawing and washing) are free of leukocytes. Filtered blood is now generally used for sensitized patients, and red cell cryopreservation is mainly of value for the indefinite storage of blood with rare phenotypes.

Platelet concentrates Platelet concentrates can be obtained from the donor units of blood by centrifugation, or in larger quantities using cell separators. As platelet concentrates are invariably contaminated with red cells, ABO and rhesus compatibility between donor and recipient should be maintained. Platelets are best stored at room temperature, preferably with constant agitation, and should be used as soon as possible (and not after 5 days from collection). Platelets stored at 4°C survive less well but have greater initial activity in the recipient. Platelets are administered to thrombocytopenic patients with bleeding manifestations, and prophylactically to those with very severe thrombocytopenia or who are about to have invasive procedures. The accepted threshold for prophylactic platelet transfusion under usual circumstances has recently been reduced from 20 x 109/L to 10 x 109/L. Fresh frozen plasma Fresh frozen plasma (FFP) contains the plasma proteins

1229

TABLE 23.19 indications for use of fresh frozen plasma Acquired coagulation disorders Liver disease Over-anticoagulation with oral anticoagulants Following massive transfusion with stored blood (if indicated by clotting screen) Congenital coagulation disorders Factor XI deficiency Minor bleeds in von Willebrand's disease Factor V deficiency Factor Vli deficiency Factor X deficiency Factor XIII deficiency Thrombotic thrombocytopenic purpura Angioneurotic oedema (FFP provides C1 esterase inhibitor)

and labile clotting factors. The uses of FFP are confined to those in Table 23.19, as it is essential that fresh plasma is used primarily for the production of other plasma products. It should not be used as a plasma expander. Plosmo protein fraction Plasma protein fraction is the solution that remains after the removal from plasma of cryoprecipitate, fibrinogen and immunoglobulins. It is largely composed of albumin. The solution is heat-treated to destroy HIV, hepatitis and CMV viruses, and is used as a volume expander when red cells are not required, and for replacement therapy in hypoalbuminic states. The use of albumin in the severely ill patient who develops hypoalbuminaemia is controversial but should probably be avoided. Freeze-dried salt-poor albumin Freeze-dried salt-poor albumin is of limited use but may be of value in some patients with nephrotic syndrome or liver disease. Artificial plasma expanders Hydroxyethyl starch is a very useful and safe plasma expander. High molecular weight dextrans are also used, but anaphylactic reactions occasionally occur and there may also be occasional interference with subsequent crossmatching (rouleau formation). Gelatin solutions are also safe but only remain in the circulation for a relatively short period.

1230

Cryoprecipitate When FFP is just thawed to between 4°C and 8°C, a white gelatinous material remains as cryoprecipitate, which can be removed and refrozen. This substance enters solution when thawed at 37°C. Cryoprecipitate contains approximately 50% of the original factor VIII present, including von Willebrand factor. It also contains high levels of fibrinogen, but no factor IX. It is now rarely used except

in some cases of disseminated intravascular coagulation (DIC), where fibrinogen is required as well as other clotting factors. Factor VIII concentrates Highly concentrated factor VIII preparations are available in freeze-dried forms. They are less bulky than cryoprecipitate, can be stored at 4°C, and contain less fibrinogen than cryoprecipitate, all of which properties make them suitable for major bleeds. Because they are produced from pooled plasma collections they potentially contain viruses, including HIV, although heat treatment eliminates HIV and hepatitis viruses. This process does, however, reduce the functional factor VIII content and thus adds to the expense. Porcine and bovine factor VIII concentrates are occasionally useful in patients who have developed antifactor VIII antibodies. Genetically engineered factor VIII is now increasingly used because, although expensive, it is not contaminated by viruses. Factor IX concentrates Factor IX concentrates are used in the treatment of congenital factor IX deficiency not responding to FFP, and occasionally in liver disease. These preparations also contain factors II, VII (depending on the method of preparation) and X. Activated clotting factors may also be present, which makes the concentrate potentially thrombogenic but provides a way to bypass the factor VIII requirement in haemophiliacs with antifactor VIII antibodies. Special 'activated' factor IX concentrates are available for this purpose, but must be used with great caution. Freeze-dried fibrinogen Freeze-dried fibrinogen is available for use in congenital fibrinogen deficiency and dysfibrinogenaemia.

Complications of blood transfusion Serological reactions If blood has been incorrectly cross-matched (or not crossmatched), or if (more commonly) there has been a clerical error and the patient has antibodies to donor red cell antigens, rapid complement-dependent lysis of the transfused cells may occur. Rarely, immediate haemolysis may also be due to high-litre anti-A or anti-B IgG antibodies in the donor blood, when group O blood is given to A or B recipients. Symptoms may arise within minutes or up to several hours after the transfusion has started, and include fever and rigors, headache, lumbar pain, abdominal discomfort and vomiting, and chest pain. In severe cases the patient becomes shocked and then suffers acute renal failure and DIC. When an immediate serological reaction is suspected, the transfusion must be stopped immediately and appropriate action taken (Table 23.20). Serological reactions may also be delayed. This occurs when an antibody to donor red cells, which was not present in the patient's serum at the time of transfusion, develops rapidly afterwards. This is almost invariably a secondary

TABLE 23.20 Plan of action for a suspected immediate haemolytic transfusion reaction 1. STOP TRANSFUSION 2. Maintain venous access (give saline initially) 3. Check names, groups and numbers on the blood pack and blood transfusion report forms 4. Return blood pack to laboratory with: Clotted blood sample - re-check group of patient and donor pack - perform a direct antiglobulin test - repeat cross-match and identify any antibodies Heparinised blood sample - check for free Hb in plasma Citrated sample - check clotting screen Sequestrene sample - check [Hb] and platelet count 5. Give intravenous hydrocortisone and chlorpheniramine 6. Maintain venous return if shock develops - give saline, plasma and whole blood if necessary 7. Maintain urine output by using intravenous diuretics after establishment of adequate venous return 8. Replenish clotting factors and platelets if DIC develops

antibody response in previously transfused individuals. Haemolysis usually occurs between 1 and 2 weeks after transfusion. It should also be noted that a transfusion may produce sensitization to donor red cells. Although this may not cause haemolysis, future transfusions may be compromised and in young women there may be a risk of haemolytic disease of the newborn. Febrile reactions In multiply transfused patients febrile reactions may accompany transfusion owing to the development of antibodies to leukocyte and platelet antigens. The fever usually develops several hours after starting the transfusion and may last for up to 12 hours. Slowing the rate of transfusion, and intravenous chlorpheniramine or hydrocortisone, will reduce the problem. The introduction of the routine use of filtered blood has reduced this problem. Infections Blood rarely becomes contaminated with bacteria, but organisms able to grow at 4°C (such as Pseudomonas and coliforms) produce bacteraemic shock and can be rapidly fatal. Many viruses can be transmitted by blood transfusion. Blood donations are screened for hepatitis B and C,

and transmission of these agents is rare. CMV transmission may occur, as the virus can be dormant in leukocytes. In immunocompromised patients without anti-CMV antibodies, and in neonates, blood from CMV-negative donors should be given. The extremely small risk of HIV transmission from blood donated in the UK has been further reduced by screening the donated blood for anti-HIV antibodies. Blood in the UK is not currently screened for HTLV-1. The case for doing so is that the incidence of clinical disease (paraperesis) appears to be higher if the virus is contracted by transfusion rather than in utero or in early life. Infectious mononucleosis may occasionally be transmitted. Other contaminating organisms include Brucella, Plasmodium, Trypanosoma, Leishmania and Filaria. Syphilis transmission is rare, as all blood is prescreened for antibodies to Treponema pallidum and positive units are discarded.

23

Transfusion siderosis Each unit of blood contains about 0.25 g of iron and so, with frequent transfusions, iron overload with parenchymal tissue damage may occur. Serious problems arise after about 30 g of iron accumulation. When repeated transfusion is anticipated, desferrioxamine therapy must therefore be considered. Ion toxicity Blood is stored in citrate, which can chelate calcium and sometimes cause tetany. However, as citrate is rapidly metabolized in the liver, citrate toxicity only occurs in severe liver disease and during rapid and massive blood transfusion. Stored blood leaks [K+] from red cells, which may cause problems in patients who already have a raised plasma [K+], or with massive transfusions, especially exchange transfusion in neonates. Stored blood also contains high levels of NH4+ and should therefore be avoided in liver disease. Problems of massive transfusion Large-volume blood transfusions given over a short period

SUMMARY 7 Complications of blood transfusion • Haemolytic reactions Serological - immediate - delayed - sensitization Thermal - faulty blood warmers • Febrile reactions • Infections • Circulatory overload • Thrombophlebitis at transfusion site • Transfusion siderosis • Air embolism (with use of central lines) • Ion toxicity (e.g. citrate and potassium) • Special problems associated with massive transfusion

1231

of time may be associated with special problems. Where stored blood has been used there is a theoretical risk of toxicity from citrate, hydrogen ions (acidosis) and potassium ions, but these problems are in fact rare. Dilution of platelets and clotting factors does occur, and must be corrected by replacement therapy. Guidelines The incidence of serious hazards of transfusion, such as virus transmission, has decreased markedly in recent decades. The incidence of the wrong blood being given to a patient has not changed, however, and this probably accounts for one death in every 500000 units transfused. For this reason, guidelines have been drawn up in the UK, which include the procedures for requesting blood, collecting pretransfusion samples, compatibility testing, issuing of blood products, their administration and documentation, and the management and reporting of adverse events. Similar guidelines are in place in many other countries. 1

FIG. 23.20 Diagrammatic representation of the prenatal mechanism of haemolytic disease of the newborn (HDN)

FURTHER READING ON BLOOD TRANSFUSION Guidelines. The administration of blood and blood components and the management of transfused patients. Transfusion Med 1999;9: 227-238.

IMMUNE HAEMOLYTIC DISEASE OF THE NEWBORN

Aetiology In immune haemolytic disease of the newborn (HDN), IgG antibodies produced by the mother against fetal red cell antigens cross the placenta and produce haemolysis in the fetus (Fig. 23.20). In 90% of cases the antibodies are directed to antigens of the rhesus group, and severe disease is mainly caused by anti-D antibodies. Other antibodies causing occasional problems are shown in Table 23.21. In the UK, 85% of the population are Rh-positive (D+) and 13% of UK marriages are between a dd (D-) woman and a D+ man. Three in four of their children will be D+. Sensitization of the mother requires the passage of a considerable quantity (approximately 0.5 mL) of fetal cells into the maternal circulation, and this usually happens at birth. Firstborn children are therefore rarely affected. However, the mother is now primed, and can produce a secondary antibody response to the small quantity of fetal red cells

1

1232

MCQ 23.11

TABLE 23.21 Antibodies causing haemolytic disease of the newborn* Anti-rhesus (in order of incidence) Anti-D Anti-C + D Anti-E (Anti-C) (often severe) (Anti-D + E) (Anti-C + E) (Anti-e)

Anti-Kelt Anti-Duffy Anti-Kidd Anti-A + Anti-B

* Parentheses indicate rarity.

that enter the maternal circulation during a subsequent normal pregnancy. Group O mothers are less frequently sensitized if the fetus is group A or, to a lesser extent, group B - presumably because the fetal cells are rapidly cleared from the maternal circulation by naturally occurring antiA and anti-B antibodies. It should also be noted that rhesus sensitization can occur with antepartum haemorrhages, obstetric manipulations, Rh-positive blood transfusions and other blood products. ABO incompatibility is a rare cause of HDN, as most individuals produce only IgM antibodies, which do not cross the placenta. Only occasionally will group O women produce high-titre IgG anti-A or anti-B when carrying an A+ or B+ fetus. It should be noted in these cases that, at birth, the cord cells often give a negative DAT (probably because of the low ABO antigen density on cord cells), and this may make the diagnosis very difficult.

Clinical features

23

The affected fetus becomes anaemic, and produces a reticulocytosis and many nucleated red cells in the peripheral blood (erythroblastosis fetalis). As the anaemia progresses cardiac failure develops, with scalp oedema, pericardial effusions and ascites (hydrops). Hyperbilirubinaemia is not a problem in utero because of placental clearance, but after birth haemolysis continues until all the maternal antibody has been used up, and severe jaundice may develop quickly. High levels of unconjugated bilirubin can cause severe damage to the central nervous system, especially in premature infants.

Approach to the monitoring of pregnancy in Rh-negative women All pregnant women should have a red cell group performed at the booking clinic at 12 weeks' gestation. The serum should also be screened against a cell panel at this stage to look for antibodies, which, if found, must then be identified. This should not be restricted to Rhnegative women (cde/cde), as anti-c antibodies, as well as other rarer antibodies, would then be missed. In the case of Rh-negative women it is also usual to genotype the father to determine whether he is Rh-positive and DD or Dd. Antibody screening should ideally be repeated in Rh-negative women at 24 weeks, 34 weeks and at delivery if it is a first pregnancy, and even more frequently in later pregnancies. If an antibody screen is positive, it should be repeated at 4-weekly intervals throughout the second trimester and at 2-weekly intervals during the last trimester. It must be noted that the level of maternal antibody correlates poorly with the severity of HDN, but rising antibody levels suggest an affected fetus and amniocentesis has traditionally been performed if the anti-D titre rises to greater than 1:16 (4mg/mL). The purpose of amniocentesis is to measure the bile pigment levels in the fetal blood, by determining the absorption at 450 nm. The value obtained must be plotted on a graph of optical density of the amniotic fluid versus gestation, and interpretation is made using well-standardized criteria (Fig. 23.21). If a value is obtained in zone A, the fetus is severely affected and at high risk of death. Therapeutic intervention is therefore necessary. If in zone B, great vigilance is required and amniocentesis should be repeated after 2 weeks. Amniocentesis also allows the rhesus genotype of the fetus to be determined rapidly by DNA techniques when the father is a hereozygote and the phenotype of the fetus is not clear. The previous obstetric history must also be taken into account when deciding if and when to carry out further investigations. In first affected fetuses it is likely that the disease will be mild, whereas it is more likely to be severe in subsequent pregnancies, with a fivefold greater mortality. If a mother has had a previous severely affected fetus, further investigations should be considered even if the antibody litres are low.

FIG. 23.21 Chart of optical density of the amniotic fluid versus gestation, showing ranges of risk A Fetus at high risk. B Fetus at risk. C Fetus at low risk.

Recent attention has focused on non-invasive techniques for determining the severity of an affected fetus. Ultrasound investigation is relatively simple but the presence of ascites, which is usually the first feature of an affected fetus, occurs relatively late, when the haematocrit is already reduced to 15-18%. Doppler measurement of blood flow rates in the middle cerebral artery is a more sensitive measure of developing anaemia, but is not widely available.

Management of HDN Antenatal Intrauterine transfusions can be given to severely affected fetuses, either by the intraperitoneal route from 24 weeks' gestation onward, or by injection (fetoscopic or ultrasound guided) into an umbilical blood vessel from 16 weeks onwards. The blood given is washed O Rh-negative (cde/cde) and is cross-matched with the mother's serum. It should also be from an anti-CMV negative individual. The mainstay of management remains the induction of premature labour. In most severely affected fetuses this is done at 32 weeks, and later in less severely affected fetuses. Postnatal Exchange transfusion should be performed immediately after birth in severely anaemic or hydropic infants. The best indicator of severity at birth is the cord blood haemoglobin concentration: values below 12.5g/dL are indicative of the need for exchange. The bilirubin level is less useful, but a value above 70mmol/L probably indicates the need for exchange. At a later stage bilirubin estimations are paramount, and exchanges must be performed to keep this well below an accepted value, i.e. below 240mmol/L for infants delivered between 30 and 31 weeks, below 290mmol/L for those delivered between 31 and 34 weeks, and below 350mmol/L for 'older' infants. These values should be lowered if the infant is clinically unwell.

1233

In exchange transfusion, fresh blood collected into citrate phosphate dextrose is used. The blood should be O negative, compatible with both the mother's and the infant's serum, and CMV negative. Usually a two-volume exchange (Ivol = wt (kg) x 90 mL) is performed; this removes antibody-coated red cells which would eventually be destroyed, removes unbound antibody and reduces the bilirubin level. In mildly affected infants, phototherapy may augment bilirubin breakdown and avoid the necessity for exchange transfusion.

Prevention of HDN Rh-negative women should not be given Rh-positive blood or blood products. At childbirth, Rh-negative women should be given intramuscular anti-D within 72 hours of delivery of an Rh-positive child, in order to neutralize any fetal cells in the circulation and prevent sensitization. The recommended dose of 500 iu should be sufficient to neutralize approximately 4mL of fetal blood. A Kleihauer test should be performed on the mother's blood (fetal cells stain darkly, adult cells very weakly) and, if fetal cells are detected at a frequency of more than 1 in 600, further anti-D should be given. Anti-D should also be given to Rh-negative women for threatened abortions, abortions, haemorrhages and obstetric manoeuvres: 250 iu are given before 20 weeks' gestation and 500 iu thereafter. The antibody crosses the placenta only slowly and the fetus is not harmed. Despite such measures, nearly 1% of women still become sensitized during their first pregnancy. It has therefore recently been recommended that all Rh-negative women with a potential Rh-positive child should receive at least 500 iu of anti-D at 28 weeks' and at 34-36 weeks' gestation, to minimize sensitization from silent fetal to maternal blood transfer in utero. One problem with this strategy is that this prophylactic antibody administration can interfere with the determination of immune antibody formation. It is most important, therefore, that the 28-week prophylactic antibody is not given until the serum sample for detection of immune antibodies has been taken. 1

NON-MALIGNANT LEUKOCYTE ABNORMALITIES

Leukocyte abnormalities can be considered as qualitative or quantitative.

1234

1

MCQ 23.12

4

MCQ 23.13

2

Fig. 4.11

0 Fig. 4.10

Infection is the commonest cause and the response usually varies with different organisms and at different phases of the disease. Thus, acute pyogenic infections cause an initial neutrophilia, but may give rise to monocytosis in the recovery period. Parasitic infections typically give rise to eosinophilia and viral infections to lymphocytosis, although considerable variation to this general rule may occur. The reactive lymphocytes may appear atypical, and this is particularly prominent in infectious mononucleosis. Neutrophilia also occurs in response to all forms of tissue injury or inflammation, whereas eosinophilia is usually associated with inflammation that has an allergic basis. Basophilia is only rarely a reactive condition, and always suggests an underlying myeloproliferative disorder. The causes of a decreased neutrophil or lymphocyte count are shown in Table 23.22. Minor components of the leukocyte population may also decrease, but this is not usually detected on a routine differential count. Although the cytopenias must be due to either decreased production or increased loss/destruction, it is difficult to classify the causes in this way as some are multifactorial (e.g. neutropenia in acute infections) and the mechanism is not always well understood (e.g. lymphopenia in advanced Hodgkin's

TABLE 23.22 Causes of low leukocyte count in the peripheral blood Neutrophils

Lymphocytes

Marrow aplasia Marrow infiltration Megaloblastic anaemia Cyclical neutropenia Congenital agranulocytosis (Kostman's syndrome)

Severe marrow aplasia Severe marrow intiltration Severe megaloblastic anamia

Some acute infections Typhoid, brucella, miliary TB Protozoa Fungi Rickettsia Viral HIV infection Collagen disorders Exposure to high-dose irradiation Immune destruction Idiopathic Associated with drugs Hypersplenism

Congenital immunodeficiency disorders Rarely in acute infections

HIV infection Collagen disorders Lymphomas Exposure to irradiation Immune destruction

Hypersplenism Intestinal loss due to lymphatic obstruction

Bold type indicates that the relevant cytopenia is common in that condition, it does not mean that the particular condition is a common cause of the cytopenia

23

TABLE 23.23 Aetiology of phagocytic functional abnormalities Abnormal phagocytic function

Disorder Primary

Secondary

Movement

Lazy leukocyte syndrome

Renal failure Diabetes Malnutrition Immunoglobulin and complement (opsonins) deficiency

Recognition

Phagocytosis

Chediak-Higashi syndrome

Severe malnutrition Vitamin E deficiency

Killing

Chronic granulomatous disease

Severe iron deficiency Post-irradiation

disease). Qualitative lymphocyte abnormalities are discussed in Chapter 4. Functional abnormalities of phagocytes also occur and may be primary or secondary (Table 23.23). The primary abnormalities include: • Chronic granulomatous disease is rare, with an incidence of approximately 1 per million per annum. There is a reduced or absent respiratory burst activity in neutrophils, eosinophils and monocytes, such that phagocytosis does not lead to free radical production and bacterial killing. It is X-linked in about 60% of cases, and in the remainder is autosomal recessive. The variable inheritance depends on which component of the oxidase system is affected, with the X-linked form being due to an abnormality of the gp91phox subunit of cytochrome b558 (Fig. 23.22). The diagnosis is made by demonstration of an inability of the neutrophils to reduce nitroblue tetrazolium (NET test). 2 The disease usually becomes apparent in the first year of life, when recurrent infections develop with catalase-positive organisms such as Staphyloccocus aureus, Gram-negative bacilli and Aspergillus. The increased rate of infections is accompanied by a poorly understood failure to switch off the inflammatory process, so that granulomata develop. Chronic ill-health occurs, and most patients eventually die from overwhelming infection. © Treatment is mainly with antibiotics, although in some forms of the disease treatment with interferon y may reduce the frequency of infections. Successful bone marrow transplantation has been carried out in some patients, and this disease is one of the most promising targets for gene therapy. • Chediak-Higashi syndrome, a rare autosomal recessive disorder in which there is oculocutaneous albinism, neurological deficit, a bleeding tendency and frequent pyogenic infections. Inclusion bodies are visible in the

FIG. 23.22 The oxidase system A Resting cell: The shaded components of the cytochrome b558 complex that may be involved in chronic granulomatous disease are shown. B Stimulated cell: On stimulation the components of cytochrome b558 associate. NADPH releases hydrogen and an electron allowing the formation of oxygen-free radicals that are bactericidae.

leukocytes. It is caused by mutations in the lysosomal trafficking gene known as LYST. The secondary causes of abnormal neutrophil function are extensive, but their true significance in vivo is not clear. 4

HAEMATOLOGICAL MALIGNANCY The nature and aetiology of haematological malignancies have been more extensively studied than in most other tumours, largely because of the ease with which singlecell suspensions can be obtained from blood, marrow and lymph nodes. The insights gained from these studies can be applied to many other types of neoplasia.

Pathogenesis Nearly all haematological malignancies examined have been shown to be clonal in origin. The B-cell malignancies express light-cham-restricted surface immunoglobulin (if

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the cells are sufficiently mature to express surface immunoglobulin), and nearly all cases show a clonal rearrangement of the immunoglobulin genes. Similarly, T-cell malignancies have been shown to have clonal rearrangements of the T-cell antigen receptor genes. Some of these malignancies (and also the myeloid leukaemias) may have clonal chromosomal abnormalities, such as alterations in chromosome number or chromosome translocations. Myeloproliferative disorders such as polycythaemia rubra vera were shown to be clonal by studies in black women who are heterozygous for G6PD isoenzymes. G6PD is coded on the X-chromosome. Because one of the two X chromosomes in women is inactivated in each cell early in embryogenesis, a clonal population expresses only one G6PD isoenzyme. More recent studies have looked at this X-chromosome inactivation at the DNA or RNA level, which allows most females to be investigated. These studies have confirmed that many cases of myeloproliferative disease are clonal, but have also shown that a significant proportion of patients diagnosed with essential thrombocythaemia do not have a clonal population of platelets or other myeloid cells. The phenotype of malignant cells is usually similar to that of their normal counterparts. The phenotype of blast cells in acute myeloid leukaemia (AML) is thus usually identical to that of a rare population of normal primitive cells, although the Auer rods sometimes seen in AML cells are not seen in normal adult cells. The common-ALL antigen (p. 1247) is a normal early lymphoid differentiation antigen. Leukaemic cells may, however, express an unusual combination of antigens not seen in normal cells. Blast cells in acute leukaemia are not completely homogeneous. Some cells have a more primitive phenotype than the main cell population. In chronic myeloid leukaemia (CML), G6PD isoenzyme studies have shown that, although most malignant cells are late granulocytic cells, the clonal disorder also affects red cells, platelets and some B lymphocytes. The 'leukaemic hit' must therefore have occurred at the multipotential stem cell level. Similar findings have been reported in cases of adult AML. The oncogenic event occurs at a multipotential stem cell level, but the malignant cells are still able to differentiate in part down all the myeloid pathways. A 'differentiation block' is, however, present at the myeloblast stage, and these cells therefore accumulate. This level of differentiation block may change over time, and the blastic transformation that occurs in CML probably represents such a process. In vitro studies have demonstrated that leukaemic cell growth is often not autonomous. In polycythaemia rubra vera (PRV) the erythroid progenitors, like their normal counterparts, will only grow in the presence of erythropoietin, although their sensitivity to erythropoietin and other growth factors is considerably greater than normal. The growth rate of leukaemic cells is also thought to be about the same as (or even slower than) that of normal cells, so that expansion of the leukaemic mass is often not due to markedly accelerated growth. In chronic myeloid leukaemia it is possible that there is an alteration in the

SUMMARY 8 Features of haematological

malignancies

• Clonal • Malignant cells have normal counterparts • Malignant populations have stem cells more primitive than the majority of the malignant population • The level of 'differentiation block' may change • Growth is not autonomous • The growth rate is not necessarily higher than in normal cellular counterparts • Growth rates are not always constant

balance between stem cell self-renewal and commitment/ differentiation. Initially, a malignant clone with a slightly higher self-renewal rate will produce fewer end cells, but eventually it will produce an exponentially increasing population of end cells. A similar process may occur in the acute leukaemias, but here cell population growth is also affected by the differentiation block, which reduces the cell death rate associated with terminal differentiation. In some of the haematological malignancies, specific gene abnormalities (e.g. upregulation of the bcl2 gene in follicular lymphomas associated with t[14;18]) reduce the normally expected level of apoptosis. It should be noted that the growth rate in the haematological malignancies is not necessarily constant over time. In multiple myeloma, for example, treatment will often induce a plateau phase, during which the tumour is kinetically quiescent and resistant to further chemotherapy. If chemotherapy is stopped at this stage the plateau phase is often maintained for many months.

Aetiology The aetiological factors associated with haematological malignancies have been widely studied. Hereditary/congenital factors Familial tendencies to acquire haematological malignancies are relatively weak, with the exception of identical twins. Here, if one twin develops acute leukaemia the risk of the remaining twin is reported to be 25%, although most of this high risk is accounted for by twins presenting with leukaemia in the first 18 months of life, where there has been prenatal transmission of the leukaemia via the linked circulation. There are in addition a variety of congenital disorders, such as Down's syndrome, Bloom's syndrome and Fanconi's anaemia, in which the incidence of leukaemia is markedly increased. Ionizing radiation and drugs Exposure to excessive ionizing radiation increases the risk of all haematological malignancies except chronic lymphocytic leukaemia. Many drugs have also been proposed as carcinogens, but the data are only firm for benzene. Both ionizing radiation and benzene directly damage DNA.

Genetic abnormalities Gross chromosomal abnormalities, such as additional chromosomes, deletions or major translocations, can be detected in many cases of leukaemia or lymphoma, and certain of these have prognostic significance. Thus, acute lymphoblastic leukaemia patients with a t(4;ll) translocation have a very poor prognosis, whereas patients with hyperdiploid (more than 50 chromosomes) blast cells respond very well to treatment. At a finer level dysregulation of multiple genes can often be detected, many of which are so-called proto-oncogenes. Of particular interest in the haematological malignancies is the frequent presence of balanced translocations which result in upregulation of the expression of a protooncogene, as a result of its becoming sited under the influence of a different promoter. In Burkitt's lymphoma, for example, most patients have a translocation of the long arm of chromosome 8 to the long arm of chromosome 14, close to the region coding for immunoglobulin heavy chains. The breakpoint on chromosome 8 is close to the 8q 24 band, which is the site of the c-myc oncogene, and the high c-myc expression found in this tumour is due to the ectopic siting of the c-myc oncogene under the influence of the immunoglobulin heavy-chain promoter which is active in B cells. In some situations a translocation can result in a gene being expressed that is not usually expressed at all in that cell lineage or tissue type. In other circumstances the aberrant location of a proto-oncogene can lead to the production of an abnormal fusion mRNA species and protein product. Thus, in the Philadelphia (Ph') chromosome, which is present in most cases of CML, there is a translocation between chromosome 9 and chromosome 22. The translocation site on chromosome 9 is within the c-abl sequence, at a splicing site between the 5' and 3' ends of this gene. In the Ph' chromosome, a region of chromosome 22 known as the breakpoint cluster region (bcr), becomes joined to the 3' end of c-abl, leading to the production of a unique fusion gene product (Fig. 23.23). The precise functions of many oncogene products are still unknown, but most of the proto-oncogenes studied to date have been found to code for growth factor receptors, tyrosine kinases, other signal transduction molecules or transcription factors. In addition to the possible role of structural abnormalities in, or ectopic siting of, protooncogenes in malignant transformation, there may be further gene sequences which normally suppress or inhibit tumour formation. Such genes have been called antioncogenes, and mutations in these genes might also give rise to malignant change. Mutations of the p53 gene have been implicated in some cases of blastic transformation in CML and some types of high-grade non-Hodgkin's lymphoma, and absence of the retinoblastoma gene product has been found in some AMLs. Although many malignancies in the animal kingdom can be transmitted by retroviruses containing sequences similar to cellular proto-oncogenes, this has not been

23

FIG. 23.23 Diagrammatic representation of c-afl/gene A in the normal gene there is variable spacing to give four species of mRNA. B In the Philadelphia (Ph') chromosome the bcr from chromosome 22 joins the 3' end of the c-abl gene to give a novel hybrid gene.

described in humans. Human T-cell lymphotrophic virus 1 (HTLV-1) is a retrovirus and is undoubtedly associated with certain T-cell leukaemia/lymphomas, but it does not contain a gene sequence with a normal cellular counterpart. The precise mechanism of oncogenesis is not known, but may involve an indirect increase in growth factor (interleukin-2) receptor expression. The vast majority of patients infected with HTLV-1 do not develop lymphoproliferative diseases. HTLV-1 neoplasms none the less comprise a large proportion of the haematological malignancies in southwest Japan and the Caribbean basin, but only a small proportion elsewhere. The Epstein-Barr virus is associated with Burkitt's lymphoma. The mechanism of transformation, which occurs in small numbers of individuals (mainly in areas of Africa), is again obscure. The virus has also been implicated in the pathogenesis of non-Hodgkin's lymphoma in immunosuppressed patients and some cases of Hodgkin's disease.

SUMMARY 9 Aetiological factors in haemotological malignancies • • • •

Familial and congenital associations Ionizing irradiation Chemical carcinogens Chromosome abnormalities including over-expression of protooncogenes • Viruses: HTLV-1, EBV

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MYELOPROLIFERATIVE DISORDERS The myeloproliferative disorders are defined as neoplastic proliferations of the myeloid stem cell and its progeny. This is a simplification, in that the multipotential stem cell may also be involved in the malignant process, with additional involvement of the lymphocyte series. Although the level of leukaemic transformation is at the most primitive stem cell level, the individual disease entities are recognized by the predominant cell type accumulating in the blood and marrow (Fig. 23.24). Intermediate states and transitions between one entity and another may occur. AML is clearly a myeloproliferative disorder, although it is common to consider only the chronic proliferations under this heading. Fibrosis frequently occurs as a reaction to the malignant proliferation, especially if there is a prominent megakaryocytic element. Occasionally, marked fibrosis is the presenting feature, and it is then known as primary myelofibrosis; it is, none the less, a secondary process.

CHRONIC MYELOID LEUKAEMIA Chronic myeloid leukaemia (CML) is a disorder of the multipotent stem cell in which the myeloid progenitor cell compartment, and subsequently the maturing granulocytic cell compartment, becomes grossly expanded. The erythroid, megakaryocytic and B-lymphoid cells are also part of the malignant clone; their accumulation is not usually prominent, although polycythaemia and thrombocytosis may occur. Over 90% of cases have the Philadelphia chromosome, in which there is a translocation from the long arm of chromosome 22 to the long arm of chromosome 9, with the resultant production of an abnormal c-abl gene product (p. 1237) with a dysregulated kinase that is constitutively active, located within the cytoplasm, and has increased activity compared to the normal protein. Even in cases of apparent Philadelphia-negative CML, detailed molecular analysis has often shown a translocation involving the bcr and abl genes. The mechanism by which the bcr-abl kinase is associated with malignant transformation is not definitely known, but may involve reduced apoptosis (programmed cell death).

Clinical features of chronic-phase CML CML occurs predominantly in those over 30 years of age, although childhood variants do occur (p. 1240). There is a slight male predominance and the annual incidence is reported to be about 1 per 100000 in the UK and 1.6 per

1

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Fig. 23.5

FIG. 23.24 The myeloproliferative disorders

100000 in the US. CML is initially an indolent disease that can, in the chronic phase, be readily controlled by chemotherapy, but transformation to an accelerated phase is almost invariable. Typically, there is slow onset of symptoms of anaemia, often accompanied by fatigue and weight loss. The spleen is almost always palpable and may become enormous. Bone and splenic discomfort may occur, and occasionally severe splenic pain due to infarction may arise. Lymphadenopathy does not generally occur. Infections and bleeding are rare at presentation.

Haematological features of the chronic phase 1 The most striking peripheral blood abnormality is the rise in white cell count; there is an increase in neutrophils, basophils and eosinophils. Many precursor cells, particularly myelocytes, are present, and up to 5% of the circulating leukocytes may be blast cells. The haemoglobin tends to fall as the white cell count rises, although occasionally it may be high at presentation. The platelet count is variable. The bone marrow shows myeloid hyperplasia and sometimes an increase in reticulin.

Differential diagnosis The main differential diagnosis of CML is that of reactive leukocytosis due to infection or inflammation. A leukaemoid reaction (a non-neoplastic leukocytosis of marked degree) can usually be distinguished from CML, as splenomegaly is not common in the former, and eosinophilia and basophilia are not usually a component of the leukocyte-

RECENT ADVANCES IN CML STI 571 produces a high response rate in chronic-phase disease, even in patients resistant to interferon. When used as initial therapy it results in more good remissions and longer disease-free survival than a interferon. The impact on overall survival is not yet known, but there are good grounds for optimism.

sis. The neutrophil alkaline phosphatase (NAP) level (detected by cytochemical staining) is typically very low in CML and high in reactive leukocytoses. The final arbiter in difficult cases is the demonstration of the Philadelphia chromosome or bcr-abl rearrangement in CML. Chronic myelomonocytic leukaemia with a high count may also cause confusion, but in this condition monocytes are plentiful and eosinophils and basophils are not usually increased (p. 1245). Primary myelofibrosis may also be associated with an initial leukocytosis, but in this disease there are also usually red cell changes attributable to marrow fibrosis, the NAP score is raised, and the Philadelphia chromosome is absent.

Management of chronic phase The options for treating chronic-phase CML vary from supportive care and relatively non-toxic oral cytotoxic agents through to mismatched unrelated donor transplants. There are no randomized trials comparing transplant and non-transplant options, and the choice of whether or not to transplant requires constant re-evaluation as nontransplant options improve and safer transplant strategies are developed. Non-transplant options The non-transplant options have been essentially palliative. Blood transfusions should be given as necessary and any infections treated vigorously. Allopurinol is often given to prevent secondary gout, especially if there is hyperuricaemia. Cytotoxic therapy is given to normalize the blood count and shrink the spleen. Occasionally, a very high leukocyte count at presentation can lead to hyperviscosity and thrombotic events such as confusion and priapism. Should this occur, or if the leukocyte count is over 200 x 109/L, leukopheresis is advisable until chemotherapy has decreased the rate of white cell production. Busulphan was introduced as the treatment of choice in the 1950s, but this was replaced in the 1970s by hydroxyurea, which has superior efficacy and fewer side-effects. These treatments may induce haematological remissions but the malignant clone can still be detected in the bone marrow by cytogenetic studies. oc-Interferon was introduced for the treatment of chronic-phase CML in the 1980s, and randomized trials have demonstrated a haematological response in most patients, major cytogenetic responses in about one-third, and improved overall

survival compared to hydroxyurea. Survival is generally longest in those who have a major or complete cytogenetic response. In the 1990s the addition of low-dose cytosine arabinoside to cc-interferon was reported to increase response rates further and improve survival, but at the cost of greater side-effects. More recently a specific tyrosine kinase inhibitor with specific activity against abl (STI 571) has been added to the armamentarium. The preliminary results are very encouraging, and many patients are reported to achieve a cytogenetic remission. Transplant option For many younger patients who have an HLA-identical sibling high-dose chemo/radiotherapy and allogeneic bone marrow transplantation during the chronic phase has been the treatment of choice. A 10-year disease-free survival of about 50% has been achieved in several large series. Comparison with the results of non-transplant strategies shows a higher initial mortality with transplantation, but better long-term overall survival. Good results have also been achieved using well-matched unrelated donors, but the situation with mismatched transplants is less clear. Most studies have suggested that the optimal results of transplantation are obtained when it is performed in the first year from diagnosis, which inevitably poses a dilemma for both patient and physican, balancing the short-term risks against potential long-term gains. The recent advent of STI 571 is necessitating further re-evaluation of the role and timing of transplantation. The effect of a-interferon therapy prior to transplantation is controversial, but some studies have suggested that an extended period of interferon therapy, or its use immediately before transplantation, can have a deleterious effect. A common practice, therefore, is to use hydroxyurea rather than interferon at diagnosis if it is planned to proceed immediately to a transplant and, if a patient is already on interferon, to discontinue this for at least 3 months before the transplant. The most commonly used transplant cytotoxic regimens are cyclophosphamide plus total body irradiation, or cyclophosphamide plus busulphan. The results are broadly similar. When cyclosporin (with or without methotrexate) is used as graft-versus-host disease (GVHD) prophylaxis, GVHD remains a significant problem but the rate of relapse of leukaemia is low (10-15% with matched sibling donors). Depletion of T cells from the donor bone marrow reduces the incidence of GVHD but markedly increases the risk of relapse. This illustrates the importance in CML of a graft-versus-leukaemia (GVL) effect in preventing relapse after transplantation. Patients who relapse after transplantation may respond to withdrawal of immunosuppression if they are still receiving it. Approximately 80% of patients will achieve a remission with donor lymphocyte infusions (DLI), whereby lymphocytes from the donor of the transplant are used to boost the GVL effect. This approach is, however, complicated by the risk of developing aplasia or life-threatening GVHD. These risks are greatest when

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large numbers of lymphocytes are infused soon after the transplant. Lymphocyte infusion should either be delayed for at least a year from transplantation, or should first be given at very low doses and then slowly titrated upward over a period of many months, depending on the response and the side-effects experienced. Smaller lymphocyte infusions are probably required for small-volume disease. There may therefore be a role for monitoring disease recurrence post transplantation by polymerase chain reaction (PCR) of the bcr-abl fusion gene. To date, DLIinduced remissions have proved to be durable in over 80% of patients who achieve complete remission.

Clinical features of acute transformation Acute transformation of CML may take the form of increasing myelofibrosis or transition to an acute leukaemia. On average it occurs within 3 years of onset, although there is considerable individual variation. Many clinical events may herald transformation, including increasing anaemia, fever, increasing spleen size and bone pain. A patient is considered to have entered an accelerated phase when the therapy (which was previously effective) can no longer control the symptoms, signs and haematological features of the disease. In a myelofibrotic transformation there is progressive anaemia, thrombocytopenia, and possibly even neutropenia. The spleen enlarges markedly and may cause severe discomfort. In blastic transformation the features are those of marrow failure, as they are with other types of acute leukaemia (p. 1245).

Haematological features of acute transformation Acute transformation may be heralded by a fall in the haemoglobin or platelet count, or by a rise in the white cell count while still on therapy. There may be a rise in the basophil and blast cell count and in the NAP score. In a myelofibrotic transformation the blood picture is similar to that seen in any case of marrow fibrosis, with leukoerythroblastic anaemia (primitive red and white cell precursors in the blood) and marked poikilocytosis with teardrop forms. In a blastic crisis blast cells predominate in the blood and marrow. In about 80% of cases these are myeloblasts, but in the remaining 20% of cases they are pre-B lymphoblasts, which express the common acute lymphoblastic leukaemia antigen (CD10). This illustrates the fact that CML involves a multipotent stem cell with both myeloid and lymphoid potential. At the time of accelerated phase or blast crisis, cytogenetic analysis frequently reveals clonal abnormalities additional to the Philadelphia chromosome.

1 MCQ 23.14 1240

2

Case 23.3

0 Fig. 23.6

Management of the acute phase In a myelofibrotic transformation transfusion should be given for symptomatic anaemia. Splenectomy must occasionally be considered for spleen pain, or if splenic pooling in a large spleen is considered to contribute to the anaemia or other cytopenia. Local irradiation may ease splenic pain, but it rarely causes a long-lasting reduction of spleen size. In blastic transformation acute leukaemia therapy of appropriate type is given (p. 1245). Remissions, in which there is return of chronic-phase CML, may be achieved, but they are usually brief in duration. Allogeneic transplantation in acute-phase CML has not been very successful. 1

Chronic myeloproliferative disorders in childhood Diseases resembling CML may occur (rarely) in infancy and childhood. So-called juvenile CML presents in infancy with anaemia, infection, facial rashes, lymphadenopathy and hepatosplenomegaly. The white cell count is elevated, with a prominent monocytosis. The HbF is markedly raised in most cases. Mutations of the neurofibromatosis-1 gene (NF-1) are frequent in the malignant cells. The disease is rapidly progressive, with death usually due to marrow failure rather than transformation to acute leukaemia. Therapy is currently unsatisfactory. A variant form of juvenile CML which occurs in infancy is the myeloproliferative disease associated with monosomy 7 in the malignant clone. The HbF level is not markedly raised in this condition. The prognosis is again very poor. Adult-type CML with a Philadelphia chromosome occasionally occurs in older children and has a natural history similar to that seen in adults.

FURTHER READING ON CHRONIC MYELOID LEUKAEMIA Druker B J, Lydon N B 2000 Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myeloid leukaemia. J Clin Invest 105: 3-7 Silver R T et al 1999 An evidenced-based analysis of the effect of busulphan, hydroxyurea, interferon, and allogeneic bone marrow transplantation in treating the chronic phase of chronic myeloid leukaemia. Blood 94:1517-1536

POLYCYTHAEMIA RUBRA VERA 2 Polycythaemia denotes an increase in the red cell mass. If due to a malignant myeloproliferative disorder, this is known as polycythaemia rubra vera (PRV); if due to a raised level of erythropoietin, it is known as secondary polycythaemia. A raised haemoglobin concentration may also occur as a result of decreased plasma volume without an increase in the red cell mass; this is known as pseudopolycythaemia or stress polycythaemia (Fig. 23.25). PRV is

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FIG. 23.25 Approach to the diagnosis of a raised haemoglobin (Hb) level

TABLE 23.24 Clinical features of polycythaemia rubra vera Cause

Effect

Haemopoietic proliferation

Gout Hepatosplenomegaly Splenomegaly

Increased haematocrit

Hypertension Cerebral ischaemia Myocardial ischaemia Other thrombotic events

Multifactorial

Pruritus Peptic ulceration Bleeding

a malignant disorder of the multipotential haemopoietic stem cell, with predominant expansion of the mature erythroid cell population. The erythroid progenitors have increased sensitivity to erythropoietin and other growth factors, although the mechanism is not known. There is often also an increase in granulocytic cells and platelets, in keeping with the stem cell nature of this disease.

Clinical features PRV is largely a disease of the middle-aged and elderly. It has been reported slightly more often in males than in females. The symptoms and signs of the disease © are shown in Table 23.24, but it should be noted that symptoms may be minimal. Splenomegaly is present in 75% of cases, but diagnostic difficulties arise mainly in patients without splenomegaly. The major symptoms and causes of death are due to the hyperviscosity associated with a raised haematocrit (Fig. 23.26A). Despite the elevated [Hb],

FIG. 23.26 Relationship of (A) blood viscosity and (B) cerebral blood flow to the haematocrit (Hct) As the haematocrit rises, there is a marked rise in viscosity and fall in blood flow.

blood flow and oxygen delivery to critical organs are actually reduced, particularly to the brain (Fig. 23.26B). Pruritus is common and may in part be related to basophil production; iron deficiency may exacerbate this complaint. Peptic ulceration is very common. This is mainly due to hyperviscosity, but may be exacerbated by excessive histamine release from basophils. Gastrointestinal bleeding from gastric erosions is not infrequent.

Haematological features Haematological investigations show that the [Hb] and red cell count are usually raised, but if iron deficiency occurs the [Hb] may fall to within the normal range. The red cells are then microcytic and the red cell count remains high. The neutrophil count is modestly raised in three-quarters of patients and the platelet count in about half. The increased neutrophil production gives rise to a raised Bi2 level, secondary to an increased B12-binding protein release. The NAP score is usually raised (unlike the situation in CML). The bone marrow shows gross erythroid hyperplasia. Some fibrosis may be apparent. Chromosome analysis is usually normal at presentation.

Diagnosis The first step in diagnosis is to demonstrate a raised red cell mass. The patient's red cells are labelled with 51Cr, the total radioactivity bound to the red cells measured, and the

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TABLE 23.25 National (USA) PRV Study Group criteria for the diagnosis of polycythaemia rubra vera A

Red cell mass Normal 02 saturation

B

Splenomegaly Platelets Leukocytes (more than 12 x 109/L) NAP score B12 (more than 900 pg/mL)

C

PRV is diagnosed if both A and B group symptoms are present; or if group A symptoms are present with any two symptoms from group C.

red cells reinjected. Samples are taken after equilibration and the red cell mass calculated from: Red cell mass = Total counts/min injected x haematocrit Counts/min per mL of sample The result is expressed in mL/kg body weight. The next stage is to exclude secondary polycythaemia. The Pao2 should be measured and renal ultrasound performed. Polycystic kidneys and even hydronephrosis can cause a rise in erythropoietin, although polycythaemia of renal origin usually indicates a renal tumour. Other investigations to exclude an underlying cause of polycythaemia should be performed if the clinical situation merits it. If there is no splenomegaly and no raised white cell or platelet count, particular care must be taken to exclude a secondary cause. An Hb-oxygen dissociation curve is essential (especially in younger patients) to exclude the possibility of a highaffinity haemoglobin. This is an inherited abnormality which gives rise to tissue hypoxia in the presence of a normal Pao2. Erythropoietin levels are low in PRV, and this may be of diagnostic value provided assay systems are used that are sensitive in the low/normal range. The criteria adopted for the diagnosis of PRV are shown in Table 23.25. Patients with a raised red cell mass and normal Pao2 who do not have splenomegaly or two category C features should be referred to as having idiopathic erythrocytosis. Although most patients will develop a myeloproliferative disorder, this is not invariable and they should not therefore receive cytoreductive therapy at this stage. Some patients with idiopathic erythrocytosis have been shown to have a truncation mutation in the erythropoietin receptor gene, which prevents adequate downregulation of erythropoietin-induced signalling events.

1

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Case 23.3

2

MCQ 23.15

Management Supportive measures should include allopurinol for the prevention of secondary gout, especially if the uric acid level is high or if cytoreductive therapy is to be commenced. Antihistamines may help pruritus, and the symptom often improves with control of the disorder. Once PRV has been diagnosed, venesection should be commenced. Approximately one unit of blood should be removed every second day until a normal haematocrit is obtained. Younger patients may tolerate more intensive initial venesection, but in the elderly the converse applies. Regular venesection alone can also be used to maintain the haematocrit below 0.46-0.48. Venesection may cause a thrombocytosis, and cytoreductive therapy should be instituted if platelet levels rise above 600 x 109/L, as this may exacerbate the thrombotic tendency of PRV. Some authorities advocate the use of regular low-dose aspirin therapy to reduce the risks of thrombosis, although its value is unproven. Cytoreductive therapy is usually with hydroxyurea and rarely with an alkylating agent such as busulphan. 32 P (3-8 mCi) may also be used, especially in the elderly. It is given as a single i.v. bolus and results in the suppression of haemopoiesis, with minimal systemic disturbance. The injection can be repeated if necessary, but only after an interval of several months as the full effects of 32P may take this long to be seen. It is usual to discontinue 32P when a total dose of 30mCi has been given. Prognosis

Untreated, the median survival is only 2 years, most deaths being due to strokes and myocardial infarctions. With adequate therapy, however, the median survival is over 13 years. About 10% of cases transform to a myelofibrotic state and a similar number transform to an acute leukaemia (usually myeloid). Leukaemic transformation is higher in patients receiving cytoreductive therapy, particularly with 32P, which is avoided in younger patients. It is not fully clear whether or not hydroxyurea increases the risk of secondary leukaemia above that intrinsic to PRV itself. 1

Management of other forms of polycythaemia The problems of hyperviscosity in other forms of polycythaemia are similar to those in PRV. Patients with idiopathic erythrocytosis and pseudopolycythaemia should be venesected to achieve a haematocrit below 0.48. In secondary polycythaemia the situation is more complex, as erythrocytosis is secondary to hypoxia. None the less, the increased oxygen-carrying capacity of the erythrocytosis is often more than offset by the decreased blood flow to critical organs; a trial of venesection is worthwhile in patients with neurological symptoms. It can be very difficult to maintain a lowered haematocrit. 2

ESSENTIAL THROMBOCYTHAEMIA

Essential thrombocythaemia (ET) is a myeloproliferative disorder in which there is excessive proliferation of the megakaryocyte series. The megakaryocyte progenitors frequently show increased sensitivity to thrombopoietin and other growth factors in vitro, and the erythroid progenitors may show hypersensitivity to erythropoietin, as in PRV. It was considered to be a form of malignant transformation of the haemopoietic stem cell, but recent studies using X-linked chromosome inactivation patterns suggest that a significant proportion of cases have polyclonal haemopoiesis and are therefore not malignant. ET occurs predominantly in the middle-aged and elderly, with a slight predominance in females. The clinical features are shown in Table 23.26. Splenomegaly may be present, but is frequently absent owing to repeated infarction. The [Hb] is often reduced, especially if there is iron deficiency. The red cells frequently display the features of hyposplenism. The white cell count is often modestly raised and the NAP score increased. The platelet count is usually in excess of 1000 x 109/L. The bone marrow is hypercellular, with a marked proliferation of megakaryocytes, which tend to be present in clusters; myelofibrosis is often present.

Diagnosis The diagnosis of ET can be difficult, especially when the thrombocytosis is modest and there is no splenomegaly. Causes of secondary thrombocytosis must be excluded (p. 1271). Cell culture studies (seeking growth factor hypersensitivity) and platelet function tests (may be an aggregation defect in ET) can be helpful, but these tests are not totally reliable and can give false positive information.

60 years, and a platelet count in excess of 1500 x 109/L. The most commonly used platelet-lowering agents are hydroxyurea and the recently introduced anagrelide. This is a phosphodiesterase inhibitor which prevents platelet formation from megakaryocytes but does not reduce the megakaryocyte mass. Occasionally other agents, such as oc-interferon, busulphan or 32P, may be required. It is usual to attempt to reduce the platelet count below 600 x 109/L, and probably best to get it into the normal range. Prolonged survival is usual in this disorder, but there is a continuing risk of thrombosis even with therapy. Transformation to acute leukaemia does occur but is rare in patients treated only with hydroxyurea, anagrelide or ainterferon. Myelofibrosis may also occur.

23

PRIMARY MYELOFIBROSIS Primary myelofibrosis is a misnomer in that it is a reaction to an underlying myeloproliferative disorder (although this primary cause may be occult). The disease mainly affects the middle-aged and elderly, and presents with anaemia due to marrow failure and massive splenomegaly. The blood film reveals a leukoerythroblastic anaemia. A bone marrow aspirate is usually dry and a trephine biopsy shows extensive fibrosis. The diagnosis is not usually difficult, but it should be remembered that infections (particularly tuberculosis) can cause extensive marrow fibrosis. Treatment is largely supportive, with regular transfusions. Splenectomy may be indicated if the large spleen is causing local symptoms, if there is an excessive transfusion requirement, or if there is marked granulocytopenia or thrombocytopenia. The median survival is approximately 5 years. Progression to acute leukaemia occurs in 5-10% of cases.

Management Patients with a raised platelet count should probably all receive aspirin therapy unless there is a history of bleeding. Any patient at a high risk of thrombosis should also receive platelet-lowering agents. Factors indicative of high risk include a previous thrombotic episode, age over

TABLE 23.26 Clinical features of essential thrombocythaemia Cause

Effect

Myeloproliferation

Anaemia Splenomegaly (frequently absent)

High/abnormal platelets

Arterial and venous thromboses Haemorrhage Peptic ulceration

Multifactorial

ACUTE LEUKAEMIA

In acute leukaemia there is an accumulation in the blood and marrow of primitive haemopoietic cells (blast cells). Untreated, the course is rapidly progressive in the large majority of patients. The disease is rare, with an annual incidence of 4.4 per 100000, although in children acute leukaemia - particularly acute lymphoblastic leukaemia is the commonest form of malignancy. Acute leukaemia is divided into: • Acute lymphoblastic leukaemia (ALL) • Acute myeloid leukaemia (AML), which is also called acute non-lymphoblastic leukaemia (ANLL). Each broad category can be further divided using morphological, cytochemical, immunological and genetic criteria.

1243

Clinical features Acute leukaemia typically presents with the features of marrow failure - anaemia, infection and bleeding. The latter may be particularly severe in promyelocytic variants of AML(M3), where disseminated intravascular coagulation is a common complication. 1 In ALL onset is nearly always rapid, but there may be a preceding myelodysplastic phase in AML, with variable cytopenias lasting months or even years. In ALL there is no such preleukaemia phase, although occasional cases present with an aplastic picture; the malignant proliferation then becomes apparent during the ensuing 3 months. Hepatosplenomegaly is common in acute leukaemia, and lymphadenopathy is often present in ALL. Bone and joint pain may occur, particularly in ALL. Infiltration of soft tissues such as the skin, gums and perineum may occur, and usually indicates a monocytic type of AML. CNS disease is rare at presentation, although it is a common site of relapse in ALL. A wide range of metabolic disturbances may also be present at diagnosis, including hyperuricaemia, hyponatraemia and hypokalaemia. These changes may all be exacerbated by treatment.

ACUTE MYELOID LEUKAEMIA The annual incidence of AML is approximately 3.4 per 100000. Although the disease does occur in children and young adults, it is more common in the middle-aged and elderly (Fig. 23.27).

Diagnosis The blood count typically reveals a normocytic or macrocytic anaemia, often with marked anisocytosis and poikilocytosis on the blood film. The platelet count is usually reduced and the white count is usually - although not invariably - raised, with myeloblasts being the predominant cells. Neutrophils are usually reduced in number and may appear dysplastic. There are relatively few intermediate myelocytes in the blood (unlike the situation in CML). The bone marrow is hypercellular but may produce a dry tap. The majority of cells are myeloblasts (over 30% required for diagnosis), and the remaining haemopoietic cells may show marked dysplastic changes. In some cases pathognomonic 'Auer' rods are seen in the myeloid cells. 2

Classification Most cases of AML can be readily identified using morphological criteria, although some may be difficult to distinguish from ALL. The diagnosis of AML can be sup-

1

1244

Fig. 23.7

2

Fig. 23.8

FIG. 23.27 Annual death rate for different types of leukaemia at different ages

ported by cytochemical, immunological and genetic studies where appropriate (Table 23.27). The subdivisions of AML are based on the nature of any differentiation that is present, using morphological and cytochemical criteria (Table 23.28).

Chromosome analysis Chromosomal abnormalities are seen in about 50% of cases using Giemsa banding analysis, and more frequently with high-resolution techniques. These include chromosomal losses, duplications and specific translocations. The t(8; 21) translocation is associated with some M2 leukaemias, and an inverted chromosome 16 is associated with M4-type AML with a marrow eosinophilia. The t(15; 17) translocation occurs in almost all cases of M3 leukaemia, resulting in the production of an abnormal retinoic acid receptor. The t(8; 21), (15; 17) and inverted 16 translocations are associated with a relatively good chance of survival; -7, -5q, -3q and complex karyotypes with a relatively poor prognosis. Other cytogenetic abnormalities and the absence of a chromosomal abnormality are considered to be standard risk. The mechanism whereby some of these chromosomal changes play a part in the development, or progression, of the leukaemic process is now becoming a little clearer (Fig. 23.28). The AML-1 gene product normally associates with the core-binding factor beta (CBFB) to form a transcriptional complex involved in the expression of a number of genes associated with myeloid differentiation. In the t(8; 21) translocation the AML-1 gene on chromosome 21 becomes fused to the ETO gene on chromosome 8. In some way the fusion gene acts as a 'dominant negative' and interrupts this function. In the inv(16) translocation the breakpoint actually occurs within the CBF|3 gene. This same transcriptional complex is also involved in the t(12; 21) translocation found in ALL.

TABLE 23.27 Differentiation between myeloblasts and lymphoblasts Myeloblasts Morphology Cell size Cytoplasm Granules in cytoplasm Auer rods Nucleoli

MO

AML without maturation: Blasts are Sudan black and peroxidase negative but show CD 13 or CD 33.

M1

AML without maturation: More than 3% peroxidase or Sudan black positive blasts; some blasts may have occasional granules or Auer rods.

M2

AML with maturation: Evidence of maturation at, or beyond, the promyelocyte stage.

M3

Promyelocytic leukaemia: Majority of cells promyelocytes. Note that leukaemic promyelocytes may be hyper- or hypogranular.

M4

Myelomonocytic leukaemia: Monocytic cells more than 20% of blood or marrow. Granulocytic cells more than 20% of marrow. Demonstration of fluoride-sensitive non-specific esterase staining aids the diagnosis of monocytic cells.

M5

Monocytic leukaemia: a) Poorly differentiated monoblasts. b) Monoblasts, promonocytes and monocytes. Granulocytic cells less than 20% of marrow.

M6

Erythroleukaemia: Erythropoietic component exceeds 50%, or 30% if associated with severe dyserythropoiesis. Myeloblasts must still constitute more than 30% of marrow cells.

M7

Megakaryocytic leukaemia: Identification of megakaryoblasts aided by electron microscopic demonstration of platelet-specific peroxidase or platelet-specific surface antigens. This disease often presents as acute myelofibrosis in which the blasts are few in number in the marrow.

Lymphoblasts

Moderate to large Moderate to abundant Often in some cells May be present Often more than two

Small to moderate Scanty to moderate Rare Absent One or two

+

-

-

+

Immunology Nuclear terminal deoxynucleotidyl transferase (Tdt) CD10 antigen (CALLA) CD19 antigen (pan-B)

- (Occasionally +) -

CD7 antigen (pan-T) CD33 HLA-DR

- (rarely +) + +

+ + + (common ALL and null ALL) + (T-ALL) + (- in T-ALL)

Genetics Ig light-chain gene rearrangement

-

+ (common ALL and null ALL)

T-cell receptor gene rearrangement

-

+ (T-ALL)

Cytochemistry Peroxidase/ Sudan black PAS

TABLE 23.28 Subdivisions of acute myeloid leukaemia

23

Management Intensive blood product, antibiotic and psychological support is required during the hypoplastic period induced by the disease and its treatment. Disseminated intravascular coagulation may occur, particularly in acute promyelocytic leukaemia, and this requires vigorous platelet and clotting factor support. The induction therapy used in AML is very intensive, as it is necessary to induce a hypoplastic marrow in order to achieve remission. The most effective and commonly used drugs are the anthracycline daunorubicin and the antimetabolite cytosine arabinoside. In some regimens an additional agent, such as 6-thioguanine, is also included, although it is not clear that this increases the complete response rate or improves long-term survival. Remission is obtained in about 80% of younger patients, although this may take several induction courses. Once remission has been obtained it is usual to give several further courses of induction-type therapy, which is often referred to as consolidation. Consolidation regimens usually contain cytosine arabinoside, and there is good

FIG. 23.28 Involvement of the core binding factor in acute leukaemia

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RECENT ADVANCES IN CHROMOSOME ANALYSIS The chromosomal breakpoints in t(8; 21) involve the AML-1 gene on chromosome 21 and the ETO gene on chromosome 8. The AML-1 gene codes for a protein which associates with 'core-binding factor |3' (CBF-P) and this heterodimer binds DNA and induces a number of myeloid genes. In the inv(16) karyotype, the breakpoint occurs in the CBF-fi gene, so the same transcription factor complex is affected. evidence that high-dose cytosine is preferable to lower doses of this agent in preventing relapse. It is still not clear how many courses of induction and consolidation therapy should be given, and current trials are comparing four with five courses. In the context of this very intensive induction/consolidation there appears to be no role for low-dose maintenance therapy as in ALL. In cases of M3 leukaemia all trans retinoic acid (ATRA) is given in combination with both the induction and consolidation chemotherapy. ATRA causes differentiation of the leukaemic clone, reduces the risk of disseminated intravascular haemolysis associated with tumour lysis, and also reduces the risks of disease relapse. High-dose therapy with haemopoietic stem cell support in first remission represents an extreme form of consolidation. There is convincing evidence that autologous transplantation after four cycles of induction/consolidation reduces the relapse rate compared to no further therapy, but unfortunately most of this benefit is offset by the procedure-related mortality. Allogeneic transplantation is associated with an even lower relapse rate, presumably owing to lack of reinfusion of leukaemic cells, and possibly also to a graft-versus-leukaemia effect. There is also an even higher procedure-related mortality. On balance, most authorities consider that allogeneic transplantation in first remission is the preferred option for young patients with standard- or poor-risk disease who have an HLA-matched sibling donor. This is only a minority of patients. The cytoreductive therapy used in allogeneic transplantation is usually a combination of cyclophosphamide and total body irradiation. T-cell depletion to reduce graft-versushost disease is not associated with the great increase in relapse that is observed in CML, suggesting that the graftversus-leukaemia is less important for cure in AML. In patients who relapse, a second remission can sometimes be obtained. The chances are better in those who relapse after ceasing chemotherapy. However, second remissions are almost invariably short-lived unless an

TABLE 23.29 Risk groups in AML Good

Standard Poor

Favourable cytogenetics, i.e. t(8;21) inv(16) t(15;17) or promyelocytic leukaemia regardless of response to first cycle of chemotherapy No favourable or adverse cytogenetics. Less than 15% blasts remain in the marrow after the first cycle of chemotherapy Adverse cytogenetics, i.e. -5, del(5q), -7, abn(3q), complex karyotype or not in good-risk group and blasts not reduced to <15% in the marrow after the first cycle of induction chemotherapy

allogeneic transplant can be performed. The results of transplantation at this stage are less good than in first remission. 1

Prognosis The results of treatment have improved dramatically over the last three decades. For adult patients between the ages of 15 and 59 the overall survival at 5 years now exceeds 40%, compared to only 5% in 1970, and in children the current survival at 5 years approximates 60%. The results in patients over the age of 60 unfortunately remains poor. Patients can be separated into good, standard and poor risk on the basis of cytogenetic analysis at presentation and the response to the first course of chemotherapy induction (Table 23.29). In adults between the ages of 15 and 59 years the 5-year survival in good-, standard- and poorrisk categories is approximately 70%, 45% and 10%, respectively. Recently it has been found that mutations in the Flt-3 gene occur in nearly 30% of adults with AML and predict strongly for relapse from remission. This parameter is therefore likely to be incorporated into risk stratification systems. Recipients of allogeneic grafts have an overall long-term (5-year) survival of approximately 50%, this figure being somewhat higher in the under-25s. Half of the deaths are due to transplant-related complications, and half to leukaemia.

ACUTE LYMPHOBLASTIC LEUKAEMIA The annual incidence of ALL in the UK is approximately 1.0 per 100000. The incidence peaks in mid-childhood (see Fig. 23.27). There is a slight excess in males.

Diagnosis

1

1246

Case 23.4

The haematological findings are similar to those found in AML (p. 1244), except that the anaemia is nearly always normocytic; myelodysplastic features are not seen; and lymphoblasts predominate in the marrow and usually also the blood.

23

TABLE 23.30 Subeategories of acute lymplioblastic leukaemia based on lineage and differentiation stage Cell lineage

Differentiation stage

Alternative name

Incidence in children

Incidence in adults

B lineage

Very early Early Late

Null cell ALL Common ALL B-cell ALL

12% 75% <1%

38% 50% 2%

T lineage

Very early and early

T-cell ALL

12%

10%

Classification The morphological, cytochemical, immunological and genetic features of malignant lymphoblasts are shown in Table 23.27. ALL has been subdivided into three morphological variants (L1-L3) by the French-American-British (FAB) Cooperative Group, although this is of limited value in determining prognosis and therapy. ALL may also be classified on immunological and genetic criteria (Table 23.30).

Chromosome analysis Cytogenetic abnormalities are detected in about two-thirds of cases by routine banding techniques. Both numerical and structural changes are seen. Unlike AML, hyperdiploidy (more than 50 chromosomes present) is not infrequent and may be associated with a good prognosis. The Philadelphia chromosome [t(9;22) translocation] is present in 5% of childhood ALL and approximately 20% of adult cases. These patients have a poor prognosis. Other specific translocations also occur, for example a t(8; 14) translocation is found in most cases of L3 leukaemia (as well as in Burkitt's lymphoma), and t(4; 11), involving the MLL gene at 1lq23, is frequent in infantile leukaemia. Infants with MLL rearranged ALL have a very poor prognosis. The t(12; 21) is an infrequent translocation at the gross cytogenetic level (see Fig. 23.28), but the fusion gene can be detected by molecular techniques in 15-25% of all B-lineage childhood ALL. The prognosis is excellent.

Management The treatment strategy in ALL is shown in Figure 23.29. In the early 1970s, remission was induced with vincristine and prednisone; both drugs have specificity for lymphoblasts and do not cause severe haematological suppression. Since then, regimens have become more intensive and the differences from the induction regimens used in AML are less marked. With modern anthracycline-containing regimens, over 95% of children and over 85% of adults with ALL obtain remission, although there is concern about the long-term cardiotoxic effects of anthracyclines, particularly in young children, and the dose of these drugs has recently been reduced. Most induction regimens also contain L-asparaginase.

FIG. 23.29 Schematic representation of the treatment of acute leukaemia

Once remission is obtained, it is now common practice to give a further intensive consolidation course before commencing maintenance therapy. Maintenance is less intensive than induction therapy, and cyclical combinations of 6-mercaptopurine, methotrexate, vincristine and prednisone are usually given. Unlike the situation in AML, there is reasonable evidence that maintenance should be given for at least 2 years in ALL. In many centres a further ablative therapy course is given after about 6 months; this is known as late intensification, and appears to be particularly valuable in high-risk cases. Craniospinal prophylaxis must also be given during remission, to prevent relapse in this 'privileged site'. The combination of cranial irradiation (18Gy in 10 daily fractions) and repeated injections of intrathecal methotrexate or cytosine arabinoside was used routinely, but cranial radiation is now reserved for the most high-risk cases, with agents such as high-dose methotrexate, which cross the

1247

blood-brain barrier, being used instead in standard-risk cases. Testicular irradiation has also been used as prophylaxis against relapse at this site (10% of relapses in boys), but this has made little impact on survival and causes hypogonadism and infertility. The role of allogeneic bone marrow transplantation in ALL is still not fully defined. It is not justified in the large majority of children in first remission, because recent intensive regimens are so effective even in high-risk cases. It may have a role in first-remission adults. Once a relapse has occurred, bone marrow transplantation in second remission is probably the treatment of choice if the patient is under 40 years of age and a matched donor is available. Results with matched, unrelated transplants are good in children but less so in adults.

Nearly all patients with ALL achieve remission, but relapse is still a major problem. The factors influencing survival are shown in Table 23.31. The immunological phenotype is clearly related to prognosis, with common ALL doing well and T- or B-ALL badly, but phenotyping probably provides little additional prognostic information beyond that obtained from the age, sex and presenting white cell count. Many regimens identify the high-risk group at presentation, and more intensive therapy is then given. With some regimens this has reduced the survival difference between the good- and the poor-risk cases, at least in children, both groups having a projected 5-year survival in excess of 70%. Death usually follows once relapse occurs, but second remissions may be protracted, especially if relapse occurs late after stopping therapy. Allogeneic bone marrow transplantation may cure some patients in second remission, but the relapse rate is high; long-term survival is probably less than 30%. CNS leukaemia is rare at presentation but does occasionally occur at that time, during therapy prior to cranial prophylaxis, or as a later manifestation of relapse. It may give rise to raised intracranial pressure, focal signs or cranial nerve lesions. Diagnosis is based on the finding of blast cells in the CSF, but it is sometimes necessary to repeat this on several occasions to obtain a positive result. CT and MRI scanning can be helpful, but may be negative in the presence of meningeal disease. Treatment usually starts with intrathecal therapy (cytosine arabinoside, methotrexate and steroids) once or twice a week until the blasts clear. In all cases systemic therapy must also be given because the risk of bone marrow relapse is high. A remission is usually consolidated with either high-dose cytosine arabinoside or high-dose methotrexate, which both cross the blood-brain barrier. Finally, a bone marrow transplant

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• • • • • •

High peripheral white count Age less than 2 years or over 10 years Male sex Certain chromosomal abnormalities FAB L3 type Immunological Null ALL T-cell ALL Worsening prognosis Common ALL

TABLE 23.32 Late effects of leukaemia therapy

Prognosis

1

TABLE 23.31 Factors at presentation of acute lymphoblastic leukaemia indicative of a poor prognosis

Case 23.5

2

MCQ 23.16

• Endocrine deficiencies Short stature Obesity Osteoporosis • Neuropsychiatric abnormalities • Cardiac impairment • Second malignancies

with total body irradiation or cranial irradiation is usually considered. 1

Late effects of leukaemia The success of leukaemia therapy is at the cost of both short- and long-term side-effects (Table 23.32), the latter being particularly problematic when treatment is given to young children. Over 40% of children treated in the 1970s have either endocrine or neuropsychiatric problems. The most devasting problem is the occurrence of second malignancies. Occasionally this is because the patient suffers from an underlying cancer predisposition syndrome, and sometimes it is a direct result of treatment. Gliomas following cranial irradiation are one such example, but are fortunately rare. Endocrine problems are frequent, particularly if there has been cranial irradiation or, in boys, testicular irradiation. These include short stature, obesity, early puberty in girls and possibly an increased incidence of polycystic ovary syndrome, and osteoporosis if growth hormone deficiency develops and remains untreated. Subtle learning difficulties and psychiatric problems are also manifest. Once again, this is thought to be worse following cranial irradiation, but the full impact of alternative drug-CNS prophylaxis requires further evaluation. Considerable attention has also been drawn to the development of anthracycline-induced cardiac abnormalities. Few individuals have yet developed heart failure, but up to

30% of individuals treated as children in the 1980s have a decreased ventricular shortening fraction. Risk factors are a cumulative dose of daunorubicin >300mg/m2, young age at treatment (<5 years), and possibly female gender. ©

MYELODYSPLASIA Myelodysplasia is an acquired state of haemopoietic dysfunction in which there is cytopenia (involving one or more cell lines) without evidence of peripheral destruction and a cellular marrow. Haemopoiesis is ineffective, and morphological abnormalities are prominent in blood and marrow. Anaemia is common, and there is frequently a mild to moderate macrocytosis, anisocytosis and poikilocytosis. The neutrophil count is often low, and the neutrophils exhibit abnormalities of granulation. The platelet count may also be reduced. A monocytosis may occur in some cases. The bone marrow shows dysplastic changes in one or more cell lines, the blast cell count may be raised, and an iron stain may reveal ringed sideroblasts. Clonal chromosomal abnormalities are detected in 50-60% of cases, and many other cases also undoubtedly represent a clonal expansion. The myelodysplastic syndromes (MDS) have been subdivided by the French-American-British (FAB) Group and more recently by the WHO (Table 23.33). It should be noted that the term 'refractory anaemia' in the FAB classification includes 'refractory neutropenia or thrombocytopenia' due to ineffective production as well as anaemia. In the WHO classification the 5q-syndrome is singled out as a separate entity, and chronic myelomonocytic leukaemia (CMML) is in a separate 'Myelodysplastic/myeloproliferative disease' category.

TABLE 23.33 Classification of the myelodysplastic states FAB classification

WHO

Myelodysplastic syndromes Refractory anaemia (RA) (<5% blasts)

Myelodysplastic syndromes Refractory anaemia with ringed sideroblasts without ringed sideroblasts

Acquired idiopathic sideroblastic anaemia

Refractory cytopenia with multilineage dysplasia

Refractory anaemia with excess blasts (5-20% blasts) (RAEB)

Refractory anaemia with excess blasts

Refractory anaemia with excess blasts in transformation (RAEBT) (21-30% blasts)

5q-syndrome

Chronic myelomonocytic leukaemia (CMML) (<20% blasts)

Myelodysplastic/myeloproliferative disorders Chronic myelomonocytic leukaemia Atypical chronic myelogenous leukaemia Juvenile myelomonocytic leukaemia

MDS unclassifiable

Clinical features The MDS are a group of diseases that occur predominantly in the elderly, but can arise at any age. Patients usually present with symptoms attributable to the cytopenia. Fever not related to infection, bone pain and splenomegaly occasionally occur. The MDS clearly represent a spectrum of disorders from mild marrow dysfunction to almost frank leukaemia. Many cases of refractory anaemia with ringed sideroblasts and normal white count and platelets remain stable for many years, whereas refractory anaemia with excess blasts can be difficult to differentiate from acute leukaemia at presentation, and usually progresses rapidly. The features suggestive of a poor prognosis are the involvement of more than one cell lineage and a high blast cell count, but even in these cases the term 'preleukaemia' is best avoided. This is because the term can only be used with certainty in retrospect, and because many of the deaths in severe MDS arise from worsening cytopenias, rather than from transformation to acute leukaemia.

23

Management The conventional approach to the management of the MDS is to provide supportive therapy, only instituting acute leukaemia therapy when leukaemic progression occurs. The response to treatment at this later stage is not good, and it may therefore be appropriate to institute more aggressive therapy earlier in young patients with MDS who exhibit poor prognostic features. Haemopoietic growth factors may increase the white count but the clinical benefit is uncertain.

FURTHER READING ON ACUTE LEUKAEMIA Hoelzer D 1999 Acute lymphoblastic leukaemia in adults. In: Degos L, Linch D C and Lowenberg B, eds. Textbook of malignant haematology. London: Martin Dunitz, 539-562. Lowenberg B, Burnett A K 1999 Acute myeloid leukaemia in adults. In: Degos L, Linch D C and Lowenberg B, eds. Textbook of malignant haematology. London: Martin Dunitz, 743-770.

MALIGNANT LYMPHOPROLIFERATIVE DISORDERS There is a spectrum of neoplastic proliferations of lymphoid and other cells (such as histiocytes) that comprise the normal lymphoreticular system. The lymphoid leukaemias, both acute and chronic, are usually considered as distinct from the lymphomas, which preferentially involve nodes and spleen. Overlap is, however, frequent. Lymphocyte proliferation is a normal response to antigenic challenge, and diagnostic confusion between reactive and neoplastic nodes can arise. Features suggesting malignancy include effacement of the normal node architecture; ex-

1249

FIG. 23.30 B cell lymphoprollferative diseases and their putative relationships to normal B lymphocytes

tension beyond the usual confines of the node; and the presence of a uniform population of cells. The latter is often absent, however, partly because the malignant clone may be represented by cells at more than one stage of differentiation, and partly because a marked reactive proliferation may also occur in the same node. It is possible on clinical, morphological and immunological criteria to define distinct entities within the spectrum of the lymphoproliferative disorders, but it is difficult in some cases to relate a malignant proliferation to the differentiation level of its normal cell counterpart, as the morphology of the lymphoid cells reflects the proliferative status of the cell as much as its stage of differentiation. Figures 23.30 and 23.31 outline B- and T- cell differentiation pathways, and give an approximation of the corresponding malignancies.

HODGKIN'S LYMPHOMA Hodgkin's lymphoma (HL) is a clinically and histologically distinct malignant lymphoma which is typically of B-cell origin, although the B cells have not undergone full development, may have a crippling mutation of the immunoglobulin gene and do not express surface immunoglobulin. Such crippled cells should normally undergo apoptosis, and malignant change probably requires an initial immortalizing event to prevent apoptosis and then subsequent oncogenic mutations. Infection with EBV could represent one such early immortalizing event.

1250

1

Figs 23.9,

4

Figs 23.13, 23.14

23.10

2

Fig. 23.11

0 Fig. 23.12

Stem cells

Acute lymphoblastic leukaemia

Thymocytes

Acute lymphoblastic leukaemia Lymphoblastic lymphomas Cutaneous lymphomas

Helper/inducer T cells

Occasional T-cell chronic lymphocytic leukaemia T-prolymphocytic lymphomas HTLV-I associated lymphomas Some non-Hodgkin's lymphomas

Suppressor/cytotoxic T cells

Chronic lymphocytic leukaemias Some non-Hodgkin's lymphomas

FIG. 23.31 T cell lymphoproliferative diseases and their putative relationships to normal T lymphocytes The HTLV-I associated malignancies typically have a helper inducer phenotype (CD4+) but have suppressor function in vitro.

Clinical features The annual incidence of HL in the UK is approximately 2.4 per 100000. It is uncommon in childhood, with a peak incidence in early adulthood. Patients most commonly present with lymphadenopathy, especially in the cervical region. 1 When more than one region is involved the areas are usually contiguous, consistent with the view that spread is predominantly through the lymphatics in the early stages. The lymph nodes may or may not be tender, and may initially fluctuate in size. Alcohol-related pain in the nodes may occur but is rare. Hepatosplenomegaly occurs with more advanced disease, and there can be infiltration of almost all organs.

Systemic symptoms are frequent, especially in disseminated disease, although some patients with extensive tumour bulk feel well. Intense generalized itching (pruritus) is common. Anaemia occurs in about 35% of patients and is correlated with advanced disease rather than marrow infiltration, which is found in less than 10% of cases. Neutrophilia is common and eosinophilia occurs in 15% of patients. Lymphopenia is frequent in disseminated disease, but even in patients with normal lymphocyte numbers there is often a functional T-cell deficit, the cause of which is not fully understood. Clinical depression of cell-mediated immunity is most clearly manifest as herpes zoster infection. ©

Histological classification The diagnosis of HL is made from histological diagnosis of affected tissue, usually lymph node. The malignant Reed-Sternberg cells and their mononuclear counterparts are present in variable (often small) numbers in an appropriate reactive background of lymphocytes, eosinophils and fibrous tissue. The Reed-Sternberg cell is classically a large binucleate cell with vesicular nuclei and prominent eosinophilic nucleoli. 3 These cells may appear to be in lacunae, especially if fibrosis is present. The modified Rye classification of 1971 has been incorporated largely unchanged into the REAL and WHO classifications (Table 23.34) and is primarily dependent on the composition of the reactive elements. An important change is that nodular lymphocyte-predominant Hodgkin's lymphoma is now recognized as different from

SUMMARY 10 Treatment of Hodgkin's lymphoma according to stage IA IB Radiotherapy IIA IIB Chemotherapy (occasionally radiotherapy) IIA IIIB IVA IVB

Chemotherapy

TABLE 23.34 WHO classification of Hodgkin's lymphoma Nodular lymphocyte-predominant Hodgkin's lymphoma Classic Hodgkin's lymphoma (HL) Nodular sclerosis HL (grades 1 and 2) Lymphocyte-rich classic HL Mixed-cellularity HL Lymphocyte depletion

other types of classic Hodgkin's lymphoma, and that the phenotype of the malignant cells differs markedly (Table 23.35). It shows a male predominance, most commonly presents with localized asymptomatic disease, tends to be indolent and slowly progressive, but can transform after many years into a large B-cell lymphoma. Lymphocytedepleted HD is now rarely diagnosed, and most patients previously diagnosed with this entity are now referred to as having non-Hodgkin's lymphoma.

23

Staging Accurate staging provides important prognostic information and dictates the appropriate treatment strategy. A thorough history and examination is required, involving chest X-ray,liver function tests and CT scanning of the abdomen. 4 Lymphangiography is now rarely used but will demonstrate abnormal node architecture in relatively small nodes. Gallium scanning and positron emission tomography (PET) are not particularly helpful with initial staging, but can help determine whether a residual mass at the end of treatment represents active disease. The amended Ann Arbor staging system is usually used (Table 23.36). This was designed primarily to determine which patients could be effectively treated with radiotherapy.

TABLE 23.35 The phenotype of neoplastic cells in classic and nodular lymphocyte-predominant forms of Hodgkin's lymphoma

CD 20 Other B-cell antigens CD 30 CD 15

Classic HL Reed-Sternberg cells

Lymphocyte and histiocytic cells of nodular lymphocytepredominant HL

Occ positive Usually negative Positive Usually positive

Usually positive Usually positive Sometimes positive Negative

TABLE 23.36 The Ann Arbor staging system Stage I Single lymph node region involved, sometimes with local spread to extralymphatic tissue (IE). Stage II Involvement of two or more node regions on the same side of the diaphragm, sometimes with local spread to extralymphatic tissue (IIE). Stage III Involvement of nodes on both sides of the diaphragm. (The spleen is considered as a 'node'.) Stage IV Diffuse or disseminated involvement of one or more extralymphatic organs. Each stage is also divided into A or B according to absence or presence of systemic symptoms; these include a sustained fever (>38°C), weight loss (more than 10% of body weight in 6 months) and night sweats, but not pruritus.

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FIG. 23.32 Irradiation fields used in the treatment of Hodgkin's lymphoma A Mantle field. B Inverted Y field. C Total nodal irradiation.

Laparotomy and splenectomy were introduced to improve tumour localization but these are now performed infrequently, for two reasons. First, they add little to overall survival because most patients with occult intraabdominal disease, treated 'inappropriately' with radiotherapy to the lymph nodes above the diaphragm, can later be rescued with chemotherapy when intra-abdominal disease becomes apparent. Second, splenectomy is associated with a significant low but continuous risk of certain infections.

Management

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• Localized disease (stages IA and IIA) without symptoms is conventionally treated by radiotherapy alone. It is usual to irradiate all node areas above or below the diaphragm, according to the site of the disease. These large fields are known as mantle fields and inverted Y fields (Fig. 23.32). The overall relapse rate following a mantle field for supradiaphragmatic disease is high (approximately 35%). Most relapses are outside the irradiated field. It is usual to give chemotherapy as well as radiotherapy when there is a large mediastinal mass, as the risk of local relapse is higher. Some centres give adjuvant chemotherapy for many other cases of localized disease and it may then be possible to combine short courses of chemotherapy with limited radiation fields. Combined-modality therapy minimizes relapse but does not necessarily improve survival, as chemotherapy salvage is highly effective in patients who have failed radiotherapy alone. • Patients with stage IIB disease have a very high relapse rate following radiotherapy, and are therefore usually treated by chemotherapy. • Stage IIIA disease can be effectively treated by total

nodal irradiation (mantle and inverted Y), but again most centres prefer to use chemotherapy rather than employ such extended radiation fields. If the patient relapses soon after total nodal irradiation has been given, it is very difficult to treat with chemotherapy because of lasting myelosuppression caused by the radiotherapy. • Patients with stage IIIB and IV disease must be treated with chemotherapy. The standard treatment used to be 6-8 monthly cycles of MOPP (mustine, vincristine, procarbazine, prednisone) combination therapy, or minor modifications of this. Chlorambucil can replace mustine with less toxicity, and vinblastine causes less neurotoxicity than vincristine, albeit with more myelotoxicity. Improved results have been obtained with the ABVD regimen (adriamycin, bleomycin, vinblastine, dacarbazine), and this is probably now regarded as the goldstandard regimen. Some centres combine ABVD or similar regimens with MOPP-type regimens, in either

RECENT ADVANCES IN AUTOLOGOUS PBSC The use of autologous bone marrow has been largely replaced by the use of autologous peripheral blood stem cells (PBSC). There are few circulating stem cells in the steady state, but levels rise dramatically after chemotherapy and administration of G-CSF or GMCSF. In this situation, an adequate PBSC harvest can often be obtained from a single leukopheresis. PBSC transplantation leads to more rapid engraftment compared with bone marrow transplantation, especially of the platelet lineage.

23

CASE STUDY 23.3 HODGKIN'S LYMPHOMA An 18-year-old female student of Asian origin had a persistent nonproductive cough for 6 months, which was worse at night. A trial of a salbutamol inhaler had not helped. On re-examination by her GP a small node (about 1x1 cm) was noted in the right supraclavicular fossa. More detailed questioning revealed a 3month history of diffuse pruritus and vague chest pains after drinking alcohol. She was otherwise well. A chest X-ray was performed and revealed a large anterior mediastinal mass which in transverse diameter was about one-third the width of the thorax.

Questions 1. What is the most likely diagnosis? 2. Give three diagnoses to be considered. 3. What diagnostic test would you perform? Discussion The presence of a large mediastinal mass with a supraclavicular node in an 18-year-old is most likely to be Hodgkin's lymphoma. This supposition is supported by the pruritus and the alcohol-related pain. Other diagnoses to be considered include non-Hodgkin's lymphoma and other mediastinal tumours, such as thymoma and sarcoma. The differential diagnosis of lymph node enlargement includes tuberculosis and sarcoidosis, but neither of these causes a very large mediastinal mass.

'alternating' or 'hybrid' regimens. Even more intensive regimens have been developed. Although they result in a lower failure rate, there is concern about both shortand long-term toxicity. There is no value in protracted maintenance therapy. In some centres radiotherapy to sites of previous bulk disease is also given following chemotherapy-induced remission, but its value is unproven. • Relapse of local disease may be amenable to further radiotherapy if tissue limits have not been reached in that region. Alternatively, chemotherapy can be used. If relapse occurs several years after stopping therapy in patients who received initial chemotherapy, it is often possible to induce a further remission with the same drugs. If the patient is resistant to primary therapy, or if relapse has occurred soon after stopping the initial drugs, then a regimen using drugs that might be noncross-resistant should be tried. It is now usual practice to consolidate any second response to high-dose therapy with autologous haemopoietic stem cell support. The most commonly used high-dose regimen is BEAM (BCNU, etoposide, Ara-c and melphalan) The long-term progression-free survival after high-dose therapy is about 50%.

Prognosis The prognosis of Hodgkin's lymphoma improved greatly

The key diagnostic test is an excision biopsy of the supraclavicular node. This revealed nodular sclerosing Hodgkin's lymphoma. Staging investigations, including CT scan of the abdomen and pelvis, revealed no other sites of disease and she was staged as IIA. In view of the large size of the mediastinal mass, initial radiotherapy would have involved irradiating a large portion of the lungs. She was therefore given three cycles of combination chemotherapy (ABVD), and after considerable shrinkage of the mediastinal mass mantle field radiotherapy was given. Following treatment there was still a residual mediastinal mass of about 3x2 cm, but this is presumed to be scar tissue as she has been in remission for 7 years without the mass changing in size.

in the 1940s with the introduction of high-voltage radiotherapy, and in the 1960s with the introduction of effective combination chemotherapy. Since then, slow steady progress has been made owing to improved first-line chemotherapy, better supportive care and effective salvage therapy. The overall 10-year survival in HD now approximates 80%, but both the complete remission (CR) rate and the long-term survival are influenced by a number of parameters (Table 23.37). Age is very important, with patients over 50 faring much worse. Most relapses occur in the first few years, although late relapses do occasionally occur. The improvements in survival have focused attention on the long-term effects of treatment.

TABLE 23.37 Poor prognostic factors in Hodgkin's lymphoma Serum albumin Haemoglobin Male sex Stage IV disease Age > 45 years White count Lymphocyte count

<4g/dL <10.5g/dL

>15x10 9 /L <0.6x107L

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Fertility is a major issue in younger patients, and regimens that do not contain mustine or cyclophosphamide, such as ABVD, are much less likely to cause infertility. Interestingly, high-dose therapy does not regularly induce infertility in patients who were fertile prior to receiving this treatment modality. Second malignancies are disturbingly frequent in some long-term series, both myelodysplasia/acute myeloid leukaemia and solid tumours. Leukaemia usually follows multiple rounds of chemotherapy, with a peak incidence about 7 years from diagnosis. Solid tumours are numerically more important and arise secondary to both chemotherapy and radiotherapy. The most frequent second malignancy is lung cancer, and it is essential that any patient who has received thoracic irradiation is strongly advised against smoking. 1

IMON-HODGKIN'S LYMPHOMA Non-Hodgkin's lymphoma (NHL) is more common than HL; the annual incidence in Europe is approximately 12 per 100000 and is rising at over 4% per year. NHL does occasionally occur in children and adolescents, but is most common in the elderly. The malignant cells in childhood lymphomas usually have an immature phenotype, with precursor T-cell-lymphoblastic lymphomas, Burkitt's lymphoma and diffuse large B-cell lymphomas predominating. With intensive therapy most of the childhood lymphomas are curable, with long-term survival in the region of 90%. The principles of treatment are similar to those used in adults, but wide-field irradiation is avoided whenever possible because of skeletal deformity in later life.

Clinical features Most patients have lymphadenopathy at presentation 0 but, unlike the situation in HL, the spread is not contiguous and disseminated disease at presentation is common. Patients with histologically low-grade disease are frequently asymptomatic, whereas those with high-grade disease tend to have symptoms of fever, anorexia and weight loss. A multiplicity of local symptoms can arise from nodal pressure or extranodal disease. These include obstruction of the superior vena cava; abdominal distension and back pain due to enlarged para-aortic nodes; bone pain from erosion or metastases in bone; chylous ascites and chylothorax from rupture of lymphatic channels; and cutaneous, pulmonary and hepatic infiltration. NHL can also arise as primary tumours of the gastrointestinal tract,

brain, thyroid, bone, orbit and testis, and are discussed in the respective chapters. Anaemia may arise from marrow infiltration, hypersplenism or autoimmune haemolysis; the latter is more frequent in the low-grade lymphomas. Low levels of paraprotein are often present in the low-grade lymphomas, although hypergammaglobulinaemia in NHL is usually polyclonal.

Histological classification Most NHL (70%) are tumours of the follicular centre B cell, which appear either as small cells with a cleaved nucleus (centrocytes) or as larger cells with less marked nuclear cleavage (centroblasts). In these follicular centre cell lymphomas the tumour may make large follicles (follicular appearance) or the node may be diffusely replaced by sheets of tumour cells (diffuse appearance). 0 There is not always a clear dividing line between the two, and different lymph nodes may show both diffuse and follicular change in the same patient. As the follicular lymphoma progresses, it may also change to a diffuse appearance. Some B-cell lymphomas represent a stage prior to the follicle centre (e.g. mantle cell lymphoma) and some a later stage. About 10% of lymphomas have a T-cell origin, and this includes the cutaneous T-cell lymphomas such as mycosis fungoides and Sezary's syndrome. Many classifications of NHL have been developed, and an abbreviated form of the recent WHO classification is shown in Table 23.38. It has the advantage of reproducibility and widespread consensus. Both the WHO classification and its immediate predecessor, the Revised European and American Lymphoma (REAL) classification, represent listings of the different clinicopathological entities and do not define tumour grade or group lymphomas into therapeutic categories. From a clinical standpoint it is often helpful to make such groupings, however, as shown in Table 23.38, in order to systematize therapy. The low-grade lymphomas tend to grow more slowly than high-grade ones and will often respond to relatively 'mild' chemotherapy. Cure is infrequent, however, and a relapsing and remitting course follows. In the high-grade lymphomas cure can be achieved in about half the patients, and by about 10 years the overall survival of the low-grade and high-grade lymphomas crosses over (Fig. 23.33). It should be noted that follicular lymphomas (low grade) and large B-cell lymphomas (high grade) each account for nearly one-third of all lymphomas. Entities such as mantle cell lymphoma remain difficult to categorize in terms of grade because although the lymphoma may appear indolent microscopically, the prognosis is very poor.

Staging

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1

MCQ 23.17

4

Case 23.6

2

Fig. 23.15

0 Fig. 23.16

The Ann Arbor staging system is used in NHL, but is less useful than in HL as most cases of low-grade disease are already stage IV at presentation. Marrow infiltration is particularly common in these cases. Accurate staging is

TABLE 23.38 Abbreviated WHO classification of nonHodgkin's lymphomas Lymphocyte subtype

FIG. 23.33 Comparison of survival with low- and high-grade nonHodgkin's lymphoma The initial death rate is high with high-grade tumours, but the curve then flattens with 40% of patients cured. A steady, slower, death rate occurs with low-grade tumours, with little evidence of cure.

important if patients are involved in clinical trials, as stage may affect prognosis.

Management Low-grade lymphomas Small lymphocytic lymphomas and chronic lymphocytic leukaemia (CLL) are considered in the WHO classification to be different presentations of the same disease entity. Therapy is essentially the same and is discussed in the section on CLL (page 1258). Extranodal marginal-zone B-cell lymphomas of MALT type are lymphomas that arise in mucosa-associated lymphoid tissue. The commonest site is the stomach, where the lymphoma (usually low grade initially) arises at sites of chronic inflammation secondary to Helicobacter pylori infection. 4 Approximately 70% of such lymphomas go into complete remission with anti-Helicobacter therapy (see Chapter 15, p. 780), although PCR studies suggest that in most patients the original malignant clone persists.

SUMMARY 11 Therapeutic strategies in nonHodgkin's lymphomas Low-grade Stages I & II (excluding gut) Stages III & IV

Local radiotherapy Single-agent chemotherapy with/without radiotherapy if symptomatic

High-grade Stage Stage Stage Stage

I II III IV

Local radiotherapy/combination chemotherapy Combination chemotherapy Combination chemotherapy Combination chemotherapy

B-cell B-cell chronic lymphocytic leukaemia Extranodal marginal-zone B-cell lymphoma of MALT type FOLLICULAR LYMPHOMA Mantle cell lymphoma DIFFUSE LARGE B-CELL LYMPHOMA

23

Grade T-cell Low Low

Low Variable High

Anaplastic large cell lymphoma (T/null) Peripheral T-cell lymphoma, not otherwise characterized

High High

Rarer entities (<5% of all lymphomas) Burkitt's lymphoma

Precursor T-cell lymphoblastic lymphoma Mycosis fungoides/Sezary's syndrome Angioimmunoblastic lymphoma Adult T-cell lymphoma/leukaemia

High, with marked risk of CNS disease High, with marked risk of CNS disease variable High High, with marked risk of CNS disease

There is thus still some uncertainty about the long-term efficacy of antibiotic therapy for this condition, bearing in mind that reinfection with Helicobacter is likely to be common. Whether or not therapy such as chlorambucil or CVP (cyclophosphamide, vincristine and prednisolone) should be given is still unclear, but increasingly a careful 'watch and wait' approach is used after Helicobacter eradication. There are many other sites where MALT-type lymphomas can arise, one such being the parotid gland, where the lymphoma may arise on the background of Sjogren's disease. Follicular lymphomas occasionally present with very localized disease and in such cases radiotherapy should be given. About half of clinically stage IA patients will remain disease free at 10 years following radiotherapy, with the majority presumably being cured. However, most patients have disseminated disease which is generally incurable, so that therapy is essentially palliative in nature. With this in mind, there is no advantage to initiating treatment at diagnosis if the patient is asymptomatic and does not have significant organ dys-

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function, such as marrow failure. A 'watch and wait' policy can be adopted and, on average, therapy can be delayed in the asymptomatic patient for over 2 years. When treatment is required it has been usual to start with relatively non-toxic regimens, such as single-agent chlorambucil (5-10mg/day) given daily for 2 weeks, alternating with 2 weeks' rest or shorter pulses of higher dose. CVP (cyclophosphamide, vincristine and prednisolone) is an alternative relatively non-toxic regimen. Most patients respond to such treatment, although the response is often only partial and relapse usually occurs. More recently, fludarabine, either alone or in combination with other agents, has been used for initial therapy. The response rate is a little higher, but as yet there is no evidence that its early use leads to prolonged overall survival. The same can be said for the use of more intensive anthracycline-containing regimens such as CHOP (cyclophosphamide, hydroxydaunorubicin (also known as adriamycin), oncovin, also known as vincristine, and prednisolone). Once a good response has been achieved, therapy can be discontinued and the patient carefully followed up. ccInterferon, given once a response has been obtained, can prolong the duration of a remission and may even prolong survival if it is administered after a more intensive anthracycline-containing regimen. It is, however, expensive, causes significant side-effects and is not universally used. Treatment of relapse depends upon the initial therapy used and the duration of the first response. If the first remission was long then it is reasonable to use the same therapy that induced that remission. If not, one of the alternative regimens is used. Most patients will have a number of relapses and remissions and will ultimately receive a range of different treatments. A humanized CD20 monoclonal antibody has recently been introduced for the treatment of relapsed disease. A response, almost always partial, is obtained in about half the recipients and in responding patients lasts on average for about 1 year. It has the major advantage of minimal toxicity and frequent effectiveness in tumours that have become insensitive to chemotherapy. Very high-dose chemotherapy and autologous stem cell transplantation may have a role in second or subsequent response. There are no data from randomized trials, but the information available suggests that it can prolong remissions. It is not yet clear whether any patients are cured by such procedures. Allogeneic transplantation may be curative and merits consideration in younger patients, possibly even at an early stage of the disease. Each remission tends to be shorter than the previous one, and eventually a state of chemoresistance is achieved. In addition, the disease can transform at any time to a more aggressive form of lymphoma (large B-cell lymphoma).

1

1256

Case 23.7

2

Fig. 23.17 3

MCQ23.18

When this occurs treatment is given as for other high-grade lymphomas and, if a remission is obtained, a high-dose therapy procedure may be indicated. Mantle cell lymphomas typically appear histologically as low-grade lymphomas, being composed of a monomorphic population of small cells. They tend to present with very advanced disease and respond poorly to treatment. Overall they have a worse prognosis at 5 years than most other forms of lymphoma. In recent years the tendency has been to treat these lymphomas with combination chemotherapy regimens used for high-grade lymphomas, but there is little evidence that this has improved the outlook. High-grade lymphomas Diffuse large B-cell lymphomas are infrequently stage I, and in these cases full-dose local radiotherapy is often curative. The most commonly used approach is to give involved field radiotherapy (40 Gy) after three cycles of CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone). This approach may also be appropriate in some cases of stage II disease. In all other stages chemotherapy is usually used alone unless there are residual masses at the end of therapy, when consolidation with radiotherapy may be used. The CHOP regimen is the 'gold standard', and although there have been many attempts to improve upon it the results have generally been disappointing. CHOP is usually given as 6-8 3-weekly cycles, and there is no benefit from protracted maintenance therapy. CNS prophylaxis is not usually warranted but should probably be given if there is disease of the central facial sinuses or the testes, where there is a major risk of associated CNS involvement. An International Prognostic Index has been derived for the high-grade lymphomas, particularly the large cell lymphomas. Age is a key factor, and in the younger patients (<60 years) the most important factors are stage, performance status and LDH levels (Table 23.39). Patients with poor prognostic disease are frequently considered for experimental intensive therapy strategies.

TABLE 23.39 International Prognostic Index in patients <60yrs with histologically aggressive NHL

Index Low

Low-intermediate High-intermediate High

No. of poor prognosis risk factors*

Complete remission rate (%)

Overall survival at 5 years (%)

0 1

92

83

2

78 57

69 46

3

46

32

*Poor prognostic factors are: stage III/IV, poor performance status or raised LDH. Above data taken from Shipp et al 1993 A predictive model for aggressive non-Hodgkin's lymphoma. N Engl J Med 329: 967-994

If patients fail to achieve a remission with CHOP, or subsequently relapse, salvage therapy with different drug regimens is used. If the disease is still chemosensitive and the bone marrow is clear of disease, stem cells can be collected and high-dose therapy administered (usually the BEAM regimen). Forty to 50% of such patients who receive an autograft can be cured, but they are a highly selected group. 1 Anaplastic large cell lymphomas, although histologically very aggressive, have a relatively good prognosis. They are treated in the same way as the diffuse large Bcell lymphomas. Peripheral T-cell lymphomas not otherwise classified comprise about 5% of NHL. Their prognosis is worse than that of diffuse large B-cell lymphomas, with a 5-year survival of approximately 35%. They are treated with chemotherapy. There is no evidence that alternative therapies to CHOP are superior. Burkitt's lymphoma was first described as a disease endemic to parts of Africa, often presenting in children with tumours of the jaw. It was later found to be associated with incorporation of the Epstein-Barr virus (EBV) into the genome of the malignant cells. It comprises a homogeneous population of small non-cleaved cells with close to a 100% proliferation fraction. The hallmark of the disease is the upregulation of the c-myc proto-oncogene, usually in association with t(8;14)(q24;q32). Endemic forms of the disease also exist, often presenting with large, rapidly growing abdominal tumours in both children and adults. In addition, Burkitt's lymphoma is a frequent occurrence in the immunosuppressed, especially patients with AIDS. This type of lymphoma responds extremely well to very intensive chemotherapy, which must include CNS prophylaxis as there is a high predilection for spread to the CNS, which is a sanctuary site. With such therapy the cure rate exceeds 70% even in adults. There is also an entity referred to as Burkitt-like lymphoma, but its relationship to Burkitt's lymphoma is not clear. Precursor T-lymphoblastic lymphoma is a clinical variant of T-cell acute lymphoblastic leukaemia (T-ALL), typically presenting with a large mediastinal mass and only minor involvement of the bone marrow. 0 It is usually treated with ALL protocols, including CNS prophylaxis. The outcome is excellent in children but less satisfactory in adults. There is some evidence that adults may benefit from a high-dose therapy and stem cell transplant procedure in first remission. Mycosis fungoides and its leukaemic conterpart Sezary's syndrome occur most commonly in middle-aged males. They are manifestations of cutaneous T-cell lymphoma. In both cases the malignant cell is a CD4+ mature T cell, the nucleus of which frequently has a highly convoluted and bizarre morphological appearance. These Sezary cells may also occur in the blood in light-sensitive eczemas. Mycosis fungoides often begins as an eczematous reaction, which may mimic psoriasis. Many patients have skin rash for years before diagnosis. A precise definition of when the disorder should be considered malignant is difficult.

Demonstration of clonality by T-cell receptor gene rearrangement is of value. In the later stages of mycosis fungoides the skin lesions form plaques, tumours and fungating ulcers. Erythroderma (p. 409) may occur, which is often highly pruritic. In the Sezary syndrome there is leukaemia, generalized lymphadenopathy and hepatosplenomegaly in addition to skin infiltration (usually erythroderma). The lesions of mycosis fungoides can be treated with topical steroids, topical cytotoxic agents, psoralens with ultraviolet light (PUVA) (p. 399) or radiotherapy. When there is visceral involvement systemic cytotoxic therapy is required, although the response is often brief in duration. Interferon-oc is of value. The median survival of all stages of mycosis fungoides is 5 years, but is much less if there is a leukaemic element, and very much longer if the disease is diagnosed at an early stage. Angioimmunoblastic lymphomas typically present with lymphadenopathy, hepatosplenomegaly and hypergammaglobulinaemia. The patient is often febrile and autoimmune haemolytic anaemia is common. Histologically, the node is infiltrated by a mixed proliferation of immunoblasts, plasma cells, lymphocytes, eosinophils and small blood vessels. There is a related condition known as angioimmunoblastic lymphadenopathy, which can be selflimiting and responsive to steroids, although in most cases a malignant T-cell lymphoma becomes apparent. Adult T-cell lymphoma/leukaemia is rare entity in the UK but is common in southwest Japan and the Caribbean basin. It is of particular interest because it is caused by the human T-cell lymphotropic virus (HTLV-1). The infectivity of this virus is low, and only a small proportion of patients who have been infected with HTLV-1 develop T-cell lymphomas. These involve phenotypic CD4+ cells and often behave in a very aggressive manner. Widespread visceral involvement with a leukaemic element is usual, and central nervous system involvement and hypercalcaemia are common. The response to chemotherapy is usually poor. Some patients do, however, have prolonged remissions with 5-azacytidine and oc-interferon therapy. 3

23

HISTIOCYTE DISORDERS Histiocytic medullary reticulosis This is a rare malignant proliferation of monocytic/ histiocytic cells that usually presents with fever and pancytopenia. The histiocytes in the marrow exhibit haemophagocytosis. The disease responds poorly to chemotherapy and is normally rapidly fatal. This condition may be difficult to differentiate from virus-induced histiocytosis, which is a potentially self-limiting disorder.

Langerhans' cell histiocytosis (histiocytosis X) Langerhans' cell histiocytosis is a spectrum of disorders previously known by a number of eponyms - unifocal

1257

eosinophilic granuloma, Hand-Schuller-Christian disease and Letterer-Siwe syndrome. They are clonal proliferations of Langerhans' cells (histiocytes found in the dermis) but are of uncertain malignancy. The lesions are characterized by variable proliferation of histiocytes, with the formation of giant cells and granulomata, and infiltration by eosinophils, foam cells and fibrosis. The Langerhans' cells have characteristic electronmicroscopic (EM) inclusions. The lesions are responsive to intralesional steroids, local radiation and systemic chemotherapy. Because remissions occur spontaneously, especially in childhood, a conservative approach is adopted whenever possible.

CHRONIC LYMPHOCYTIC LEUKAEMIA The annual incidence of chronic lymphocytic leukaemia (CLL) in the UK is approximately 6 per 100000. It does not occur in children and is rare in young adults, but the incidence rises steeply with advanced age. It is nearly twice as common in males as in females.

Clinical and laboratory features CLL usually presents with lymphadenopathy with or without splenomegaly. Some early cases are discovered on an incidental blood count. As the disease progresses there is insidious development of anaemia. Occasionally, the onset of anaemia may be rapid and severe in degree. This usually indicates the development of autoimmune haemolytic anaemia. There is also an increased incidence of bacterial and, to a lesser extent, viral infections. Laboratory investigations show that the lymphocyte count is very variable, from just above normal up to 300 x 109/L. Most are small, mature lymphocytes and a variable number are larger cells with a nucleolus but still with a mature nuclear chromatin pattern (prolymphocvtes). Smudge cells are also numerous on the blood film. 1 In over 95% of cases the lymphocytes are B cells which express low levels of light-chain-restricted surface immunoglobulin. They also express pan-B antigens and the CDS antigen - a pan-T antigen expressed on cells transiently during B-cell differentiation. Surface marker analysis with demonstration of light-chain-restriction may be particularly helpful in making the diagnosis of CLL when the lymphocyte count is only marginally raised. Biopsy of affected nodes (which is seldom necessary to make the diagnosis) shows a low-grade diffuse lymphocytic lymphoma, with cells identical to those in the blood. Analysis of the immunoglobulin gene sequence reveals hypermutation in most cases, but a proportion do not, suggesting that this subset arises from before the germinal centre

1258

1

Fig. 23.18

2

4

Figs 23.19-23.20

Case 23.8

3

MCQ 23.19

stage of differentiation. Hypogammaglobulinaemia due to suppression of normal immunoglobulin production occurs at some stage of the disease in about one-third of cases; paraproteins (usually IgM) occur in about 5% of cases.

Management As with the disseminated small lymphocytic lymphomas, treatment is only indicated if the patient is symptomatic or has critical organ dysfunction. Initial treatment is usually with chlorambucil (2-10mg/day). In good responders it is often possible to stop therapy, as it is not necessary or feasible to strive for a complete remission. Steroids are of value if the patient has thrombocytopenia or an autoimmune haemolytic anaemia. As the disease progresses resistance to chemotherapy occurs, with an increasing lymphocyte count, lymphadenopathy, hepatosplenomegaly and bone marrow failure. In such patients combination chemotherapy will frequently bring the disease under control, but this is usually only temporary. Fludarabine and 2-CDA are also useful agents which are being explored as first-line therapy, as well as for use in relapsed patients. In some patients progression is associated with increasing numbers of prolymphocytes in the blood; rarely, there is transformation to a histologically aggressive lymphoma (Richter's syndrome).

Prognosis The median survival exceeds 5 years, but patients presenting with advanced disease have a much shorter survival. Poor prognostic features at presentation include large numbers of prolymphocytes on the blood film, massive splenomegaly and marrow failure. Patients without immunoglobulin gene hypermutation have a worse prognosis. 2

Prolymphocytic leukaemia Prolymphocytic leukaemia (PLL) is a variant of CLL in which the majority of peripheral blood cells are prolymphocytes. In most cases these are B cells, but a significant proportion of cases are of mature T-cell origin. In PLL the leukocyte count tends to be high, and massive splenomegaly is common, often with little lymphadenopathy. The prognosis is poor compared to typical CLL.

Hairy cell leukaemia This is a chronic B-cell lymphoproliferative disorder in which the malignant cells have a typical 'hairy appearance' with multiple fine cytoplasmic projections. Fancytopenia and splenomegaly are usual, but lymphadenopathy is uncommon. There is often fibrosis of the marrow, with a dry tap. The treatment of choice is deoxycoformycin or 2-chlorodeoxyadenosine, the latter often being associated with prolonged remissions. In severely pancytopenic patients in whom it is difficult to give the above agents

a prior 2-4-month course of oc-interferon may be helpful. Rarely, in patients with very large spleens and moderate or little bone marrow involvement a splenectomy should be considered.

T-cell chronic leukaemias T-cell chronic leukaemia encompasses several rare entities with distinct natural histories. CD4+ proliferations generally have an aggressive natural history, whereas the CD8+ proliferations are comparatively benign. The cells in CD8+ T-cell chronic leukaemia are usually large granular lymphocytes, the lymphocyte count is only moderately raised, and although the marrow infiltration is usually not total, very severe red cell aplasia or neutropenia may occur. The precise pathogenesis of these cytopenias is not clear. The disease may remain stable for many years, and a complete remission is often obtained with single-agent cytotoxic therapy. T-cell granular lymphocytic leukaemia has been associated with rheumatoid arthritis. ©

TUMOURS OF IMMUNOGLOBULINPRODUCING CELLS This term refers to monoclonal proliferations of B cells at a relatively late stage of differentiation. The cells are usually secreting immunoglobulin, in which case the abnormal proliferation is accompanied by an abnormal band on serum protein electrophoresis. The monoclonal immunoglobulin is called a paraprotein.

Multiple myeloma Multiple myeloma is a malignant B-cell proliferation in the bone marrow, in which the predominant cell type is the plasma cell. This disease occurs predominantly in the elderly, and the annual incidence is approximately 6 per 100000. Clinical and laboratory features The development of the symptoms and signs of multiple myeloma is shown in Figure 23.34.

DIRECT EFFECTS OF PLASMA CELL PROLIFERATION

Direct effects of plasma cell proliferation The proliferation of plasma cells within the marrow leads to skeletal destruction. The bone destruction is mainly due to the release of osteoclast-activating factors by the plasma cells, rather than to a direct expansion of the plasma cells within the bones. Widespread osteoporosis and lytic lesions without osteoblastic reaction (no sclerosis and normal alkaline phosphatase) occur in most cases. Multiple lytic lesions of the skull and crush fractures of the spine are particularly common. 4 Hypercalcaemia in association with bone resorption occurs in 30% of cases at some stage of the disease, not infrequently at presentation. This gives rise to thirst, polyuria and dehydration, constipation and abdominal pains, lethargy, confusion and coma. The plasma cell proliferation frequently causes a mild to moderate anaemia. This is due in part to replacement of the marrow space by tumour, but the proliferation may also suppress haemopoiesis. Neutropenia and thrombocytopenia are rarely severe at presentation, but may become so following chemotherapy or with very advanced disease. The cytopenia may also be exaggerated by the increase in plasma volume that may accompany paraproteinaemia. Plasma protein abnormalities Paraproteins do not usually cause symptoms but, when in sufficient quantity, they may cause hyperviscosity, with lethargy, confusion, loss of vision and coma. This is particularly likely to occur with IgA paraproteins, as the IgA molecules have a tendency to polymerize, thereby greatly increasing their intrinsic viscosity. Paraproteins may cause a haemorrhagic tendency, mainly through non-specific coating and interference with platelet function. Some paraproteins are also cryoglobulins (p. 1262) and may give rise to Raynaud's phenomenon. More importantly, myeloma is accompanied by suppression of normal immunoglobulin production (hypogammaglobulinaemid), and infection is thus a major cause of morbidity and mortality. The mechanism of suppression of normal antibody production is obscure, but it is severe and usually persists even in patients whose paraprotein disappears on treatment. Multifactorial Renal dysfunction commonly occurs at presentation or

PLASMA PROTEIN ABNORMALITIES

Plasmacytomas

Marrow dysfunction

Skeletal destruction

Paraprotein

Hypogammaglobulinaemia

Bone and soft tissue tumours

Anaemia (Neutropenia) (Thrombocytopenia)

Bone pain Fractures Hypercalcaemia

Hyperviscosity syndrome (Cold sensitivity) (Bleeding tendency)

Infections

FIG. 23.34 Development of symptoms and signs in multiple myeloma

23

MULTIFACTORIAL

Neurological dysfunction

Renal failure

1259

with advancing disease. There are multiple causes, including light-chain precipitation in the renal tubules and amyloid deposition in the glomeruli. Hypercalcaemia causes impaired glomerular function and a failure of renal tubular function, resulting in an inability to concentrate the urine. As a result, many patients are dehydrated at presentation; the prerenal element in the renal failure must be recognized and treated by salt and water replacement. Other causes of renal damage include hyperuricaemia with tubular deposition of urate, and myeloma infiltration of the kidney. Myeloma deposits extruding from bone (particularly collapsed vertebrae) may cause cord compression or root lesions. Cranial nerve lesions due to compression occur rarely. Peripheral neuropathies may also arise as a nonmetastatic manifestation of malignancy. Investigation Mild anaemia is common, but leukopenia and thrombocytopenia are less so unless as a result of treatment. Plasma cells are only rarely seen in the peripheral blood. If a paraprotein is present, rouleau formation and a high ESR are usually found. Bone marrow examination usually shows a plasmacytosis (more than 10%), but the disease can be 'patchy' and the sample not fully representative. 1 The plasma cells often have an abnormal appearance, with a centrally placed nucleus, which is often bi- or trinucleate. The total serum y-globulin level is usually increased because of the paraprotein, and the serum albumin often reduced. Plasma protein electrophoresis reveals a narrow monoclonal band in over 75% of cases (Fig. 23.35). The incidence of the different types of immunoglobulin production in myeloma is shown in Table 23.40). Light chains are rapidly metabolized and often do not give rise to a serum paraprotein. They can nearly always be detected by immunoelectrophoresis of the urine; free light chains can also be detected in the urine of many patients who have a paraprotein composed of intact immunoglobulin - socalled Bence-Jones proteinuria. Serum pYmicroglobulin (a protein associated with class I HLA antigens) levels are usually raised and give an indication of the myeloma mass. The investigation of the patient with suspected myeloma should also include a skeletal survey, and estimation of urea, creatinine and electrolytes, calcium, phosphate and uric acid. Diagnostic criteria The three major diagnostic criteria for myeloma are: • Bone marrow plasmacytosis (greater than 20%, but lower level acceptable if proven to be monoclonal); • Lytic lesions on X-ray (severe osteoporosis is acceptable if marrow plasmacytosis is greater than 30%);

1 1260

Fig. 23.21

2

Case 23.9

TABLE 23.40 Approximate incidence of different types of immunoglobulin production in myeloma Immunoglobulin

Incidence (%)

IgG IgA

55 (IgG + urinary light chain in 35%) 20 (IgA + urinary light chain in 15%) 20 2

Light chain only IgD IgE

IgM

very rare

Non-secretory

FIG. 23.35 Densitometry traces of serum protein electrophoresis from a normal individual and a patient with multiple myeloma

• Paraprotein in blood or urine. At least two of these criteria should be present for a definitive diagnosis, as each feature alone can be due to other diseases (Table 23.41). Where there is doubt, it is often advisable to wait and reassess later. Management Most patients are symptomatic at presentation and merit immediate therapy. Occasionally, patients are asymptomatic and do not have advanced bone disease, a high level of paraprotein or organ dysfunction. In these cases treatment can be delayed. Supportive therapy Immediate therapy is supportive. Pain must be controlled, and if there are fractures this may require a continuous infusion of opiates. Local radiotherapy is often strikingly effective in the relief of bone pain. Vertebral collapse and

TA8LE 23.41 Differential diagnosis of myeloma

TABLE 23.42 Prognostic categories in myeloma

Symptom

Differential diagnosis

Prognosis

Criteria

Paraproteinaemia

Benign monoclonal gammopathies Malignant lymphoproliferative disorders Reactive - Infections Autoimmune disease Liver disease Non-lymphoid tumours

Good

Posthydration urea less than 8mmol/L [Hb] greater than 10g/dL No or few symptoms

Intermediate

Patient in neither good nor poor prognostic categories

Poor

Posthydration urea greater than 10mmol/L and restricted activity; or [Hb] less than 7.5g/dL and restricted activity

Bone marrow plasmacytosis

Lytic lesions

Chronic infections Chronic inflammatory disorders Liver disease Other tumours Multiple metastases 'Spotty osteoporosis' Multiple eosinophilic granulomas Hyperparathyroidism Primary amyloid Hydatid disease Fibrous dysplasia

spinal pain must be treated promptly, as there is a risk of cord compression resulting in paraplegia. Radiotherapy is the treatment of choice. Careful attention must be paid to the fluid status: in patients with renal dysfunction or hypercalcaemia a high fluid intake is essential. Prompt rehydration will often prevent permanent renal damage. In some patients with renal tubular damage there is a chronic inability to conserve fluid, and the weight and standing and lying blood pressures must be carefully followed in these patients. Hypercalcaemia is treated in the usual way with fluids, loop diuretics and steroids (p. 974). Bisphosphonates should be given, as there is good evidence that they reduce the frequency of symptomatic bone lesions. Infections are common and must be treated vigorously. The hyperviscosity syndrome will respond temporarily to plasma exchange. Specific therapy Standard specific therapy for myeloma has been with the alkylating agent melphalan, approximately 7mg/m2 daily for 4 days every 3 weeks, provided renal function is normal. The absorption of melphalan is variable, and some suppression of the blood count is a useful marker that enough drug is being absorbed. Intermediate-dose prednisone (60mg/m2/day) is usually given in addition over the treatment days, but is of limited value in the absence of bone pain or hypercalcaemia. Approximately 50% of patients have a good initial response, with a decrease in myeloma mass and fall of paraprotein to a stable plateau level. Disappearance of paraprotein with normalization of the marrow is rare (5% of cases). Improved responses have been claimed for some combination chemotherapy regi-

23

mens, but these are more toxic and it is not certain that they are preferable to melphalan if this is given at adequate dosage. In the plateau phase therapy can be discontinued until progression occurs. Continuous oc-interferon may prolong the plateau phase, and recent meta-analyses suggest there is a small impact upon survival. In patients who become resistant to melphalan second-line therapies are available; these include drugs such as anthracyclines, nitrosoureas, vinca alkaloids and very high-dose steroids. These regimens are less effective if these drugs have been used initially. The duration of response is usually short. Very high-dose therapy (e.g. melphalan 200mg/m2, or total body irradiation) with autologous stem cell support may be a useful salvage strategy. High-dose therapy has also been used as part of planned initial therapy, and a randomized trial suggests that this prolongs survival and improves quality of life, although it is not curative. Further studies are required. Allogeneic transplantation has been used in the occasional younger patient, and some may be cured. The procedure related mortality is high. Prognosis The overall survival is poor, with a median survival of approximately 2-3 years (marginally better in younger patients), although occasional long-term survivors do occur. It is possible to categorize patients at diagnosis into good, intermediate and poor prognostic groups on the basis of the [Hb], urea (posthydration) and performance status (Table 23.42). The B2-microglobulin level is also a valuable prognostic indicator. Good-prognosis patients have a 2-year survival of about 75%, and poor-prognosis patients about 10%. ©

Plasmacytomas Plasmacytomas are collections of plasma cells at a single site. They are usually part of a more generalized myeloma,

RECENT ADVANCES IN MULTIPLE MYELOMA Administration of the bisphosphonate 'clodronate' during the plateau phase causes minor but significant reduction in bone disease at the time of progression.

1261

but isolated tumours do occur without evidence of widespread disease. Many of the latter patients will go on to develop myeloma. Full-dose radiotherapy should be given to solitary plasmacytomas, followed by chemotherapy if there is persistence of paraproteinaemia (usually only at low levels). Careful long-term follow-up is required.

Waldenstrom's macroglobulinaemia This is a rare, low-grade B-cell malignancy that presents in the elderly as a lymphoma or chronic leukaemia. Biopsy of affected tissue shows a diffuse lymphocytic lymphoma with plasmacytoid differentiation. Similar cells are seen in the marrow and in the blood. The hallmark of this disease is the production of large quantities of IgM paraprotein, leading to symptoms of hyperviscosity, haemorrhagic tendencies and cold sensitivity (cryoglobulins in 30%). Weight loss, lymphadenopathy and hepatosplenomegaly are all common, but lytic bone lesions and renal failure are rare (unlike the situation in myeloma). No therapy is necessary in asymptomatic patients, although they must be followed up carefully. When symptoms arise, therapy with alkylating agents such as chlorambucil, fludarabine or 2-CDA will often produce a satisfactory, albeit incomplete, response. There are no comparative randomized trials, but 2-CDA is probably the treatment of choice. Hyperviscosity syndrome may respond to plasmapheresis while the disease is being brought under control with chemotherapy. The median survival is about 5 years.

Cryoglobulinaemia Cryoglobulins are immunoglobulins that precipitate when cooled. They may be monoclonal, polyclonal or mixed. The monoclonal cryoglobulins are usually indicative of a lymphoproliferative disease, and the polyclonal varieties are often reactive and transient. A mixed monoclonal and polyclonal cryoglobulin is not infrequently associated with autoimmune disease. Clinically, their presence may give rise to Raynaud's phenomenon, acrocyanosis, vascular purpura, arthralgia and - in the most severe cases - renal failure, hepatic failure and isolated neurological lesions. The blood film typically shows marked agglutination of red cells and the ESR may be spuriously low at room temperature, although normal if performed at 37°C. The mainstay of treatment is the avoidance of cold and treatment of any underlying conditions, such as a lymphoma. Plasmapheresis may have a role if there are severe symptoms.

Heavy-chain disease Heavy-chain disease (HCD) refers to rare B-cell proliferations in which there is secretion of heavy chains 1

1262

MCQ 23.20

uncoupled to light chains. Serum electrophoresis usually shows hypogammaglobulinaemia without a clear monoclonal band. Immunoelectrophoresis is therefore required to demonstrate the abnormal heavy chain unassociated with light chain. Immunoelectrophoresis of the urine is often helpful. a-HCD occurs mainly in the Mediterranean countries, Asia and South America. It typically presents with abdominal pain, malabsorption and clubbing. Lymphadenopathy and hepatosplenomegaly are not usually present and (because of the malabsorption) coeliac disease is often suspected. In the early phases the mucosa is infiltrated with polyclonal plasma cells and lymphocytes, and the disease is called immune proliferative disease of the small intestine. Later, a frankly invasive lymphoma develops. The production of a chains diminishes as the lymphoma progresses. The disease may respond to tetracycline in its early stages, but the established lymphoma is not very responsive to treatment. y-HCD occurs mainly in the elderly and presents with weakness, fever, palatal oedema, lymphadenopathy and hepatosplenomegaly. The marrow is usually infiltrated with lymphocytic cells, and pancytopenia is common. The course is variable, but death occurs in most cases. u-HCD is rare and is usually associated with typical chronic lymphocytic leukaemia in which the plasma contains u heavy chains. 1

FURTHER READING ON MALIGNANT LYMPHOPROLIFERATIVE DISORDERS Diehl V 1996 Hodgkin's disease. Bailliere's Clin Haematol 9-3. Harris N L, Jaffe E S, Diebold J et al 1999 World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the clinical advisory committee meeting - Airlie House, Virginia, November 1997. J Clin Oncol 17: 3835-3849. Linch D C 1996 Non-Hodgkin's lymphoma. Bailliere's Clin Haematol 9-4.

AMYLOIDOSIS Amyloidosis is a generic term for a group of conditions in which there is waxy infiltration of the tissues, the amyloid infiltrate staining pink with haematoxylin and eosin, and

SUMMARY 12 Aetiological classification of amyloidosis • • • • •

Amyloid associated with immunoglobulin-producing tumours Reactive systemic amyloidosis Heredofamilial amyloidosis Local amyloid associated with endocrine tumours Amyloid of ageing

green with Congo red. The amyloid material is birefringent and is composed of fibrils formed into (3-pleated sheets. It is composed of a number of different types of protein and all types contain a glycoprotein known as amyloid P, which is in dynamic equilibrium with serum amyloid P (SAP). The amyloid infiltrates ultimately damage normal tissue by means of pressure, atrophy and hypoxia.

Classification The amyloidoses are best classified on an aetiological basis, depending on whether the disease is acquired or inherited and on the type of protein in the amyloid (Table 23.43). The amyloid associated with immunoglobulin-producing tumours (AL and, less frequently, AH) is what was formerly known as primary amyloid, as well as 'amyloid associated with myeloma'. The primary amyloid is best thought of as early myeloma without lytic bone lesions. A monoclonal band detected by electrophoresis in blood or urine appears during the course of the disease in nearly all cases, but at diagnosis immunofixation may be required to demonstrate the low levels that may be present. The amyloid deposits in this type of amyloidosis are made up of intact im-

TABLE 23.43 Classification of amyloidoses Type

Amyloid protein

Other name

Immunoglobulin light chains Immunoglobulin heavy chains (Apo) serum amyloid A protein

Primary amyloid Primary amyloid Secondary or reactive systemic amyloid Dialysis-associated amyloid Senile systemic amyloid

Acquired AL AH

AA AB2M ATTR

Serum p2M Plasma transthyretin (3-amyloid protein precursor (APR)

Non-familial Alzheimer's disease Sporadic CreutzfeldtJakob disease Endocrine amyloidosis

Peptide hormones or fragments thereof

Hereditary AA ATTR

(Apo) serum amyloid A protein Genetic variants of transthyretin

Others

Prion protein precursor

Apolipoprotein genetic variant Gelsolin genetic variant Lysozyme genetic variant Fibrinogen a-chain genetic variant (3-amyloid precursor protein genetic variant Prion protein precursor genetic variant

munoglobulin chains or parts of the variable domains. Some myeloma proteins are more likely to form amyloid than others, and A. light chains of the yVI subclass are particularly amyloidogenic. In AA amyloid or the reactive systemic amyloidoses which typically occur in association with chronic infections (e.g. bronchiectasis), chronic inflammatory disorders (e.g. rheumatoid arthritis) or neoplastic disorders - the amyloid is composed primarily of an acute-phase protein called amyloid A protein. Ap2M amyloid, as its name implies, is composed of pYmicroglobulin and is associated with chronic dialysis. A(3 amyloid is a form found locally within the brain in Alzheimer's disease. The familial forms of amyloid can be broadly divided into neuropathic and nonneuropathic, and are often due to genetic variants of the proteins involved in acquired forms of the disease.

23

Clinical features Amyloid can cause diverse organ dysfunction, but the features shown in Table 23.44 should always raise the possibility of amyloidosis. AL and AH were thought to have a different anatomical distribution from the other amyloid states, but the overlap is so wide that the distinction of primary and secondary is not helpful.

Diagnosis The diagnosis is made by histological inspection of infiltrated tissues. Tissues worth considering for biopsy include minor salivary glands, gingiva, subcutaneous fat, bone marrow, and gastric and rectal mucosa. Tissues such as liver and kidney should probably not be biopsied as a first-line investigation because of the greater risks involved. Appropriate tests should also be performed to exclude myeloma, even when the patient has another chronic disorder. The total burden of amyloid protein (and response to treatment) can be assessed by scans. Following the injection of 123 I SAP, this is taken up by the amyloid rather than being cleared at the normal rate.

Management and prognosis

Familial Mediterranean fever Familial amyloid polyneuropathy

This is primarily supportive, with specific treatment of any underlying disease. Care should be taken with the administration of diuretics or digitalis, as these can precipitate

TABLE 23.44 Clinical features suggestive of amyloidosis • • • • • • •

Nephrotic syndrome and renal failure Peripheral neuropathy with or without a carpal tunnel syndrome Restrictive cardiomyopathy Malabsorption and protein losing enteropathy Polyarthropathy Skin nodules, infiltrates and periorbital purpura Macroglossia

1263

severe hypotension or dysrhythmias, respectively. In AL and AH a trial of melphalan and prednisolone should be given. Randomized trials have demonstrated an improvement in survival, but most patients show no reponse. If this fails, other myeloma-type regimens can be tried. There are reports that amyloid will sometimes regress with the daunorubicin derivative 4'iododeoxydaunorubicin, but further studies are required. The limited experience of high-dose melphalan and autologous stem cell transplantation in AL and AH is encouraging, although the procedure-related mortality is high in the presence of cardiac involvement; also, the patients transplanted to date have been highly selected and are probably those that would have survived longest with more conventional therapy. The median survival of patients with AL and AH is about 2 years, but is approximately 10 years in AA. 1

INJURY

Exposure of subendothelial basement membrane andcollagen

Local vasoconstriction

Release of tissue thromboplastins

Activation of intrinsic coagulation cascade

Activation of extrinsic coagulation cascade

Platelet adhesion

Platelet aggregation to form the platelet plug

NORMAL HAEMOSTASIS The haemostatic processes involve a complex sequence of interacting events which serve both to protect the integrity of the vascular system and to re-establish patency of small segments which become occluded (Fig. 23.36). There is initial vasoconstriction at the site of injury, but this is transient and not a major component of the haemostatic mechanism. The major component of haemostasis is the formation of a platelet plug, followed by the laying down and cross-binding of fibrin.

Activation of common pathway to form fibrin

THROMBUS FORMATION FIG. 23.36 The mechanisms of haemostasis The process of platelet aggregation and activation is shown in grey, and the formation of fibrin in blue.

Platelets Injury exposes collagen and the subendothelial basement membranes. Circulating platelets adhere to these structures, aided by fibronectin and high molecular weight multimers of factor VIII complex (factor VIII von Willebrand factor = fVIIIvWF), which coat the surface of the platelets. Following the adhesion of a single layer of platelets to the damaged vascular endothelium, further platelets become activated, stick to one another, aggregate, and ultimately form a platelet plug. The aggregation is mediated via a large and range of factors which are produced at the site of injury and which react with receptors on the platelet surface. Many of these factors - such as ADP, serotonin and thromboxane A2 - are themselves released by activated platelets (Fig. 23.37), producing positive feedback. ADP is also released from damaged red cells at the site of injury. Thrombin is a potent aggregatory agent, so the activation of the common pathway in the coagulation cascade further stimulates the formation of a platelet plug.

FIG. 23.37 Diagrammatic cross-sectional view of a platelet

The process of platelet aggregation and activation is mediated by at least two separate biochemical pathways: 1

1264

MCQ 23.21

• Ligands such as ADP or collagen bind to specific receptors. This leads to the activation of membrane phospholipases, with the release of arachidonic acid from the platelet membrane phospholipids. A propor-

Platelet

Endothelial cell

Phospolipid

Pnospholiprd

Arachidonic acid

Arachidonic acid

INJURY

23 Exposure of tissue thromboblastins

Exposure of negatively charged endothelium

Inhibition < Cyclooxygenase

Activation of contact systems

Cyclic endoperoxfdes

Cyclic endoperaxides

FXI

FXIa

FX

ThromboxaneA 2 (TXA 2 cAMP

Prostacyclin(PGI 2 )

FIX

Calcium mobilization Inhibition Granule release

FVIII

FIXa Ca 2+ Phospholipid F Villa

Ca 2 + Phospholipid

FXa ADP serotonin FIG. 23.38 Arachidonic acid metabolism in platelets and endothelial cells

Prothrombin

Platelet activation and aggregation also has a role in the coagulation cascade that becomes activated at the site of injury. vWF, factor V and fibrinogen are stored in granules and released on activation. More importantly, the platelet undergoes a configurational change during the activation process, such that anionic phospholipid micelles are translocated to the platelet surface and become available to facilitate the formation of coagulation complexes, leading to the generation of factors IXa, Xa and thrombin.

The coagulation cascade In the coagulation cascade a series of amplification reactions occur during which an inert precursor is converted to an active serine protease, with the ultimate formation of fibrin. The coagulation cascade has been conventionally divided into an intrinsic and an extrinsic pathway, which converge on a common pathway (Fig. 23.39). This schema is useful as it provides a framework for the understanding of the routine coagulation tests. It is, however, a gross oversimplification and not really representative of events in vivo. The major thrombostatic mechanism following damage

Ca 2+ Phospholipid FVa

FV

Thrombin

Fibrinogen

tion of arachidonic acid is then converted to the cyclic endoperoxides, and then to thromboxane A2 (TXA2). TXA2 is biologically highly active, and mediates a rise in intracellular [Ca2+] and platelet granule release (Fig. 23.38), which promotes further platelet aggregation. • Thrombin and high concentrations of collagen bring about a rise in intracellular [Ca2+] and degranulation by a mechanism distinct from that of arachidonic acid metabolism and TXA2 generation.

FVII

FVIIa

• Fibrin monomer FXIII

Cross-linked fibrin FIG. 23.39 The coagulation cascade The extrinsic pathway is shown in blue.

to the vasculature is the exposure of tissue factor to the blood with activation of factor VII. This leads directly to the activation of factor X (extrinsic pathway). In addition, complexes of tissue factor and factor VIIa generate small amounts of activated factor IX (intrinsic pathway). The small quantities of activated factor IX and X lead to the generation of small quantities of thrombin, which activate factors XI, VIII and V, thereby enhancing the generation of further thrombin. The exposure of negatively charged endothelium and the activation of contact factors (factor XII, high molecular weight kininogen and prekallikrein complex) is relatively unimportant in normal haemostasis, as factor XI can be activated by thrombin as discussed above. As a consequence, individuals with a deficiency of contact factors have only a mild bleeding tendency. The activation of factor X and prothrombin requires the presence of calcium ions and a phospholipid surface. Activated factor VIII is also required as a cofactor for factor X activation, and factor V serves as a cofactor for prothrombin conversion to thrombin. Factor VIII procoagulant activity is referred to as factor VIIIC (antibodies to this moiety detect factor VIIICAg). Factor VIIIC has a molecular weight of approximately 220 kDa and is synthesized in the liver, spleen, other parts of

1265

Endothelial cells

Platelets

Liver and RE system

vWF submit

fVIIIC

ENDOTHELIAL AND TISSUE DAMAGE Exposure of negatively charged endothelium Contact factor activation Plasminogen

vWF with associated factor VIII

Haemostatic inhibitory systems A complex system of physiological inhibitors and feedback control mechanisms exists to control and limit excessive or inappropriate activation of the haemostatic system and thus help maintain vascular patency. Endothelial cell inhibitors Vascular endothelial cells synthesize prostacyclin from arachidonic acid (Fig. 23.38). Prostacyclin causes vasodilation and potent inhibition of platelet adhesion and aggregation. It is released in increased quantities when the vessel wall is stressed or injured, and binds locally to spe-

1

1266

MCQ 23.22

2

Figs 23.22-23.25

Circulating inhibitors

Fibrin

Plasmins

Antiplasmins

FIG. 23.40 Schematic representation of the production and structure of the vWF:factor VIII complex

the RE system and the kidney. The factor VIIIC moiety then binds to vWF (Fig. 23.40), which is synthesized in vascular endothelial cells and (to a much lesser extent) in megakaryocytes. The vWF protein consists of subunits with a molecular weight of 200-240 kDa (detected immunologically as vWFAg, previously called factor VHI-related antigen (factor VIIIRag)). The subunits polymerize to form multimers of varying size ranging up to 20 000 kDa. These are required for functional activity, both to prolong the half-life of factor VIIIC and to participate in platelet adhesion to the damaged vessel wall. Ristocetin-induced platelet aggregation is dependent on the high molecular weight vWF multimers, and this test is therefore used to measure vWF activity (vWF:RiCoF). Thrombin digests fibrinogen to form fibrin monomers, which are readily converted to fibrin polymers. This is associated with the release of fibrinopeptides. The loose fibrin polymer is stabilized by cross-linking owing to the transglutaminase activity of factor XIII, which is also activated by thrombin.

Release of tissue plasminogen activator

Fibrin degradation products FIG. 23.41 The fibrinolytic system

cine platelet membrane receptors which mediate the activation of adenylate cyclase and a consequent rise in cyclic-AMP. This blocks aggregation through inhibition of platelet arachidonic acid metabolism and calcium flux. Endothelial cells also synthesize tissue plasminogen activator (t-PA) and a variety of inhibitory molecules, including plasminogen activator inhibitor, tissue factor pathway inhibitor, glycosaminoglycans which potentiate antithrombin, and thrombomodulin which catalyses the thrombinmediated activation of protein C (see below). Coagulation inhibitors A natural system of coagulation inhibitors exists to limit the activity of the coagulation cascade. Antithrombin III is the major inhibitor of thrombin (factor IIa) and factor Xa, and also inhibits factors IXa, Xa and kallikrein. Other plasma thrombin inhibitors include a2-macroglobulin and heparin cofactor II. Cl-esterase inhibitor is the principle inhibitor of kallikrein and factor VIIa. Protein C, a vitamin K-dependent protein which is activated by thrombin and inactivates factors V and VIII, and protein S - also a vitamin K-dependent protein - serve as cofactors for activated protein C. Both proteins act as modulators of the fibrinolytic system. Tissue factor pathway inhibitor (TFPI) circulates in the plasma and may be released from the endothelium by heparin. It forms a complex with tissue factor and factors VIIa and Xa, inhibiting their procoagulant activity and thus limiting the extrinsic pathway. The fibrinolytic system The fibrinolytic system is activated simultaneously with the intrinsic coagulation system via the contact factors (factor XII, kallikrein and urokinase-type plasminogen activator (u-PA) (Fig. 23.41). The inactive circulating proenzyme plasminogen is converted to the active serine protease

plasmin, which hydrolyses fibrin into soluble fibrin degradation products. Plasminogen can also be activated by tissue plasminogen activator (tPA) released from endothelial cells and from traumatized tissues. Several factors ensure that plasminogen conversion to plasmin is largely restricted to the site of trauma and thrombus formation: • Plasminogen activators are inactivated by circulating inhibitors and are also degraded in the liver. • The affinity of tPA for plasminogen is greatly increased when the tPA is bound to a fibrin complex, and this protects t-PA from inhibition. • Any circulating plasmin is rapidly bound to a2antiplasmin, which has far less affinity for plasmin bound to fibrin. 1

DIAGNOSIS OF DISORDERED HAEMOSTASIS History and examination A detailed history and examination are of paramount importance and will often indicate the cause of bleeding (Fig. 23.42). • It must first be determined whether bleeding is a localized problem, such as a gastric ulcer, or a generalized bleeding tendency. (It must be remembered that minor defects in haemostasis may only be brought to light by specific injuries). • The type of bleeding should be ascertained: purpura and mucosal bleeding usually suggest a platelet disorder, whereas confluent skin bruises and haemarthroses are more indicative of coagulation disorders. 0 • The length of the bleeding history and the age at onset must be noted and a family history taken. It is often

Full blood count and film Coagulation screening tests (PT.APTT.TT)

Bleeding time

23

Screening tests A full blood count and blood film will detect anaemia and thrombocytopenia (the commonest platelet defect), and platelet morphology should be noted. Occasionally the blood film also reveals the cause of bleeding, such as DIC or acute leukaemia. The coagulation screening tests - the prothrombin time (PT), activated partial thromboplastin time (APTT) and the thrombin time (TT) - are then performed. Prothrombin time The PT examines the extrinsic and common pathways. Excess tissue thromboplastin and calcium ions are added to citrated plasma and time to clot formation is measured. The normal range is typically 10-14 seconds, and prolongation of more than 2 seconds compared to control is suggestive of defective factors VII, X, V or II, or the presence of an inhibitor to these factors. The PT is relatively insensitive to the level of fibrinogen. Activated partial thromboplastin time The APTT screens the intrinsic coagulation cascade and the common pathway. Platelet-poor plasma is incubated with kaolin or other activators to provide contact activation in the presence of added phospholipid, and the clotting time after recalcification is noted. The normal range is typically approximately 30-40 seconds, but this varies between analysers and reagents. An abnormal result indicates deficiencies of one or more of factors XII, XI, IX, VIII, X, V, II or I (i.e. not factor VII), or the presence of acquired inhibitors. Thrombin time The TT is performed by adding thrombin to plasma, thereby bypassing the extrinsic and intrinsic systems, and measuring the time to clot formation. It is a measure of thrombin-fibrinogen reaction and is particularly useful for assessing fibrinogen and detecting inhibitors such as fibrin degradation products or heparin. The results of screening tests in several clinical conditions are shown in Table 23.45.

HISTORY AND EXAMINATION Type of bleeding Duration of history Family history Intercurrent disease DRUGS

Specific factor assays

informative to ask specific questions, e.g. 'Has any member of the family had excessive bleeding after dental extractions?' • Attention must be paid to any previous medical history of the current illness. • A detailed drug history is essential, including overthe-counter medicines.

Platelet aggregation studies

FIG. 23.42 Approach to investigation of a patient with a bleeding disorder

Further tests Where an abnormality is detected in the intrinsic or extrinsic coagulation cascade, the test is repeated using a 50/50 mixture of the patient's plasma and normal plasma. If this corrects the test, there is a deficiency in one or more of the factors assayed by the test. If full correction does not occur, then this implies the presence of a coagulation inhibitor.

1267

TABLE 23.45 Results of coagulation screening tesls In different clinical conditions (N = normal)

TABLE 23.46 Causes of thrombocytopenia Decreased production of platelets Congenital

Clinical condition

Acquired Marrow hypoplasia Marrow replacement Megaloblastic anaemia Specific platelet suppression by drugs Occasional viral infections

Haemophilia A Von Willebrand's disease Factor VII deficiency Liver disease Disseminated intravascular coagulation Warfarin Heparin N = normal.

Specific factors can be measured functionally by the use of mixtures of the patient's plasma with plasma known to be deficient in a single factor. Thus, if a prolonged APTT is obtained which is corrected by normal plasma but not by plasma from a patient with factor IX deficiency, then this implies that the patient is also deficient in factor IX. Some factors can also be measured immunologically, and the measurement of vWFAg is essential in differentiating between haemophilia and von Willebrand's disease. The functional activity of vWF is determined by ristocetin platelet aggregation studies. When a bleeding disorder is strongly suspected and the platelet count and clotting screen are normal, a template bleeding time should be performed; if prolonged (normal bleeding time is less than 10 minutes), this is indicative of a vessel wall or platelet defect. The latter includes von Willebrand's disease, in which the platelet/vessel wall interaction is defective; the bleeding time may be abnormal in mild von Willebrand's disease when the APTT is within the normal range. Platelet aggregation studies are performed both to help detect the rare congenital platelet abnormalities and to determine the level of vWF ristocetin cofactor activity. Platelet aggregation is based on the fact that platelet-rich plasma is turbid but clears as platelets aggregate; this is measured by increased light transmission. 1

PLATELET DISORDERS I: THROMBOCYTOPENIA Thrombocytopenia is the most common disorder of platelets and may be due to either decreased production

1

1268

MCQ 23.23

0 Fig. 23.23

3

Case 23.10

Increased destruction of platelets Immune thrombocytopenia Idiopathic Viral infections (including HIV) Associated with drugs Isoimmune neonatal thrombocytopenia Post-transfusion purpura Microangiopathic platelet destruction Disseminated intravascular coagulation Haemolytic uraemic syndrome Thrombotic thrombocytopenic purpura Severe sepsis Massive transfusions

or increased destruction (Table 23.46). The two mechanisms can usually be differentiated by bone marrow examination: megakaryocyte numbers are decreased in production thrombocytopenias, and increased where there is excessive platelet destruction. In some circumstances (e.g. severe infection) both mechanisms may be operative.

PRODUCTION THROMBOCYTOPENIAS Production thrombocytopenias may be congenital or acquired. There are a number of rare congenital disorders in which thrombocytopenia occurs, or where there are normal numbers of qualitatively defective platelets. Several of these rare disorders have an associated storage pool defect, such that there are defective platelet nucleotide stores resulting in defective aggregation at sites of vascular injury. In vitro, this is manifest as loss of the secondary aggregation wave to ADP. The acquired production thrombocytopenias may be due to: • Generalized marrow hypoproduction, as in aplastic anaemia • Megaloblastic anaemia • Less commonly, a megakaryocyte-specific suppression. This may occur with chronic alcohol ingestion and (rarely) with some drugs, such as the thiazide diuretics.

INCREASED PLATELET DESTRUCTION I: IMMUNE THROMBOCYTOPENIC PURPURA The commonest cause of thrombocytopenia is immune destruction. In many children immune thrombocytopenic purpura (ITP) follows a recent viral infection, whereas in some adults there is an underlying predisposing cause, such as a collagen vascular disease or a lymphoproliferative disorder. In many cases, however, it is idiopathic. Whatever the aetiology, the mechanism of platelet destruction is similar, namely opsonization of platelets by plateletspecific autoantibodies, leading to phagocytosis of the platelets by the RE system. It should be noted that it is not possible to identify platelet-associated antibodies in every case. This may reflect lack of sensitivity of the test used, but should always alert one to alternative diagnoses.

nisolone may produce a more rapid response. The response is often suboptimal, or the dose of steroids necessary to maintain a remission is high, with unacceptable sideeffects. Splenectomy is then beneficial in 50-75% of cases. This may reduce antibody levels and, more importantly, removes a major site of RE platelet destruction. In splenectomy-resistant patients immunosuppression with azathioprine, cyclophosphamide or chlorambucil may be of value. Vinca alkaloids may also be effective. Temporary respite can often be achieved by intravenous infusion of large doses of immunoglobulin preparations, which result in RE blockade. This is extremely expensive, but may be warranted in a life-threatening situation. In Rh-positive individuals an injection of anti-D immunoglobulin will often produce similar RE blockade. Unfortunately, anti-D is in short supply.

23

At birth

Clinical and laboratory features The peak incidence in childhood is between the ages of 2 and 5 years, at a time when children are most at risk for the common exanthemata. In both children and adults there is a sudden onset of purpura, easy bruising, and frequently also epistaxis. 2 Gastrointestinal bleeding occurs occasionally, but clinically significant intracerebral bleeding is rare. Fatalities in children are extremely unusual, even with very low platelet counts. The exception is babies born to mothers with ITP, who become affected owing to transplacental passage of antibody. If severely affected, such babies are at risk, during delivery and in the early neonatal period, of cerebral haemorrhage and even death. The haemoglobin and white cell count are usually normal, although atypical lymphocytes may be seen on the blood film if there has been a recent viral infection. Very occasionally the haemoglobin is reduced, owing either to blood loss or to concomitant immune haemolysis. The platelet count is variably reduced, but in the presence of purpura is usually less than 50 x 109/L. Some of the platelets may appear large.

Management Childhood ITP in childhood is usually self-limiting, and treatment is rarely necessary, even with a very low platelet count. Occasionally, bleeding may be troublesome and prednisone should be given (approximately Img/kg, and reduced as quickly as possible). Rarely, the disease becomes chronic and splenectomy may be considered. This is seldom justifiable, however, as the benefits must be balanced against the operative risks and the problems of postsplenectomy infection. Also, late spontaneous remissions do occur in children. Adults In adults, it is usual to give a trial of oral corticosteroids if the platelet count is very low. High-dose i.v. methylpred-

The neonate born to a mother with ITP merits further consideration. The infant is usually only severely affected if the mother has severe ITP, but this is not invariable. Particular attention must be paid to women with ITP who have had a successful splenectomy: their platelet count may be normal but their babies severely affected. If the mother has a low platelet count, a course of steroids or intravenous immunoglobulin should probably be given several days before delivery (if this can be anticipated). The birth should be as atraumatic as possible, and protracted labours must be avoided. At birth, the baby's platelet count must be checked and monitored daily for several days, as late falls are not infrequent. If the thrombocytopenia is very severe in the neonate, it is probably wise to give a short course of steroids and to minimize bouts of crying (which increase intracerebral pressure). Some centres would consider exchange transfusion to reduce the antibody titre. ©

Drug-induced immune thrombocytopenia Drugs may induce immune thrombocytopenia by serving as haptens, with subsequent absorption of immune complexes onto the platelets. Quinidine may produce thrombocytopenia by this mechanism. Alternatively, the drug may interact with a platelet protein, with the production of specific drug-platelet-protein antibody. When druginduced thrombocytopenia occurs, it is usually reversible within several days of stopping the offending drug.

Isoimmune neonatal thrombocytopenia The mechanism of isoimmune neonatal thrombocytopenia is similar to that of isoimmune neonatal haemolysis, and usually occurs when the mother (but not the baby) lacks the platelet Al antigen present in 98% of the population. Treatment of the infant is usually not necessary, but in extreme situations maternal (PLA-1-negative) platelets should be given. Intrauterine transfusion should be considered where a previously affected fetus died in utero.

1269

Post-transfusion purpura

Laboratory features

This is an unusual cause of thrombocytopenia, which occurs in PL A-1-negative individuals about 1 week after a transfusion of blood containing PLA-1-positive platelets. The antibodies formed to the PLA-1 antigen bind to autologous platelets, probably as preformed immune complexes, and cause thrombocytopenia.

In the appropriate clinical setting the finding of a microangiopathic blood film is highly suggestive of the diagnosis. At least in the early stages the clotting screen is virtually normal, thereby differentiating this cause of thrombocytopenia from disseminated intravascular coagulation (DIG). The hydroxybutyrate dehydrogenase level (HBD) is raised as a component of the haemolysis, and this parameter is often valuable in assessing daily progress.

INCREASED PLATELET DESTRUCTION II: MICROANGIOPATHIC DESTRUCTION Microangiopathic platelet destruction occurs in the presence of extensive small vessel disease. As blood passes through the damaged vessels, the platelets are removed and the red cells subjected to extreme shearing stresses, resulting in a concomitant haemolytic anaemia. Thus, the blood film typically shows red cell fragmentation and polychromasia (reticulocytosis), as well as thrombocytopenia.

HAEMOLYTIC URAEMIC SYNDROME AND THROMBOTIC THROMBOCYTOPENIC PURPURA Haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) have many features in common, although they are distinct clinical entities and may have quite different aetiological mechanisms. In both disorders there appears to be a breakdown in the normal platelet/vessel wall interaction, with excessive adhesion of platelets to intact endothelium. The cause in HUS is not known, but considerable progress has been made in determining the pathogenesis of TTP. It appears that the formation of platelet thrombi is caused by a failure to breakdown von Willebrand factor because of reduced activity of 'von Willebrand factor-cleaving protease', an enzyme that has not yet been fully characterized. In about two-thirds of acquired TTP this is secondary to inhibitory IgG antibodies, indicating that TTP is an autoimmune disorder, albeit often self-limiting. Rarely a chronic relapsing form of TTP can occur, and in some cases there appears to be an absence of the 'von Willebrand factor-cleaving protease' rather than just reduced activity.

Management Vigorous medical support for organ failure is paramount. Early dialysis in HUS is indicated. Large quantities of fresh frozen plasma (FFP) are beneficial in many cases requiring daily plasma exchange. In TTP the FFP presumably provides a source of 'von Willebrand factor-cleaving protease', and the plasma exchange helps to remove the inhibitory antibodies. A short course of steroids is also recommended in TTP.

Disseminated intravascular coagulation In disseminated intravascular coagulation (DIC) there is widespread deposition of fibrin and platelets within the microcirculation, with consumption of coagulation factors and platelets (Fig. 23.43). The presence of fibrin degradation products exacerbates the bleeding tendency, by inhibiting the polymerization of fibrin. Clinical features The causes of DIC are varied (Table 23.47) but sepsis is the most common. Precipitating factors include the release of procoagulant materials from damaged leukocytes and endothelial cells, and widespread activation of the contact factor system. In severe cases there is widespread bruising and oozing from mucous membranes and venepuncture sites, but DIC is more often subclinical and merely a laboratory finding. Although small vessel occlusions do occur, clinically apparent thromboses are not commonly detected. Laboratory features Thrombocytopenia and a normocytic anaemia with red cell

Clinical features

1270

HUS usually presents in young children with the triad of haemolytic anaemia, purpura and acute renal failure. TTP occurs predominantly in young adults (18-40 years). There is haemolytic anaemia, purpura, hepatic damage and neurological impairment, which in the acute form may cause clouding of consciousness and coma. Digital ischaemia and small vessel infarcts may occur. Renal function is initially well preserved. TTP may also become chronic or undergo multiple relapses. The mortality in HUS with good supportive care is below 10%, and is similar in TTP if treated aggressively in experienced centres.

FIG. 23.43 The pathogenesis of disseminated intravascular coagulation

fragmentation are seen, although in mild cases the latter may not be noticed. There is prolongation of the PT, APPT and TT, the last being most affected, especially in mild cases. Fibrin degradation products (FDPs), produced by the proteolytic action of plasmin on fibrin and fibrinogen, are found in raised amounts in the serum, although it must

TABLE 21.47 Causes of disseminated intravascular coagulation

be remembered that serum FDPs are also raised after major trauma or surgery, and in renal failure without DIC. The measurement of FDPs is therefore not the primary screening test for DIC and is only indicated if the TT is significantly prolonged. The measurement of D-dimer production from the plasmin digestion of cross-linked fibrin offers better specificity and may be measured in EDTA or citrated plasma.

23

Management The underlying cause of DIC should be treated vigorously, and full supportive measures given. Hypoxia and hypovolaemia must be corrected, and platelets and clotting factors replaced as necessary, usually with fresh frozen plasma. Heparin was once used in DIC, to try and break the cycle of thrombosis and haemorrhage, but such treatment is dangerous and is not now recommended.

Sepsis Gram-negative septicaemia Meningococcal septicaemia Shock Hypovolaemia Anaphylaxis Obstetric complications Amniotic fluid embolism Intrauterine death Abruptio placentae Tissue factor release Severe trauma Burns Promyelocytic leukaemia Haemolytic transfusion reactions Acute pancreatitis

Other causes of microangiopathic thrombocytopenia Microangiopathic haemolytic anaemia and/or thrombocytopenia may also occur in malignant hypertension, in preeclampsia, and in association with giant haemangiomas.

QUALITATIVE PLATELET ABNORMALITIES

There are several rare congenital disorders in which platelet function is abnormal (Table 23.48), as well as

TABLE 23.48 Congenital primary platelet disorders Syndrome

Inheritance

Fanconi's anaemia

Platelet aggregation

Other features

Autosomal recessive

Normal

Multiple skeletal/organ abnormalities (p. 1211)

Amegakaryocytic thrombocytopenia

Variable

Normal

Absent radii and skeletal abnormalities in some cases

Wiskott-Aldrich syndrome

X-linked

Reduction in secondary aggregation wave (storage pool defect)

Eczema Immunodeficiency

May-Hegglin syndrome

Autosomal dominant

(variable) Giant size

Normal

Inclusion bodies in leukocytes

Bernard-Soulier syndrome

Autosomal recessive

Normal or Giant size

Glanzmann's thrombasthenia

Autosomal recessive

Normal

Grey platelet syndrome

Platelet count

aggregation to ristocetin aggregation to ADP, adrenaline and collagen Normal aggregation to ristocetin

Slightly 4

Myelofibrosis may occur

Chediak-Higashi syndrome

Autosomal recessive

Normal

Reduction in secondary aggregation wave to ADP (storage pool defect)

Oculocutaneous albinism, phagocytic defect Neurological impairment

Hermansky-Pudlak syndrome

Autosomal recessive

Normal

Reduction in secondary aggregation wave to ADP (storage pool defect)

Albinism

1271

the more common von Willebrand's disease. Qualitative platelet abnormalities may also be acquired in a variety of systemic disorders (particularly uraemia and liver disease), and the platelet defect may contribute to any bleeding diathesis in these conditions. Platelet function may also be abnormal in the myeloproliferative diseases, owing both to the production of abnormal platelets from a malignant stem cell and to a poorly understood failure to produce normal high molecular weight multimers of vWF. Platelets may also function poorly in the presence of paraproteinaemia, owing to non-specific protein coating of the platelets. The commonest acquired platelet abnormality, however, is due to the ingestion of aspirin and other antiplatelet drugs (p. 1277).

PLATELET DISORDERS II: THROMBOCYTOSIS The myeloproliferative disorders may give rise to very elevated platelet counts, especially in essential thrombocythaemia. If the platelet count is only moderately raised, it may be difficult to differentiate primary from secondary causes. The platelet count rarely exceeds 1500 x 109/L in secondary thrombocytosis, but may do so following splenectomy. Here, the platelet count rises within hours or days and usually falls to the high normal range in the ensuing weeks, although the thrombocytosis is occasionally persistent. The thrombocytosis post splenectomy is accompanied by a modest leukocytosis (usually transient) and the permanent appearance of abnormally shaped red cells, spherocytes, target cells and Howell-Jolly bodies. Probably the most common cause of secondary thrombocytosis is the stress of major surgery. Other forms of stress, such as exercise, may also cause the platelet count

SUMMARY 13 Aetiology of thrombocytosis Primary Myeloproliferative disorders

1272

4

MCQ 23.25

Patients with primary thrombocytosis may present with bleeding or thrombotic problems (p. 1242). Thrombotic phenomena attributable to a secondary thrombocytosis are unusual and rarely require treatment. In patients with thrombocytosis in whom thrombotic events have occurred, treatment with antiplatelet agents is advisable. 1

HEREDITARY COAGULATION DISORDERS HAEMOPHILIA A Haemophilia A (classic haemophilia) is an X-linked recessive disorder which affects males and is transmitted by female carriers. The incidence in the UK is approximately 12 per 100000. About one-third of cases represent new mutations not present in either parent. There is low or absent factor VIIIC owing to a mutation in the factor VIII gene, but vWFAg and vWF:RiCof are normal (pp. 1264-1265). The factor VIII gene is huge, spanning 186kb, and deletions, insertions and point mutations at various sites can all cause haemophilia A. A frequent recurring abnormality in severe haemophiliacs is an inversion in intron 22 of the factor VIII gene, which results in a truncated and unstable protein product.

The clinical severity of haemophilia A is very variable and dependent on the level of factor VIIIC (Table 23.49). In the absence of trauma or surgery in the first few months

Post splenectomy Bleeding or haemolysis Postoperative period Following extreme exercise Inflammatory states Collagen vascular diseases Malignant neoplasms Vinca alkaloid drugs

MCQ 23.24

Clinical features

Clinical features

Secondary

1

to rise. Both bleeding and haemolysis may stimulate a thrombocytosis, and this may be more marked if there is concomitant iron deficiency. This may imply that the physiological stimuli for increased red cell production crossreact with megakaryopoiesis, but the detailed mechanisms are not understood. All forms of inflammation can cause a rise in the platelet count, but it appears to be particularly common in the inflammatory bowel disorders and in sarcoidosis. The neoplasms most often associated with thrombocytosis are lymphomas and gut carcinomas.

TABLE 23.49 Severity of haemophilia A

2

Fig. 23.24

3

Case 23.11

Clinical manifestations

Factor VIIIC levels (% of normal)

Severe Moderate Mild

Less than 1% 1-5% Over 5%

of life, the disease does not usually present until the child starts to crawl or walk. In mild cases the diagnosis may be further delayed. There is easy bruising, soft tissue muscle bleeding and haemarthrosis, often appearing spontaneously and not related to obvious trauma. 0 The repeated joint bleeds may lead ultimately to restriction of movement and deformity. Less commonly there is retroperitoneal haemorrhage, spontaneous haematuria and pseudotumour formation in the long bones or pelvis, secondary to recurrent subperiosteal haemorrhage and new bone formation. Severe psychological and family problems may also arise as a result of the chronic disease and its treatment.

Diagnosis The diagnosis is suspected from the history and the finding of a prolonged APTT, and proved by demonstration of a low factor VIIIC level in a specific assay. Assessment of the ratio of factor VIIIC to vWFAg can be used in about 80% of cases to identify female carriers, but such tests have largely been replaced by gene-tracking analysis in the family. Daughters of haemophiliacs are of course obligate carriers (p. 64). Prenatal diagnosis is available for male fetuses of known carriers by analysis of factor VIIIC and factor VIII CAg levels in the fetal blood, or by analysis of DNA from chorionic villus samples.

Management Bleeding episodes require prompt treatment with factor VIII replacement. Approximately 0.5 units are required per kg body weight to raise the factor VIII level by 1 %. Thus, if a level of 100% is required in a 70kg severe haemophiliac, a dose of approximately 3500 units should be given. The injections are repeated to maintain a trough level above 20% for minor bleeds, and above 60% for major trauma or surgery. The half-life of injected factor VIII is approximately 12 hours, and so it is usual to give it twice daily during an acute episode. The dose and fre-

SUMMARY 14 Management of haemophilia A Treatment Factor VIII replacement Pain relief Rest Oral antifibrinolytics (e.g. tranexamic acid) DDAVP Complications Joint damage Development of inhibitory antibodies Transmission of viral infection, e.g. HIV Psychological trauma

quency of administration can be modified according to preand postinjection factor VIIIC levels. Some patients keep a stock of factor VIII at home and will inject themselves at the first sign of a bleed, thereby often averting a severe problem. In very severe cases, prophylactic factor VIII injected by the patient at home twice a week may markedly reduce the frequency of haemorrhagic incidents. Recombinant factor VIII is the treatment of choice in haemophilia, and its use is particularly recommended in newly diagnosed patients. Bleeding episodes (especially into joints) are very painful and adequate analgesia must be given, often with opiates. During acute bleeds rest is required, followed by gradual mobilization. The optimal management of haemophilia requires a team approach, with interested haematologists, physiotherapists and orthopaedic surgeons working together to minimize permanent joint damage. Oral antifibrinolytics (e.g. tranexamic acid) may aid haemostasis and are particularly useful in mild haemophilia after dental procedures. For minor procedures in very mild haemophilia DDAVP (l-deamino-8-D-arginine vasopressin) may circumvent the need for factor VIII, as it may lead to a temporary rise in autologous factor VIII production.

23

Complications of therapy Inhibitory antibodies develop in some severe haemophiliacs after factor VIII administration, which makes treatment extremely difficult. Should this occur, massive doses of factor VIII may temporarily swamp an inhibitor, or factor IX concentrate containing some activated clotting factors may be used to circumvent the need for factor VIII. Although the latter approach carries some risk of precipitating thrombosis, with modern material this is probably small. In life-threatening situations purified porcine factor VIII can be given, as the antibodies do not usually crossreact with the pig protein. However, antiporcine antibodies tend to form rapidly, and limit recurrent use. In desperate situations immunosuppression and even plasmapheresis may have a role in reducing the inhibitor level. Recently, recombinant human factor Vila has been introduced: it is highly efficacious but very expensive. Transmission of viral infections, especially HIV, was a serious complication of factor VIII concentrate administration, and many older severe haemophiliacs are HIV antibody positive. There are some differences in the natural history of HIV infection in haemophiliacs compared to other patient groups, with Kaposi's sarcoma rarely occurring. However, the sterilization of factor VIII concentrates virtually eliminated this problem. The risk of transmission of hepatitis C is also very small. Recombinant factor VIII is also very safe but is expensive. The treatment of haemophilia may have psychological consequences. Needle phobias in children and narcotic analgesic abuse in adults are uncommon but severe problems3434.

1273

VON WILLEBRAND'S DISEASE

FACTOR XI DEFICIENCY

Von Willebrand's disease is a syndrome, rather than a single disease entity, and is usually transmitted in an autosomal dominant fashion. The incidence is greater than that for haemophilia A. Different types are recognized. In the commonest variety (type I) there is deficiency of vWFAg (see Fig. 23.40), with consequent low vWF activity as measured by ristocetin aggregation. Factor VIIIC levels are also low, as the half-life of factor VIIIC is reduced when not bound to the vWFAg. In type IIA, vWFAg is quantitatively normal but unable to form high molecular weight multimers, so that vWF activity is reduced. In the rare type IIB disease the qualitatively abnormal vWF binds to platelets with increased affinity, so that high molecular weight multimers are depleted from the plasma. In this form of von Willebrand's disease platelets aggregate to low doses of ristocetin. Type III disease is also rare. Here vWFAg is completely absent and factor VIIIC is barely detectable. In almost all forms of von Willebrand's disease the bleeding time is prolonged.

Factor XI deficiency is particularly frequent in Ashkenazi Jews. It can cause a mild to severe bleeding diathesis, but this usually only becomes apparent following trauma. Treatment is with fresh frozen plasma or factor XI concentrate.

The causes of acquired coagulation disorders are outlined in Figure 23.44.

Clinical features

Vitamin K deficiency

Bleeding is generally less severe than in haemophilia A, with skin and mucous membrane bleeding predominating. Many cases only become apparent after dental extractions.

Vitamin K is a fat-soluble vitamin which carboxylates specific glutamic acid residues on factors II, VII, IX and X. This enables them to bind calcium ions and undergo a conformational change facilitating binding to phospholipid. This increases the stability of coagulation complexes and enhances the reactions of the coagulation cascade. Vitamin K deficiency may arise readily in newborn infants, in malabsorption states, and in patients with marginal stores who are severely ill and receive protracted broad-spectrum antibiotic therapy. In addition, oral anticoagulants of the warfarin and phenindione family lead to increased accumulation of phylloquinone epoxide (an inactive product of vitamin KI), with a consequent net reduction in carboxylation of factors II, VII, IX and X. Vitamin K deficiency leads to a bruising tendency, with a prolonged PT and APTT but a normal TT. It is reversible following vitamin K administration, although its effects take several hours to appear.

Diagnosis The bleeding time is usually prolonged and is the best indicator of clinical severity. vWFAg is usually reduced, as is vWF:RiCof. The factor VIIIC level is more variable, but is usually low and thus causes a prolonged APTT with a normal PT. However, it must be noted that factor VIII levels rise as acute-phase reactants, and one set of normal factor VIII parameters does not exclude von Willebrand's disease. vWF multimer analyses are helpful for subclassification, as increasingly are DNA studies.

Management Minor bleeding or surgical episodes can often be contained by the use of DDAVP and tranexamic acid, although DDAVP is likely to be less effective in variants where vWFAg is qualitatively abnormal and unable to form high molecular weight multimers, or is totally absent. In more serious circumstances vWF replacement should be given in the form of cryoprecipitate, factor VIII concentrate, or high-purity vWF concentrates. 1

Q Case 23.12

1274

OTHER CONGENITAL COAGULATION FACTOR ABNORMALITIES Other congenital coagulation factor abnormalities are summarized in Table 23.50.

ACQUIRED COAGULATION DISORDERS

Liver disease The aetiology of the bleeding tendency in liver disease is multifactorial (p. 839). There is decreased production of the vitamin-K-dependent factors, followed by decreased factor V production, and in some cases the production of decreased or abnormal fibrinogen (dysfibrinogenaemia). If there is biliary obstruction the clotting factor deficiencies may be exacerbated by malabsorption of the fat-soluble vitamin K. This, together with the presence of ill-defined inhibitors, accounts for the difficulty in correcting the coagulation defects with fresh frozen plasma. The liver is the major site of degradation of activated factors, and hepatic insufficiency may therefore lead to

Abnormal/ reduced production

VITAMIN K DEFICENCY LIVER DISEASE ORAL ANTICOAGULANTS

Consumption

DIC Excess fibrinolysis

Dilution

MASSIVE TRANSFUSION

Loss of factors

Nephrotic syndrome Amyloid

Drugs

Heparin

COAGULATION FACTORS

Immune mediated

Idiopathic autoimmune diseases Lymphoproliferative disorders Lupus anticoagulant

FIG. 23.44 Acquired coagulation disorders and their causes Capital letters indicate the commoner causes.

DIC and excessive fibrinolysis. There may also be hypersplenism and thrombocytopenia associated with the liver disease, and qualitative platelet defects have been reported. Excessive alcohol may also directly suppress platelet production. In liver disease the PT and APTT are frequently prolonged. Prolongation of the TT - indicating hypo/dysfibrinogenaemia or DIG - is less common. A 5-day course of vitamin K should be given if there are bleeding problems, although the benefit is marginal. Fresh frozen plasma can be given if clinically required, although the clinical and laboratory responses are often poor. Platelets should be given to bleeding thrombocytopenic patients.

Disseminated intravascular coagulation and fibrinolysis DIG is discussed on page 1270. Very rarely, excess fibrinolysis occurs without DIG, owing to high levels of plasminogen activator. This may follow major trauma, extensive surgery and carcinoma (especially prostate) in which there is excessive release of tPA; some snake venoms; and in severe liver disease in which there is failure to inactivate tPA. Generalized fibrinolysis is also produced by streptokinase therapy.

Acquired inhibitors Specific anti-factor-VIIIC antibodies may arise in severe

haemophiliacs following factor VIII therapy. They may also arise in other individuals, often in association with autoimmune disease (such as rheumatoid arthritis, lymphoproliferative disease and other malignancies), but they may also occur postpartum and are frequently idiopathic in origin. Less commonly, antibodies to other clotting factors may also develop. Anti-factor-VIII antibodies may be produced in systemic lupus erythematosus (SLE) and occasionally highaffinity antiprothrombin antibodies are produced, which cause plasma depletion of prothrombin. The lupus anticoagulant occurs frequently in SLE and in the so-called antiphospholipid syndrome. The inhibitor appears to be low-affinity antibodies against prothrombin and pYglycoprotein-1, which inhibit the coagulation reactions that occur on phospholipid surfaces. Antibodies to cardiolipin frequently coexist. The lupus anticoagulant results in prolongation of the APTT, which fails to correct on mixing of patient and normal plasma. Other phospholipiddependent coagulation tests may also be affected. Patients with lupus anticoagulants rarely bleed, but thromboses and spontaneous abortions are common. Many are asymptomatic.

23

ANTICOAGULANTS AND ANTITHROMBOTIC DRUGS This group of drugs includes both inhibitors of platelets and the coagulation cascade, and activators of fibrinolysis.

HEPARIN Mechanism of action The heparins are a group of negatively charged polysaccharide sulphates (glycosaminoglycans) which combine with antithrombin III, thereby increasing its activity against the activated serine proteases thrombin and factor Xa. The effect is almost immediate. Heparin may also have some effects on platelets, but these are less important.

Indications The indications for the use of heparin are outlined in Table 23.51. Heparin helps prevent pulmonary embolism in patients with popliteal femoral and iliac vein thromboses. Its value in more superficial, or calf vein, thromboses is less certain, but it is usually given if the patient has significant symptoms. Heparin is also frequently used to prevent the development of thromboembolism in high-risk situations, e.g. following major gynaecological or abdominothoracic surgery. The low-dose subcutaneous heparin given in these circumstances has some antithrombotic effect, but does not in general cause postoperative haemorrhage.

1275

TABLE 23.50 Less common congenital coagulation factor deficiencies Abnormal factor

Inheritance

Bleeding disorder

Fibrinogen Afibrinogenaemia Dysfibrinogenaemia

Autosomal recessive

Surprisingly mild Mild

Thrombin Factor V Factor VII Factor IX (haemophilia B or Christmas disease) Factor X Factor XII Factor XIII

Autosomal recessive Autosomal recessive Autosomal recessive X-listed

Severe Mild Severe Severe

Autosomal recessive Autosomal recessive Variable

Severe Very mild/absent Mild

Low-dose subcutaneous heparin for thromboprophylaxis is usually given into the abdominal wall or thigh in a dose of 5000units b.d. Laboratory control is not necessary.

Complications If bleeding occurs the heparin infusion should be stopped and, if necessary, reversed with protamine sulphate and the response monitored by laboratory tests such as the APTT or TT. Heparin may cause hypersensitivity reactions and acute thrombocytopenia, but this is rare before 7 days of therapy. In patients receiving long-term heparin, alopecia and osteoporosis may occur and antithrombin III may be depleted. Low molecular weight heparins produce less thrombocytopenia. The most common complication is haemorrhage, and full anticoagulation should therefore be undertaken with great caution in patients with an active or potentially active bleeding site, severe hypertension, liver disease, haemorrhagic tendency of any form, or immediately following surgery (especially to the eye or CNS).

TABLE 23.51 Indications for the use of heparin • • • • •

Treatment of deep vein thrombosis Treatment of pulmonary embolism Treatment of acute arterial occlusions During cardiac bypass surgery Thromboembolic prophylaxis

Administration Full-dose heparin is given as a loading dose of 5000-10000 units, followed by a continuous infusion of 25000-40000 units/day depending on patient size and laboratory tests. Heparin affects all the routine coagulation tests, but none is entirely satisfactory for the control of heparin therapy. The APTT is usually used and should be 1.5-2.5 times the normal control, although this range varies depending on the reagent and analyser used. Measurement of anti-Xa activity is a better test but is expensive. The target range is 0.35-0.7 IU/mL. Following a thromboembolic episode, heparin should be given for 5-7 days. Low molecular weight heparins have a longer half-life and only need daily administration, which is valuable for long-term use. They may also allow outpatient management during the early phases of anticoagulation, thereby offsetting the higher cost of the low molecular weight heparins. A commonly used regimen is 200IU/kg, with a maximum daily dose of 18000IU. They can only be monitored by anti-Xa assay, but in many situations no laboratory monitoring is necessary.

0 Case 23.13

1276

ORAL ANTICOAGULANTS Mechanism of action Bishydroxycoumarin (warfarin) and phenindione (dindevan) interfere with vitamin K metabolism by augmenting the formation of the inactive derivative phylloquinone epoxide. Lack of active vitamin K leads to the formation of factors II, VII, IX and X in which certain specific glutamic residues have not been carboxylated. These acarboxy factors cannot interact with calcium and phospholipids, and cannot therefore participate normally in the clotting cascade.

Indications The indications for use of oral anticoagulants (Table 23.52) are still controversial in many circumstances because of conflicting trial results, as is the duration of therapy. It should be noted that warfarin is not currently recommended for bioprosthetic heart valves in the absence of atrial fibrillation, ischaemic stroke, peripheral arterial thrombosis and grafts, coronary artery thrombosis and coronary angioplasty. In all these circumstances aspirin is currently the first-line therapy. Previous sudies showing a survival advantage to warfarinization are no longer thought to be valid in the era of thrombolysis and aspirin therapy.

Administration Anticoagulation is usually started with intravenous heparin, commonly given for 5 days. Oral anticoagulants are also started at the same time, their maximum effect taking 5 days to develop. A loading dose of warfarin (lOmg/day for 3 days, or a similar regimen) is given, and

TABLE 23.52 Indications for oral anticoagulation Indication

Target INR

Recurrence of venous thromboembolism when no longer on warfarin therapy Recurrence of venous thromboembolism while on warfarin therapy Antiphospholipid syndrome Atrial fibrillation* Rheumatic heart disease without atrial fibrillation Mural thrombus Cardiomyopathy Mechanical heart valves

2.5

6 months 6 months 6 weeks (longer if risk factors persist) Unclear

3.5

Unclear (possibly lifelong)

3.5

Long-term Long-term Long-term

2.5 2.5 2.5 3.5

Drugs diminishing warfarin activity

Gut

Cimetidine (moderate) Liquid paraffin (minor)

Colestyramine (cholestyramine) minor

Circulation

Sulfinpyrazone (marked) Clofibrate (moderate) Amiodarone (moderate) Dipyridamole (minor)

Type of drug

2.5 2.5

2.5

Drugs potentiating warfarin activity

Duration

Pulmonary embolus Proximal deep vein thrombosis Calf vein thrombosis

2.5

TABU 23.53 Drugs modulating warfarin activity

3 months Long-term Long-term

CNS

the dose adjusted thereafter according to the results of a PT. The therapeutic range is an international normalized ratio (INR) of 2.5-3.5, depending on the indication for anticoagulation. The INR is the ratio of the patient's PT to the control PT, raised to the power of the so-called international sensitivity index of the thromboplastin/coagulation combination used. If the patient is also receiving heparin, the heparin in the sample must first be neutralized with protamine sulphate if the APTT is greater than 2.5 times control. The half-life of warfarin is 30-60 hours, so daily administration gives rise to fairly stable steady-state levels. Once good control has been achieved, monthly checks on the PT are usually acceptable. Drugs that inhibit liver enzyme degradation of oral anticoagulants, such as cimetidine and sulphonamides (including co-trimoxazole), will potentiate the anticoagulant effect. By contrast, barbiturates and rifampicin (which induce liver enzymes) will decrease the activity of oral anticoagulants. Broadspectrum antibiotics, which interfere with vitamin K biosynthesis by intestinal flora, will augment the action of oral anticoagulants; cholestyramine reduces their effect by preventing anticoagulant absorption. The list of possible drug interactions is enormous; some of the more common are shown in Table 23.53. It is essential to use a reference source of drug interactions when changing concurrent drug therapy, and the PT must be monitored frequently in these circumstances.

Complications The major complication of anticoagulation is bleeding. As with heparin, some patients are at particular risk (p. 1276), but haemorrhagic disaster can occur in any patient and diligent control is therefore essential at all times. Most impor-

Carbamazepine (minor) Primidone (minor) Barbiturates (minor)

Endocrine

Levothyroxine (moderate) Anabolic steroids (moderate) Steroids (minor)

Anti-inflammatory

Salicylates (moderate) Phenylbutazone (moderate) Mefenamic acid (moderate) Azapropazone (moderate)

Antibiotics

Co-trimoxazoie (moderate) Metronidazole (moderate) Erythromycin (minor)

*Not really clear that warfarin superior to aspirin: further trials required.

23

Oral contraceptives (minor)

Rifampicin (minor)

tantly, patients should not receive long-term therapy unless it is absolutely necessary. If the INR is found to be between 3.0 and 6.0 (assuming target of 2.5), the warfarin should be reduced or stopped for a few days and then restarted at a lower dose. If the INR is between 6.0 and 8.0 and there is only minor or no bleeding, the warfarin should be stopped and only restarted when the INR is less than 5.0. If the INR exceeds 8.0 and there is no bleeding it may still be reasonable to just stop the warfarin, but it is common practice in this situation to give oral vitamin K, 0.5-2.5 mg. If there is a significant bleeding problem the anticoagulation should be reversed regardless of the INR. This is most readily achieved with 50 units/kg prothrombin complex concentrate (factors II, VII, IX and X). If the latter is not available fresh frozen plasma (FFP) is infused at a dose of 15mL/kg; 5mg of vitamin K should also be given, either orally or intravenously. Additional (but rare) side-effects of warfarin include skin rashes, diarrhoea, jaundice and alopecia. 1

ANTICOAGULATION IN PREGNANCY Pregnancy is itself a prothrombotic state, owing to both local pressure on the venous -system from an enlarged uterus, and an increase in coagulability and decrease in fibrinolysis. Thromboembolic disease occurs in approxi-

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mately two per 1000 pregnancies. Other pregnant women require prophylactic anticoagulation because of previous thromboses, or high-risk situations such as prosthetic heart valves. Warfarin crosses the placenta and may cause chondrodysplasia punctata and abnormal development of the brain and face. The risk is greatest in the first 3 months, but is still present in the second trimester. Heparin should therefore be used for prophylaxis, as it does not cross the placenta. Low molecular weight heparin is usually given because of its ease of administration. Unfortunately, subcutaneous heparin is not as effective as full-dose intravenous heparin or oral warfarin, and is probably not therefore acceptable for the safety of mothers with the most high-risk prosthetic heart valves. A difficult compromise must be achieved after detailed discussion with the parents, if the pregnancy is to continue. For an acute thromboembolism in the first trimester, full intravenous heparinization should be given, followed by subcutaneous heparin (l0000 units b.d.). Some clinicians change to warfarin for the second trimester, but this still carries some risk of fetal malformation. In the third trimester subcutaneous heparin should again be used, as warfarinization may cause serious bleeding in both mother and baby at the time of delivery, or at the very least the warfarin should be discontinued at least 2 or 3 weeks before the expected date of delivery. Warfarin can be started 10 days after delivery, even in mothers who are breastfeeding. Some women become pregnant while taking warfarin and may not report it to their doctor until the pregnancy is well advanced into the first trimester. Clearly, all fertile women should be warned about the problems of pregnancy when warfarinization is commenced. In the antiphospholipid syndrome recurrent miscarriage is common and the combination of aspirin and heparin has been shown to be superior to aspirin alone for the production of a live birth. 1

ANTIPLATELET AGENTS Mechanism of action The mechanisms of action of the more commonly used antiplatelet agents are shown in Table 23.54. The inhibition of platelet cyclo-oxygenase by aspirin is irreversible, and the effects of a single dose will last several days until new platelets are produced. Aspirin also inhibits endothelial cyclo-oxygenase, which blocks prostacyclin production, a potent natural antiplatelet agent. Endothelial cells (unlike platelets) are nucleated, and continue to synthesize cyclooxygenase; as a result, the aspirin effect is short-lived. Thus,

1

1278

MCQ 23.26

TABLE 23.54 Drugs interfering with platelet function Drug

Mechanism of action

Aspirin

Irreversible acetylation of platelet cyclo-oxygenase, with blockade of platelet prostaglandin production Competitive inhibitor of cyclo-oxygenase

Sulfinpyrazone (Anturan) Dipyridamole (Persantin) Rheopro (Absiximat)

Reversible inhibition of platelet phosphodiesterase Blockade of Gpllb/llla receptors, with the prevention of fibrinogen binding

TABLE 23.55 Possible indications for the use of antiplatelet agents Cerebral transient ischaemic episodes Peripheral arterial thrombosis and grafts Coronary artery thrombosis and graft thrombosis Coronary angioplasty and coronary stents Antiphospholipid syndrome in pregnancy (plus low-dose heparin)

in theory, the maximal antiplatelet effect of aspirin may be achieved simply by a twice-weekly regimen, although most trial evidence is based on daily doses. Sulfinpyrazone similarly blocks cyclo-oxygenase, but its effect is reversible. Dipyridamole reversibly suppresses platelet cyclic-AMP levels, with consequent inhibition of agonist-mediated rises in intracellular calcium ions. Rheopro is a chimeric (humanized) monoclonal antibody which binds to glycoprotein Ilb/IIIa on the platelet surface and prevents fibrinogen binding, thus inhibiting aggregation. The blockade lasts for the lifespan of the platelet.

Indications Some of the possible indications for antiplatelet agents are shown in Table 23.55, although it must be noted that the data from clinical trials are not conclusive in all circumstances.

Administration and complications There is no universally accepted optimum regimen. Aspirin (300 mg daily) with or without dipyridamole (50-200 mg q.d.s. - higher doses may not be tolerated) is widely used. Antiplatelet agents do increase trie bleeding time, but this alone causes few problems. Aspirin may, however, lead to gastric erosions and major bleeding from this site. Dipyridamole causes migrainous type headaches in many patients at the start of therapy, although these usually subside within a few weeks.

INTRAVASCULAR FIBRINOLYTIC THERAPY

TABLE 23.56 Indications for the use of fibrinolytic therapy

Mechanisms of action

Myocardial infarction

Streptokinase (which is derived from (3-haemolytic streptococci) combines with plasminogen and leads to the formation of the fibrinolytic compound plasmin. Urokinase (which is isolated from human urine) has a similar mechanism of action. It is a less toxic, naturally occurring compound but is very expensive to purify. The naturally occurring tissue plasminogen activator (tPA) has been produced by recombinant DNA technology and is particularly useful in a patient who has had Streptokinase in the previous year.

Indications The major indication is in acute myocardial infarction (Ch. 12, p. 559) and aspirin and a thrombolytic agent should be administered without delay, provided there are no contraindications. These include recent surgery, pregnancy or strokes, intracranial tumours or previous intracerebral bleed, bleeding diatheses, and known or suspected pericarditis or dissecting aneurysm. Other uses are shown in Table 23.56.

Administration Streptokinase is antigenic and most patients have circulating antibodies as a result of previous streptococcal infections. These must first be neutralized by a loading dose, which is then followed by continuous infusion for 3-7 days. There is no consensus as to the optimum dosage schedule, although after myocardial infarction a single infusion dose has been shown to be effective. Fibrinolytic therapy reduces the fibrinogen level, markedly prolongs the TT and causes a rise in fibrin degradation products; these data are of little help, however, in monitoring the dosage. Ideally, Streptokinase is infused locally, i.e. using a pulmonary artery catheter for pulmonary embolism.

Complications Streptokinase therapy is potentially hazardous. Bleeding, especially from drip sites, is very common and can be fatal. All patients receiving Streptokinase should therefore have blood cross-matched and available. Fevers and other allergic phenomena are not infrequent, and it is common practice to give prophylactic steroids. Hopes that tPA would have equal efficacy and fewer side-effects have not been realized.

Oral fibrinolytic agents A variety of oral drugs, such as the biguanides (e.g. metformin) and anabolic steroids (e.g. stanozolol), increase fibrinolytic activity and may have occasional value in

23

Peripheral arterial thromboembolism Arterial thrombosis Embolism from a known source, such as atrial fibrillation Embolism more than 5 days old (if sooner, surgical embolectomy should be attempted) and less than 14 days Failed embolectomy Vascular graft occlusion (not if immediately post surgery) Venous thromboembolic disease Acute massive pulmonary embolism Deep venous thrombosis causing critical limb ischaemia Unblocking thrombosed haemodialysis shunts and indwelling central venous catheters

patients with recurrent venous and arterial thromboses who are on oral anticoagulants. These agents do, however, have major potential side-effects, e.g. hypoglycaemia and masculinization, unrelated to their fibrinolytic function.

FURTHER READING ON ANTICOAGULANTS AND ANTITHROMBOTIC DRUGS Guidelines on oral anticoagulation, 3rd edn. 1998 Brit J Haematol 101: 374-387. Wood K (ed) 1994 British Committee for Standards in Haematology Guidelines on the Use and Monitoring of Heparin. In: Standard haematology practice 2. Oxford: Blackwell Science, 150-165.

HYPERCOAGULABLE STATES Patients with a tendency to thrombosis are defined as having thrombophilia, and the term inherited thrombophilia is used when it is due to an inherited genetic defect. Possible causes are shown in Table 23.57. The full investigation of thrombophilia is both extremely time-consuming and expensive. All patients presenting with a thromboembolic episode should be thoroughly examined to exclude local causes of circulatory stasis, and systemic diseases associated with hypercoagulability. A full blood count should be performed to exclude polycythaemia or thrombocytosis. Further studies are only cost-effective in selected cases. The criteria for selection of patients to investigate (Table 23.58) vary from country to country and need to be constantly re-evaluated. They are designed primarily to allow detection of the hereditary thrombophilias, the most common of which are factor V Leiden, the prothrombin gene mutation and hyperhomocysteinaemia. Part of the rationale for these tests has been that patients with a

1279

TABLE 23.17 Causes of a thrombotic diathesis Inherited hypercoagulable states Factor V Leiden Antithrombin III deficiency Protein C deficiency Protein S deficiency Prothrombin gene mutation (G->A) at position 20210 Dysfibrinogenaemia (very rare) Acquired coagulable states Circulatory stasis

e.g. immobilization, pelvic tumours, polycythaemia, hyperleukocytosis and hyperviscosity

Trauma and surgery Pregnancy, including postpartum Oestrogen use Antiphospholipid syndrome Hyperhomocysteinaemia

TABLE 23.58 Investigation of a prethrombotic state • • • • • • • • • • •

Full blood count Liver function tests Analysis of plasma lipids Protein electrophoresis to exclude hypergammaglobulinaemia Coagulation screen with particular attention to abnormalities due to dysfibrinogenaemia, or a lupus anticoagulant Euglobin clot lysis time as an index of the fibrinolytic pathway Antithrombin III levels Factor V Leiden detection Protein C levels (also protein S levels if available) Platelet aggregometry to detect hyperaggregable platelets or Measurement of platelet release products (PF4, p-TG) within the plasma

genetic defect should have indefinite anticoagulation. This view has been questioned, and lifelong anticoagulation should probably be reserved for those who have had more than one spontaneous thrombosis, or who have had a lifethreatening event, or who have more than one mutation or have ATIII deficiency. This being so, it can be argued that it is not necessary to carry out a screen in anyone who has had just one non-lifethreatening deep venous thrombosis. The USA Physicians Health Study showed that 26% of men aged over 60 having their first idiopathic venous thrombosis had the factor V

1 1280

MCQ 23.27

Leiden gene. It has been suggested that it may be worth screening for this and the prothrombin gene mutation in all such cases, and possibly also for antiphospholipid antibodies and hyperhomocysteinaemia. Tests for ATII, protein C and protein S deficiency disorders, which have a .lower frequency, should be reserved for the more selected cases. Raised steady-state levels of factor VIIIC may carry a significant thrombotic risk. The aetiology is not yet known and the test is not routinely performed in screening for thrombophilia.

Factor V Leiden Factor V Leiden is the commonest form of inherited thrombophilia in Caucasian populations, where it is found in 1-8% of individuals. The mutation is virtually absent in African blacks, Chinese and Japanese. There is a point mutation in factor V (Arg506Gln), which gives rise to resistance to activated protein C. In heterozygotes the risk of deep venous thrombosis is raised about sevenfold and in homozygotes 80-fold. In heterozygotes taking oral contraceptives the risk of deep venous thrombosis has been reported to be raised 35-fold. In the Leiden Thrombophilia Study it was present in nearly 20% of venous thrombosis patients.

Prothrombin gene mutation There is a G to A substitution at nucleotide 20210 in the 3' untranslated region of the prothrombin gene, which gives rise to elevated plasma levels. It occurs in about 1-2.3% of the Caucasian population and confers about a threefold increased risk of deep venous thrombosis.

Hyperhomocysteinaemia The presence of hyperhomocysteinaemia increases the risk of deep venous thrombosis by about two to threefold, and elevated levels of homocysteine are also correlated with atherosclerosis. In some populations the incidence of mild and moderate hyperhomocysteinaemia is very high and is due to poor folate intake. Randomized trials of folate supplementation to reduce coronary artery disease are in progress. Homocysteine may damage the endothelium directly, inhibit the expression of thrombomodulin, increase tissue factor, and may also influence the levels of factors V, XII (increased) and protein C (decreased).

Antithrombin III deficiency Antithrombin III (AT-III) deficiency may be either congenital or acquired. Congenital This is an autosomal dominant condition in which there is decreased synthesis of AT-III or synthesis of a dysfunctional molecule. The incidence is estimated to be 20-50 per

TABLE 23.59 Screening tests for a hypercoagulable state Full blood count Liver function tests Plasma viscosity/protein electrophoresis Detection of factor V Leiden Resistance to activated protein C in a clotting assay DNA test (PCR)

and this may contribute to the prethrombotic state in these situations. AT-III levels may also fall with severe proteinuria, thereby contributing to the documented thrombotic tendency in the nephrotic syndrome. L-Asparaginase therapy, used in acute lymphoblastic leukaemia, can also deplete AT-III levels and precipitate thrombosis. AT-III synthesis is reduced in liver disease, but bleeding (rather than thrombosis) is usually the problem in this situation.

Prothrombin gene mutation by DNA test

Protein C and protein S deficiency

Measurement of fasting plasma homocysteine levels (normal diet)

Protein C deficiency is an autosomal dominant condition, with an incidence probably similar to that of AT-III deficiency. The clinical course is also similar. Extensive skin necrosis has been noted in some patients following the initiation of anticoagulants. Protein S deficiency (autosomal dominant) is probably less common, but may still account for up to 10% of thromboses in the high-risk categories shown in Table 23.59.

Functional assays of antithrombin III Functional assays of protein C Functional or immunological assays of protein S Detection of lupus anticoagulant clotting tests detection of antiphospholipid antibodies

100000. Affected individuals have functional AT-III levels of 40-70% (normal range 70-130%). The disease typically presents with venous thromboses in early adulthood. Thromboses are particularly common after starting the contraceptive pill, during pregnancy or following surgery. Heparin is usually given in the short term, but is less effective here than in other situations, as AT-III is required as a cofactor for heparin. The administration of heparin also actually causes the AT-III level to fall further. For these reasons, fresh frozen plasma (or AT-III concentrates, if available) should also be given in the acute stages. Longterm oral anticoagulants do reduce the incidence of recurrent thromboses and increase the circulatory levels of AT-III.

Acquired As noted above, AT-III levels may fall with the contraceptive pill, during surgery, and after major surgery or trauma,

23

Antiphospholipid syndrome The lupus anticoagulant is associated with an increased incidence of thrombosis, although it is detected by the prolongation of the APTT. It is discussed on page 1275. 1

FURTHER READING ON HYPERCOAGULABLE STATES Guidelines on the investigation and management of the antiphospholipid syndrome. 2000 Br J Haematol 109: 704-715. Ridker P M, Hennekens C H, Lindpaintner K et al 1995 Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke and venous thrombosis in apparently healthy men. N Engl J Med 332:912-917. Wood K (ed) 1994 British Committee for Standards in Haematology Guidelines: The investigation and management of thrombophilia in standard haematology practice 2. Oxford: Blackwell Science 112-117.

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24

Neurological Disease

PRINCIPLES OF EXAMINATION

John W Scadding and Jeremy Gibbs

Neurological diagnosis 1283 Headache 1306 Migraine 1307 Facial pain 1312 Dizziness and vertigo 1315 Syncope and epilepsy 1320 Cerebrovascular disease 1330 Dementia 1345 Cerebral tumours 1351 Hydrocephalus 1358 Extrapyramidal disease 1361 Head injury 1369 Cerebral palsy 1373 Cerebellar ataxias 1375 Diseases of the spinal cord 1376 Diseases affecting spinal roots 1385 Motor neuron diseases 1388

tial in patients with episodes of impaired consciousness or impairment of higher mental function. The major neurological symptoms that should be covered by the history are listed in Table 24.1, and the typical features of the history are discussed in each section of this chapter.

Diseases of peripheral nerves and plexuses 1391 Diseases affecting the neuromuscular junction 1400 Muscle disease 1402 Demyelinating diseases 1408 Bacterial infections of the nervous system 1413 Viral infections of the nervous system 1422 Neurological manifestations of AIDS 1427 Neurosyphilis and other rare infections 1428 Neurological aspects of systemic disease, including malignancy 1430 Alcohol and the nervous system 1435 Toxic and drug-induced disorders 1441

NEUROLOGICAL DIAGNOSIS HISTORY-TAKING In many patients with neurological disease diagnosis depends entirely on the history; in patients with blackouts or headache, for example, there are usually no physical signs. Anatomical localization of lesions can also often be correctly identified from the history, and the timing and sequence of development of the symptoms will usually give some idea as to the nature of the underlying pathology. Supplementary history from relatives or witnesses is essen-

The neurological examination is often seen as long and difficult. Table 24.2 lists the full examination. However, in nearly all patients the examination can be abbreviated in certain areas. In patients with neurological disease the history usually provides a clear indication of where within the nervous system the problem lies, and, for example, in a patient with a history suggesting a spinal cord disturbance, who is able to give a clear and coherent history, time need not be wasted in performing a detailed mental state examination. A brief screening examination, for use in patients not suspected of having neurological disease, is given in Table 24.3.

Level of consciousness The neurological examination starts with an assessment of the patient's level of consciousness. When this is impaired to any significant degree it is best described by the Glasgow Coma Scale (Table 24.4). This system has the advantage that it is simple, objective and easily applied by both medical and nursing staff without the use of imprecise terms such as 'drowsy', 'stuporose' or 'comatose'. It is particularly useful for sequential monitoring of the consciousness level.

Examination of the comatose patient Detailed neurological examination in many patients permits an assessment of the site of the lesion. It is important to differentiate coma due to diffuse cerebral disease (either metabolic or inflammatory) from focal causes, either discrete brainstem lesions or focal cerebral hemisphere lesions associated with raised intracranial pressure and secondary brainstem compression (Table 24.5). The first step in examining a patient in coma is to assess cardiorespiratory function. When vital functions and the level of coma have been assessed, general examination may provide important clues. A rash may indicate meningococcal septicaemia with meningitis, purpura may indicate a bleeding disorder associated with a cerebral haemorrhage, and signs of portal hypertension raise the possibility of hepatic encephalopathy. The skull and scalp should be examined for head injury. Neurological examination should include: • Examination for neck stiffness, indicating meningitis or subarachnoid haemorrhage. However, in deeply unconscious patients this nociceptive reflex may be absent. • Examination ofthefundi, primarily to look for evidence

1283

TABLE 24.1 Symptom review in neurological diagnosis

TABLE 24.3 Short neurological examination

• • • • • • •

1. Mental state Orientation If patient gives a clear history, no need to test further

Loss of consciousness Higher mental functions Headaches Vision Hearing Dizziness Unsteadiness

• • • • •

Speech Swallowing Limb weakness Limb numbness and paraesthesiae Bladder and bowel control

TABLE 24.2 Full neurological examination 1. Mental state Level of consciousness Orientation Speech General knowledge Memory Retention and recall Reasoning and judgement Reading, writing, calculation Object recognition Praxis Perception Mood and affect 2. Gait and station Normal gait Heel-toe walking Romberg's test 3. Cranial nerves I: Olfaction II: Acuity, fields, colour vision, fundi III, IV, VI: Eye movements, nystagmus, pupils V: Facial and oral sensation. Masticatory muscles VII: Facial muscles, taste VIII: Hearing, Rinne and Weber tests IX: Pharyngeal sensation, gag reflex X: Speech, phonation, palatal movement, swallowing XI: Sternomastoids, trapezii XII: Tongue

1284

4. Motor system Posture, involuntary movements Muscle bulk, fasciculation Tone Power Coordination Reflexes 5. Sensory system Light touch, pinprick, temperature, vibration and position sense Two-point discrimination Stereognosis Tactile localization Inattention 6. General Bruits Skull size and shape Spinal deformity Pes cavus Neck rigidity Skin changes

of raised intracranial pressure. Comatose patients frequently have small pupils, which should not be dilated with mydriatics. Normal pupillary responses and reflex eye movements indicate that coma is likely to be due to diffuse disease, rather than focal brainstem pathology. The pupils are examined for equality of size and reac-

2. Gait Watch gait 3. Cranial nerves Assess: visual fields for hemianopia pupils eye movements fundi facial sensation to light touch facial movement speech (assessed during history) palatal movement shoulder shrug tongue movement 4. Motor system Muscle bulk Tone Power: shoulder abduction elbow flexion and extension grip finger abduction hip flexion and extension knee flexion and extension ankle dorsiflexion and plantar flexion Tendon reflexes, plantar responses 5. Sensory system Only test if patient has sensory symptoms, or if preceding parts of examination indicate possible abnormality

tion to light. Cerebral hemisphere space-occupying lesions may cause herniation of the temporal lobe through the tentorium (coning); this frequently compresses the third cranial nerve, producing a large unreactive pupil, with downward, outward gaze of one eye and limitation of all reflex movement of the affected eye, except abduction. Pupillary constriction (pinpoint pupils) are often seen in acute pontine lesions and opiate overdose. Metabolic causes of coma tend to cause loss of reflex eye movements, but pupillary reflexes are preserved. • Reflex eye movements are examined by the 'doll's head' manoeuvre or by caloric testing (p. 1300). An acute cerebral hemisphere lesion may produce conjugate deviation of the eyes towards the side of the lesion. Lesions within the brainstem may produce a variety of partial or complete gaze palsies and pupillary abnormalities. Lesions in the pons tend to produce conjugate gaze away from

TABLE 24.4 Glasgow Coma Seals

TABLE 24,5 Causes of coma

Category

Score

Eye opening Spontaneous To speech To pain None

4 3 2 1

Best verbal response Orientated Confused Inappropriate Incomprehensible None

5 4 3 2 1

Brainstem lesions Infarction Brainstem haemorrhage Cerebellar haemorrhage Tumour Abscess Thiamine deficiency (Wernicke-Korsakoff syndrome) Brainstem encephalitis

Best motor response Obeying commands Localizing Flexing Extending None

5 4 3 2 1

particularly when complicated by hydrocephalus

Cerebral hemisphere lesions with secondary brainstem compression Extradural haemorrhage Subdural haemorrhage Intracerebral haemorrhage Abscess Tumour Large infarct Cerebral venous sinus thrombosis

Metabolic disturbances* Drug overdose Diabetes - hypoglycaemia ketoacidosis hyperosmolar coma Hyponatraemia Hypernatraemia Hypercalcaemia Uraemia Hepatic failure Hypothyroidism Hypoadrenalism

Diffuse neurological disease affecting cerebral hemispheres and brainstem Epilepsy Head injury Subarachnoid haemorrhage Meningitis Encephalitis Hypertensive encephalopathy Encephalopathy in SLE

Hypopituitarism Respiratory failure (C02 narcosis) Severe heart failure Hyperpyrexia Hypothermia Porphyria

The scores applied to each category of the grading system are summed to give an overall value, ranging from 3 to 14.

the side of the lesion. Pressure from above, arising from cerebral hemisphere disease, causes progressive loss of brainstem function, with gradual loss of pupil reflexes, reflex eye movements and other brainstem reflexes. • Other brainstem reflexes examined in comatose patients include the corneal reflexes (V), facial grimacing induced by pressure over the supraorbital nerve (V and VII), gag and coughing reflexes (IX and X), and the rate, depth and pattern of breathing. Most irregular patterns of breathing suggest brainstem pathology. The exception is Cheyne-Stokes breathing, which is now recognized to occur with both brainstem lesions and diffuse bilateral cerebral hemisphere disease. • Examination of the limbs in the comatose patient should include observation of any spontaneous movements and, in particular, any asymmetry, indicating a unilateral hemisphere or brainstem lesion. Muscle tone is usually not diagnostically helpful, although in patients with drug overdose or with a metabolic cause of coma the tone is usually flaccid. Tendon reflexes and plantar responses are often of localizing value, but may be abnormal, and sometimes asymmetrical, with diffuse cerebral insults such as metabolic causes of coma (Table 24.5). An attempt can thus be made to differentiate the three main types of lesion causing coma. With intrinsic brainstem lesions there are focal abnormalities in the brainstem reflexes, often with cranial nerve abnormalities, which are present from the time of the first examination and often persist unchanged. In addition,

24

Psychogenic coma

*Also commonly cause an acute or subacute confusional state (p. 1289).

there will be bilateral pyramidal tract signs in the limbs and there is likely to be an irregular breathing pattern. In brainstem compression by lesions above the tentorium, brainstem signs appear in a progressive way. Early on, there is likely to be either a hemiparesis or asymmetrical bilateral pyramidal signs in the limbs. A unilateral third cranial nerve palsy may be an isolated early focal sign, owing to compression of the nerve by herniation of the temporal lobe through the tentorium. Because pressure above the tentorium is raised, there may be papilloedema. In diffuse neurological disease affecting the cerebral hemispheres and brainstem, and in metabolic causes of coma, pupillary and eye movement reflexes tend to be normal, although in deep metabolic coma pupillary responses are preserved and reflex eye movements are lost. Pyramidal signs in the limbs are symmetrical. In overdose,

1285

particularly of opiates, breathing tends to be regular but shallow.

Mental state examination When it has been established that the conscious level is normal, examination of the mental state may proceed. Full testing is a lengthy process and includes tests of cognitive function and sometimes a formal psychiatric assessment (Ch. 8). The broad outlines of the functions forming the mental state are described here, followed by a suggested scheme of testing of cognitive function, the 'mini-mental state' examination, which takes only 5-10 minutes to perform. Some cognitive functions are clearly localized in the brain, e.g. language and calculation in the dominant hemisphere, and impairment provides information of localizing value. Other functions, such as memory, are less clearly lateralized, and others, such as reasoning ability, are so complex as to be of little localizing value. However, it is usually possible to decide whether there is a focal or a global impairment of cognitive function, this being the diagnostically important conclusion.

Speech

1286

Speech will already have been assessed to some extent during the history. There are three major abnormalities. Dysphasia is a difficulty with comprehension or expression of language which results from a lesion of the dominant cerebral hemisphere. (Strictly, aphasia means a complete inability to comprehend speech or to communicate in speech, but the terms may be used interchangeably). In all right-handed people and in about 50% of left-handed people this is the left hemisphere. In motor or expressive dysphasia there is no defect of comprehension of the spoken or written word and, through gesture or writing, the patient can demonstrate that he or she understands what is being said. In expressive dysphasia the patient cannot find the right words and has grammatical difficulty. In mild forms the speech will be hesitant, with pauses owing to difficulty in finding particular words (nominal dysphasia). In severe cases the patient may be speechless. Patients with expressive dysphasia usually appear frustrated by the defect. By contrast, in receptive or sensory dysphasia the patient does not fully comprehend spoken or written language. This results in an inability to understand what the examiner is saying and a failure to monitor his or her own speech. The speech is usually fluent and there is a tendency to talk in jargon. Expressive dysphasia is produced by lesions of Broca's area in the frontal lobe, and receptive dysphasia is produced by lesions more posteriorly, in Wernicke's area in the temporal lobe. In many patients the lesion produces a mixed dysphasia. Dysarthria refers to a difficulty in articulation of speech. Any neuromuscular disorder affecting the control of the muscles involved in articulation may give rise to dysarthria.

Dysphonia refers to a defect in voice production. Neurological causes include Parkinson's disease, myasthenia gravis and recurrent laryngeal nerve palsy. Dysphonia may also result from disorders directly affecting the vocal cords or ventilatory function. Reading Comprehension of the written word is also a function of the dominant hemisphere and impairment is often associated with dysphasia for spoken language. The patient is asked to read aloud. The patient is dyslexic if unable to read the words correctly or fails to understand what was read.

Writing As with calculation and reading, writing is also a function of the dominant hemisphere, particularly the region of the angular gyrus. Dysgraphia - the inability to write - is usually associated with dysphasia. Attention, orientation and alertness The patient should be orientated in time, place and person. They should be able to give the day, date, the name of the hospital and their home address. Alertness and attention may be simply tested by asking the patient to count backwards from 30; a time to do this exceeding 30 seconds is abnormal. Both attention and immediate recall (registration) can also be tested by asking the patient to repeat back a series of digits, first forwards and then (with another sequence) in reverse order. If these tests show evidence of disorientation or marked inattention, more detailed testing of intellectual function is likely to be unreliable.

Memory It is important to test both recent and remote memory. Recent memory is particularly affected in disease of the temporal lobes and certain nuclei in the thalamus. Shortterm memory can be tested by asking the patient to remember a name and address and some unrelated material, such as the name of a flower and a colour. These should be repeated back immediately and then after an interval of 5 or 10 minutes. The patient's account of very recent personal events will also reflect the integrity of short-term memory. Remote memory is tested by asking questions about the patient's childhood, where they used to live, education and previous employment. Impairment of remote memory occurs in more severe lesions of the temporal lobes. Reasoning The patient should have some insight into their condition and the ways in which it affects them. Judgement refers to the patient's ability to form an acceptable opinion given a particular set of circumstances. For example, if the patient is asked what they would do on seeing a set of keys lying in the road, and answers 'Throw them in the dustbin', this would reasonably be considered to show poor judge-

ment. Abstraction is tested by asking the patient the meaning of some proverbs. However, this is closely linked to academic achievement, and in some patients a better test is to ask about similarities and differences between objects. Impairment of insight, judgement and abstraction tend to occur together, and indicate disturbance of frontal lobe function. Calculation The ability to calculate depends on the integrity of the angular gyrus of the parietal lobe in the dominant hemisphere and is thus frequently disturbed in lesions producing dysphasia. Dyscalculia - the inability to perform simple calculations - is assessed by asking the patient to make serial deductions of 7 from 100, noting the time taken and the number of mistakes, and by other simple tests of mathematical ability. Object recognition and agnosia The inability to recognize objects in the absence of any defect of primary sensation is termed agnosia. To test for visual agnosia, the patient is presented with simple objects and asked to name them; failure indicates a lesion of the visual association cortex in the posterior parietal region. With extensive lesions in this area the patient may be unable to recognize familiar faces (prosopagnosia) or familiar places, and may be unable to find their way about their own home (topographagnosia). Visual agnosia can be tested in the presence of expressive dysphasia by asking the patient to match an object against a picture of a similar object. Astereognosis, or tactile agnosia, is an inability to identify a simple object placed in the hand, with the eyes closed; this indicates a contralateral parietal lobe lesion. With severe parietal lobe lesions the patient may completely ignore and fail to identify a limb or the whole of the contralateral side of the body (autotophagnosia). Agnosia is more easily recognized with lesions of the non-dominant hemisphere; with lesions in the dominant hemisphere, there is frequently associated dysphasia, which makes it difficult to detect agnosia. Praxis Praxis is the ability to perform a planned motor task, and dyspraxia (apraxia) is the inability to do this in the absence of paralysis. Motor dyspraxia may be due to a lesion of the dominant premotor frontal cortex or the anterior corpus callosum, or to diffuse cortical disease. It is tested by asking the patient to mime simple tasks such as combing the hair or brushing the teeth, or to copy unusual hand postures demonstrated by the examiner. Constructional dyspraxia, which is more common with lesions of the non-dominant hemisphere, is the inability to construct shapes - by drawing or other means - either on request or when asked to copy a particular design. It is usually tested by asking the patient to copy a drawing of a three-dimensional cube, or to draw a clock face or a bicycle.

Perception Disorders of perception are common in psychiatric disorders (p. 207), but also occur in organic brain disease. Visual, olfactory and gustatory hallucinations are relatively common in temporal lobe epilepsy. It is important to use the terms delusion, illusion and hallucination correctly. A delusion is a firmly held false belief. Delusions are common in normal people, but tend to be more firmly held and more bizarre in patients with major psychotic illness. An illusion is a false interpretation of a sensory perception. Again, illusions may occur in normal people, but also occur with acute organic brain syndromes. Hallucinations are false sensory perceptions which have no external stimulus. Hallucinations occur with temporoparietal lesions, most commonly in temporal lobe epilepsy and with acute organic brain syndromes. Prolonged hallucinations, usually auditory, occurring without impairment of consciousness, are suggestive of a psychotic disorder.

24

Mood Abnormalities of mood are often obvious from the way in which the patient presents their history. Depression, elation, lability, irritability and anxiety are the main disorders. Many patients will attempt to conceal abnormalities and will need to be questioned directly, sometimes with additional history from relatives. Abnormalities of mood usually indicate a psychiatric disorder but may also be an early feature of dementia or encephalopathy. Excessive lability of mood, however, suggests bilateral frontal disease. Affect Affect is the emotional response to a particular situation. A patient with hemiplegia who is euphoric can be said to have an inappropriate affect, suggesting a frontal lesion. It can be difficult to decide whether affect is appropriate or not, particularly in patients with long-standing disease who have come to terms with their disability.

Mini-mental state examination The mini-mental state examination (MMSE) provides a rapid means of testing cognitive function (Table 24.6). Any abnormality detected should prompt a more detailed psychological assessment. The MMSE can be applied to patients who are drowsy or stuporose, but this must be recorded.

LESIONS OF THE LOBES OF THE BRAIN Localized lesions of the different lobes of the brain produce readily recognizable clinical syndromes (Figs 24.1 and 24.2). The lesions that most often produce focal deficits are tumours and areas of infarction. Frontal lobe Lesions of the frontal lobe commonly produce a con-

1287

TABLE 24.6 Mini-mental state examination Max. score

Test Orientation What is the (year) (season) (date) (day) (month)? Where are you (country) (county) (town) (hospital) (ward)? Retention Name three objects, then ask patient to repeat these. Give 1 point for each correct answer. Then repeat them until patient learns all three. Count the number of trials and record

5 5

( ) ( )

3

( ) FIG. 24.1 The lobes of the brain

Calculation and attention Serial 7's. 1 point for each correct answer. Stop after five answers. If patient cannot, or will not, do this, ask the patient to spell 'world' backwards. Score 0-5 points Recall Ask patient to name the three objects learned earlier. Give 1 point for each correct answer

Patient's score

5

( )

3

( )

9

( )

language' Name a pencil and a watch (2 points). Repetition: ask patient to repeat a short sentence (0 or 1 point). 3-stage command: Take a piece of paper in your right hand, fold it in half and put it on the floor' (3 points). Read and obey the following: 'Close your eyes' (0 or 1 point). Ask patient to write a sentence of his/her own choice. It must contain a subject and verb and make sense (0 or 1 point). Copying: ask patient to copy two intersecting pentagons (0 or 1 point) Total score

FIG. 24.2 Functional localization within the left hemisphere (medial surface of posterior part shown on right)

30

( )

tralateral hemiparesis owing to involvement of the motor area and upper part of the corticospinal tract. However, a hemiparesis is not invariable with frontal lobe lesions. Involvement of Broca's area will produce an expressive dysphasia. Mental changes are common with frontal lobe lesions. There is often some degree of intellectual impairment, consisting of poor attention span, some loss of retention and recall, impairment of judgement and loss of

1

1288

MCQ 24.1

insight. Mood changes are prominent, with periods of euphoria or depression. The affect is typically fatuous or frivolous, and behaviour may become disinhibited; these effects together may lead to considerable social disruption. Bladder and bowel control may be lost, leading to incontinence, sometimes with an inappropriate lack of concern. Fits are common with frontal lobe lesions. Parietal lobe Abnormalities of cortical sensation are prominent (see above). Impairment of tasks involving visuospatial skills and apraxia is common. Topographagnosia is the difficulty experienced by patients, particularly those with nondominant parietal lobe lesions, in finding their way in familiar places. Prosopagnosia is the inability to recognize familiar faces. Apraxia leads to serious practical problems, such as an inability to dress and perform other simple tasks, e.g. eating and shaving. Involvement of the visual radiation produces a lower homonymous quadrantanopia. Temporal lobe A lesion involving Wernicke's area, which lies in the

24

FIG. 24.3 Anatomy of the visual pathway A Lesions at points 1-8 produce the visual field defects shown. B The arrangement of the visual radiation is shown in a lateral view. Lesions of the upper and medially situated part of the radiation in the parietal lobe produce a lower quadrantanopia, and lesions of the lower and laterally placed part of the radiation in the temporal lobe produce an upper quadrantanopia. Note that macular sparing occurs with lesions of the radiation or cortex.

posterior part of the temporal lobe, produces a receptive dysphasia. In addition, temporal lobe lesions produce memory impairment. Involvement of the visual radiation leads to an upper homonymous quadrantanopia.

GAIT AND STATION

Occipital lobe

The ability to stand and walk depends on the integrity of many different neurological functions, both motor and sensory. These include:

A lesion involving the visual cortex will produce a hemianopic visual field defect (Fig. 24.3). Lesions more anterior in the occipital lobe, in the visual association areas, may lead to visual agnosia and agnosia for colours. Fits are commonest with frontal and temporal lobe lesions, less common with parietal lesions, and least common with occipital lesions. 1

• Position sense from muscles and joints in the limbs and also in the trunk and neck; • Sensory input from vision and from the labyrinths in the inner ear; • Motor functions, which include upper and lower motor neurons, the basal ganglia and cerebellum and, of course, the muscles and joints themselves.

Acute confusional states Acutely confused patients are, to a variable extent, disorientated; their ability to concentrate and their memory are impaired, they have difficulty following even simple instructions, their attention is poor, and they are often drowsy. Acute confusional states are often associated with delirium, a state characterized by restlessness, agitation, irritability and, sometimes, frightening hallucinations. Acute confusional states can occur with focal cerebral hemisphere lesions, but are more common with metabolic disturbances, which may eventually result in stupor and coma (Table 24.5), and with abrupt withdrawal of drugs, including barbiturates, alcohol and, occasionally, benzodiazepines. Confusion is a feature of dementia and some psychiatric diseases, particularly the psychoses. However, in contrast to other causes of acute confusional states, psychiatric disease and dementia do not cause drowsiness.

Much can be learned from careful observation of the gait: certain types of gait disorder are easily recognized and provide immediate information about the causative lesion. Station refers to the ability of the patient to stand and the posture of the stance. Examples of abnormalities include the stooped stance of a patient with Parkinson's disease, and the wide-based stance of a patient with cerebellar disease. It is relevant to observe how easily the patient is able to stand up, and whether assistance is required and, if so, how much. The ability to walk is then assessed. In patients whose gait appears normal, or only mildly abnormal, two further tests are useful. Tandem gait. The patient is asked to walk heel-to-toe along a straight line (tandem gait). This is a fairly severe test of balance and coordination and, in the presence of normal power, failure usually indicates an impairment of cerebellar function, of vestibular function, or of postural sensation (sensory ataxia). Romberg's test. If the tandem gait test is normal, the

1289

patient is asked to stand with the feet together and then to close the eyes (Romberg's test). An inability to maintain balance indicates an impairment of either postural sensation or vestibular function. Some abnormalities of gait are easily recognized. For example, in a spastic gait the patient walks slowly, with obvious stiffness in the legs and, sometimes, with scissoring due to thigh adductor spasm. A hemiplegic gait is recognized by dragging, weakness and spasticity of one leg. The patient with a parkinsonian gait has a stooped posture and, when asked to walk, may have difficulty in initiating movement (start hesitation) and tends to take small shuffling steps which quicken (the festinant gait). With an ataxic gait the patient is unsteady when standing and usually adopts a broad base; walking appears unsteady, with lurching from side to side, and the gait resembles that of a drunkard. There may be associated nystagmus. In a steppage gait, resulting from bilateral footdrop (as found, for example, in a peripheral neuropathy), the patient has to flex the leg at the hip more than usual in order to prevent catching the toes. The gait has the appearance of someone trying to step up and there is usually an associated stamping as each foot hits the ground, particularly when weakness is combined with severe proprioceptive loss. A waddling gait is produced by proximal weakness at the hip girdle. There is an inability to tilt the pelvis normally when swinging each leg through to take the next step, and this is compensated for by exaggerated lateral movements of the trunk, producing a waddling movement. In an apraxic gait the patient is able to stand but is unable to perform the planned motor function involved in walking. If the patient can walk, the gait is usually smallpaced and shuffling. A limping gait is very common, the usual cause being some painful musculoskeletal, rather than neurological, condition affecting the leg.

CRANIAL NERVES Olfactory nerve Testing of olfactory function is not essential in every patient but it is paticularly important in certain situations. In patients with frontal lobe tumours, e.g. olfactory groove meningiomas, there may be unilateral anosmia because of direct compression of the nerve. Bilateral anosmia or hyposmia is common following colds and with sinusitis. Impairment of smell is common in heavy smokers. Bilateral anosmia may also be produced by head injuries which

1 1290

MCQ 24.1

damage the nerves as they pass through the cribriform plate; this is usually permanent. Smell is tested in each nostril separately. Test substances include camphor, peppermint, cloves, lavender and other distinctive strongsmelling substances, but not chemical irritants, such as ammonia, which stimulate trigeminal afferents.

Optic nerve The assessment of optic nerve function includes measurement of visual acuity, colour vision, the visual fields, and examination of the fundi. The efferent pupillary responses are mediated by the third nerve (p. 1272); the optic nerve provides the afferent limb of the light reflex. Visual acuity Distant and near vision are examined. Distant vision is assessed using a Snellen chart. The patient is positioned 6 m from the chart and each eye is tested separately. If the patient has glasses, these should be worn. The patient is asked to read the smallest line that can be seen, and the acuity is recorded as 6 (which is the numerator and is the maximum distance at which a subject with normal vision can clearly read the type) over the number of the smallest size of print the patient can see. Normal vision is 6/6. Because refractive error is common, acuity should be retested, using a pinhole, if abnormal. Near vision is tested using standard test types and, again, it is important to state whether glasses have been used. Colour vision is particularly dependent on macular and optic nerve function. Colour desaturation, particularly to red, is the earliest and most sensitive indicator of impaired optic nerve function. Standard charts (Ishihara) for testing colour vision are available and should be used in patients suspected of having any lesion of the retina, optic nerve or optic chiasm, as long as acuity is not severely impaired. Visual fields A working knowledge of the neuroanatomy of the visual pathway is essential when examining the visual fields (Fig. 24.3). Light from the temporal half of the visual field is focused on the nasal half of the retina, and light from the nasal half of the visual field on the temporal half of the retina, with inversion of the images. There are no rods or cones over the optic nerve head, producing a blind spot in the visual field situated a few degrees lateral to central vision. The optic nerve exits from the orbit through the optic foramen and, with the optic nerve from the other side, forms the optic chiasm. The fibres from the temporal halves of each retina pass through the chiasm, without decussating, into the optic tract on the same side. The nasal fibres decussate, the optic tract on each side therefore consisting of fibres from the nasal half of the contralateral retina and the temporal half of the ipsilateral retina. The fibres pass to the lateral geniculate body and thence, via the optic radiation, to the occipital cortex. The fibres concerned with pupillary reflexes pass from the lateral

TABLE 24.7 Visual field defects

TABLE 24.8 Common visual field defects

Site of lesion

Visual field defect

Defect

Causes

Optic nerve

Partial or complete monocular loss of vision, with reduction or absence of direct pupillary light reflex

Homonymous hemianopia

Stroke Tumour

Optic chiasm

Bitemporal hemianopia, often asymmetrical, starting in one temporal field Pituitary tumour with suprasellar extension initially produces an upper bitemporal quadrantanopia (due to image inversion in retina), then progresses to bitemporal hemianopia

Quadrantanopia

Stroke Tumour

Bitemporal hemianopia

Pituitary tumour Craniopharyngioma

Monocular field loss

Vascular occlusion Retinal disease Optic neuritis Optic nerve compression

Enlarged blind spot

Papilloedema

Optic tract

Homonymous hemianopia

Parietal lobe

Involves medial part of optic radiation, resulting in a lower homonymous quadrantanopia

Temporal lobe

Involves lateral part of optic radiation, resulting in an upper homonymous quadrantanopia

Extensive temporoparietal lesion, or occipital lobe

Complete hemianopia, with macular sparing

Both occipital lobes

Cortical blindness, but pupillary reflexes preserved

geniculate body to the pretectal nucleus in the midbrain. The upper and lower fibres of the visual radiation pass through the parietal and temporal lobes, respectively, before reaching the occipital cortex. Lesions at different points in the optic pathway produce characteristic visual field defects (Fig. 24.3 and Table 24.7). The visual fields are tested by comparing the patient's visual field with that of the examiner. Each eye is tested separately. The peripheral field is usually screened briefly using movements of the examiner's fingers in the four quadrants, but when suspicion of a defect is high, more detailed assessment is necessary using a small white target, or comparing the quality of the colour of a red-headed pin in different quadrants. Any visual field loss can be mapped out by placing the pin within the area of loss and moving it from this position into the areas of normal vision. In this way, it is possible to detect all quadrantic and hemianopic defects and discrete areas of visual field loss (scotomas). The patient's blind spot, which represents a discrete scotoma, can be mapped out. A red pin is more sensitive for detecting central scotomas in which the only defect may be impairment of colour vision, e.g. as may be the case in optic neuritis. Visual field defects can be documented more fully by using a perimeter for the peripheral fields and a Bjerrum screen for testing the central fields. The common causes of visual field defects are given in Table 24.8. O Optic fundi Examination of the optic fundi (Fig. 24.4) should include scrutiny of the blood vessels, retina and choroid and the

24

optic discs. The anterior part of the eye can be examined using the 10+ lens on the ophthalmoscope. Abnormalities of blood vessels Hypertensive and sclerotic changes are the most commonly seen blood vessel abnormalities. Hypertensive changes are graded thus: • Grade 1: Arteriolar narrowing. • Grade 2: Narrowing with arteriovenous nipping where arteries cross veins. • Grade 3: Changes as for grade 2, together with haemorrhages and/or exudates. • Grade 4: Changes as for grade 3, with papilloedema. Sclerotic changes in retinal arterioles are commonly associated with hypertension (Fig. 24.5), but also occur in normotensive people and are increased in diabetes (Figs. 24.6 and 24.7) and hyperlipidaemias. The changes are narrowing, tortuosity, and an increase in the light reflex (silver wiring). Arterial emboli. Emboli, usually arising from atheromatous plaques in the carotid artery in the neck at the level of the bifurcation, are occasionally seen. They may be cholesterol emboli, which are highly refractile and often multiple, or platelet emboli, which appear white. Small emboli may be asymptomatic, and usually move peripherally fairly rapidly. Larger emboli produce amaurotic attacks affecting part or the whole of vision in that eye. Venous occlusion. Thrombosis of the central retinal vein (Fig. 24.8) occurs in polycythaemia rubra vera but may occur spontaneously. Vision may be relatively well preserved; the ophthalmoscopic appearances are venous engorgement and multiple haemorrhages, together with swelling of the optic disc. Central retinal artery occlusion (Fig. 24.9) causes complete monocular blindness and is associated with a pale retina with very narrow pale vessels. The blood supply

1291

of the macular region is from the choroidal circulation, so this part of the retina has a pinker appearance, sometimes described as a cherry-red spot. Other causes of retinal haemorrhage. Any cause of raised intracranial pressure will produce venous engorgement, which may produce retinal haemorrhages and papilloedema. In subarachnoid haemorrhage, subhyaloid haemorrhages may occur, which are large and well defined and have a horizontal level in the upright posture. Bleeding disorders may produce retinal haemorrhages. Abnormalities of the retina and choroid Pigmentary degeneration of the retina. Retinitis pigmentosa is the most common type of pigmentary degeneration affecting the retina. It is hereditary in the great majority of cases, usually as an autosomal recessive trait, although sometimes as an autosomal dominant or sex-linked recessive trait. Ophthalmoscopy shows a lace-like network of thin pigmented lines, sometimes with larger areas of confluent pigmentary change. Similar pigmentary changes may be seen in other conditions, including spinocerebellar degenerations (p. 1375). Refsum's disease (p. 1399) and mitochondrial cytopathy (pp. 1407-1408). Chorioretinitis. Inflammatory disease of the retina and underlying choroid may produce scarring, with pale areas where the retina has been destroyed, together with pigmentary change. Chorioretinitis may be caused by intrauterine infection with toxoplasmosis or cytomegalovirus; syphilis may produce similar changes. Optic discs The normal optic disc has clearly defined margins and a central depression (optic cup) where the arteries and veins enter and leave the eye. In most people venous pulsations can be seen in the large veins on the optic disc, but when intracranial pressure rises these pulsations disappear. The two main abnormalities of the optic disc are papilloedema and optic atrophy. Papilloedema (Fig. 24.10) means oedema of the optic disc, caused either by local haemodynamic changes, raised intracranial pressure or inflammation of the optic disc (Table 24.9). O Early changes include hyperaemia of the disc, and venous dilatation with absent venous pulsation. Swelling of the optic disc produces elevation and blurring of the disc margins. Small haemorrhages may appear at the disc margin. With more severe papilloedema haemorrhages become larger, and the disc becomes further elevated and enlarged, giving rise to an enlarged blind spot in the visual field, usually detectable by confrontation. Folds may appear in the retina, together with white exudates with indistinct margins ('soft' exudates). O

1 1292

MCQ 24.2

2

Fig. 24.1

Indistinct optic disc margins are often present in hypermetropic people, but should not be confused with papilloedema. Occasionally, hyaline bodies are present on the optic nerve head; these may mimic papilloedema and are known as drusen. The other condition that is sometimes confused with papilloedema is the presence of myelinated nerve fibres spreading from the optic disc onto the surrounding retina. Optic atrophy (Fig. 24.11) may result when papilloedema has been present for a prolonged period, whatever the cause, and it may also develop gradually in a number of other disease processes (Table 24.10). The appearance is a pale white optic disc, which is flat and has sharp margins.

Third, fourth and sixth cranial nerves Clinical anatomy The third nerve contains motor fibres to all the extraocular muscles except the lateral rectus and superior oblique, afferent proprioceptive fibres from these muscles, and motor parasympathetic fibres to the pupil which produce constriction. The motor fibres arise from the third-nerve nucleus in the midbrain, ventral to the aqueduct (Figs 24.12 and 24.13). The important relations of the nerve between the brainstem and the eye are its proximity to the posterior communicating artery (site of aneurysm), its course over the tentorial edge close to the uncus of the temporal lobe (compression during 'coning'), and its passage through the lateral wall of the cavernous sinus, before entry into the orbit through the superior orbital fissure. The motor parasympathetic fibres to the pupil arise in the upper part of the oculomotor nucleus (Edinger-Westphal nucleus), pass through the midbrain and reach the orbit together with the oculomotor motor fibres. Within the orbit, the parasympathetic fibres enter the ciliary ganglion; from here, the postganglionic fibres pass to the ciliary and sphincter pupillae muscles as the short ciliary nerves. The fourth nerve, supplying superior oblique, has its nucleus in the midbrain ventral to the aqueduct at the level of the inferior colliculus (Fig. 24.12). The nerve follows a similar course to the third nerve and runs along the lateral wall of the cavernous sinus, entering the orbit through the superior orbital fissure. The sixth nerve, supplying the lateral rectus muscle, arises from the nucleus in the upper pons, ventral to the floor of the fourth ventricle. The fibres pass forwards and downwards to emerge near the midline, in the sulcus between the pons and medulla. The nerve lies on the ventral surface of the pons, and enters the cavernous sinus below the posterior clinoid process. It passes through the sinus and enters the orbit through the superior orbital fissure. The directions of gaze for testing individual extraocular muscles are summarized in Figure 24.14. The oblique muscles are attached to the eye behind the equator of the globe. Thus, superior oblique depresses the eye and inferior oblique elevates the eye during adduction. Elevation of the eyelid involves two muscles, the levator muscles

FIG. 24.5 Hypertensive retinopathy (left) [A] There are several small haemorrhages and multiple cottonwool spots which, with or without papilloedema, indicate severe accelerated or 'malignant' hypertension. B The same fundus following treatment of the hypertension, showing partial resolution of the abnormal changes, particularly the cotton wool spots.

24

FIG. 24.4 Normal optic fundus

FIG. 24.6 Diabetic retinopathy

FIG. 24.9 Central retinal vein thrombosis Note gross optic disc swelling and surrounding retinal haemorrhage.

FIG. 24.7 Proliferative retinopathy, showing new vessels in the disc

FIG. 24.10 Papilloedema

supplied by the third nerve, and Muller's muscle supplied by the cervical sympathetic. Thus, any lesion affecting the superior division of the oculomotor nerve is likely to be associated with ptosis. Pupillary reflexes The anatomy of the light and near vision pupillary reflexes is shown in Figure 24.15. Size. The pupils should be round and regular and equal

FIG. 24.8 Central retinal artery occlusion The retinal arteries are attenuated and the retina has a pale appearance, following occlusion of the central retinal artery.

FIG. 24.11 Bilateral optic atrophy Pathological pallor of discs, in this case due to demyelinating optic neuropathy.

in size. Mild degrees of inequality (anisocoria) can be normal, but a major difference in the size of the pupils is pathological. Light reflex. The pupils are first tested to light, with observations of the direct response in the ipsilateral eye and the consensual response in the contralateral eye. Both should respond equally and briskly. Cataracts or corneal opacities will reduce the light stimulus. Degenerative disease of the retina results in a reduced afferent input, as

1293

TABLE 24.8 Causes of papilloedema Raised intracranial pressure Tumour Abscess Hypertension Hydrocephalus Venous sinus thrombosis Meningitis Encephalitis Subarachnoid haemorrhage Intracerebal haemorrhage C02 retention Cerebral oedema due to trauma Venous obstruction Central retinal vein thrombosis Cavernous sinus thrombosis Caroticocavernous tistula (carotid aneurysm) Thrombosis or obstruction of SVC Orbital lesions, e.g. cellulitis, tumours, thyroid eye disease Anterior optic neuritis (papillitis) Isolated lesion Multiple sclerosis Meningitis, tuberculosis, syphilis Sarcoidosis

Optic nerve tumours Glioma Meningioma Blood disease Severe anaemia Polycythaemia rubra vera DIC Thrombocytopenic purpura Leukaemia Sickle cell disease Toxic and deficiency Methyl alcohol Uraemia Arsenic Raised CSF protein Guillain-Barre syndrome Spinal cord tumour FIG. 24.12 Diagrammatic outline of the cranial nerve nuclei within the brainstem

TABLE 24.10 Causes of optic atrophy Optic nerve compression Pituitary tumour Carotid aneurysm Glaucoma Optic nerve tumour Sphenoid meningioma Olfactory groove meningioma Optic neuritis Following long-standing papilloedema Central retinal artery occlusion Toxic/metabolic Diabetes Methyl alcohol

1294

Tobacco Quinine Ethambutol Lead and arsenic Anaemia Secondary to retinal disease Senile macular degeneration Retinitis pigmentosa Severe chorioretinitis Secondary to trauma Orbital fracture Hereditary Leber's optic atrophy Hereditary ataxias Spinocerebellar degenerations

may lesions of the optic nerve, chiasm or optic tracts. Local disease of the eye, such as iridocyclitis, may cause adhesions preventing pupillary constriction. A lesion of the third nerve nucleus or third nerve, or of the ciliary ganglion

FIG. 24.13 Ventral surface of the brainstem and cerebellar hemispheres showing the sites of emergence of the cranial nerves

or short ciliary nerves, will also result in an impaired or absent pupillary reflex. By examining the direct and consensual light reflexes in the two eyes, it is possible to determine whether a pupillary abnormality is due to a lesion of the afferent or efferent limb of the reflex. Near vision reflex. The near vision or convergence reflex is tested by asking the patient to fix their gaze on an object held at a comfortable distance from the eyes, and then to follow the object as it is brought nearer. The reflex depends on an intact visual pathway to the visual cortex, and from

24

FIG. 24.14 Actions and innervation of the extraocular muscles (right eye)

there to the pretectal area and on to the Edinger-Westphal nucleus. From here, the efferent limb of the reflex is the same as for the light reflex. The tonic pupil (Holmes-Adie syndrome) is a large pupil which has a poor or absent response to light, but which does show constriction on convergence. The response to near vision is usually slow, and the pupil then gradually reverts to its previous size. The tonic pupil usually affects one eye initially but may then become bilateral. It may be an isolated abnormality or may occur in association with diminished or absent tendon reflexes. The lesion of the tonic pupil is thought to be in the ciliary ganglion, with defective reinnervation such that the majority of regenerated fibres are involved in the convergence reflex only (Fig. 24.16). The Argyll Robertson pupil is usually associated with neurosyphilis. In contrast to a tonic pupil, the Argyll Robertson pupil is often small and irregular. The response to light is reduced or absent and the pupil fails to dilate in the dark. The response to near vision is better than the response to light. The lesion producing the Argyll Robertson pupil is probably immediately rostral to the Edinger-Westphal nucleus, affecting the light reflex but not the fibres serving the near vision reflex (which are located in a more ventral position). Homer's syndrome is produced by a lesion of the cervical sympathetic fibres. It comprises miosis (whereby the pupil is smaller than the normal contralateral pupil), ptosis, apparent enophthalmos due to the ptosis, and loss of sweating on the ipsilateral side of the face (Fig. 24.16). The sympathetic pathway which supplies the head originates in the hypothalamus, passes down through the lateral brainstem and cervical spinal cord and then exits in the Tl and, to a lesser extent, C8 anterior spinal roots. The fibres leave these roots via the white rami communicans and enter the cervical sympathetic ganglia. From the cer-

FIG. 24.15 Light and near vision pupillary reflexes The afferent pathways to the brainstem for the light reflex are shown as a continuous blue line and that to the occipital cortex for the near vision reflex is shown as a dashed blue line. For the light reflex, fibres from the lateral geniculate nucleus (1) pass to the pretectal nucleus (2) in the midbrain. After synapsing, fibres pass to the ipsilateral and contralateral Edinger-Westphal nucleus (3), which is part of the oculomotor nuclear complex. From here, fibres travel in the third nerve (4) to the ciliary ganglion (5), and postganglionic fibres pass from here to innervate the iris and ciliary muscles. Afferent fibres for the near vision reflex pass to the occipital cortex (6); impulses are then relayed to the nucleus of the superior colliculus (7). From here, there are bilateral connections to the Edinger-Westphal nucleus (3). For clarity, only the contralateral connection is shown on the diagram.

vical ganglia, branches travel with the carotid artery into the head. A lesion affecting any part of this pathway will produce Horner's syndrome. Examination of eye movements The range of movement in each eye is assessed and the patient asked to report any diplopia. In disturbances of conjugate gaze there will be no diplopia, but movement of both eyes will be incomplete in certain directions. Diplopia may be caused by lesions at the level of the nuclei in the brainstem supplying the extraocular muscles or their internuclear connections, or lesions affecting the peripheral nerves or the extraocular muscles themselves. The eye movements are routinely tested by asking the patient to look up, down, and to each side, and then to follow the examiner's finger moving laterally 'and medially, upwards and downwards. The eyes are also observed for nystagmus - an involuntary rhythmic movement of the eyes which may be present at rest or in certain directions of gaze, and which persists when the eyes are still. Conjugate eye movements Conjugate movements are both voluntary and reflex in nature. A disturbance of voluntary conjugate movement refers to an inability to gaze in a particular direction on

1295

Left third nerve lesion • Large pupil unreactive to either direct or contralateral illumination, due to efferent defect (parasympathetic) • Eye deviated down and out • Ptosis (often complete) Left Horner's syndrome • Lesion of sympathetic pathway • Small pupil with little or no dilation to shade • Partial ptosis • May be reduced sweating on that side of face Right afferent pupillary defect • Optic nerve lesion in right eye (e.g. MS) . Light shone into the unaffected left eye produces normal consensual pupillary constriction (intact left afferent pathway, both efferent pathways intact) • Switching the light quickly to the abnormal right eye is followed by consensual dilatation of both pupils, due to impaired afferent (optic nerve) response to the stimulus Right Holmes-Adie pupil • Large pupil which reacts poorly and only very slowly to light; usually better to accommodation • Rarely may remain smaller than the normal pupil for a while after prolonged intense illumination (tonic response) • Tendon reflexes may be diminished FIG. 24.16 Summary of the common causes of pupillary asymmetry and altered reactions

1296

command. A disturbance of reflex conjugate eye movement refers to an inability to follow a moving object presented to a conscious patient who understands the command. Reflex conjugate eye movements may also be tested in unconscious patients, by observing the eyes and moving the head in a horizontal or vertical plane. If the reflex eye movements are intact, this induces movements of the eyes known as doll's eye movements. Destructive or irritative lesions involving supranuclear pathways to the eye movements may produce conjugate deviation of the eyes at rest. An acute destructive lesion in one frontal lobe causes conjugate deviation of the eyes towards the side of the lesion, whereas an irritative lesion leads to conjugate deviation of the eyes away from the side of the lesion. A destructive lesion involving supranuclear fibres below the decussation of the fibres in the upper part of the brainstem leads to conjugate deviation of the eyes away from the side of the lesion. An extensive lesion in the upper midbrain may involve the supranuclear fibres bilaterally. This leads to severe impairment of involuntary eye movements, but the eyes remain conjugate and there is no diplopia. Reflex eye movements produced by head turning (doll's eye movements) or by vestibular (caloric) stimulation are normal.

Physiology of eye movements Conjugate gaze is coordinated in the pons. There are inputs from a number of centres in the visual and frontal cortex, the vestibular system and the cerebellum. Fibres from the pons pass to the nuclei controlling the extraocular muscles, the medial longitudinal fasciculus being one of the pathways. Reflex conjugate eye movements when following an object depend on visual perception; thus, visual acuity and all the structures on which this depends must be normal. From the primary visual area, fibres pass anteriorly to the associated visual cortical areas in the occipital lobe. From here, corticotectal fibres concerned with upward gaze pass to the tectum in the midbrain, and corticotegmental fibres concerned with horizontal gaze pass to the pons. Impairment of upward gaze may occur with lesions involving the corticotectal pathway; the causes include cerebral infarction, multiple sclerosis and, occasionally, a pineal tumour. Doll's eye movements. The centres controlling eye movements receive a vestibular input which is responsible for the reflex conjugate doll's eye movements. In an unconscious patient, doll's eye movements depend on the vestibular apparatus and its brainstem connections with the centres for conjugate eye movements. The head is

turned from side to side and, if intact, the reflex will induce lateral conjugate deviation of the eyes in the direction opposite to the direction of the head movement. Similar eye movements will be induced by flexion and extension of the neck. The absence of doll's eye movements indicates bilateral lesions of the brainstem connections and is usually associated with a very poor prognosis. Eye movement disorders due to pontine lesions Lesions in the pons are commonly associated with disorders of eye movements. The common abnormalities include involvement of the sixth nerve or its nucleus. This leads to paralysis of the lateral rectus and, if the lesion is at nuclear level, there may be conjugate gaze paralysis to the ipsilateral side. It is often associated with a facial nerve palsy, owing to the proximity of the seventh nerve nucleus. Lesions of the medial longitudinal fasciculus lead to paralysis of the ipsilateral medial rectus, producing defective adduction of the ipsilateral eye. On gaze to the contralateral side there may be nystagmus, greater in the abducting eye (ataxic nystagmus). This combination of signs is known as an internuclear ophthalmoplegia, which, particularly in younger adults, is likely to be due to demyelinating disease (multiple sclerosis, p. 1408). Pontine lesions affecting the medial longitudinal fasciculus may also produce skew deviation, in which one eye is elevated relative to the other. This usually leads to tilting of the head to compensate for the dysconjugate position of the eyes. Paralysis of extraocular muscles Third-nerve palsy leads to outward and, usually, slightly downward deviation of the eye on the affected side. If the pupillary constrictor fibres are also involved in the lesion there will be dilatation of the pupil (internal ophthalmoplegia). Ptosis is also present (Fig. 24.16). Sixth-nerve palsy. A lesion of the sixth nerve produces paralysis of the lateral rectus muscle, leading to inward deviation of the affected eye at rest and an inability to abduct this eye. Fourth nerve palsy is difficult to detect and the changes induced by a complete fourth-nerve palsy may be very mild. There is limitation of depression of the affected eye when adducted; this leads to diplopia, with the false image being below and lateral to the true image and also oblique to it. On covering the normal eye, the eye with the fourthnerve palsy deviates downwards and inwards. The head tends to be tilted towards the normal side to compensate for the oblique separation of images. Nystagmus may be congenital or may occur as a result of disturbances of visual acuity, vestibular function or cerebellar function; it may be drug induced. Nystagmus is discussed in more detail on page 1299.

Trigeminal nerve Clinical anatomy The anatomy of the trigeminal nerve is shown in Figure 24.17. Figure 24.21 (p. 1313) shows the cutaneous territo-

24

FIG. 24.17 Anatomy of the trigeminal and facial nerves The motor branches of the fifth nerve are not shown; these come off the mandibular division at various points along its course to supply the muscles of mastication. See text for details of the central connections and intracranial course of the two nerves.

ries of the divisions of the trigeminal nerve, and Table 24.18 (p. 1310) lists the non-cutaneous innervation. The sensory root of the trigeminal nerve passes from the Gasserian ganglion to enter the pons at the junction of the pons and the middle cerebellar peduncle. The main sensory nucleus subserves tactile sensation; fibres subserving pain and temperature sensation enter the spinal tract and nucleus, which extends downwards into the upper segments of the cervical spinal cord as low as C4 (Fig. 24.12). The fibres entering the spinal nucleus are arranged so that those from around the mouth enter the spinal nucleus in the medulla, and fibres from further out on the face enter the nucleus at progressively lower levels. Examination The routine examination of the trigeminal nerve consists of assessment of both motor and sensory functions. The masseter and temporalis muscles are palpated with the jaw tightly clenched, and the pterygoids are tested by asking the patient to move the jaw laterally and resist pressure to maintain this posture. Sensation is tested to light touch and pinprick in all three divisions of the nerve, and the corneal reflex should also be tested. The afferent limb of this reflex is the ophthalmic division of the trigeminal nerve, and the efferent limb producing a blink response is the facial nerve. A small wisp of cotton wool is gently stroked on the cornea. It is important that the patient is asked to look to one side, so that the approaching cotton wool is not seen, as the visual threat will produce a blink response. The

1297

1298

reflex produces bilateral blinking; thus, if there is an ipsilateral seventh-nerve palsy a blink will still occur on the contralateral side. The jaw jerk should normally be present, but a brisk jaw jerk indicates bilateral upper motor neuron lesions.

associated with a sixth-nerve palsy producing weakness of abduction of the eye. To test taste, four solutions - sweet, salt, sour and bitter - are applied carefully on each side of the tongue.

Seventh cranial nerve

Eighth cranial nerve

Clinical anatomy The complex anatomy of the seventh cranial nerve is shown in Figure 24.17. The functions of the facial nerve tested routinely are the power of the facial muscles and taste. The seventh nerve has its nucleus in the lower part of the pons, the nerve emerging between the pons and the medulla just medial to the eighth nerve in the cerebellopontine angle (Figs 24.12 and 24.13). It then enters the internal auditory canal, together with the eighth nerve, and passes to the geniculate ganglion. The main part of the facial nerve enters the facial canal, where it gives off the chorda tympani and a branch to the stapedius muscle, before leaving the skull through the stylomastoid foramen. The taste fibres from the anterior two-thirds of the tongue pass through the lingual nerve and then join the facial nerve via the chorda tympani. The cell bodies of these fibres are in the geniculate ganglion and, after joining the facial nerve, they enter the tractus solitarius and synapse with cells of the dorsal visceral grey nucleus. From here, there are projections to the thalamus and hypothalamus.

Clinical anatomy The eighth cranial nerve comprises the cochlear and vestibular nerves (Fig. 24.18). The cochlear nerve passes from the inner ear through the internal auditory canal and enters the upper medulla at the level of the inferior cerebellar peduncle. Within the medulla the auditory fibres reach the dorsal and ventral cochlear nuclei, where they synapse; fibres from these nuclei cross the midline as the trapezoid body, and enter the lateral lemniscus on the opposite side. They terminate in the inferior colliculus, and the further projection is thence to the medial geniculate body and the auditory radiation to the temporal cortex. There are bilateral connections in the cochlear nuclei and at sites above this level, so that unilateral lesions of the temporal cortex and the brainstem do not produce deafness. Unilateral lesions of the cochlear nucleus or the eighth nerve will produce unilateral deafness.

Examination Severe facial weakness may be obvious at rest, with loss of the nasolabial fold, sagging of the lower eyelid and drooping of the side of the mouth. Partial weakness may not be obvious at rest. To test the facial muscles, the patient should be asked to close the eyes tightly and resist attempts to open the eyelids, and to grimace, hold the lips together tightly, and blow out the cheeks. With an upper motor neuron lesion the lower facial muscles are much weaker than the upper. This is because there are bilateral corticobulbar projections to the neurons of the seventh nerve nucleus supplying the upper facial muscles, whereas that to the neurons supplying the lower facial muscles is unilateral. In lower motor neuron lesions, all the muscles are usually equally affected. If the nerve is affected distal to the stylomastoid foramen, there is paralysis of the facial muscles but preservation of taste. A lesion of the nerve proximal to the point where the chorda tympani joins it will involve taste on the same side of the anterior two-thirds of the tongue. An injury of the facial nerve in the facial canal proximal to the origin of the nerve to the stapedius muscle will also produce an abnormal loudness of sound in the ear on the same side (hyperacusis). A lesion of the facial nerve proximal to the geniculate ganglion will additionally produce absence of lachrymation on the same side, owing to involvement of the greater superficial petrosal nerve. Finally, damage to the facial nerve in the pons is often

Examination of hearing The ability to hear a watch ticking a few inches from the ear indicates normal hearing; alternatively, the examiner whispers numbers at a slight distance from the ear, with the contralateral ear occluded, and asks the patient to repeat what was said. In most instances this assessment of hearing is adequate, but audiometry may be required in some patients. In Rinne's test, air and bone conduction are tested using a 128 cycles per second tuning fork. Air conduction should be better than bone conduction, and this is tested first by placing the tuning fork in front of the ear, and second by placing the base of the tuning fork on the mastoid process. If the latter is heard more loudly than the former, it indicates a conductive deafness due to disease of the middle ear. In nerve deafness, both air and bone conduction are diminished compared with the other side, but air conduction should still be better than bone conduction. In Weber's test the tuning fork is placed on the middle of the forehead and the patient is asked whether the sound is heard in the middle or off to one side. In conductive deafness the sound is lateralized towards the affected side, whereas in disease of the cochlea or nerve deafness the sound is lateralized towards the unaffected side. Vestibular division The vestibular division of the nerve carries fibres from the vestibular apparatus, comprising the saccule, utricle and three semicircular canals. The cell bodies of these fibres lie within the internal auditory meatus, and the centrally directed axons of the cell bodies pass to the upper medulla, together with the auditory division of the eighth

24

FIG. 24.18 Peripheral and central connections of the eighth cranial nerve

nerve, and then pass to the flocculonodular lobe of the cerebellum and the four vestibular nuclei. All four vestibular nuclei have connections with the cerebellum and with the medial longitudinal fasciculus, by which they are connected with the third, fourth and sixth cranial nerves. The cortical projections from the vestibular nuclei are diffuse and poorly understood. Vertigo The major symptom of vestibular disease is vertigo. This can be defined as an hallucination of movement, either of the patient himself or of their surroundings. It is often associated with sympathetic overactivity, producing nausea, vomiting, tachycardia and, rarely, diarrhoea. When it is severe, balance will be impaired and the patient will be unable to walk or even stand. Vertigo is discussed more fully on page 1317. Nystagmus Nystagmus is a rhythmical involuntary movement of the eyes, usually evident during maintenance of horizontal or vertical gaze, but occasionally in the primary position as well. It may result from any disorder of the mechanisms maintaining conjugate gaze (p. 1296), most often from lesions involving the vestibular system or cerebellar pathways. Vestibular lesions may be peripheral (labyrinthine) or central (in the brainstem). Nystagmus may also be a drug-induced phenomenon, typically caused by anticonvulsants or benzodiazepines, and probably as a result of their effects on the brainstem and cerebellum. Rarely, nystagmus may occur as a congenital disorder, either in isola-

tion or as a secondary consequence of lifelong visual impairment from the time of birth (amblyopia). The typical clinical appearance of nystagmus is of failure to sustain gaze, with a slow drift back towards the primary position, which is rhythmically interrupted by rapid corrective jerks in the direction of attempted gaze ('sawtooth', or 'jerk' nystagmus). In severe unilateral vestibular lesions or during provocative tests, the jerks may persist in the mid-position (second-degree nystagmus) or even when looking in the direction of the slow component (thirddegree nystagmus). Congenital ocular nystagmus is also present in all positions of gaze but the movements are usually pendular, having equal velocity and amplitude in each direction. Non-ocular congenital nystagmus may be pendular or 'sawtooth' in type, sometimes variable in amplitude and often very marked with little accompanying visual disturbance. Acquired nystagmus of similar severity is usually accompanied by vertigo, or at least oscillopsia, an unpleasant awareness of movement of the visual environment, which may impair acuity. A systematic approach to nystagmus is summarized in Table 24.11. Tests of vestibular function Vertigo is often accompanied by nystagmus, owing to an abnormal stimulus arising in one labyrinth or to acute loss of function in one labyrinth. The slow phase of the nystagmus is induced by vestibular stimulation; it is in the direction of the movement of the endolymph and has a fast phase of recovery. Vestibular nystagmus is increased on

1299

TABLE 24.11 Analysis of nystagmus

Vestibular system

Site of lesion

Pathophysiology

Clinical features

Labyrinth

Idiopathic Inflammatory Trauma Meniere's disease Vascular Toxic (alcohol, aminoglycosides)

Horizontal or rotatory. Beats away from side of labyrinthine lesion

Eighth nerve (rare)

Acoustic neuroma

Cerebellum and brainstem

MS Vascular lesions Wernicke's encephalopathy Trauma Drugs Degenerative disorders Brainstem encephalitis Tumours

Horizontal, rotatory or vertical. May be complex and dysconjugate, as in internuclear ophthalmoplegia (p. 1410)

Ocular disease

Albinism, cataracts, retinal lesions

Usually rapid and pendular, present in all directions of gaze

Normal vision, site unknown

Pathology unknown

May be pendular in mid-position Often very marked on lateral gaze

Brainstem (vestibular nuclei and cerebellar connections)

Cerebellum Congenital nystagmus

turning the head or the eyes in the direction of the fast phase. Vestibular nystagmus can be induced either by sudden head movements (of which the most reliable technique is the use of a rotating chair) or by caloric testing, which is simpler to perform. The labyrinth is stimulated by irrigating each external auditory meatus with water, first at 30°C and then at 44°C. For most purposes only the cold water test is necessary. The test is performed with the patient lying on their back with the head held flexed to about 30° above the horizontal. Nystagmus is induced by the cold water and normally persists for about 2 minutes. The response is absent if there is total destruction of the vestibular apparatus or vestibular division of the eighth nerve; less severe degrees of damage produce impairment, rather than absence, of the response. If the vestibular lesion is irritative and nystagmus is already present, it will increase with caloric testing.

Ninth cranial nerve Of the many functions of the glossopharyngeal nerve, sensation of the posterior third of the tongue and the

1

1300

Fig. 24.2

2

MCQ 24.3

Usually horizontal, beating towards side of cerebellar lesion. Downbeating with flocculonodular lesions (rare)

pharyngeal wall is the only one tested routinely. As well as supplying sensation to this area, the nerve also supplies motor fibres to the stylopharyngeus muscle, secretormotor fibres to the parotid gland, and taste to the posterior third of the tongue. The nerve passes between the internal jugular vein and the internal carotid artery, enters the skull through the jugular foramen and joins the medulla between the inferior olive and the inferior cerebellar peduncle (Figs 24.12 and 24.13). Light touch of the posterior third of the tongue and the pharyngeal wall can be tested using an orange stick. All but the lightest stimuli in this area will produce a gag reflex. This consists of elevation of the palate, retraction of the tongue and contraction of the pharyngeal muscles. The afferent limb of this reflex is the glossopharyngeal nerve, and the efferent limb is the vagus nerve. The gag reflex is more likely to be absent with lesions of the glossopharyngeal nerve than of the vagus.

Tenth cranial nerve As well as supplying general visceral efferent preganglionic fibres to the thoracic and abdominal viscera and visceral afferents, the vagus nerve supplies motor fibres to the intrinsic muscles of the larynx, the cricothyroid muscle and the pharyngeal musculature; it also supplies sensation to the pharyngeal wall, the epiglottis, the base of the tongue and the larynx, and a small sensory branch to the external auditory meatus.

The nerve rises from the dorsal nucleus and the nucleus ambiguus in the medulla (Fig. 24.12). It exits from the medulla, passes through the jugular foramen, and then enters the carotid sheath and passes down through the neck and into the thorax. The recurrent laryngeal nerve winds around the subclavian artery on the right side, before ascending between the oesophagus and the trachea to enter the larynx. On the left, the recurrent laryngeal nerve winds around the arch of the aorta and ascends to the larynx. Examination Articulation of speech, the ability to phonate, palatal movement and swallowing are the principal clinical tests of vagal function. Dysarthria may occur with impairment of vagal function, but may also occur in edentulous people or those with poorly fitted dentures. Other causes include facial weakness, weakness of the tongue, or impaired coordination of movement caused by a pyramidal, extrapyramidal or cerebellar defect. Some causes of dysarthria produce characteristic speech abnormalities: • Edentulous people have difficulty in pronouncing the consonants 's', 'th' and 't'. • Patients with a seventh-nerve palsy have particular difficulty with lip movements, and hence, most difficulty in pronouncing the consonants 'b' and 'p'. • Weakness of the tongue leads to difficulty in the pronunciation of the consonants 'd' and 't'. • Palatal paralysis causes a nasal quality to the voice, and difficulty in pronouncing the consonants 'k','q' and 'ch'. This is more marked if the paralysis is bilateral. • Cerebellar lesions produce so-called scanning speech, which has an interrupted quality. • Bilateral upper motor neuron lesions induce speech which is slow, spastic, and sometimes grunting. • Extrapyramidal disease causes dysarthria which is slurring and often associated with dysphonia. The speech may peter out in mid-sentence and there may be difficulty in initiating speech. Soft palate. Movement of the soft palate is tested by asking the patient to say 'ah'. This produces palatal elevation and the uvula should remain in the midline as the palate rises. A palatal paralysis on one side will produce deviation of the uvula towards the normal side. Laryngeal function is tested by listening to the voice. This may be hoarse or husky and of low volume. The ability to sing is lost in either unilateral or bilateral vocal cord paralysis. Swallowing is tested by asking the patient to drink some water. Regurgitation of liquid through the nose indicates palatal weakness and the patient with dysphagia may cough as fluid spills into the trachea.

Eleventh cranial nerve The eleventh cranial nerve supplies the sternomastoid and trapezius muscles. The motor cells lie in the upper five

cervical segments, the nerve passing upwards through the foramen magnum and into the posterior fossa, where it joins the bulbar accessory nerve which is part of the vagus nerve. Together, they leave the skull through the jugular foramen, with the glossopharyngeal and vagus nerves. The spinal accessory fibres then descend in the neck to supply the sternomastoid and trapezius muscles. The sternomastoid muscles contract together to flex the neck, and each one acts to turn the head towards the opposite side. The patient's ability to turn the head against resistance is tested and the sternomastoid can be both seen and palpated. The trapezius is tested by asking the patient to shrug their shoulders against resistance.

24

Twelfth cranial nerve The hypoglossal nucleus lies in the dorsal part of the medulla (Fig. 24.12, p. 1294). The nerve leaves the medulla and passes out of the posterior fossa through the anterior condylar foramen. It then passes anteriorly through the neck and reaches the tongue. To test the tongue, the patient is first asked to open their mouth and the tongue is examined lying at rest in the floor of the mouth. The bulk of the tongue is assessed. Wasting and fasciculation indicate a lower motor neuron lesion. Tremor in the tongue can be difficult to distinguish from fasciculation. Protrusion of the tongue should be in the midline. A weakness on one side will lead to the tongue being protruded towards the weak side. Lower motor neuron lesions produce ipsilateral wasting of the tongue, with weakness. O Only occasionally, with an acute severe upper motor neuron lesion, is there deviation to the opposite side. 0

THE MOTOR SYSTEM The motor unit - consisting of an anterior horn cell or motor neuron of a cranial nucleus, the peripheral axon and the muscle it supplies - is influenced by activity in the cortex, via the corticospinal tracts, the cerebellum, the basal ganglia, the vestibular system and afferent information, largely postural sensation. Routine examination of the motor system allows the identification of dysfunction of one or more of these centres influencing movement (Fig. 24.19).

Motor system lesions Cortex and corticospinal (pyramidal) tract lesions Lesions of the cortex or corticospinal tract lead to an increase in tone without muscle wasting, except after long periods, as a result of disuse. There is no fasciculation. The distribution of weakness with pyramidal lesions is characteristic. In the upper limbs the flexor muscles remain stronger than the extensors and, in the leg the extensors remain stronger than the flexors. The tendon reflexes are brisk and the plantar response is extensor.

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FIG. 24.19 Summary of anatomy and clinical features of lesions affecting the motor system

Basal ganglia The term extrapyramidal disease is loosely used to refer to disease of the basal ganglia; this causes a number of motor abnormalities, including a rest tremor (which often disappears or is reduced with purposeful movement), and other involuntary movements, including chorea, athetosis, dystonia and ballismus. Basal ganglia lesions may also lead to akinesia or hypokinesia (poverty of movement), difficulty in initiating movements, slowness of movement (bradykinesia) and rigidity in the muscles, with a characteristic irregular increase in tone, producing 'cogwheeling' (p. 1362). The tendon reflexes in extrapyramidal disease are usually normal. Cerebellum Cerebellar disease produces incoordination. There is often a tremor which develops on action, and this may involve the trunk as well as the limbs. Head tremor is called titubation. Speech may be involved, typically producing a scanning dysarthria. Muscle tone is normal, or sometimes reduced, and reflexes may be sluggish. Cerebellar lesions do not lead to weakness, though incoordination may cause disabling loss of function (p. 1375).

1

1302

MCQ 24.4

Lower motor neuron lesions Lesions of the anterior horn cell or the lower motor neuron at any point will lead to denervation of the muscle supplied. This produces muscle wasting, fasciculation, a reduction in muscle tone, and depressed or absent tendon reflexes. Muscle disease Disease of the muscles themselves produces weakness. In many acquired muscle diseases weakness is mainly in the large proximal hip and shoulder girdle muscles, and is often accompanied by wasting. Tendon reflexes are preserved and plantar responses are flexor. Muscle tone is reduced, in proportion to the degree of muscular wasting and weakness.

Examination of the motor system The motor system is examined in the following order. 1. Posture and involuntary movements Inspection of the patient may reveal a number of abnormalities of posture which are helpful in diagnosis, e.g. the patient with a hemiplegia whose affected arm is held flexed, or the patient with Parkinson's disease with masklike facies and a flexed posture of the trunk. The patient is also observed for involuntary movements at rest. These are common in extrapyramidal disease. 2. Muscle bulk The bulk of the muscles in the limbs and on the trunk is

assessed. Wasted muscles should be carefully examined for fasciculation. 3. Muscle tone With complete relaxation there should be little resistance to passive movement of limbs. With pyramidal tract lesions there is a spastic increase in tone, which is usually a constant resistance to movement. However, with rapid passive movement the clasp-knife phenomenon may be elicited, in which there is an increase in tone followed by a sudden decrease. Sudden passive movement about a joint may elicit clonus, which reflects a disinhibited stretch reflex. This is most easily obtained at the ankle in the calf muscles, though it may be present in any spastic muscle group. In extrapyramidal disease the increase in tone is intermittent and feels like a ratchet (cogwheel rigidity). Tone may be reduced in a severe neuropathy or myopathy leading to marked muscle wasting, and also, occasionally, in cerebellar disease. 4. Power Power should be tested with attention to the segmental innervation of the muscles being tested. It is usual to do this in the order set out in Table 24.12. Power of trunk flexion and extension should be tested as well as that of muscles in the limbs. It is useful to grade power in each muscle group. A number of scales have been suggested. In the UK, the most widely used scale is that of the Medical Research Council: Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 -

no movement at all flicker of movement movement with gravity eliminated movement against gravity movement against resistance. This covers a wide range of power and is usually subdivided in grades 4-, 4 and 4+. Grade 5 - normal power. 5. Coordination Tests of coordination are of little value if marked weakness is present. In the upper limbs, the finger-nose test assesses the presence of an action tremor, and coordination is further tested by rapid repetitive movements, such as tapping the back of one hand with the other, and fine finger movements, such as touching each finger in turn with the thumb of the same hand. Physiological tremor is a fine tremor of the outstretched hands and fingers which does not impair coordination to any significant degree. Incoordination due to an action tremor on finger-nose testing is termed past-pointing or dysmetria, and is seen in cerebellar disease. Impairment of rapid repetitive movements is dysdiadochokinesis. Further tests of coordination in the upper limbs are writing and use of a knife and fork. In the legs the heel-shin test is the equivalent of the finger-nose test, and foot-tapping on the examiner's hand is a test of rapid repetitive movement. O 6. Reflexes The main reflexes tested are listed in Table 24.13. In

routine practice it is usually necessary only to test the jaw jerk, the tendon reflexes, the plantar reflexes and the abdominal reflexes. The reflexes may be absent in peripheral neuropathy. They may be reduced in cerebellar disease or, in the case of a corticospinal tract lesion, they may be increased and accompanied by an extensor plantar response. The abdominal reflexes may be absent with a corticospinal tract lesion. They are otherwise usually present in the young, but may disappear with age and obesity. The glabellar reflex is performed by tapping the forehead

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TABLE 24.12 Innervation of muscle groups* Muscle/muscle group

Segmental/nerve innervation

Diaphragm Rhomboid Serratus anterior Supraspinatus Infraspinatus Pectoralis major Deltoid Biceps/brachialis Triceps Brachioradialis Wrist extensors Wrist flexors - carpi radialis carpi ulnaris Finger extensors Finger flexors Abductor pollicis brevis Abductor pollicis longus

C3, 4, 5 C4, 5

Interossei Upper abdominal Lower abdominal Iliopsoas Adductors of hip Abductors of hip Extensors of hip Knee flexion Knee extension Dorsiflexion of foot Plantarflexion of foot Toe extension Extensor hallucis longus Extensor digitorum brevis Toe flexion Inversion of foot Eversion of foot

C4, 5, 6 C4, 5, 6 C4, 5, 6 C5, 6, 7, 8, T1 C5, 6 C5, 6 C6, 7, 8 C5, 6 C5, 6, 7, 8 C6, 7 C7, 8, T1 C6, 7, 8 C7, 8, T1 C8, T1 C7, 8 C8, T1 T6-9

Radial Radial Radial Median Ulnar Radial Median Median Radial Ulnar

T10-L1 L1, 2, 3 L2, 3, 4 L4, 5, S1 L5, S1, 2 L4, 5, S1,2 L2, 3, 4 L4,5 81,2 L5, S1 L5

81 S1,2 L4, 5 L5, S1

*Those shown in bold type are those routinely tested.

1303

between the eyebrows with a finger, from behind the patient so that the finger cannot be seen. This is positive if there is persistent closing of the eyes, the reflex indicating damage of the frontopontine pathways to the facial nerve nucleus. It is an early sign in Parkinson's disease and it is also seen in dementia, with cerebral atrophy and with frontal lobe tumours.

TABLE 24.13 Segmental reflex levels Reflex

Level

Glabellar Snout Sucking Palmomental Grasp

Corticopontine Corticopontine Frontal Frontal Frontal

Jaw

Pons

Biceps Supinator Triceps Finger

C5, 6 C5, 6 C7, 8 C7, 8, T1

Abdominal - upper lower

T9,10 T11,12

Knee Ankle Plantar Cremasteric Anal

L2, 3, 4 S1 Corticospinai tract (afferent L5, S1) L1.2 S3, 4, 5

The snout reflex is elicited by tapping the nose and is positive if this induces excessive grimacing of the face. Like the glabellar reflex, it indicates frontal lobe disease. The sucking reflex is also a frontal lobe sign. It is positive when stroking of the lip produces pouting and sucking movements of the lips. It is a normal reflex in young babies but usually disappears within the first 18 months of life. It is seen with diffuse lesions affecting the frontal lobes. The chewing reflex also indicates diffuse frontal disease. A tongue depressor is placed in the mouth, and this provokes reflex chewing movements. The grasp reflex also indicates frontal lobe disease. The patient's palm is stroked and this elicits reflex grasping which becomes stronger if attempts are made to remove the fingers from the grasp. Sometimes stroking of the dorsum of the patient's fingers of the same hand will inhibit the reflex and allow release of the examiner's fingers from the grasp. These reflexes, indicating frontal lobe damage, are collectively known as the primitive reflexes. Table 24.14 summarizes the main findings on examination of the motor system with various types of neurological deficit. O

SENSORY SYSTEM Primary sensations The primary sensations tested are light touch, pinprick, temperature, vibration and joint position sense. A working knowledge of peripheral nerve and dermatomal anatomy is essential (Fig. 24.20). Light touch is tested with a wisp of cotton wool; pinprick with a disposable pin, not a hypo-

TABLE 24.14 Motor system examination Deficit

Muscle bulk

Fasciculation

Tremor

Tone

Power

Coordination

Reflexes

Plantars

Gait

Lower motor neuron (including anterior horn cell)

Reduced

Usually

—

Reduced

Reduced

Impaired with severe weakness

Reduced or absent

Flexor

Steppage

Upper motor

Normal

-

-

Increased (spastic)

Usually reduced

Sometimes impaired

Increased

Extensor

Spastic or hemiplegic

Extrapyramidal

Normal

-

+ (at rest)

Increased (cogwheel)

Normal

Impaired (slow)

Normal

Flexor

Stooped hypokinetic

Cerebellar

Normal

-

+ (on action)

Normal or reduced

Normal

Impaired

Normal or reduced

Flexor

Ataxic

Myopathy

Wasting proximally

—

Reduced

Proximal weakness

Impaired in proportion to weakness

Normal or reduced

Flexor

Waddling

1

1304

MCQ 24.5

dermic needle. Temperature sensation is tested with tubes filled with hot or cold water, vibration with a 128 cycles per second tuning fork, and joint position should be tested initially in the distal interphalangeal joints of the fingers and toes. Body charts are useful to record the sensory abnormalities.

24

Sensory system lesions Sensory tract lesions Lesions of the spinal cord and lesions rostral to this may affect the sensory tracts in a differential way. For example, in cervical spinal cord compression from a prolapsed disc, it is common to find that loss of postural and vibration sense (dorsal columns) is more marked than pinprick and temperature sensation, whereas, with an intramedullary lesion of the spinal cord involving decussating spinothalamic tract fibres, there will be a dissociated impairment of pain and temperature at the level of the lesion.

FIG. 24.20 Peripheral nerve and dermatomal anatomy A Dermatomal fields. B Sensory territories of selected peripheral nerves of clinical importance.

Cortical sensation More complex types of sensory disturbance occur with lesions affecting the parietal lobe. Two-point discrimination, the ability to detect two separate stimuli closely applied on the finger, is normally 3-5 mm on the finger pulps. Parietal lesions impair discrimination. Sensory extinction of one of a pair of simultaneously applied stimuli on each side of the body is also a feature of parietal lobe lesions. The patient is asked to close the eyes, and the examiner then touches one side of the body with a pin and asks the patient to report on which side the stimulus was felt. The patient with a parietal lobe lesion will be able to identify correctly a single right-sided or left-sided stimulus, but with paired stimuli will only report feeling the pin on the side contralateral to the normal parietal lobe. Graphaesthesia is the ability to identify figures or letters drawn on the palm of the hand with an orange stick, with the eyes closed. This ability may be lost in the hand contralateral to a parietal lobe lesion. Stereognosis is the ability to manipulate objects within the hand and identify them correctly. Coins are usually used for this purpose. A contralateral parietal lobe lesion may lead to astereognosis. Tactile localization is the ability to identify the part of the body touched briefly by the examiner. The patient is asked to localize the point touched by the examiner by placing his or her own finger on the same spot. Again, this is impaired with a contralateral parietal lobe lesion. Identification of body parts is also impaired with a parietal lobe lesion. Such a patient is unable to identify their different fingers correctly and show them to the examiner. With severe lesions, this agnosia of parts of the body may lead to denial of the existence of part of the body or even the whole of one side of the body. Some patterns of sensory deficit are included in Table 24.15.

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TABLE 24.15 Common patterns of neurological deficit • Diffuse cerebral Dementia, with or without physical signs, depending on cause Fits Gait dyspraxia • Cerebral hemisphere Hemiparesis, dysphasia, sensory loss, visual loss (hemi- or quadrantanopia) and other specific features, depending on lobe affected May be raised intracranial pressure, sometimes with false localizing signs (e.g. third-nerve palsy) Fits, focal or generalized • Extrapyramidal Akinesia, bradykinesia Abnormal posture Rest tremor Cogwheel rigidity Chorea, dystonia, ballismus • Cerebellum Ataxia of trunk with midline lesions Ipsilateral ataxia of limbs and nystagmus with cerebellar hemisphere lesions Dysarthria • Expanding pituitary lesions Bitemporal visual field loss, usually asymmetrical Hypopituitarism - usually partial Sometimes optic atrophy Sometimes ocular movement palsies • Brainstem Cranial nerve lesions at the level of the brainstem lesion UMN signs in brainstem below level of lesion, and in limbs Limbs signs often bilateral Sensory impairment variable - often contralateral spinothalamic (ST) loss Bulbar (medulla) involvement common - dysarthria, dysphagia, impaired breathing Variable bladder and bowel involvement Cerebellar signs very common Impairment of consciousness common with acute lesions, unless ventrally placed Mass lesions may be associated with hydrocephalus due to aqueduct obstruction

FURTHER READING ON NEUROLOGICAL DIAGNOSIS

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Bickerstaff E R, Spillane J A 1989 Neurological examination in clinical practice, 5th edn. Oxford: Blackwell Scientific. Lindsay K W, Bone I, Callander R 1991 Neurology and neurosurgery illustrated, 2nd edn. Edinburgh: Churchill Livingstone. O'Brien M D (ed) 2000 Aids to the examination of the peripheral nervous system. Edinburgh: W B Saunders. Plum F, Posner J B 1984 Diagnosis of stupor and coma, 3rd edn. Philadelphia: F A Davis.

• Spinal cord May be root signs at level of lesion Bilateral UMN (pyramidal tract) weakness below level of lesion Extensor plantars and brisk reflexes below lesion Abdominal reflexes reduced or absent May be sensory level on trunk - this may be at or below the level of the lesion Sensory loss in limbs may be of dorsal column (DC) or spinothalamic (ST) type, or affect all modalities Intrinsic cord lesions more likely to cause ST loss Compressive cord lesions more likely to cause DC loss Bladder and bowel involvement very common and may be the major early symptom • Anterior horn cell Wasting, fasciculation, weakness. In motor neuron disease, a combination of LMN and UMN signs • Cauda equina Multiple lumbosacral root lesions. Often asymmetrical Bladder and bowel involvement common Absent reflexes at affected root levels • Nerve roots Motor (LMN) and/or sensory loss in a root distribution Tendon reflex absent if it affects appropriate root • Peripheral nerve Mononeuropathy: motor (LMN) and/or sensory loss in distribution of a single peripheral nerve Multifacal neuropathy: asymmetrical, patchy motor and/or sensory deficit attributable to multiple peripheral nerve lesions Polyneuropathy: symmetrical motor (LMN) and/or sensory deficit most marked distally. Usually legs more affected than arms. Reflexes variably absent, depending on type and extent of neuropathy • Neuromuscular junction Fatiguable weakness affecting any voluntary muscle • Muscle disease Usually proximal wasting and weakness Reduced or absent reflexes if wasting severe Plantars flexor. No sensory deficit No bladder or bowel involvement

HEADACHE Headache is one of the commonest symptoms in medicine (Table 24.16). It does not usually indicate serious intracranial disease and often accompanies systemic illnesses as a non-specific symptom. In most patients presenting with headache there are no abnormal physical signs, so that the diagnosis depends entirely upon an accurate history.

TABLE 24.16 Classification and causes of headache PRIMARY HEADACHES Migraine

Primary non-migrainous headaches Tension-type headache Cluster headache Paroxysmal hemicranias (rare) SECONDARY HEADACHES Cervical headache Medication misuse headache Diseases affecting blood vessels Intracranial Intracerebral haemorrhage Cerebral thrombosis Cerebral embolism Berry aneurysm Arteriovenous malformation Cortical thrombophlebitis Hypertensive encepalopathy Cerebral arteritis Extracranial Giant cell (temporal) arteritis Carotid and vertebral artery dissection Raised intracranial pressure Tumours Abscess Encephalitis Hydrocephalus Benign intracranial hypertension Pituitary tumours Acute trauma with oedema Subdural haematoma

Meningeal irritation Meningitis Subarachnoid haemorrhage Postictal headache Post-traumatic headache Diseases of the skull and sinuses Sinusitis Fractures Mastoiditis Paget's disease Bone tumours Ear disease Acute otitis media Chronic suppurative otitis media Diseases of eyes and orbits Glaucoma Iritis Orbital tumour Causes of painful ophthaimoplegia Toxic and metabolic causes Infections with fever Hypercapnia Hypoxia Hypoglycaemia Alcoholic hangover Haematological disease

Anaemia Polycythaemia Coital cephalgia Psychogenic headache

Aetiology A number of intracranial and extracranial structures may give rise to headache. It may be due to referred pain from the muscles and joints of the cervical spine; disease of the sinuses, temporomandibular joints, teeth, ears and eyes may all produce headache rather than local pain. Raised and reduced intracranial pressure can both cause headache. Intracerebral arteries innervated by the trigeminal nerve are sensitive to stretch and pressure, and the leptomeninges are also very sensitive to distortion and inflammation. Subarachnoid haemorrhage and meningitis usually produce severe headache. Spasm, dilatation or inflammation of branches of the external carotid artery may lead to headache. A number of metabolic disturbances such as hypoglycaemia and hypercapnia are asso-

ciated with headache; in these, the mechanisms of pain are largely unknown.

24

Taking a history When taking a history of headache, a structured approach along the following lines is suggested: 1. When did the headaches start? 2. How often do the headaches occur? Are they continuous or episodic? 3. How long does each headache last? 4. How severe is the headache and how does it affect daily activities, including work and sleep? 5. Where is the headache felt? Is it localized or generalized? 6. Are there associated symptoms, particularly any visual or gastrointestinal symptoms? 7. What has been the effect of treatment already tried?

MIGRAINE Definition and types of migraine Migraine is defined as an episodic headache, usually lasting 6-24 hours, which is associated with transient visual and/or gastrointestinal disturbances and sometimes other neurological deficits. Minimum diagnostic criteria are listed in Table 24.17. Classic migraine refers to headache with anorexia, nausea and often vomiting, which is preceded or accompanied by an aura of visual, sensory, motor or mood disturbances. Common migraine describes similar headaches without an aura.

Clinical features Migraine affects about 5% of the population. In about a third of patients it starts before the age of 10 years. In childhood the main complaint is often abdominal pain (bilious attacks). There is usually vomiting, and low-grade fever is also common. Appendicitis or mesenteric adenitis are differential diagnoses, but there is often a history of more than one attack, and sometimes many.

TABLE 24.17 Minimum diagnostic criteria for migraine Episodic attacks of headache lasting 4-72 hours Two of. Unilateral Throbbing Aggravated by movement Moderate/severe pain

with the following features: One of. Nausea/vomiting Photophobia Phonophobia

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CASE STUDY 24.1 PROGRESSIVELY SEVERE HEADACHES, WITH TINGLING IN THE HAND, IN A 49-YEAR-OLD MAN WITH A HISTORY OF MIGRAINE A man of 49 years presented to his GP with a long history of headaches. These had started when he was 15 and at that time occurred 3-4 times a year. On each occasion the headache was preceded by a visual disturbance, in which flashing zigzag lines spread from the left upper field to involve most of the visual field, obscuring his central vision. This cleared completely within 20 minutes, to be followed immediately by a generalized throbbing headache which rapidly became severe. It was associated with nausea, vomiting, photophobia and phonophobia. He had to lie down and after several hours the headache gradually improved, though he usually felt washed out for 24 hours after resolution of the headache. In his 30s these headaches became less frequent, occurring once or twice a year. Over the 6 months before presenting to his GP he had developed headaches that occurred several times a week and then daily, gradually becoming more severe. They were not associated with visual disturbance or the other features of his previous headaches, but 3 months after their onset he noticed intermittent tingling in his right hand, with mild numbness. After a few weeks these symptoms spread to the

right side of his face. The treatment he normally took for his longstanding headaches did not relieve these headaches of recent onset. His previous health, apart from the headaches, had been good. He had smoked 20 cigarettes daily since the age of 18. There was a family history of heart disease and stroke, several relatives having died from these conditions in their 50s and 60s. On examination there were no abnormal neurological signs, and general examination was also normal.

Questions 1, What is the nature of Ms headaches? 2, What treatment might be Offered? 3, Do the recent headaches require investigation? Discussion The long-standing headaches are typical of migraine. For headaches as infrequent as this man's, one would try to provide effective treatment for the acute attacks. Paracetamol or aspirin, together with domperidone or metoclopramide, taken promptly at the onset of the attack, is often effective and all that is needed. If this

The majority of patients have their first attack of migraine before the age of 30 years; onset over the age of 35 is rare and should raise suspicion of an alternative cause for the headache. Some patients experience a prodrome for up to 24 hours before the onset of an attack, which may include mood changes (either depression or euphoria), excessive physical or mental energy, or lethargy, and avoidance of or craving for certain foods. The visual aura may take various forms. The patient may describe flashing dots, spreading scintillating scotomas, sometimes with well-marked angulated geometric 1 1308

MCQ 24.6

does not work, one of the triptans could be used. This man's headaches were not frequent enough to warrant prophylactic treatment. The recent history indicated a quite different type of headache, which became persistent and gradually more severe. Worryingly, it was associated with progressive unilateral sensory symptoms, suggesting a left hemisphere lesion. The normal neurological examination does not exclude serious pathology, and urgent investigation with brain imaging (preferably MRI) is needed, together with a chest X-ray as he is a smoker. The chest X-ray was normal and the brain MRI showed a left parietal mixed signal lesion, with mass effect and surrounding oedema and areas of pathological gadolinium contrast enhancement. The lesion was solitary and large and the radiological diagnosis was a primary brain tumour. Subsequent biopsy showed a grade III astrocytoma. No attempt was made to resect the tumour as this would have been likely to lead to additional deficit (sensory, and possibly a hemiparesis and dysphasia in this right-handed man), and he was subsequently treated with radiotherapy.

shapes (teichopsia, fortification spectra), fragmentation, or 'frosting' of vision. These disturbances may start in peripheral or central vision. They are often described by the patient as affecting one eye, but an inability to read during the visual disturbance indicates that it is homonymous. The usual duration of the visual symptoms is about 30 minutes. If other neurological symptoms develop in attacks, their onset is often during or just after the visual aura. Numbness and paraesthesiae, affecting one or both arms, the face, tongue and lips, are common, sometimes associated with, unilateral or bilateral limb weakness and dysphasia. These symptoms, like the visual disturbances, develop over several minutes, helping to distinguish them from either a typical transient cerebral ischaemic attack (p. 1331) or focal epilepsy (p. 1323).

The headache itself is often unilateral, but may change sides in different attacks and is frequently generalized. It may be throbbing or a dull ache. It is often accompanied by photophobia and phonophobia. Nausea is common, and a proportion of patients find that vomiting eases the headache and heralds the end of the attack. Syncope and diarrhoea may occur in some patients. The severity of many migraine headaches is indicated by the inability to continue with normal activities, and patients frequently prefer to lie down in a darkened room. Some patients sleep during attacks and wake to find the headache improved or resolved. Migraine usually occurs less than once a month, and many patients experience only a few attacks during their lives. Migraine occurring more than once a fortnight is rare. Daily headaches over weeks or months are not migrainous. Many patients with migraine seem to be prone to tension headaches, which call for different management. Migraine usually decreases in frequency and severity after the age of about 50, in women often coinciding with the menopause. O

Rare forms of migraine Hemiplegic migraine. This is a rare form of migraine in which a profound hemiplegia, sometimes with dysphasia and hemianopia, precedes the development of headache by 30-60 minutes. The weakness and other focal deficits usually resolve quickly; occasionally, however, they may improve only gradually and, very occasionally a permanent deficit may result. Hemiplegic migraine sometimes occurs as a familial condition, in which case only this type of migraine occurs. Basilar migraine. This is an unusual form of migraine in which brainstem disturbances are common, including impairment of consciousness, vertigo, dysarthria, diplopia and limb weakness. Ophthalmoplegic migraine. In this very rare condition headache is followed by transient unilateral ophthalmoplegia with ptosis, which may last for several days.

Provoking factors Migraineurs report a wide variety of provoking factors for their attacks. The most frequent are stress, relaxation after a period of stress, altered sleep patterns (including lying-in at weekends), alcohol, exercise, bright lights and hunger. In some women, attacks occur mainly at the time of menstruation. Oral contraceptive medication may exacerbate migraine (in which case it should be withdrawn), but often has no effect. A few patients give a clear history of specific food sensitivity: the commonest foods are chocolate, cheese and red wine. However, the role of such specific sensitivities has probably been exaggerated in migraineurs as a whole.

Mechanism of headache in migraine The pain of headache arises from the intracranial extra-

cerebral vessels and the meninges, rather than from the brain itself. The pain-producing innervation of the head projects through branches of the ophthalmic division of the trigeminal nerve to the trigeminocervical complex. There are serotonin (5-HT1B) receptors on the large extracerebral intracranial vessels which cause vasoconstriction, and there are 5-HT1D receptors on the peripheral branches of the trigeminal nerve and its central terminals in the trigeminal nucleus. The triptans and some other drugs used in the treatment of migraine lead to vasoconstriction and neuronal inhibition, which is the likely therapeutic mechanism of these agents. There is overlap of afferents from the upper part of the neck with trigeminal neurons in the lower part of the trigeminocervical nucleus, and this may explain the very common complaint of neck pain with headache, even when there is no evidence of any primary pathology in the neck. It is now considered that migraine may result from an episodic dysfunction of brainstem or diencephalic sensory modulation systems, which exert control over the trigeminocervical complex, the evidence being that, during attacks of migraine, functional imaging using positron emission tomography has shown abnormal activity in the dorsal midbrain and dorsolateral pons. The episodic dysfunction, particularly in those genetically predisposed to migraine, may be provoked by a wide range of external factors, such as fatigue, hunger, alcohol, various foodstuffs and mental stress.

24

Management See Tables 24.18, 24.19 and 24.20. Acute attacks Most patients will experience attacks less frequently than once a month. In these patients, vigorous early treatment of the acute attack with an adequate dose of an analgesic, such as aspirin, paracetamol or dihydrocodeine, together with an antiemetic such as metoclopramide, domperidone or prochlorperazine, is often all that is necessary. Emphasis should be placed on early treatment. Often, patients will have up to 30 minutes of prodromal symptoms before the onset of headache. Many patients are helped by lying in a darkened room, others by sleeping. Identification and avoidance of provoking factors are important and often neglected aspects of treatment. Ergotamine was the first disease-specific drug, and is effective in migraine, but is frequently associated with side-effects of nausea and vomiting. Usually, the drug is not necessary; however, in a few patients relief of headache can only be achieved with ergotamine, which can be taken either orally by inhalation or by suppository. Regular frequent use of ergotamine can, rarely, cause peripheral ischaemia and gangrene. The introduction of sumatriptan and then other triptans in the last few years has been a major step forward in migraine treatment. The likely mechanism of action of these drugs has already been discussed. The triptans are generally well tolerated and are now used in preference to ergotamine, but are expensive.

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TABLE 24.18 Management of acute migraine attacks

TABLE 24.20 Migraine treatment stratification

Non-pharmacological Avoidance of provoking factors Stress Altered sleeping patterns Alcohol Unaccustomed exercise Irregular eating Specific foods Oral contraceptive treatment

Clinical situation

Treatment options

First treatment

Analgesic + antiemetic

Failure to respond to analgesia and antiemetic

Rapid effect: sumatriptan 25-100 mg po rizatriptan 10 mg po zolmitriptan 2.5 mgpo

Pharmacological Disease non-specific Aspirin Paracetamol Dihydrocodeine Ibuprofen Naproxen With domperidone or metoclopramide

Slower effect/better tolerated: naratriptan 2.5mgpo

600-900 mg 1000mg 30-60 mg 400-800 mg 500-1000 mg 10mg 10mg

sumatriptan 20mg nasally ergotamine 2 mg sl/pr

Triptans ineffective

ergotamine

Rapid-onset severe migraine

sumatriptan 6 mg sc

Many patients will find the prompt treatment with a combination of an analgesic and an antiemetic is as effective as the triptans. A scheme for choice of acute attack treatment is shown in Table 24.20.

Disease specific Triptans: Sumatriptan 25-100 mg Naratriptan 2.5mg Rizatriptan 10mg Zolmitriptan 2.5mg Eletriptan 40 mg Ergotamine 1-2mg

FREQUENT ATTACKS PREVENTIVE TREATMENT

TABLE 24. 19 Migraine - preventive treatments

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Early nausea/vomiting

Drug

Dose

Major unwanted effects

Propranolol

40-240 mg

Fatigue Reduced exercise tolerance Postural hypotension Bronchoconstriction

Pizotifen

0.5-2.5 mg

Drowsiness Weight gain

Amitriptyline

10-75mg

Drowsiness Dry mouth

Valproate

600-1000 mg

Weight gain Sedation Tremor Alopecia Potentially teratogenic

Methysergide

1-4 mg*

Sedation Cramps Retroperitoneal fibrosis

*At least one month every 6 months without treatment.

Patients with two or more debilitating attacks of migraine per month, unresponsive to acute treatment, must be considered for preventive treatment, though this should be a last resort, as all the drugs used may be associated with unwanted effects (Table 24.19), which may be unacceptable in the predominantly young and active population of migraine patients.

TENSION-TYPE HEADACHE Tension-type headaches are the most common type of headache. Pain is often described as continuous, lasting for days or weeks at a time, and some patients report that they are never free from headache. Sleep is rarely disturbed and patients are usually able to continue with their activities. There are no specific associated symptoms and analgesics have limited or no effect. The diagnostic criteria for tension-type headache (TTH), suggested by the International Headache Society, are shown in Table 24.21. TTH is known as episodic if headache occurs on fewer than 15 days each month, and chronic if more frequent than this. TTH are commonly generalized, occipital or frontal, and are described as a dull ache, a band around the head, or a pressure feeling, sometimes with superimposed short-lived localized stabbing pains. TTH is often associated with pain and stiffness in the neck. TTH may be provoked by fatigue

TABLE 24.21 Tension-type headache: diagnostic criteria A At least 10 episodes; fewer than 15 days per month for episodic TTH B Headache lasting 30 minutes to 7 days C At least two of the following: Pressure, tight quality Bilateral location Mild to moderate intensity No aggravation with mild exertion D Both of the following: No nausea or vomiting Photophobia and phonophobia are absent - one or other allowed E Other causes of headache are excluded

and by psychological factors, including stress, anxiety, anger and a depressive tendency, but in many patients such factors are absent. Studies in patients with TTH have shown reduced pain thresholds, but the relevance of this observation to the pathogenesis of TTH is uncertain. Neurological examination is normal, but there may be tenderness of the pericranial muscles (posterior nuchal and temporalis). TTH usually responds poorly to analgesic drugs, though these are often taken in large quantities by patients. This may induce medication misuse headache (see below), presenting the clinician with a considerable therapeutic challenge. It is best to persuade patients to adopt a non-pharmacological approach to treatment, which involves physiotherapy, particularly when there is marked pericranial muscle pain and tenderness, relaxation techniques, stress management and, if available, EMG biofeedback training. Analgesics should be withdrawn, and a low-dose (10-50 mg daily) tricyclic antidepressant, for a period of a few weeks, will help some patients. Reassuring the patient that there is no serious underlying intracranial cause for their headache is an important part of treatment.

TRANSFORMED MIGRAINE

It is common for patients with a clear past history of migraine to develop, years later, frequent non-migrainous headaches, often of tension type but usually non-specific. The term transformed migraine describes such patients. These headaches tend to be erroneously treated as migraine, and this emphasizes the need for careful historytaking in all patients with headache.

CERVICAL HEADACHE The overlap in afferent fibres arising from the upper three cervical segments with the caudal part of the trigeminal

nucleus offers an explanation for the frequent occurrence of headache with upper cervical spine disease. The cervical structures innervated include the atlanto-occipital, atlantoaxial and C2-3 zygapophyseal joints, the suboccipital and upper posterior neck muscles, the trapezii and sternomastoids, the spinal dura mater, the vertebral artery and the C2-3 intervertebral disc. Neck trauma and arthritis (both osteo- and rheumatoid) are the common causes of cervical headache; rarer causes include congenital abnormalities, compression of the C2 nerve root, leading to occipital neuralgia, and vertebral artery dissection.

24

CHRONIC DAILY HEADACHE

This term, now in fairly widespread use, refers to all causes of headache occurring on more than 15 days each month. It includes chronic tension-type headaches, non-specific daily headache, transformed migraine, chronic cluster headache (see Facial pain), medication misuse headache, cervical headache, post-traumatic headache and any other daily headaches related to chronic intracranial disease. It has little clinical usefulness as so defined, and the cause and categorization of the type of headache in each patient requires careful evaluation.

MEDICATION MISUSE HEADACHE

(MMH)

This is headache caused by inappropriate use of drugs normally used to treat headache. It seems paradoxical that these drugs may cause headache, and the mechanism is not clear, but it is a widespread problem. Simple analgesics, non-steroidal anti-inflammatory drugs, weak and strong opiates, ergotamine and the triptans have all been implicated. Any patient taking five or more tablets daily for their headache is at risk of developing MMH on top of their primary headache. In one study of MMH the mean duration of the underlying primary headache was 20 years, the mean time to medication misuse was 10 years, the mean duration of daily headache was 6 years, and the mean age of presentation with MMH was 46 years. MMH is an under-recognized cause of headache. Treatment includes withdrawal of the offending drug or drugs; in some patients this can be achieved under cover of short-term antidepressant medication.

POST-TRAUMATIC HEADACHE

The incidence of minor head injury is at least 200/ 100000/year, and post-traumatic headache (PTH) occurs in 30-80%. PTH is usually non-specific in nature, often daily, and most commonly resembles tension-type headache. In patients with associated injury, as for example with whiplash injuries, the PTH is associated with neck pain and

1311

the headache may be of cervical type. Many patients will have other symptoms as part of a post-traumatic syndrome (PTS, see p. 219). Patients with PTS often benefit from antidepressant medication.

cussional headaches for months, or even years, after head injury. The mechanism of such headaches is unknown. Suggestions of a relationship with impending litigation in some patients may hold some truth, but for most this is not the case.

INTRACEREBRAL BLOOD VESSELS AND HEADACHE

Meningeal irritation Headache with meningeal irritation is usually associated with neck stiffness. Meningitis and subarachnoid haemorrhage are the main causes. Localized disease involving the meninges, such as meningioma, focal metastatic tumour deposits and subdural haematoma, may each cause headache, which may be felt as localized or generalized pain.

A number of diseases affecting the cerebral circulation may cause headache. The most dramatic is subarachnoid haemorrhage, most commonly caused by rupture of a berry aneurysm (p. 1343). The headache is abrupt in onset, usually very severe, and often associated with vomiting and impairment of consciousness. Any headache of instantaneous onset should raise the possibility of an aneurysm. Small leaks from aneurysms, causing headache alone, are common in the weeks or months before a larger, more severe bleed. In some instances enlargement of an aneurysm, rather than rupture, may cause headache, and this type is usually not so severe. Haemorrhage within the brain substance itself may occur in arteriovenous malformations or with hypertension, but many occur as apparently spontaneous events without any underlying hypertension or demonstrable vascular pathology. Bleeding causes an acute rise in intracranial pressure which usually causes severe headache. Cerebral thrombosis or embolism is usually painless, but a small number of patients with thrombotic stroke will complain of headache, which can be transiently severe. Dissection of either carotid or vertebral arteries frequently causes headache. Hypertensive encephalopathy (p. 1338) may cause headache, but this is usually overshadowed by fits and impairment of consciousness. Giant cell (temporal) arteritis is a cause of severe headache in the elderly (p. 1183), O and headache is often a prominent symptom in the much rarer intracranial arteritides.

Postictal headache Epileptic convulsions are often followed by headache. This usually lasts for less than 24 hours, but may be severe. There is often postictal drowsiness, confusion and fever; in addition, the cerebrospinal fluid (CSF) cell count and protein level may both be slightly elevated. This means that unless a clear history of a fit is obtained from a relative or friend, the situation can be diagnostically difficult and, in particular, meningitis should be considered. Other causes of headache Table 24.16 lists several other focal conditions that may present with headache, rather than pain localized to the region of pathology. Coital cephalgia is a rare condition, seen mainly in men, in which headache, often abrupt in onset, occurs during or just after intercourse. It may be severe, and the clinical picture may resemble that of subarachnoid haemorrhage (which, of course, may also be provoked by intercourse). Patients require careful assessment, and in doubtful cases it is better to examine a normal CSF than to miss a subarachnoid haemorrhage. Headache as a symptom of psychiatric disease is extremely common.

FURTHER READING ON HEADACHE OTHER INTRACRANIAL CAUSES OF HEADACHE

With the exception of those due to diseases of the cerebral circulation, most intracranial causes of headache act by irritation, traction or displacement of the dural lining of the brain, or distortion of blood vessels. It is likely that this is also the mechanism of headache due to raised intracranial pressure. Expanding pituitary tumours cause pain by local pressure in the pituitary fossa. Headache immediately following cranial trauma is very common (p. 1370) and a minority of patients will continue to complain of postcon-

Fig. 24.3

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Goadsby P J 1999 Mechanisms and management of headache. J Roy Coll Phys 33:228-234. Lance J W, Goadsby P J 1998 Mechanism and management of headache, 6th edn. Oxford: Butterworth-Heinemann.

FACIAL RAIN Most patients with facial pain have no signs. The presence of trigeminal sensory loss or other abnormal physical signs suggests a structural cause. A working knowledge of the cutaneous and non-cutaneous innervation of the trigeminal nerve is necessary (Fig. 24.21 and Table 24.22), and a recognition that pain may be referred to the face from diseases affecting deeper structures. It is clinically useful to classify the causes of facial pain

according to the site of the lesion, these being local causes (Table 24.23), lesions between the cavernous sinus and the pons (Table 24.24) and central lesions (Table 24.25). The facial neuralgias (Table 24.26) cause the greatest diagnostic difficulty. Most lesions that involve the trigeminal nerve produce sensory impairment and, sometimes, paraesthesia rather than pain.

TRIGEMINAL NEURALGIA

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Trigeminal neuralgia (tic douloureux) is a severe paroxysmal pain with a lancinating shock-like quality. It occurs in women more than men, with a ratio of 3:1, with onset usually over the age of 50, though it may occur much earlier than this. It is sometimes seen in association with multiple sclerosis, but it may occur in young people without any associated disease.

Pathology

FIG. 24.21 Cutaneous fields of the three trigeminal divisions (V1, V2, V3) and two upper cervical dermatomes (C2, C3)

The cause of the condition is uncertain. The fact that there is no detectable trigeminal sensory impairment on routine testing indicates that the lesion must be minimal. In patients with intractable trigeminal neuralgia coming to operation, it has been observed that, in the posterior fossa, the superior cerebellar artery may be unusually tortuous, producing compression of the trigeminal root. Histologically, minor degenerative changes are seen both in the trigeminal ganglion and in trigeminal root fibres.

Clinical features Trigeminal neuralgia nearly always occurs in a maxillary or TABLE 24.22 Non-cutaneous trigeminal innervation Division

Structures innervated

Ophthalmic

Eye, including cornea Mucosa of frontal sinus and upper part of nose

Maxillary

Lateral wall and floor of nasal cavity Upper jaw and teeth Roof of mouth Mucosa of maxillary sinus

Mandibular

Anterior wall of external auditory meatus Temporomandibular joint Lower jaw and teeth Floor of mouth Anterior two-thirds of tongue

TABLE 24.23 Disease of local structures causing facial pain Teeth Impacted wisdom teeth Dental abscess Sinusitis Giant cell arteritis Temporomandibular joint disease Nasopharynx Tumour

Salivary glands Infection, e.g. mumps Inflammation due to duct obstruction Granuloma, e.g. sarcoidosis Tumour, e.g. lymphoma, primary tumour Eye Glaucoma Iritis Optic neuritis

TABLE 24.24 Lesions between cavernous sinus and pons causing facial pain Root Trigeminal neuralgia Cerebellopontine angle tumour Acoustic neuroma Meningioma

Basal meninges Granuloma, e.g. TB, sarcoid, syphilis Tumour, e.g. lymphoma, carcinoma Ganglion Herpes zoster Middle fossa fracture

TABLE 24.25 Central lesions causing facial pain • • • • •

Multiple sclerosis Thalamic infarcts Brainstem glioma Posterior inferior cerebellar artery thrombosis (Wallenberg syndrome) Syringomyelia/syringobulbia

TABLE 24.26 The facial neuralgias • • • •

Trigeminal neuralgia Postherpetic neuralgia Migrainous neuralgia (cluster headache) Atypical facial pain

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sidered. Thermocoagulation gangliolysis involves making a controlled radiofrequency heat lesion to the peripheral branch of the trigeminal nerve in the territory of which the pain is felt. More than 90% of patients with trigeminal neuralgia respond to this treatment, but pain often recurs after 1-2 years. The procedure is suitable for older patients. In the more invasive microvascular decompression, the trigeminal nerve compression by the superior cerebellar artery or other offending vessel is relieved. This operation often cures the pain permanently, and is particularly suitable for younger patients. FIG. 24.22 Trigeminal neuralgia The two most common sites of origin and radiation of pain are shown: mouth-ear and nose-orbit. The pain usually starts in the region of the encircled area and radiates in the directions shown.

mandibular distribution, and ophthalmic division pain is rare. It is always unilateral at any time, though later development on the contralateral side is described. The commonest sites are shown in Figure 24.22. Pain either originates in the region of the upper lip and radiates upwards over the cheek towards the eye, or originates from the angle of the mouth and radiates backwards and upwards towards the ear. Occasionally pain is migratory, occurring in different sites in different bouts of pain. Between the paroxysms of pain, which last from 10 to 60 seconds, there is usually no pain, although patients with long-standing trigeminal neuralgia may describe a dull background ache. There is always triggering of the pain in trigeminal neuralgia. Innocuous cutaneous stimuli in the upper lip or at the angle of the mouth, any movement of the face or jaw, eating or drinking, may all provoke the pain. This usually occurs in bouts of weeks or months, with long periods of freedom from pain of up to several years. In long-standing trigeminal neuralgia there may be no remission. Neurological examination reveals no abnormal physical signs, although the pain can often be provoked by cutaneous stimulation or by asking the patient to open the mouth. Many patients will be loath to speak, eat or drink during a bout of severe pain.

Management Carbamazepine Most patients respond initially to carbamazepine, which may be effective for many years. In some patients, however, although the pain is controlled, side-effects from the drug are intolerable; these include drowsiness, unsteadiness of gait, nausea and vomiting. If pain becomes unresponsive to carbamazepine it is worthwhile trying phenytoin, but surgical treatment will often need to be con-

O Case 24.1

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POSTHERPETIC NEURALGIA Shingles affecting the trigeminal nerve nearly always involves only the ophthalmic division (Fig. 24.21). Herpes zoster ophthalmicus is a disease of middle and old age, and is rare in people under 55. There is usually acute shingles and obvious scarring within the ophthalmic nerve territory. The acute zoster infection produces damage in the nerve, causing numbness and hyperalgesia. The pain is usually continuous, and has a burning or stinging quality. There may be superimposed lancinating pains.

Management Postherpetic neuralgia is extremely difficult to treat. Local measures, such as cold, sometimes heat, vibration, ultrasound and acupuncture, may all have a limited symptomatic effect. Simple analgesics have little effect. Amitriptyline and, occasionally, anticonvulsants have a beneficial effect. Opiate analgesics rarely produce much analgesia and commonly cause unwanted effects, in this largely elderly group of patients. There is no convincing evidence that local or systemic corticosteroid treatment decreases the incidence of postherpetic neuralgia, although acute neuralgia may be lessened. Idoxuridine applied locally to the rash may hasten recovery, but has no effect on the incidence of postherpetic neuralgia. Systemic aciclovir does not lessen either the incidence or the severity of postherpetic neuralgia, but does reduce the severity of the rash and so should be given for this reason.

MIGRAINOUS NEURALGIA (CLUSTER HEADACHE) Migrainous neuralgia (cluster headache) is usually considered as a migraine variant. The cause and underlying pathology of the condition are unknown. The condition occurs much more frequently in men than women, with a ratio of around 7:1.

Clinical features Migrainous neuralgia is characterized by bouts of daily

SUMMARY 1 Facial pain

ATYPICAL FACIAL PAIN

• Disease of deep structures innervated by the trigeminal nerve may produce pain referred onto the face. • Trigeminal neuralgia is a paroxysmal, lancinating pain, lasting less than a minute, in maxillary or mandibular division territory, which is triggered by cutaneous or oral stimuli. • Postherpetic neuralgia nearly always affects the ophthalmic division. It is usually a continuous pain, with cutaneous hyperaesthesia. • Migrainous neuralgia (cluster headache) is much more common in men. The pain is in the eye and on the cheek, lasts 20-30 minutes, often occurs at night and is very severe. • Atypical facial pain may be bilateral and often extends outside trigeminal territory. It is continuous, and is often associated with depression. Treatment of the depression usually relieves the pain.

Pain in the face is a surprisingly common symptom of psychological disturbance, usually depression. It is much more common in women, and the onset is usually in middle-age. Differentiation of this type of facial pain from organic causes can be extremely difficult. The pain is usually unilateral and is often confined to a trigeminal distribution. In patients in whom the pain is bilateral and clearly extends outside trigeminal territory, the diagnosis is made more easily. The pain is usually described as being continuous and severe, and may have lasted months or even years. Many patients will attribute the pain to minor dental surgery and some will have had repeated dental procedures. The pain often has a burning quality and may involve the tongue and other intraoral structures. There is, in some patients, an obvious associated depression and the response to a tricyclic antidepressant drug is usually good. Despite careful clinical assessment and sometimes extensive investigation, the cause of facial pain in a few patients cannot be determined. A trial of a tricyclic antidepressant in such patients is always worthwhile.

pain occurring for a few weeks or months at a time, with long periods of complete freedom from pain between bouts. This pattern of the pain has given rise to the alternative name of cluster headache. The pain is always unilateral and centred on the eye and the upper part of the cheek. It may be very severe and, characteristically, occurs once a day, waking the patient from sleep in the early hours. Each episode of pain lasts from 20 to 60 minutes and there may be associated unilateral facial flushing, nasal secretion on the affected side, and profuse watering of the eye with conjunctival hyperaemia. Occasionally, an ipsilateral Horner's syndrome will develop. This is usually transient, but may persist and become permanent. Alcohol provokes attacks during a cluster. Examination between the bouts of pain is usually normal though there may be a Horner's syndrome.

24

FURTHER READING ON FACIAL PAIN Barher F G. Jannetta P J, Bissonette D J et al. 1996 The long-term outcome of microvascular decompression for trigeminal neuralgia. N Engl J Med 334:1077-1083. Feinmann C, Harris M, Cawley R 1984 Psychogenic facial pain: presentation and treatment. Br Med J 288:436-438. Zakrzewska J M 1998 Trigeminal neuralgia. Major problems in neurology, Vol 28. London: W B Saunders.

DIZZINESS AND VERTIGO

Management Treatment for migraine is usually ineffective for this type of pain. Oral drugs are useless once the pain has started, as by the time the drug is absorbed from the gut the pain will have come to an end. Prophylactic treatment is thus necessary, and in most cases is successfully achieved with ergotamine. This drug may be taken orally, sublingually, by inhalation, by suppository, or by subcutaneous injection. It is usual to advise oral or sublingual treatment in the first instance, and the patient is instructed to take 2mg a few hours before the pain is due. In some patients parenteral ergotamine is more effective. The drug should be stopped periodically to see whether a spontaneous remission has occurred. Most clusters of this type of headache last for less than 3 months. Occasionally, the pain will not respond to ergotamine by any route. A number of other treatments are successful in some patients. These include oxygen inhalation at the time of the pain, verapamil, lithium and corticosteroids. O

'Dizziness' is an extremely common presenting complaint and the word may be used by different patients to describe not only vertigo but light-headedness, faintness, visual disturbance, confusion, loss of balance due to ataxia, and even feelings of weakness or loss of sensation in the legs. There are often no physical signs, and, as with headache, the diagnosis depends largely on a careful history. A normal feeling of equilibrium depends on being fully conscious and receiving appropriate afferent information from the eyes, the vestibular system, and sensory pathways from the neck, trunk and limbs (Fig. 24.23). The coordinating nuclei in the brainstem also receive modulating inputs from the cerebral cortex, basal ganglia, cerebellum and reticular formation. The vestibular system refers to the end-organs in each inner ear (semicircular canals, ampullae, utricle and saccule), the eighth nerve, the vestibular nuclei in the pons and upper medulla, and more central projections. There is continuous tonic input from each labyrinth. Changes of head posture increase the input from

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CASE STUDY 24.2 ACUTE VERTIGO IN A 46-YEAR-OLD WOMAN A 46-year-old woman got up one morning and developed severe unsteadiness which caused her to fall to the floor, as if thrown to one side. She felt sick and vomited several times during the next few hours. There was a sensation of rotation which was so intense that she had to close her eyes and lie still, avoiding all movements of her head for a while. Later in the day the dizziness gradually subsided but was exacerbated by head movement, particularly when turning sideways or lying on her left side. Over the next few days the symptoms continued to improve but there were recurrent bouts of short-lived vertigo precipitated by standing quickly, lying down, or turning on her left side in bed. These episodes became gradually less frequent and severe over a period of weeks, to such an extent that she had almost fully recovered when later interviewed in the clinic. The referral letter from her GP described extreme pallor, sweating and nystagmus when she was seen at home during the acute phase. Examination in the clinic showed no abnormality on routine neurological examination. She swayed slightly during the Romberg manoeuvre. Positional testing with the Hallpike test evoked transient vertigo and nystagmus when her head was turned down to the left. This came on after a few seconds, resolved within 15 seconds, and recurred only briefly and with diminished intensity on repetition of the manoeuvre. Her hearing was clinically intact and symmetrical. Questions 1. Where is the lesion? 2. What possible pathologies should be considered? 3. What further investigation or treatment is required?

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Discussion The history is that of acute unilateral vestibular failure. Severe prostrating vertigo with nausea and vomiting but no other focal neurological signs is characteristic of a peripheral lesion involving the labyrinthine apparatus, in this case on the left side. After recovery from the acute disabling phase there was a short period of continuing intermittent vertigo of positioning type, evoked by movements causing stimulation of the affected semicircular canal on the symptomatic side. The temporal pattern of response to the Hallpike manoeuvre was typical of a peripheral lesion. The terms 'vestibular neuronitis' or 'viral labyrinthitis' are often invoked to explain this type of illness. The symptoms do sometimes arise during or just after an upper respiratory infection, or rarely during a readily identifiable viral illness such as geniculate herpes zoster, but often the symptoms of acute vestibular dysfunction are apparently spontaneous and the pathology is not known. In older individuals very similar symptoms may result from an ischaemic episode involving the vestibular branch of the internal auditory artery, itself a branch of the anterior inferior cerebellar artery (AICA). Gradual compensation usually follows and the vertigo subsides. Systemic vasculitides may rarely affect this vestibular artery or the cochlear branch of the internal auditory artery (in which case there is sudden unilateral deafness, which does not necessarily recover). The syndrome of continuing or recurrent positioning vertigo of 'benign' type (BPPV) may follow a presumed vestibular infection, a minor head injury or an apparently spontaneous vertiginous illness. In each case it is likely that particulate otoconial debris within the semicircular canal is responsible for

the exaggerated and inappropriate vestibular response to the change of position (hence strictly positioning in preference to positional). When spontaneous recovery is not taking place reasonably quickly, treatment can include particle-repositioning manipulations of the head and neck such as the Epley manoeuvre, performed by a suitably experienced doctor or physiotherapist. Vestibular retraining exercises of Cawthorne-Cooksey or Brandt-Daroff type may also be helpful in speeding up recovery from a peripheral vestibular lesion, irrespective of the pathophysiological cause. Brainstem ischaemia due to 'vertebrobasilar insufficiency' is rarely, if ever, the cause of vertigo evoked by head turning: in the unlikely setting of cervical spondylotic osteophytes causing temporary interruption of flow in one vertebral artery, the syndrome would be expected to include other transient focal neurological symptoms of brainstem origin, not simply vertigo in isolation. This particular patient requires no further investigation or treatment unless there are later recurrent bouts of disabling vertigo, with or without cochlear symptoms (hearing loss, tinnitus, feelings of pressure in the ears) or continuing episodes of stereotyped positioning vertigo sufficient to justify the physical approaches described above. Nothing more than explanation and reassurance is required on the basis of the history so far.

symptom. Meniere's disease may, in the early stages, cause episodes of vertigo lasting less than a minute, but episodes lasting 1 or 2 days are more usual in later attacks. Vertigo from vestibular neuronitis may be severe for several days. Central lesions causing vestibular disturbances as the only symptom usually lead to vertigo of gradual onset, which is less severe than that caused by peripheral lesions. Acute severe vertigo may occur with central vascular lesions, most commonly lateral medullary infarction due to occlusion of the vertebral or posterior inferior cerebellar artery, but there are always associated neurological symptoms and signs. Non-vertiginous dizziness is a common symptom in anxious patients, sometimes associated with overbreathing, and in patients with depression.

24

Central vs. peripheral lesions Flowcharts are useful in the diagnosis of vertigo (Fig. 24.24). Having established that the patient's complaint is a symptom of a vestibular disturbance, the next important clinical distinction to make is whether the symptom is due to a central or peripheral lesion. FIG. 24.23 Anatomical structures involved in maintenance of balance (left labels) and relevant incoming sensory stimuli (right labels)

one side and decrease it from the contralateral side, causing corrective eye movements via pathways subserving the vestibuloocular reflex (VOR) and preventing a disconcerting awareness of the movement that has occurred. Any pathological process that disturbs the balance of vestibular inputs may lead to a feeling of disequilibrium, which is characterized by a false perception of movement. It is this specific feature that distinguishes vertigo from other sensations of dizziness and faintness. The apparent motion of vertigo may be clearly rotatory, particularly when severe, but in many patients the sensation has a sideto-side, up-and-down, leaning or falling quality that is difficult to describe. Vertigo may arise from lesions in the labyrinth (most common), the brainstem, or rarely in the eighth nerve itself; it may also occur briefly at the onset of a complex partial seizure, probably owing to disturbance of central vestibular projections in the temporal lobe. Vertigo is often elicited or exacerbated by movement and, when severe, it may be accompanied by nausea, vomiting, pallor and sweating. Some patients find it difficult to describe in detail their sensation of dizziness, so that the division into vertiginous and non-vertiginous dizziness may not always be certain from the history.

Clinical features and diagnosis An acute brief episode of vertigo is usually due to a peripheral labyrinthine disturbance, although central lesions, such as temporal lobe epilepsy and, very occasionally, vertebrobasilar insufficiency, can produce this isolated

Peripheral Associated deafness, tinnitus or pain in the ear, particularly when unilateral, suggests a peripheral disturbance. A very gradually progressive unilateral deafness associated with vertigo raises the possibility of an acoustic neuroma. If, in addition to a sensory neural deafness, there is a cerebellopontine angle syndrome - comprising an ipsilateral lower motor neuron facial weakness, trigeminal hypoaesthesia and ipsilateral limb ataxia - an acoustic neuroma is by far the likeliest diagnosis, although other tumours such as meningiomas may also produce this syndrome. An abrupt mild deafness or tinnitus with acute severe vertigo suggests a viral labyrinthitis or an acute vascular occlusion affecting the inner ear. Intermittent episodes of tinnitus, deafness, vertigo and pain in the ear are characteristic of Meniere's disease (p. 1320). Central With the exception of acoustic neuromas, the presence of associated neurological symptoms usually indicates that the cause of vertigo is a central lesion. Many brainstem lesions may affect the vestibular nuclei and pathways, and these pathologies will tend to produce symptoms and signs in other systems, including the cranial nerve nuclei, pyramidal and sensory tracts, together with cerebellar deficits. The aura of temporal lobe epilepsy may include vertigo, but there will be other symptoms (p. 1324), the most important being impairment of consciousness. Other causes of dizziness Any cardiac disease leading to a low cardiac output, whether chronically, exacerbated by exertion (as in aortic stenosis) or as a result of dysrhythmia, may cause dizziness. Dizziness is a common first symptom in a vasovagal fainting attack but, again, is not the only symptom. Other important causes of dizziness include ototoxic

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Examination The examination is often normal, particularly in younger patients. General examination, including lying and standing blood pressure, is as important as the neurological examination. Some patients have mild disturbances of gait and nystagmus. Clinical testing of hearing is an important part of the neurological examination. Romberg's test In Romberg's test, a patient with an acute peripheral vestibular lesion will tend to fall towards the affected side. Patients with non-organic illnesses tend to fall backwards, without immediate appropriate attempts to correct their posture; however, they will usually avoid injury by acrobatic manoeuvres to maintain balance at the last moment.

FIG. 24.24 Diagnostic flow diagrams for dizziness and associated symptoms CPA = cerebellopontine angle; CSOM = chronic suppurative otitis media; MS = multiple sclerosis.

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drugs, such as the aminoglycosides, or treatment with tranquillizers, antidepressants or neuroleptic drugs. A previous history of ear disease may also be relevant. Impaired visual acuity or eye movement disorders causing diplopia or oscillopsia may all cause patients to complain of dizziness rather than a visual symptom.

Vestibule-ocular testing Examination of the eye movements (vestibulo-ocular testing) should first establish that there is a full range of movement in each eye and that gaze remains conjugate. Slow following eye movements (pursuit) and rapid eye movements (saccadic) should be normal. Nystagmus (p. 1299). A unilateral vestibular disturbance upsets the balance of impulses from each labyrinth, tending to cause deviation of the eyes towards the side of the lesion. This is balanced by a rapid saccadic movement of the eyes towards the opposite side. Nystagmus, described in the direction of the fast component, therefore beats away from the side of the lesion. Mild nystagmus of this sort may be seen only with caloric or rotational stimulation. Routine testing for nystagmus is relatively crude and is greatly helped by electronystagmography. In a peripheral vestibular lesion, spontaneous nystagmus at 30° of lateral gaze occurs only in one direction, the eyes always remain conjugate and the nystagmus is increased by removing fixation using Frenzel's glasses. The nystagmus is most marked with acute lesions, and the central nervous system (CNS) compensates over a period of weeks so that nystagmus (and dizziness) tends to improve. In central vestibular lesions, compensation tends not to occur, the nystagmus may occur in more than one direction of gaze, the eye movements are sometimes dysconjugate, and removal of fixation has little effect. Caloric testing (p. 1300) is an easily performed and reliable measure of vestibulo-ocular reflexes. If the response to caloric testing is reduced on one side, there is said to be canal paresis, which indicates a peripheral lesion involving the labyrinth or, rarely, the eighth nerve on that side. A directional preponderance refers to an increase in the nystagmus in one direction. This occurs when there is an imbalance of the peripheral vestibular inputs or a central imbalance. In some patients there will be a mixture of these abnormalities. Optokinetic nystagmus is the normal reflex oscillation of the eyes induced by movements of the subject's surroundings. It is disturbed in central vestibular lesions, but not with peripheral lesions.

24

TABLE 24.27 Causes of dizziness

FIG. 24.25 Hallpike manoeuvre The head is held gently in position by the examiner standing at the head of the couch.

Testing for positionally induced nystagmus is particularly helpful when there is a history of dizziness provoked by certain positions of the head, usually lying down or extending the neck to look upwards. Placing the patient's head in the position which induces dizziness may also induce nystagmus. A better test is the Hallpike manoeuvre, in which the patient's head is rapidly lowered from a sitting position backwards and over the end of the bed with head turned either to the right or the left (Fig. 24.25). In benign positional vertigo (see below) of peripheral origin, nystagmus is provoked with a latent period of 2-20 seconds, disappears (adapts) within 1 minute, is associated with vertigo and fatigues with repeated testing; the fast phase of the nystagmus is towards the lower ear with the head in this posture. Positional nystagmus may sometimes be a feature of central vestibular lesions, but Hallpike's manoeuvre in these patients characteristically provokes nystagmus without vertigo. There is no latent period, nor any fatiguability, on repeated testing. The direction of the saccadic phase of nystagmus is variable. Hearing Cochlear function is routinely tested as described on page 1298, supplemented by audiometry.

Aetiology There are a number of common causes of vertigo (Table 24.27). Acute labyrinthine failure Although this condition is often referred to as 'labyrinthitis' or 'vestibular neuronitis', an inflammatory basis is seldom evident or proven. Typically the onset of vertigo is abrupt on waking in the morning. It may be severe for 1-3 days, is minimized by keeping the head still, and is provoked by any head movement. It is often associated with nausea and vomiting. There is gradual resolution of the symptoms over a few weeks, although mild symptoms may be provoked by sudden head movement for up to several

Vertiginous

Non-vertiginous

Labyrinthine labyrinthitis' Post-traumatic vestibular damage Benign positional vertigo Vascular occlusion affecting labyrinth Meniere's disease Secondary to middle ear disease Alcohol

Cardiovascular Vasovagal syncope Postural hypotension Cardiac arrhythmias Aortic stenosis HOCM Low-output cardiac failure

Eighth nerve Ototoxic drugs Acoustic neuroma Herpes zoster (Ramsay-Hunt syndrome with seventh-nerve involvement) Brainstem Multiple sclerosis Vertebrobasilar TIA or stroke Migraine Encephalitis Tumours Cerebral Temporal lobe seizures

Haematological Anaemia Polycythaemia Metabolic Hypoglycaemia Hyperventilation

Ocular Poor acuity Diplopia Oscillopsia Drugs e.g. Benzodiazepines Tricyclics Anticonvulsants

months later. Examination during the acute stage may reveal nystagmus, either spontaneously present on forward gaze or only on lateral gaze. Later, nystagmus will be absent, but caloric testing shows a unilateral canal paresis. The audiogram is normal. Complete resolution of symptoms eventually occurs in most patients, although mild symptoms may persist for months. Up to 50% of patients with acute labyrinthine failure will have had a cold or other viral infection shortly before the onset of the symptoms; it is thus often regarded as a viral or postviral syndrome. Treatment for a few days is often necessary during the acute stage. The vestibular sedatives cinnarizine or prochlorperazine are effective. Benign positional vertigo Benign positional vertigo is produced by certain head postures, most commonly lying down with the head turned to one side or extending the neck. Vertebrobasilar ischaemia is often incorrectly invoked as the cause, but the vertigo results from particles of otoconial debris within the semicircular canal, which cause inappropriate stimulation of the hair cells after head movement. The syndrome can arise after labyrinthine infection or a minor head injury, but in other cases the onset is apparently spontaneous. The Hallpike manoeuvre is characteristically positive when the head is turned down to the side of the lesion, which is usually in the posterior canal. The problem often

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TABLE 24.28 Clinical features of Ramsay-Hunt syndrome

SUMMARY 2 Dizziness

Severe unilateral earache Vesicular rash on tympanic membrane and external auditory meatus, spreading to concha Lower motor neuron facial palsy - usually severe Vertigo Deatness less common Involvement of cranial nerves IX and X features Acute confusional state Meningitis and brainstem encephalitis

• In the majority of patients presenting with dizziness the cause is a peripheral labyrinthine disturbance or syncope. • Acute episodes of vertigo with nausea and vomiting, but without other neurological symptoms, are nearly always due to a peripheral labyrinthine disturbance. • Episodes of vertebrobasilar ischaemia may produce vertigo, but almost always with other neurological symptoms. • Peripheral labyrinthine disturbances are much more likely to be associated with tinnitus and/or deafness than central lesions. • When there is doubt whether vertigo is due to a peripheral or central lesion, caloric testing is useful; a canal paresis indicates a peripheral lesion. • Long-term use of vestibular sedative drugs, such as prochlorperazine or cinnarizine, is rarely necessary. • When dizziness occurs in association with other neurological symptoms and signs, the patient should be referred for a neurological opinion.

resolves without treatment over a few weeks, but persistent symptoms can be treated by manipulative procedures to reposition the loose particles or by graded vestibular retraining exercises taught by a physiotherapist. Meniere's disease Meniere's disease results from endolymphatic hydrops (increased pressure in the membranous labyrinth) and its cause is unknown. It is characterized clinically by attacks of severe vertigo occurring several times in a few weeks, followed by long periods of remission of months or years. The onset of Meniere's disease is usually between 40 and 60 years of age, and the condition is more common in men. It is always initially unilateral, although in about 25% of patients the other ear is affected later. Each attack is usually preceded by a sensation of pressure in the ear. The subsequent onset of vertigo may be severe and is associated with nausea, vomiting, deafness and tinnitus. Between attacks, the tinnitus and deafness persist and gradually worsen. Recurrent attacks lead to increasing deafness; when hearing is completely lost, the attacks of vertigo cease. Audiometry shows a sensorineural deafness, and caloric testing an ipsilateral canal paresis. During a bout of attacks, a vestibular sedative such as cinnarizine may be helpful. In very severe cases surgical measures to destroy the labyrinth can be considered, but should not be contemplated if there is deafness in the other ear. Surgical procedures that ablate the labyrinth but preserve residual cochlear function are occasionally needed in severe cases. Vertebrobasilar ischaemia Vertigo is a common symptom of vertebrobasilar ischaemia, but the diagnosis must rest on a description of attacks, which also include one or more of the following symptoms: diplopia, bilateral visual obscurations, bilateral facial numbness or paraesthesiae (commonly circumoral), bilateral facial weakness, dysarthria, dysphagia, dysphonia, weakness or sensory loss in the limbs, and impairment of consciousness (p. 1332). 1320

Ototoxic drugs Many drugs are potentially ototoxic, and some cause per-

manent vestibular damage, particularly streptomycin and gentamicin. Multiple sclerosis Plaques of demyelination in the brainstem quite frequently cause vertigo (p. 1410). Acoustic neuroma Acoustic neuromas do not usually cause major vestibular involvement; when it does occur, vertigo is usually mild (p. 1353). Geniculate herpes zoster (Ramsay-Hunt syndrome) Geniculate herpes zoster is a rare condition, but important to recognize (Table 24.28). It is caused by involvement of the geniculate ganglion by herpes zoster, and there is often involvement of neighbouring nerves. Like other forms of shingles it tends to affect an older age group and can occasionally produce a very severe illness, with meningitis and an acute confusional state. It is uncertain whether prompt treatment with aciclovir alters the severity of the neurological features, but it may reduce the systemic symptoms, and should be given.

FURTHER READING ON DIZZINESS AND VERTIGO Twost B T 2000 Dizziness and vertigo. In: Bradley W G, Daroff R S, Fenichel G M, Marsden C D, eds Neurology in clinical practice. Oxford: Butterworth-Heinemann, 239-251.

SYNCOPE AND EPILEPSY

The term 'blackout' means different things to different people and it is important to establish in what sense the patient is using the word. When describing disturbed consciousness, a patient's recollection of events is bound to be

history from witnesses of convulsive tonic or tonicclonic movements of the limbs, with facial grimacing, jaw clenching, tongue biting and grunting noises, and irregular breathing, clearly indicates a fit. A patient who lies limp while unconscious, appears pale and sweaty, whose pulse is difficult to feel and who rapidly regains consciousness is likely to have had a syncopal attack. Nevertheless, patients with fits may also appear pale and sweaty, and tonic-clonic movements may be discrete or absent. The differential diagnosis can sometimes be impossible from the accounts given by some patients and witnesses of their attacks. Incontinence. Incontinence of urine, and sometimes faeces, is relatively common in epilepsy, and urinary incontinence occasionally occurs in syncope.

incomplete, and a detailed independent account of the episode is invaluable. The great majority of patients presenting to their doctors with blackouts will have no physical signs. The diagnosis rests entirely on a meticulous history.

Differential diagnosis of epilepsy and syncope Syncope is defined as loss of consciousness owing to transient impairment of cerebral blood flow. Epilepsy is a paroxysmal, abnormal cerebral electrical discharge associated with a clinical change; this may take a wide variety of different forms, but usually includes some impairment of consciousness. Features that help in distinguishing epilepsy from syncope, the commonest clinical differential diagnostic problem, include the following. • The time of day and circumstances of the attack. Attacks during the night, while the patient is recumbent in bed, are not likely to be syncopal. Nocturnal attacks that the patient cannot remember but which wake other members of the family, are likely to be fits. Syncopal attacks may occur during the night on getting up, often during micturition. Events causing squeamishness, or bad news, may provoke syncope. Patients with photosensitive epilepsy may have a history of attacks provoked by watching television (usually when sitting too close), or by flickering lights. • Posture. Standing for long periods, particularly in hot surroundings, often provokes syncope. • Warning of the attack. Loss of consciousness in syncope is nearly always preceded by a period of malaise, with dizziness, nausea, visual blurring and dimming, and a feeling of impending loss of consciousness. Many patients will have discovered that lying down promptly during this prodromal phase will prevent loss of consciousness. • Period of unconsciousness and postictal state. Syncope usually causes brief loss of consciousness of less than a minute. Exceptions are usually due to attempts by onlookers to sit the patient up. This merely intensifies the period of unconsciousness and may, on occasions, provoke a secondary hypoxic convulsion. Such attacks are then often mislabelled as being epileptic. Minor fits may cause a period of absence which may be momentary (see below) and which may appear to witnesses as absentmindedness, rather than impairment of consciousness. Convulsions are associated with loss of consciousness of more than 1 minute (and sometimes up to 10 or 15 minutes), followed by a period of postictal drowsiness and confusion; this is often accompanied by irritability, and occasionally by aggressive, irrational behaviour if the patient is disturbed. Patients recovering from syncope are orientated and rational. • Appearance during the period of unconsciousness. A

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SYNCOPE Syncope is very common. In a healthy young adult a blood pressure of less than 50 mmHg will reduce cerebral blood flow sufficient to cause loss of consciousness. The conditions most commonly leading to syncope are: • • • • • •

Vasovagal attacks Cardiogenic syncope Cough, sneeze and micturition syncope Breath-holding attacks Orthostatic hypotension Carotid sinus sensitivity.

Vasovagal syncope Vagal overactivity produces a bradycardia and a fall in blood pressure, which is associated with peripheral vasodilatation. Such attacks are often reflex in nature and provoked by emotional or painful circumstances. Vasovagal faints often occur in adolescents and young adults who are otherwise entirely healthy and, occasionally, children of less than 10 years are prone to fainting. Faints are more common soon after getting up. They are always postural, the symptoms starting while standing or sitting. They are more frequent in women than men, may be associated with menstruation or intercurrent febrile illness, and are more frequent after sleep deprivation and prolonged fasting. Cardiogenic syncope Heart disease may cause syncope in three main ways: • By acute dysrhythmias, as in ventricular tachycardia or heart block; • By obstruction to flow, as in aortic stenosis; • In low-output states, as with a pericardial effusion. Cardiac causes of syncope are particularly important in the older population. Syncope on exertion suggests the possibility of cardiac disease. Cough, micturition and sneeze syncope Prolonged bouts of coughing raise intrathoracic pressure,

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TABLE 24.29 Causes of orthostatic hypotension Venous pooling Prolonged standing Severe varicose veins Impaired vasomotor activity Peripheral neuropathy Diabetes Guillain-Barre syndrome Surgical sympathectomy Spinal cord lesions Syringomyelia Tabes dorsalis Familial dysautonomia Shy-Drager syndrome

Reduced muscle and vascular tone Prolonged bed rest Fluid depletion Drugs Hypotensive therapy Tranquillizers Phenothiazines Levodopa Steroid deficiency Hypopituitarism Addison's disease Chronic idiopathic orthostatic hypotension

impair venous return to the heart, and cause syncope. Sneezing occasionally induces syncope, probably by a vagal reflex mechanism. Coughing or sneezing in patients with cerebellar tonsillar herniation through the foramen magnum (Arnold-Chiari malformation) may provoke syncope, the mechanism of which is uncertain. Fainting may occur during micturition in men, particularly during the night, owing to a postural fall in the blood pressure, reflex vagal activity stimulated by a full bladder, and reduced venous return caused by straining. O Breath-holding attacks These usually occur in very young children as a reaction to emotional stress. They are sometimes seen with prolonged crying. There is prolonged breath-holding, leading to cyanosis and, eventually, loss of consciousness. Attacks usually start before the age of 18 months and stop by the age of 5 years. In severe prolonged attacks secondary hypoxic convulsions may be induced, and the child is frequently mislabelled as epileptic. Orthostatic hypotension Orthostatic hypotension refers to a fall in blood pressure on standing, which may be sufficiently profound to cause a loss of consciousness. There are numerous causes (Table 24.29). Postural hypotension may be a result of impaired sympathetic activity, as occurs in some neuropathies (diabetes being the commonest), and in central autonomic failure; the latter may occur as an isolated phenomenon, as part of the Shy-Drager syndrome associated with parkinsonism or as part of a multiple system atrophy (p. 1364).

O Case 24.2

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SUMMARY 3 Differential diagnosis of syncope

and epilepsy Always try to obtain an eyewitness account of an episode of loss of consciousness; do not diagnose epilepsy on insufficient grounds. Syncope is usually postural, with prodromal symptoms before loss of consciousness. Fits often occur without any warning. Loss of consciousness in syncope usually lasts less than a minute, in contrast to most fits. Confusion, headache and drowsiness are common after fits, but not after syncope. Excessive alcohol - either binge drinking or chronic alcoholism is a common cause of isolated fits. The interictal EEG may be normal in epilepsy. The diagnosis of epilepsy is essentially clinical and does not depend on the EEG.

Many drugs in addition to hypotensive agents can lower blood pressure sufficiently for loss of consciousness to occur. Corticosteroid deficiency, which may be due to Addison's disease, abrupt withdrawal of administered steroid or hypopituitarism, leads to hypotension exacerbated by standing. Chronic idiopathic orthostatic hypotension is a rare condition in which there is no cardiovascular sympathetic response to a fall in blood pressure induced by standing. Tachycardia, vasoconstriction and sweating (the normal responses to hypotension) are all absent. Carotid sinus sensitivity Carotid sinus sensitivity is the result of atherosclerotic disease affecting the carotid artery at its bifurcation in the neck. It is usually seen in middle-aged or elderly people in the setting of widespread vascular disease. Mild pressure over the sinus, such as that which might be caused by a tight shirt-collar, combined with head turning, causes an excessive bradycardia, hypotension and, occasionally, transient asystole which may last 10-15 seconds (Ch. 12).

EPILEPSY A number of terms are used to describe the clinical and associated electrical abnormalities of epilepsy. Epileptic attacks, fits, seizures and convulsions all refer to the same phenomenon - a paroxysmal electrical discharge affecting a group of neurons, starting in one part of the brain but often spreading to become a generalized abnormality. Classification

Fits are clinically and electrically heterogeneous. Aetiological classifications are useful reminders of the many causes of fits but must be supplemented with a classification of the type (Table 24.30). Fits are disturbing events, but there is a great difference to the patient in the impact of, for example, an absence attack of petit mal and a gen-

TABLE 24.30 Types of fit - WHO classification

TABU 24.31 Causes of fits

GENERALIZED SEIZURES Absence attacks Petit mal - 3 Hz spike and wave Atypical absences Myoclonic seizures Myoclonic jerks, single or multiple Clonic seizures Tonic-clonic seizures Grand mal, major fits Tonic seizures Atonic or akinetic seizures

• Idiopathic/constitutional

Partial seizures Simple, without impairment of consciousness Motor, sensory, aphasic, cognitive, affective, amnesic, illusional, olfactory, psychic. Includes jacksonian, temporal lobe, psychomotor epilepsy Complex partial seizures with impairment of consciousness Simple partial onset, followed by impairment of consciousness Impairment of consciousness from the onset Partial seizures, either simple or complex, evolving into generalized tonic-clonic seizures Generalized tonic-clonic seizures, with EEG but not clinical evidence of focal onset

• Hereditary and familial Petit mal Some patients with temporal lobe epilepsy Aminoacidurias Trisomy 21 Lipidoses • Developmental defects Phakomatoses Intrauterine rubella, CMV, toxoplasma Irradiation Cortical dysplasia • Birth trauma Perinatal anoxia Cerebral contusion Cerebral haemorrhage and thrombosis • Anoxia in infancy and childhood • Hippocampal sclerosis • Tumours Primary and secondary

eralized tonic-clonic convulsion. It is thus helpful to qualify a diagnosis of epilepsy with a statement about the type of attack or attacks suffered by a particular patient.

Pathophysiology Partial seizures In focal epilepsy (partial seizures), paroxysmal discharges develop in one part of the cerebral hemispheres, the temporal lobe being the most common site. If it remains focal, such activity will produce a minor fit in which the type of symptom experienced depends on the region of the brain involved; there may or may not be impairment of consciousness. In many minor temporal lobe attacks, the impairment of consciousness takes the form of brief lapses of awareness without obvious loss of consciousness observable by witnesses of the attack. In focal motor fits that remain focal, there may be no impairment of awareness or consciousness, so that the patient will be in a position to provide a complete account of events. However, focal epileptic activity may become generalized, in which case there is loss of consciousness and, usually, clinical evidence of a convulsion. Many patients will have both focal attacks and fits which are preceded by symptoms of the focal electrical disturbance. Generalized seizures Paroxysmal discharges are generated in deep sites at the hypothalamic, thalamic or upper brainstem level, and

• Vascular Mature infarcts/arteriovenous malformation

24 • Infection Febrile convulsions Viral encephalitis Bacterial meningitis Tuberculous meningitis Cerebral abscess Cysticercosis Neurosyphilis Echinococcus Toxocariasis Toxoplasmosis • Inflammatory SLE/PAN/multiple sclerosis • Metabolic Uraemia/water intoxication/ hyponatraemia/hypoglycaemia/ hypocalcaemia/hypomagnesaemia • Toxic Alcohol/drugs, e.g. barbiturates, amphetamines, lignocaine, tricyclic antidepressants, phenothiazines, lead • Degenerative Alzheimer's disease/ Creutzfeldt-Jakob disease/Huntington's disease

spread rapidly to both hemispheres simultaneously to produce generalized epileptic discharges. This type of abnormality is present in many patients with so-called idiopathic or constitutional epilepsy, and is also responsible for petit mal attacks.

Aetiology Particular causes of fits (Table 24.31) may produce fits of different kinds. Perinatal anoxia, for example, may cause either generalized or partial seizures. Idiopathic or constitutional epilepsy is a term used to refer to patients with recurrent fits in whom no cause can be identified. This is the largest group of epileptic patients, and probably includes those who have had intrauterine, birth and neonatal insults. In some patients there is a strong family history: this is often the case with petit mal, and in some patients with temporal lobe epilepsy. In most idiopathic epileptics, however, there is no family history. With recent advances in investigation, particularly MRI, patients with medically refractory epilepsy are frequently found to have subtle structural lesions, such as hippocampal sclerosis or cortical dysplasia (Fig. 24.26). Apart from the rare degenerative disorders that may

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FIG. 24.26 Structural abnormalities A Left-sided hippocampal sclerosis. The left hippocampus (arrowed) has a higher signal intensity on this T2-weighted image and is smaller than the right. B Dysembryoplastic neuroepithelial tumour (DNT). There is a mass in the parahippocampal gyrus on the right, lifting the body of the hippocampus. This was confirmed as a DNT following surgical excision. C Cortical dysplasia. Multiple heterotopic foci of grey matter are scattered throughout the deep white matter of the right parietal lobe, exerting some mass effect and distortion of the lateral ventricle.

cause epilepsy (see below and Table 24.32), genetic factors are also important in febrile convulsions and petit mal. In the latter, the typical EEG abnormality has been found in nearly 50% of siblings whether or not they have clinical fits. Factors provoking fits Some agents may cause fits in people not normally prone to having fits, e.g. alcohol (both bingeing and abrupt withdrawal, p. 1435) and drug abuse (particularly with barbiturates and amphetamines). 1 In epileptics, sleep deprivation is a common provocative factor. In some patients there is a clear relationship between fits and stressful life events. Some patients have fits only, or mainly, at night, the epileptic threshold being reduced during sleep. In some women with epilepsy the fits tend to occur just before or during menstruation (catamenial epilepsy). Photosensitivity is important in a relatively small proportion of epileptics, particularly those with petit mal and myoclonic epilepsy. Rarely, fits can be induced by music, looking at certain patterns and reading.

Types of fit Generalized seizures Petit mal Petit mal refers to brief (10-15-second) absence attacks associated with a generalized 3-second spike-and-wave dis1

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Case 24.3

charge on the EEG. The fits always start in childhood, and consist of a brief cessation of activity associated with a blank staring look and, occasionally, nodding of the head, fluttering of the eyelids and (very occasionally) small convulsive movements of the limbs. Objects may be dropped, but postural control is maintained if the child is sitting or standing. It is common for petit mal to continue into adolescence, but only occasionally into adult life. About 50% of children with petit mal will later develop grand mal fits. Tonic-clonic fits (grand mal epilepsy, major fits) In tonic-clonic fits there is abrupt loss of consciousness associated initially with a tonic phase, in which there is sustained muscular contraction affecting all muscles, including respiratory, facial and jaw muscles. Breathing may cease and the patient become cyanosed. It is during this phase that the tongue may be bitten and incontinence occurs. After a short period (usually less than 30 seconds) a clonic phase supervenes, in which there are repeated violent jerking movements of the trunk and limbs. Selfinflicted injury is common during this phase, which may last for several minutes. On cessation of the fit consciousness is slowly regained, the patient passing through a stuporose phase. There is often postictal confusion, irritability and headache; irrational behaviour may occur during this stage, which the patient cannot later remember. Many patients will have a few seconds' warning of a fit. The symptoms are often non-specific, and include malaise, dizziness, and a feeling of detachment. Patients who come to recognize these symptoms may have time to sit or lie down before losing consciousness. However, others will have no such prodrome. Management. A patient having a fit should be turned on

CASE STUDY 24.3 SUDDEN COLLAPSE AND LOSS OF CONSCIOUSNESS IN A 36-YEAR-OLD MAN A 36-year-old man collapsed suddenly at work with complete loss of consciousness. The attack was not witnessed, but his colleagues found him after an estimated interval of about 10 minutes, by which time he was gradually coming round. He was disorientated for 10 or 15 minutes and had no recollection of what had happened. He had bruised his forehead and right orbital region in the fall, and had a persisting headache and some generalized aching discomfort in his back and limbs. He had not bitten his tongue or wet himself. He was seen in the local hospital after a wait of 70 minutes in the A&E department, by which time he was fully alert and orientated with only a mild residual headache. There were no abnormal physical signs. An ECG and some routine blood tests were all normal. No diagnosis was made and he was allowed home with a recommendation that he should not drive and should consult his family doctor for further assessment. He felt perfectly well within a few days and decided there was no need to bother his GP. He was unable to do his job as a plumber without driving, and saw no reason why he should not continue to do so. Six weeks later there was a second incident, when his wife was woken at 4 am by rhythmic shaking of the bed and some loud grunting and choking sounds, which continued for at least half a minute while she tried to talk to him. By the time she had turned the light on he was lying with both arms forcibly flexed, breathing more normally but very deeply. He was immobile and unresponsive for several minutes, but then slowly regained consciousness. There was some blood on the pillow. His own first memory of the attack was of coming to his senses in the ambulance on the way to hospital. Examination in the emergency department again showed no abnormalities.

Questions 1. What is the diagnosis? 2. What further investigations are necessary? 3. How should he be advised and treated?

Discussion 1. Sudden unheralded loss of consciousness in an otherwise healthy individual has very few causes and by far the most common is a generalized seizure. Other less likely possibilities are: • Cardiac arrhythmia (usually marked bradycardia, less often VT), typically with pallor, short duration and rapid recovery; flushing as normal perfusion of the head returns; and, less commonly, a secondary seizure or prolonged postictal confusion. • Subarachnoid or intracerebral haemorrhage. Subsequent clinical features usually make the diagnosis obvious, although headache is not invariably a prominent feature. • Brainstem ischaemic attacks or infarction typically include focal neurological symptoms and signs, and do not present as loss of consciousness alone. • Hydrocephalic attacks, for example due to a colloid cyst in the third ventricle. This is a very rare cause of loss of consciousness, usually with accompanying transient headache and sometimes tonic posturing of the limbs which may resemble a seizure. The history of the first attack in this young man was highly suggestive of a generalized tonic-clonic fit, particularly the duration of unconsciousness and the postictal symptoms, which included generalized muscle pains. The observations by his wife on the second occasion leave little doubt about the diagnosis.

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2. The likelihood of an underlying structural lesion is relatively low at this age, but cranial imaging is essential, preferably with MRI, which is significantly better than CT for showing subtle pathology in the temporal lobes, low-grade tumours, small vascular malformations and unusual inflammatory disorders. Many clinicians would also do an EEG, but this very rarely contributes to the management of seizures coming on in adult life, particularly in the middle-aged and elderly; diagnosis of the attacks themselves is strictly clinical and the main value of a single interictal EEG is for clarifying a syndromic diagnosis in children and adolescents with epilepsy (absences, atypical absences, juvenile myoclonic, primary generalized tonic-clonic, 'benign Rolandic' etc.). Routine blood tests are rarely helpful unless there are clinical reasons to suspect an underlying systemic illness or a metabolic basis for the seizures, or sometimes to screen for suspected alcohol or drug misuse. 3. The nature of the seizures should be explained fully to the patient, with suitable reassurance about the high incidence and prevalence of fits in otherwise healthy individuals and the relatively good prognosis in the majority of cases. The rationale for driving restrictions requires careful discussion: even after a single seizure (or any sudden loss of consciousness without a fully remediable cause), the patient must report the incident to the DVLA and then remain free of further attacks for at least a year before driving again. Advice should also be given about other potentially dangerous activities, such as swimming, certain other sports, bathing, cooking, and exposure to heights and open machinery at home and at work. Avoidance of provocative circumstances, such as sleep deprivation and high alcohol

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CASE STUDY 24.3 CONTINUED consumption, requires emphasis in some cases. After two seizures within a few weeks there is a good case for starting antiepileptic medication in this man, particularly in view of the nature of his work and the importance of regaining his driving licence in the longer term. The drugs of first choice for symptomatic or idiopathic seizures in adult life would be carbamazepine, sodium valproate or lamotrigine. The choice of drug in a woman of childbearing age would be influenced by relative teratogenic risks and potential interaction with the contraceptive pill. Routine prescription of folic acid 5 mg daily is

also advisable in any young woman who might become pregnant while on antiepileptic medication. The primary generalized epilepsies (usually presenting in childhood and adolescence, with characteristic seizure pattern and EEG findings) require specific treatment with valproate, lamotrigine or, rarely, topiramate. Regular follow-up is important in the early stages of treatment, for further discussion and reassurance and to deal with any problems relating to medication. The occurrence of side-effects sometimes requires successive trials of three of four different drugs before a suitable

TABLE 24.32 Rarer types of epilef Atypical absences Clinically the same as petit mal; slower EEG, other abnormalities and often associated mental retardation and atrophy (Lennox-Gastaut syndrome); seizures hard to control Tonic seizures Tonic posturing only of limbs (sometimes trunk)

characteristically cause convulsive twitching of one side of the body, starting in the face, arm or leg and gradually spreading (jacksonian epilepsy). Focal sensory fits arising in the postcentral gyrus cause a similar march of sensory symptoms. Versive fits, in which the eyes and head are turned to one side, are produced by contralateral posterior frontal epileptic activity.

to their side to prevent the tongue obstructing the airway, and self-injury should be prevented as far as possible. It is a mistake to attempt to force the mouth open. Most fits are single, self-limiting events. It is unnecessary to admit known epileptics to hospital after a single fit.

Temporal lobe epilepsy Temporal lobe epileptic attacks are by far the commonest type of partial seizure. These may occur as a simple type of partial attack without loss of consciousness (psychomotor fits), with aphasia or cognitive, affective, amnesic, olfactory, illusional or psychic symptoms; or they may be complex partial seizures, in which the symptoms are followed by a period of impaired consciousness. The term 'temporal lobe epilepsy' is often used to refer to all complex partial seizures, but such attacks can arise from other parts of the brain, particularly the frontal lobes. In temporal lobe attacks the patient appears vacant and this may be associated with an inability to talk, although simple commands may be obeyed. Olfactory, epigastric and psychic phenomena, such as deja-vu and jamais-vu, are very common. During an attack, repetitive motor behaviours may occur: lip-smacking, chewing and grimacing movements are the commonest. In simple attacks at least partial awareness is preserved, whereas in complex partial seizures the patient will be amnesic for part of the attack and may not afterwards realize that anything has happened. Like other partial seizures, minor temporal lobe fits may progress to a generalized convulsion.

Partial seizures Focal epileptic discharges may arise in any part of the cerebral hemispheres, causing partial seizures. Focal motor fits

Febrile convulsions In young children, sudden rises in body temperature may provoke convulsions. Such fits are usually generalized and

Infantile spasms Brief sudden head flexion - 'salaam' attacks, often with failure of development and regression. Onset at 3-9 months. May be refractory to treatment Myoclonic epilepsy Single (or repetitive) sudden convulsive movements of limbs and trunk Mostly children with idiopathic epilepsy; attacks early in the morning Photosensitive myoclonus and epilepsy Hereditary myoclonic epilepsies - generalized seizures and myoclonus with degenerative disease, e.g. Lafora body disease: children/adolescents with myoclonus, major seizures and dementia. Death occurs within a few years. Intracellular inclusion bodies present Gangliosidoses

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regimen is established. The total duration of treatment will depend on the seizure type and cause, and to a large extent on the patient's own feelings about the risks and benefits of later drug withdrawal. Medication is usually continued for 3 or 4 years, often longer, and indefinitely in certain specific types of epilepsy. In this man's case, if the MRI scan is normal and he remains free of seizures for several years, there is a possibility that he may later come off the drug with only a low risk of recurrence of attacks.

brief; they occur between the ages of 6 months and 5 years, and only with fever. There is a small increased risk of later development of epilepsy in children who have had febrile fits, particularly if one or more of the fits has been prolonged. This may be one cause of hippocampal sclerosis. Rarer types of fit Other, rarer types of fit are described in Table 24.32. Pseudoseizures It can be difficult to determine clinically whether or not attacks are organic or 'hysterical' in nature. Many patients who have simulated or hysterical attacks also suffer organic seizures. EEG monitoring during an attack may be helpful, but in some instances continuous 24-hour recording with simultaneous video recording is necessary to establish whether the attacks are epileptic or not.

RECENT ADVANCES IN EPILEPSY

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• Magnetic resonance imaging now allows accurate diagnosis of small lesions causing epilepsy, particularly in the temporal lobes. • This, together with EEG video-telemetry, has renewed interest in the surgical treatment of epilepsy. • Stereotactic surgical techniques permit more precise lesion removal, resulting in greater efficacy in terms of seizure reduction, and lower risk of morbidity and mortality. • A number of new antiepileptic drugs have been introduced in the last few years, including lamotrigine, gabapentin, topiramate and levetiracetam. These have proved effective as adjunctive therapy, and some may control seizures when used as monotherapy. • Services for epilepsy, including counselling and support, have become more widely available.

Investigation A diagnosis of epilepsy cannot be made from an EEG, but an abnormal EEG showing clear epileptic activity supports the clinical diagnosis. An EEG should be performed in any patient presenting with an unprovoked first fit. Where alcohol or drug abuse is suspected as the underlying cause, the EEG is likely to be normal. The investigation is of most value when there is a history of focal onset and the presence of abnormal physical signs suggests a structural abnormality. Further investigation with a CT or MRI scan is then essential. MRI is now a routine investigation in the evaluation of patients with epilepsy. When available, it should always be requested for patients with seizures, particularly those with focal clinical or EEG features, because of its greater resolution than CT. Prolonged EEG recording with simultaneous video allows much more accurate diagnosis of seizure type, and this technique is also very helpful in the diagnosis of impaired consciousness whose nature cannot be established clinically. These include pseudoseizures (psychogenic fits). Meningovascular syphilis is now uncommon and serological tests are rarely of value. Lumbar puncture is of very limited value. In children in whom a metabolic disturbance is suspected, special investigation is necessary, as is the case with the phakomatoses and lipidoses.

Management Principles of medical treatment Following a single convulsion there is a 70% probability of further fits occurring in the next 2 years, and the risk is greatest in the first few weeks after the first fit. The risk can be reduced by about 20% with anticonvulsant medication, but most patients will not opt for such treatment after a single attack. Patients with very infrequent fits (every few years) may likewise prefer not to take daily treatment.

Patients with fits that are clearly only related to alcohol withdrawal (p. 1438) should not be given anticonvulsants. Having decided that treatment is necessary, the choice of drug will depend on the type of seizure, the age of the patient, the possibility of pregnancy, interaction with other medication and the likelihood of producing unacceptable side-effects. It is best to use a single drug, starting at a dose that will avoid excessive side-effects and increasing to a therapeutic level. Monitoring of blood levels of anticonvulsants is sometimes indicated, either to ensure therapeutic levels in patients who continue to have fits on treatment, or if symptoms and signs of toxicity develop. Blood levels of the shorter-acting anticonvulsants, such as valproate and clonazepam, are of little value. Follow-up is important to monitor the efficacy of treatment and the occurrence of side-effects. Patients must understand the details of their treatment. A card carried by the patient with drug information can be invaluable in an acute situation. Periodic review of the continuing need for treatment is necessary. In patients with adult onset of relatively infrequent fits, it is reasonable to consider gradual withdrawal of treatment when they have been free from fits for 2 years.

Choice of drug For petit mal, ethosuximide is the drug of choice, though alternatives in resistant cases are valproate and clonazepam (Table 24.33). For tonic-clonic seizures, or for partial seizures alone, several drugs are appropriate. Carbamazepine is now probably the drug of choice, mainly because of its low incidence of long-term side-effects, in both children and adults. Phenytoin and phenobarbital are alternatives. For tonic-clonic seizures associated with petit mal, valproate is better than carbamazepine, phenytoin or phenobarbital, but, as with other forms of epilepsy, there is considerable individual variation. Vigabatrin is a new anticonvulsant agent which is used most

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TABLE 24.33 Antiepileptic drugs: main indications and dose ranges First and second line agents Carbamazepine

Sodium valproate Phenytoin Lamotrigine Gabapentin Topiramate Tiagabine Levetiracetam

All seizure types except juvenile myoclonic epilepsy, absence attacks and related primary generalized epilepsies of early life (400-1200mg daily) All seizure types. Drug of choice for most primary generalized epilepsy syndromes (600-3000 mg daily) As for carbamazepine (200-500 mg daily) As for sodium valproate. Usually add-on but can be prescribed as monotherapy (200-500 mg daily) As for carbamazepine Licensed for add-on therapy at present (600-1 800 mg daily) As for gabapentin (200-600 mg daily) As for gabapentin (10-50mg daily) As for gabapentin (500mg-2G daily)

often as a supplementary drug in patients with seizures that are not responding to front-line drugs. Lamotrigine, gabapentin and topiramate are other newer anticonvulsants used as supplementary treatment in resistant epilepsy, and lamotrigine is effective monotherapy in some patients with focal or generalized seizures. Infantile spasms are usually refractory to all treatment, but ACTH and nitrazepam have been effective in some cases. All major anticonvulsant drugs (apart from valproate) induce liver enzymes, and this is important with concurrent drug therapy including the oral contraceptive pill. Anticonvulsant drugs in pregnancy Establishing definite evidence of teratogenicity with a particular drug is difficult, but all are thought to have some teratogenic effects, except perhaps for phenobarbitone. Phenytoin causes harelip and cleft palate, and cardiac malformations. Valproate and carbamazepine both lead to an increased incidence of neural tube defects (spina bifida, p. 1384). This can be screened for early in pregnancy with ultrasound and maternal a-fetoprotein estimation, at a stage when the fetus can be aborted if necessary. Blood levels of anticonvulsant drugs tend to fall during pregnancy. Monitoring of levels is advisable, particularly in women whose epilepsy is normally difficult to control. Serial epilepsy and status epilepticus A succession of convulsions in a single day constitutes serial epilepsy. When fits follow each other without consciousness being regained, this is known as status epilepticus. Urgent treatment is necessary to stop the fits, as continuing epileptic activity leads eventually to exhaustion

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MCQ 24.7

Less commonly used agents Phenobarbital Primidone cionazenam Clobazam Ethosuximide

As for carbamazepine, but more likely to sedate and depress (30-120 mg daily) As for phenobarbitone, and partially metabolized to it (500-1000 mg daily) Mainly myoclonic and primary generalized epilepsies, as add-on agent. Sedative (1.5-6mg daily) Add-on treatment, mainly for partial seizures. Tolerance develops (10-30mg daily) Used only for absence epilepsy when uncomplicated by myoclonic or tonic-clonic attacks, ie children with isolated petit mal (250-750 mg daily)

and cerebral damage. Initial treatment with a slow bolus of intravenous diazepam (10-30 mg) may terminate status, but its anticonvulsant action is short-lived. Further doses are likely to produce increasing sedation and the need for ventilation. A slow bolus of lorazepam is often more effective than diazepam, because of its longer duration of action. Other drugs which are used in status epilepticus include phenytoin and phenobarbital, given by slow intravenous injection. In refractory status general anaesthesia with thiopentone or propofol (now the preferred drug) is needed. Attention should be paid to maintenance antiepileptic drug treatment, as withdrawal of acute treatment for the status may lead to recurrent fitting. The cause of the status requires early consideration and appropriate investigation. Partial seizures may also occur continuously (epilepsy partialis continua). In focal motor epilepsy this takes the form of continuous jerking of one side, or part of one side, of the body. In psychomotor (temporal lobe) status the patient is confused and disorientated, will appear detached, and may not respond to questions, but will be conscious. An EEG is invaluable in identifying the cause of confusion in such patients. Surgical treatment MRI has allowed a new approach to the investigation and management of patients with long-standing and/or intractable fits. Lesions such as hippocampal sclerosis, cortical dysplasias with migrational defects, and slowly growing neoplasms, are not infrequently found in such patients, and some are helped by stereotactic surgery. The preoperative investigation of these patients, which includes EEG video-telemetry, MRI and psychological assessment, together with the neurosurgical treatment itself, is best undertaken in specialized units.

SUMMARY 4 Important practical advice for all patients with seizures • Driving (see text). • Other potentially dangerous activities (work or leisure). • Contraception - enzyme-inducing antiepileptic drugs may interfere with the pill. • Pregnancy - relative risks of teratogenicity with different drugs. • Addresses and telephone numbers of national support groups for additional information and advice.

Prognosis With the exception of patients with progressive structural or metabolic cerebral disease, in childhood or adult life, the overall prognosis is relatively good. In one large series, 20 years after initial diagnosis about 50% of patients were free from fits and off anticonvulsant treatment; a further 20% continued to take anticonvulsants and were fit-free; and fits continued in about 30% of patients who remained on treatment. Fits are less likely to remit in patients with mental retardation, abnormal neurological signs, clustering of fits, and complex partial and grand mal seizures.

Psychiatric and social factors In most patients the timing of fits is unpredictable and there is no, or only the briefest, warning of an impending attack. This alone may lead to social withdrawal and avoidance of public places. Patients are limited in their choice of work and may feel victimized by employers unwilling to continue their employment. There is still considerable social stigma attached to epilepsy, which may cause difficulties in personal relationships. Psychotic disorders may develop in a few patients with complex partial seizures. Few restrictions need to be imposed on most patients. However, the law concerning epilepsy and driving is understandably cautious. A distinction is made between nocturnal and daytime fits. Patients who have had only nocturnal fits for a period of at least 3 years may hold a licence; patients who have had even a single daytime fit may not drive for 1 year; in other cases, where there have been two or more fits, the licence will be withdrawn and will not be reinstated until a period of at least 1 year has elapsed without further attacks. Longer fit-free intervals may be required in patients with a higher risk of recurrent seizures: this applies mainly to neurosurgical cases with tumours, severe head injury or other structural lesions involving the cerebral hemispheres. A handbook issued by the Driver and Vehicle Licensing Agency provides guidance for doctors on medical standards of fitness to drive. This deals with epilepsy and all other medical conditions that may affect fitness to drive. Discussion of the law and driving is an issue that often threatens the relationship between doctor and patient. It is the doctor's duty to

inform the patient not to drive after a fit and for the patient to seek the advice of the licensing authorities. O

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NARCOLEPSY In narcolepsy, episodes of sleep occur during the day with a prodrome of an irresistible desire to sleep. The attack occur in inappropriate circumstances and can usually be distinguished from normal daytime postprandial drowsiness. Narcolepsy is associated with an abnormal EEG pattern of rapid eye movement (REM) sleep, REM sleep occurring quickly during the daytime sleeping episodes, There are three associated clinical phenomena in narcolepsy. • Cataplexy is an abrupt reduction in muscle tone leading to collapse to the ground, induced by emotion, often laughter, and loud noises. Consciousness is preserved and recovery usually occurs within a few minutes. • Sleep paralysis describes episodes of complete paralysi (without respiratory involvement) which occurs transiently on waking. It is usually short-lived - a few minutes at most. • Hypnagogic hallucinations are a feature in some patients. These are vivid, sometimes frightening hallucinations which occur as the patient is falling asleep. Narcolepsy and the related symptoms are thought to be due to abnormalities of monoaminergic pathways in the brainstem reticular-activating formation, and there is a very strong association with HLA-DR2 and DQwl. There is often a family history of the condition. Combination treatment is often required: modafinil, dexamfetamine or other stimulant drugs for narcolepsy, and clomipramine or fluoxetine for cataplexy.

OTHER SLEEP DISORDERS Narcolepsy is a rare disorder which accounts for only a small proportion of patients complaining of daytime drowsiness. In many cases the primary problem is a disturbance of night-time sleep; this may result from depressive illness, drugs (including alcohol), or sometimes intermittent nocturnal respiratory failure - sleep apnoea (p. 668). The interruption of respiration may be mechanical (obstructive sleep apnoea) or, less commonly, due to failure of neurogenic respiratory drive during sleep (central sleep apnoea). Many patients have persistent daytime drowsiness for no identifiable reason.

FURTHER READING ON SYNCOPE AND EPILEPSY Bassetti C, Aldrich M S 1996 Narcolepsy. Neurol Clin 14:545-571. Blumhardt L D 1996 Syncope. In: Oxford Textbook of Medicine, 3rd edn. Oxford: Oxford Medical Publications, 3925-3927. For Medical Practitioners. At a glance guide to the current medical

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standards of fitness to drive. Swansea: Driver and Vehicle Licensing Agency, 1999. Hopkins A P, Shorvon S D, Cascino G 1996 Epilepsy. London: Chapman & Hall, 1995. Sander J W A S, Shorvon S D 1996 Epidemiology of the epilepsies. J Neurol Neurosurg Psychiatry 61:433-443.

CEREBROVASCULAR DISEASE The term cerebrovascular disease embraces all the pathological and clinical manifestations of the following: • Disease of the cerebral arteries (atheroma being by far the commonest cause) and of the major neck vessels supplying the brain; • Disease of the heart, which may cause embolism to the brain or, rarely, ischaemia due to a critical fall in cardiac output; • Disorders of the blood, which may lead to impaired clotting, causing haemorrhage, hyperviscosity or hypercoagulable states, which increase the tendency to cerebral thrombosis. Thus, in a patient presenting with a stroke, particularly younger patients, the diagnostic net must be cast wide.

Definitions Stroke and transient ischaemic attack A stroke is an acute or subacute event in which a neurological deficit develops over minutes or hours, sometimes in a stepwise fashion, persists for at least 24 hours, and is caused by a vascular disturbance in the brain. Recovery is variable in its speed and extent, but can eventually be complete. Vascular events lasting less than 24 hours are defined by convention as transient ischaemic attacks (TIAs), although the distinction is not absolute. Some apparent TIAs may be associated with infarction on a CT scan, whereas more prolonged symptoms are not always accompanied by a visible structural lesion in the brain. In practice most TIAs are very brief, lasting only minutes or 1-2 hours at most. Most strokes are due to arterial occlusion and consequent ischaemic focal infarction of the brain, primary intracerebral haemorrhage being comparatively much less common. Subarachnoid haemorrhage, although clearly an acute intracranial vascular event, is primarily extracerebral in its origin and the underlying pathophysiology, clinical presentation and management are all quite distinct from a typical 'stroke' as defined above. The term 'cerebrovascular accident' has found widespread usage, but 'stroke' is preferable, not least because

it is a term understood and used by both doctors and patients. Epidemiology Stroke is the third most common cause of death in the UK, after heart disease and cancer. It has an incidence of 1-2 per 1000 population per year, but is much higher than this in older age groups. The incidence in men is slightly higher than in women at all ages. Stroke has a prevalence of around 5 per 1000 population. It has been estimated that about 80% of intracranial vascular events are due to cerebral infarction, 10% to spontaneous intracerebral haemorrhage and 10% to subarachnoid haemorrhage. Whereas TIAs are probably due mainly to emboli, the proportion of strokes that are embolic rather than thrombotic in situ remains uncertain.

Anatomy and physiology Cerebral circulation Figure 24.27 shows the origins of the great vessels from the aortic arch, the circle of Willis and its branches, and the areas of the brain supplied by the major intracerebral arteries. There are four branches from the terminal part of the internal carotid artery: the anterior and middle cerebrals, the anterior choroidal and the posterior communicating artery. A number of small branches are given off within the cavernous sinus. The most important of these is the ophthalmic artery, which passes anteriorly into the orbit where it divides, the central retinal artery being one of the branches. The other branches form anastamotic connections with branches of the external carotid artery. These anastamoses are a source of an important collateral circulation, which may develop after occlusion of the internal carotid artery in the neck. The vertebral arteries arise from the subclavian artery. The arteries join to form the basilar artery at the level of the lower pons. In addition to the terminal branches shown in Figure 24.27, the vertebral arteries give off the anterior and posterior spinal arteries. O Autoregulation In the normal subject cerebral blood flow (CBF) is maintained despite a wide range of blood pressures. A fall in blood pressure causes compensatory cerebral vasodilatation, and a rise produces vasoconstriction. Above a certain level, however, this autoregulation fails and, with high enough pressures, cerebral oedema develops, eventually resulting in hypertensive encephalopathy (p. 1338). Conversely, a fall of systemic blood pressure below the range of autoregulation will reduce cerebral perfusion and lead to haemodynamic cerebral ischaemia.

Causes of cerebrovascular disease O Fig. 24.4

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Atheroma Of all the causes of cerebrovascular disease listed in Table 24.34, atheroma is by far the most important, and patients

24

FIG. 24.27 The cerebral arterial supply A The origins of carotid (pale blue) and vertebral (dark blue) arteries are shown, as is their relationship to the cervical spine. B The major branches of the circle of Willis at the base of the brain are shown. C The distribution of the anterior (A), middle (M) and posterior (P) cerebral arteries are shown. The middle (M) and anterior (A) areas comprise carotid territory. Note in the upper diagram that vertebrobasilar territory includes the branches supplying the brainstem and cerebellum as well as the distribution of the posterior cerebral arteries (P). The lower section is at the level of the internal capsule.

presenting with a stroke often have evidence of peripheral or coronary vascular disease. The coexistence of cerebral and peripheral vascular disease is emphasized by the fact that a patient presenting with a first stroke is as likely to have a myocardial infarction in future as a further stroke. Atheroma tends to be most marked at branch points in the major vessels and in the carotid syphon. In relation to the cerebral circulation, the origins of the arteries from the aorta, brachiocephalic trunk and subclavian artery, the carotid bifurcation, the basilar artery and the origins of the anterior, middle and posterior cerebral arteries are all sites for atheroma formation. Atheroma may cause stenosis or complete obstruction, but thrombus commonly forms on atheromatous plaques in the absence of any haemodynamically significant stenosis. Fragments of thrombus may then break off and become lodged in a smaller artery distally. Partial obstruction or rapid lysis may lead to prompt restoration of the circulation producing the clinical picture of a TIA, but infarction results if the circulation is interrupted for more than a few minutes. Alternatively, thrombus forming on an atheromatous plaque causing stenosis may lead to complete obstruction in situ. The presence of bruits in the neck and supraclavicular fossa indicates arterial stenosis, but partial stenosis may occur without thromboembolism or any significant haemodynamic effects. The natural history of asymptomatic carotid bruits is still controversial, but recent studies suggest that it is more benign than previously thought. Other causes of cerebral embolism There are numerous other causes of cerebral embolism

apart from atheroma in the great vessels (Table 24.35). Emboli or local occlusion of the intracerebral vessels may each present with either a TIA or a stroke; it is often impossible to distinguish between local thrombosis and embolism. Risk factors The most important risk factor for stroke (Table 24.36) is hypertension. Recent studies have clearly shown that both smoking and alcohol are independent risk factors.

TRANSIENT ISCHAEMIC ATTACKS The majority of TIAs are attributed to embolism, from either the neck vessels or the heart (Table 24.35). A very small minority result from haemodynamic failure of blood flow, owing to critical reduction of perfusion pressure beyond a severely stenosed or occluded artery.

Clinical features Carotid territory TIA Transient ischaemia in the carotid territory usually produces a contralateral hemiparesis (with or without hemisensory or hemianopic disturbance), and dysphasia if the dominant hemisphere is affected. Attacks last from a few minutes to several hours; by definition, all symptoms and signs have resolved within 24 hours. Amaurosis fugax is the term used to describe transient monocular blindness. It is most often caused by embolism into the retinal circulation from an atheromatous internal carotid artery, but

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TABLE 24.34 Causes of cerebrovascular disease

TABLE 24,15 Causes of cerebral embolism

ARTERIAL DISEASE

• Carotid or vertebral artery disease

Atheroma

In situ thrombosis Artery-to-artery embolism Rupture and haemorrhage

Hypertension

Exacerbates all the above Small vessel disease (lipohyalinosis)

Congenital

Aneurysms Arteriovenous malformations Fibromuscular dysplasia Pseudoxanthoma elasticum Cystic medial necrosis

Inflammatory

Trauma

Arteritis: PAN, giant cell, Wegener's, SLE, intracerebral, Behcet's, sarcoid Radiation angiopathy Infection: basal meningitis (TB, fungi, pyogenic), syphilis, local infection in the neck Cortical thrombophlebitis secondary to infection Whiplash injury, direct trauma to the neck, angiography, producing vascular dissection or occlusion

CARDIAC Cardiac embolism Cardiac arrest Prolonged hypotension

Numerous causes (see Table 24.35) Patchy infarction in watershed areas Diffuse hypoxic-ischaemic damage

HAEMATOLOGICAL DISORDERS Prothrombotic

Polycythaemia, thrombocythaemia Antiphospholipid antibody syndrome Antithrombin III, protein C or protein S deficiency

Hyperviscosity

Myeloma, Waldenstrom's macroglobulinaemia Leukaemias

Haemorrhagic disorders

Thrombocytopenias Factor deficiencies latrogenic: heparin and warfarin

Haemoglobinopathy

Sickle cell disease

similar transient loss of vision may occasionally occur in migraine, glaucoma, or with papilloedema, retrobulbar neuritis, orbital tumours, retinal haemorrhage and retinal detachment.

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Vertebrobasilar TIA In the vertebrobasilar territory, TIA may cause vertigo, diplopia, binocular visual blurring or loss (due to occipital cortical ischaemia), facial paraesthesiae and numbness (often circumoral and bilateral), facial weakness, dysarthria, dysphagia and dysphonia, nausea and vomiting, ataxia, hemiparesis or tetraparesis, and hemisensory or four-limb sensory impairment. There is frequently impair-

- Atheroma - Dissection

• Cardiac Aortic or mitral valve disease

-

Endocarditis Rheumatic Prosthetic valve thrombosis Mural thrombosis with AF Myoxoma Mural thrombus after myocardial infarction or with aneurysm or cardiomyopathy - Cardiac surgery - Trauma - Patent foramen ovale - ASD

Left atrium Left ventricle

• Air embolism • Paradoxical embolism (from venous circulation) • Pulmonary vascular malformations

TABLE 24.36 Risk factors for TIA and stroke • Hypertension • Cardiac disease Ischaemic heart disease Causes of embolism (Table 24.35) • Peripheral vascular disease • Diabetes • Smoking

• • • • • •

Previous TIA Cervical bruit Hyperlipidaemia Raised haematocrit Alcohol Oral contraceptive pill, particularly in smokers

ment or loss of consciousness. It is an error to make a diagnosis of vertebrobasilar TIA on the basis of dizziness or loss of consciousness alone, in the absence of other symptoms suggesting a brainstem lesion. Isolated dizziness on head movement is much more likely to be due to a peripheral vestibular lesion. On rare occasions, with vertebral artery stenosis, neck movement (particularly extension) may further impair blood flow by cervical compression, leading to a vertebrobasilar TIA. Subclavian steal syndrome Subclavian steal syndrome is rare and is caused by subclavian stenosis proximal to the origin of the vertebral artery. During exercise of the arm, there is peripheral vasodilatation and blood flows retrogradely from the vertebral artery into the subclavian artery, causing vertebrobasilar ischaemia. There is usually a substantial reduction in blood pressure on the side of the subclavian stenosis, and a palpable difference between the pulses in the two arms.

Examination It is rare to witness a TIA, and patients seen between

TABLE 24.37 Investigation of TIA and stroke All patients • Full blood count, ESR • Urea and electrolytes, MSU • Blood glucose • Chest X-ray • ECG

Selected cases • Fasting lipids • Clotting screen • Antiphospholipid antibodies Antithrombin III Protein C and protein S • Autoantibodies • Blood cultures • Treponemal serology • Lumbar puncture • Echocardiography • CT or MRI scan • Doppler studies • Angiography (Fig. 24.28)

attacks will have no neurological signs apart from, occasionally, a cervical bruit. General examination is directed towards identifying associated factors such as hypertension, peripheral vascular disease and cardiac abnormalities. During an attack of amaurosis fugax emboli can occasionally be seen in the retinal arterioles; platelet emboli are white, cholesterol emboli are yellowish.

Investigation of TIA Investigation and management after TIA (or a minor stroke) are directed towards minimizing the risk of a disabling cerebral infarct in the future. A scheme of investigation is shown in Table 24.37, the more specialized tests on the right being applied selectively in appropriate cases. CT scanning is usually of little value but it may show unsuspected cerebral infarcts, and if these are bilateral there is a greater likelihood of recurrent embolism from the heart. Doppler ultrasonography is an important investigation for those patients with TIAs in carotid territory who are potential candidates for surgery, as carotid endarterectomy is appropriate for symptomatic lesions causing more than 70% stenosis. However, the risks of surgery may be unacceptably high in those with unstable coronary artery disease, severe hypertension, other serious medical disorders or advanced age. Echocardiography may be necessary if TIAs have occurred in more than one arterial territory, or if carotid Doppler studies are normal, particularly in younger patients with a suspected cardiac source of embolism that is not apparent from clinical examination.

Management and prognosis The risk of stroke in patients with TIAs varies between 5 and 15% per annum, depending on the type and frequency of attacks and their cause. Numerous episodes associated

with a 90% stenosis of one carotid artery carry a much worse prognosis than a single attack in a patient with mild hypertension. Nevertheless, high blood pressure remains the most important treatable risk factor for all types of stroke. Diabetes should be controlled, smoking stopped, alcohol consumption reduced if high, and weight loss encouraged if appropriate (although obesity is not a clear independent risk factor for stroke). There is no firm evidence that reduction of hyperlipidaemia reduces stroke risk, but this should be treated in younger patients with high levels. Attention should also be directed to the high risk of myocardial infarction in patients presenting with TIA or stroke. There has been much uncertainty about the value of antiplatelet agents, anticoagulants and reconstructive arterial surgery in the prevention of stroke.

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Antiplatelet therapy Drugs in this category include aspirin, dypyridamole, ticlopidine and clopidogrel. Review of a large number of methodologically sound trials has shown that aspirin reduces the incidence of non-fatal stroke and myocardial infarction by about 30%, and all vascular deaths by about 15%. Doses ranging from 75 to 300 mg have been shown to be effective. Larger amounts are more likely to cause GI bleeding, with no additional benefit. It is therefore reasonable to prescribe aspirin to all patents who have had a TIA or ischaemic stroke, provided there is no contraindication on other grounds. Some caution should be exercised when there is severe hypertension or a large and potentially haemorrhagic area of recent cerebral infarction. One recent multicentre trial has suggested that the combination of aspirin with controlled-release dipyridamole 200 nig twice daily is more effective for the prevention of stroke than aspirin alone. Both ticlopidine and clopidogrel have been shown to be comparable and perhaps slightly superior to aspirin, but ticlopidine may cause serious bone marrow depression and the cost of clopidogrel is 200 times that of aspirin. In patients with unacceptable side-effects from aspirin, or continuing ischaemic episodes despite its use, the substitution of one of the newer antiplatelet agents is clearly appropriate. Anticoagulants The two main indications for formal anticoagulation in patients with stroke and TIA with warfarin (preceded by heparin in acute situations) are a cardiac source of embolism and a prothrombotic disorder which may predispose to arterial thromboembolism or cerebral venous thrombosis. Relevant structural lesions in the heart include valvular disease, particularly prosthetic valves, left ventricular mural thrombus or aneurysm following myocardial infarction, dilated cardiomyopathies, and paradoxical embolism (from the venous circulation) via an atrial septal defect or patent foramen ovale. The most common cardiac source of embolic stroke, however, is non-valvular atrial fibrillation. Numerous large clinical trials have confirmed

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FIG. 24.28 Magnetic resonance angiogram A Severe tapering stenosis of the right internal carotid artery, in this case due to spontaneous dissection of the vessel. ITI A very similar lesion shown by conventional angiography with intra-arterial contrast injection.

TABLE 24.38 Prothrombotic disorders that may rarely cause cerebral ischaemic episodes Antiphospholipid syndrome Antithrombin III deficiency Factor V Leiden Protein C deficiency Protein S deficiency

the efficacy of warfarin in this setting. Only the precise timing of starting treatment is problematic in some cases (see p. 1342). The rare prothrombotic disorders that may predispose to stroke are listed in Table 24.38. When full anticoagulation is contraindicated there is some evidence to suggest that, for cardiogenic embolism, aspirin in a higher dose of 300 mg is more effective than in the now standard low dose of 75 mg. The use of heparin infusion for a slowly progressing ischaemic stroke is often suggested but is not supported by any objective evidence of its efficacy. Anticoagulation in the acute phase after an embolic cerebral infarct carries some risk of inducing haemorrhage into the lesion, but this must be balanced against the threat of further emboli (p. 1342). Rare prothrombotic haematological conditions that may justify anticoagulation in selected patients with TIA and stroke are shown in Table 24.38. Reconstructive arterial surgery In patients with TIAs or minor stroke due to platelet embolism from ulcerative plaques or stenotic lesions in the internal carotid artery, carotid endarterectomy has the theoretical value of removing the source of embolism and 1

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MCQs 24.8, 24.9

SUMMARY 5 Management of TIA • If no evidence of a cardiac source (most cases), and no contraindications, start aspirin immediately (300 mg loading, then 75 mg daily). • If cardiogenic embolism is likely, and there are no contraindications, anticoagulate immediately with heparin and then warfarin. • Screen for and minimize any other risk factors (Table 24.32), especially hypertension. • If carotid territory TIA (brain or eye) and pafient is suitable for and agreeable to carotid surgery, investigate immediately with Doppler. • For symptomatic carotid stenosis exceeding 70%, refer immediately to an experienced vascular surgeon. • If TIAs continue on as pirin, consider adding dipyridamole or substituting clopidogrel. • Use of anticoagulants for non-cardiac TIAs is unproven, as is carotid surgery for lesions with <70% stenosis.

preventing a subsequent and more disabling stroke. The indications for this procedure have remained controversial since its invention in 1954, but results of two large multicentre trials in Europe and the USA have clarified the issue to some extent: in patients with recent or continuing ischaemic symptoms attributable to severe carotid stenosis (i.e. between 70 and 99% reduction of luminal diameter), there is a high risk of an ipsilateral stroke, which is significantly reduced by carotid endarterectomy by an expert in the field. The major complication of this procedure is the very catastrophe it is designed to prevent. In certain circumstances, endarterectomy may also be justifiable to reverse a state of critically low perfusion pressure beyond a tight stenosis, but prevention of embolism is the major indication, in highly selected cases. Published trials have not shown convincing evidence to justify carotid endarterectomy in patients with asymptomatic carotid stenosis, even when the lesion is anatomically severe. Further studies are in progress. The innovative procedure of extracranial to intracranial arterial bypass surgery was practised actively for many years, particularly in North America, until a definitive

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FIG. 24.29 Acute cerebral infarction A CT scan showing an extensive right cerebral hemisphere infarct in this patient, scanned 24 hours after the onset of a complete left hemiparesis with left hemisensory loss and a left homonymous hemianopia. There is an ill-defined area of low attenuation occupying most of the right hemisphere, caused by carotid occlusion. B MRI showing acute right hemisphere infarction in middle cerebral artery territory.

able mass effect, sometimes causing life-threatening herniation at the tentorium. Cerebral oedema is usually at its most severe 4-7 days after infarction and then gradually resolves over 2-4 weeks (Fig. 24.30). There is always a possibility that an ischaemic infarct may become haemorrhagic. This is most likely if the infarct is due to an embolus which is then cleared at an early stage, allowing blood under arterial pressure to reperfuse the damaged area. An infarct may also become haemorrhagic owing to the collateral blood supply at the boundaries of the infarct.

Clinical features

FIG. 24.30 MRI showing a mature right middle cerebral artery territory infarct An extensive area of abnormal signal is present, with compensatory enlargement of the right lateral ventricle, occurring as a result of brain loss.

The cardinal clinical feature of a stroke is its abrupt onset. Occasionally there is a slow worsening over hours, or a stepwise deterioration in function over a day or two (stroke in evolution). Strokes vary enormously in both their severity and the combination of symptoms and signs. When occlusion of a major cerebral artery occurs, the extent of infarction will depend on the degree of collateral blood supply. For example, occlusion of the internal carotid artery, either at the carotid bifurcation or in the syphon (the two common sites for atheroma formation in the carotid), may cause no deficit at all if the circle of Willis is complete and flow through the other carotid and vertebrals is sufficient.

controlled clinical trial showed clearly that the operative morbidity far outweighed any potential benefits. 1

Major cerebral vessel occlusion syndromes

STROKES DUE TO CEREBRAL INFARCTION The causes of cerebral infarction are the same as for TIAs, but it is generally considered that fewer strokes than TIAs have an embolic basis. Most cerebral infarcts swell during the first few days after the acute event, with surrounding oedema (Fig. 24.29). Large infarcts may exert a consider-

The arterial territories are shown in Figure 24.27 (p. 1331). The distinction between carotid and vertebrobasilar territory strokes is essential for planning investigation and management.

Carotid territory Middle cerebral artery occlusion Middle cerebral artery and internal carotid artery occlusion may be indistinguishable clinically, and the extent of

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infarction after either is very variable. Preceding amaurosis fugax may indicate either internal carotid artery occlusion or embolism from the carotid artery as the cause of the stroke. The middle cerebral artery is also the vessel most frequently occluded by emboli from the heart. O However, some middle cerebral artery territory strokes are probably due to in situ thrombosis of the main trunk of the middle cerebral artery or its branches. The usual deficit after middle cerebral artery occlusion is a contralateral hemiparesis, affecting the arm and face more than the leg. When the dominant hemisphere is affected, dysphasia is usually expressive more than receptive. Contralateral homonymous hemianopia and a mild contralateral hemisensory loss may also be present.

and vomiting due to involvement of the vestibular nucleus and its medullary connections; dysphagia, dysphonia, ataxia and contralateral limb sensory impairment. Examination reveals an ipsilateral Horner's syndrome from involvement of descending sympathetic fibres in the medullary reticular formation, horizontal nystagmus towards the side of the cerebellar lesion, ipsilateral trigeminal pain and temperature sensory impairment. There is also, occasionally, an ipsilateral lower motor neuron facial palsy, ipsilateral palatal, vocal cord, pharyngeal and lingual palsies (which may cause severe dysphagia), ipsilateral limb ataxia and, sometimes, ataxia of gait. In addition, there is a contralateral spinothalamic limb and trunk sensory impairment. Rarely there is a contralateral hemiparesis, but this only occurs with extensive infarcts. 0

Anterior cerebral artery occlusion Unilateral occlusion of the anterior cerebral artery results in contralateral hemiparesis and hemisensory loss, in which the leg is often more severely affected than the arm. After anterior cerebral artery occlusion in the dominant hemisphere, there may be an expressive dysphasia; in either hemisphere there may be marked motor dyspraxia, causing particular difficulty in walking.

Pontine infarction An extensive pontine infarct, owing to basilar artery thrombosis, is often fatal. The signs are coma, tetraparesis, multiple cranial nerve signs (usually involving gaze palsies), nystagmus, facial paralysis and cardiorespiratory abnormalities. Bilateral infarction of the basis pontis, with relative sparing of the more dorsal parts of the pons, results in tetraparesis and, often, anarthria, and jaw, facial, palatal and tongue paralysis with preservation of consciousness. This is the so-called 'locked-in' syndrome, in which patients are only able to communicate with movement of the eyes. Less extensive pontine lesions (paramedian, lateral or tegmental) produce varying combinations of cranial nerve, long tract and cerebellar signs without such profound disability.

Vertebrobasilar territory Ischaemic lesions in the posterior circulation, caused by vertebral, basilar or branch artery occlusions, are very variable in extent. There are many described discrete syndromes, but in clinical practice the deficit in a particular patient usually does not correspond exactly to one of these. It is usually sufficient to recognize the major area of infarction within the brainstem. Infarction of the medulla Hemiparesis, tetraparesis or triparesis with lower cranial nerve palsies may occur after vertebral artery occlusion, together with disturbances of breathing and cardiovascular control due to involvement of the medullary reticular formation. Respiratory irregularities, apnoea, hypotension or hypertension, and a number of cardiac arrhythmias may result. Posterior inferior cerebellar artery occlusion (Wallenberg syndrome, lateral medullary infarction) The posterior inferior cerebellar artery (PICA) occlusion syndrome is as often due to vertebral occlusion as to occlusion of the PICA. The clinical syndrome is striking, and occurs sufficiently frequently to be recognizable as a separate entity. Symptoms usually consist of ipsilateral facial paraesthesiae or pain due to involvement of the spinal nucleus and tract of the trigeminal nerve; severe vertigo

1

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Figs 24.5, 24.6

2

Case 24.4

3

Fig. 24.6

Midbrain infarction Midbrain infarction occurring alone is unusual. Syndromes of ipsilateral third-nerve palsy with contralateral hemiparesis (Weber's syndrome) and ipsilateral third-nerve palsy with contralateral cerebellar signs (syndrome of Benedikt) are described, but are rare. Superior cerebellar artery thrombosis causing infarction of the midbrainpontine junction leads to an ipsilateral Horner's syndrome, ipsilateral nystagmus and cerebellar signs, ipsilateral lower motor neuron facial weakness, contralateral spinothalamic sensory loss in the limbs, and, sometimes, parkinsonian signs due to involvement of connections to the substantia nigra. Cerebellar infarction Pure cerebellar infarction probably occurs only rarely; most infarcts also involve the brainstem, although cerebellar signs predominate. Posterior cerebral artery occlusion The posterior cerebral arteries supply the upper part of the midbrain, the cerebral peduncles, parts of the thalmus and the subthalamic nuclei, as well as the occipital lobes. O Thus, although homonymous visual field defects predominate in posterior cerebral artery occlusion, hemiparesis, sensory disturbances and, occasionally, hemiballismus (p. 1367) may also occur. In addition to the primary visual cortex, the more anteriorly placed association cortex may

24

TABLE 24.39 Common lacunar syndromes Type

Clinical features

Lesion

Pure motor stroke

Partial hemiparesis

internal capsule

Pure sensory stroke

Partial hemisensory impairment

Internal capsule or thalamus

Hemiparesis with ataxia

Partial hemiparesis Ataxia of cerebellar type Dysarthria

Internal capsule or pons

Diffuse small vessel disease

FIG. 24.31 CT scan showing bilateral small lacunar infarcts in the corona radiata

also be damaged. Patients with extensive lesions here may deny being blind (Anton's syndrome); they will describe objects incorrectly and may wrongly be thought to be confused. Thalamic pain is a rare consequence of stroke. It arises from infarction of the lateral part of the thalamus. Thalamic stroke causes contralateral sensory loss, often with only a mild hemiparesis. The pain may come on weeks or months later and is usually continuous, severe and chronic; it has a burning quality, often with associated cutaneous hyperaesthesiae. Treatment with antidepressants, benzodiazepines or anticonvulsants is occasionally successful. Thalamic electrical stimulation may give partial relief.

Lacunar infarcts Lacunar infarction refers to small deep infarcts in the region of the internal capsule, basal ganglia, thalamus and brainstem, particularly the pons (Fig. 24.31). These are often multiple. The deficit from such strokes is usually mild. Lacunar infarction is most common in hypertension but also occurs in normotensive subjects. Lacunae occur in the territory of small, deep perforating arteries. Occlusion is likely to result from local small vessel disease, typically lipohyalinosis in hypertensive subjects, rather than embolism. Investigation and management is therefore directed towards control of risk factors rather than a search for possible embolic sources. The common lacunar syndromes are listed in Table 24.39.

The third pattern of ischaemic cerebrovascular disease is diffuse small vessel disease. It is more common in hypertensive patients. The typical presentation is difficulty in walking and dementia, which is usually progressive. There is sometimes urinary incontinence. Examination reveals intellectual impairment, often with prominent primitive reflexes, and bilateral pyramidal tract signs which affect the cranial nerve nuclei as well as the limbs. There may be a brisk jaw jerk, dysarthria (of spastic type) and dysphagia (the lower cranial nerve signs constituting a pseudobulbar palsy). The signs in the limbs are often asymmetrical, with little or no sensory impairment. The gait is characteristically small-paced, unsteady and slow, the so-called 'marche a petits pas'. It resembles a parkinsonian gait in some respects, but the patient walks more upright and with a wider base. CT scanning (Fig. 24.32) shows a variable degree of cortical atrophy and a characteristic diffuse periventricular low attenuation indicating deep white matter loss (sometimes known as Binswanger's disease). These diffuse subcortical lesions are more obvious on an MRI scan, but CT is quite adequate for establishing the diagnosis. Multi-infarct dementia Patients presenting with a history of progressive dementia are sometimes found to have diffuse subcortical small vessel disease or multiple cerebral infarcts of differing size. They usually have physical signs corresponding to some, if not all, of the lesions (Fig. 24.33). Vascular dementia is discussed more fully on pages 1350-1351.

Other patterns of ( cerebrovascular disease Migrainous infarction. Extremely rarely, a persistent deficit may follow a focal migraine attack, usually in the form of a hemianopia. It is likely that cerebral infarction is due to in situ thrombosis within a vessel critically narrowed by either spasm or oedema within its walls, or to this process of narrowing alone. Women with complicated migraine who take the contraceptive pill may be at slightly greater risk of having this type of stroke.

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FIG. 24.32 MRI (T2 weighted), axial (A, B) and coronal sections (C), showing widespread deep white matter and basal ganglia high signal lesions, typical of small vessel disease

Hypotensive cerebral infarction. Prolonged severe hypotension (e.g. after cardiac arrest) may lead to focal cerebral infarction even with normal cerebral vessels, although diffuse cortical damage is more common. Patients with pre-existing cerebral arterial narrowing are particularly at risk. Watershed infarction most commonly affects the boundary parieto-occipital area between anterior, middle and posterior cerebral artery territories. Hypertensive encephalopathy. The encephalopathy resulting from severe hypertension is characterized by coma, fits and a very high blood pressure, in excess of 220/130 mmHg. Papilloedema is invariably present. There is cerebral oedema and sometimes multiple small cerebral haemorrhages. Reduction of the blood pressure is essential (Ch. 12) and recovery is often surprisingly rapid and complete. Gradual reduction of the blood pressure over a few hours is preferable to an abrupt lowering, which is more likely to lead to ischaemia and infarction. Rare arterial disorders. Ischaemic stroke is occasionally due to an inflammatory or autoimmune arteriopathy, such as systemic or CNS vasculitis, SLE, neurosyphylis, HIV or a basal meningitic process (especially tuberculosis). Worldwide, sickle cell disease is an important cause of ischaemic stroke in children as well as in adults. Prothrombotic disorders. Rare haematological conditions predisposing to stroke are listed in Table 24.37 (page 1333).

STROKES DUE TO PRIMARY INTRACEREBRAL HAEMORRHAGE Aetiology

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The causes of spontaneous intracerebral haemorrhage are listed in Table 24.40. Haemorrhage is most commonly due to hypertension or intracerebral extension of bleeding

from a ruptured berry aneurysm. Subarachnoid haemorrhage is considered on page 1343. Cerebral infarction is about eight times as common as primary cerebral haemorrhage as the cause of stroke. Although haemorrhage without hypertension occurs, haemorrhage is much more common in hypertensive subjects. Many cerebral haemorrhages are thought to arise from Charcot-Bouchard microaneurysms, situated deep in the cerebral hemispheres, cerebellar hemispheres and pons. Lesions situated superficially in the cerebral hemispheres are more likely to be due to one of the less common causes of haemorrhage. Surrounding oedema develops within a few hours of cerebral haemorrhage; this exacerbates the spaceoccupying effect, which is much greater with haemorrhage than with infarction. Extension of a cerebral haemorrhage into the lateral ventricle carries a worse prognosis.

Clinical features of cerebral haemorrhage The clinical presentation of cerebral hemisphere haemorrhage is often indistinguishable from that of cerebral infarction. However, because intracranial pressure is more likely to be raised with haemorrhage, severe headache, vomiting and impairment of consciousness are more common. The presence of meningism indicates blood in the subarachnoid space, and therefore haemorrhage extending either from an intracerebral haemorrhage or from a primary subarachnoid source. Haemorrhage in the cerebellum produces a typical presentation of ataxia, headache and vomiting, often with vertigo. This is followed by progressive impairment of the conscious level, resulting both from brainstem compression directly due to the haematoma, and from hydrocephalus due to obstruction of CSF flow through the aqueduct of Sylvius (see Fig. 24.46). Pontine haemorrhage usually causes rapid loss of consciousness, a quadriplegia and multiple brainstem signs, and is usually fatal.

CASE STUDY 24.4 EPISODES OF RIGHT-SIDED WEAKNESS IN A 67-YEAR-OLD MAN A 67-year-old man presented with a 6-week history of episodic weakness affecting his face, arm and leg on the right side. There had been at least four separate attacks lasting a few minutes on each occasion. Some had included numbness or tingling in the affected limbs. He also reported a single episode of visual disturbance on one side, but could not remember which side or say for sure whether one or both eyes had been affected. On the day of admission to hospital the weakness had come on again and persisted for several hours, with only partial recovery. He had a myocardial infarct 3 years earlier and gave up smoking at that time. There was no history to suggest continuing angina. He had been prescribed aspirin 150mg daily, but admitted that he did not take this regularly. On examination he had very mild hemiparesis affecting his face and right hand, with normal power in the leg. His speech was slightly slurred but there was no dysphasia. His visual fields were full and there was no demonstrable sensory impairment. He was in sinus rhythm. The blood pressure was 170/95. No cardiac murmurs or cervical bruits were heard.

Questions 1. Where is the lesion? 2. What is the likely pathophysiological mechanism? 3. Is there any immediate treatment for this disorder? 4. What further investigations are required? 5. What treatment options pay then be Considered? Discussion The history is that of recurrent focal disturbance in the left hemisphere or possibly the brainstem, almost certainly due to transient cerebral ischaemia culminating in a minor stroke. It is not strictly definable as a stroke until the symptoms have persisted for more than 24 hours, but TIAs rarely last this long in practice. The distribution of weakness is more likely to result from a cortical infarct in the territory of the middle cerebral branch of the carotid artery than a small lesion in the brainstem (vertebrobasilar territory). Associated dysphasia or a clear history of transient visual loss confined to the left eye (ophthalmic branch of the internal carotid on that side) would have clinched this. A clear history of

24

transient binocular blindness, hemianopia on either side (posterior cerebral artery territory) or symptoms of brainstem origin (diplopia, vertigo, simultaneous bilateral face or limb disturbance) would have indicated a vertebrobasilar origin for the ischaemic events. The likely mechanism is recurrent embolism from an atheromatous left internal carotid artery, the heart, or possibly the aorta. Much less likely pathologies would include haemorrhagic stroke, a subdural haematoma or tumour (e.g. meningioma) with an intermittent onset of symptoms, or focal seizures from some other type of structural lesion in the left hemisphere. There is no established routine treatment for acute ischaemic stroke. Thrombolysis with rTPA has been shown to improve outcome in highly selected cases treated within the first 3 hours after the onset of symptoms rarely a practicable option. Several large trials have shown that the use of heparin in acute stroke is associated with an unacceptably high risk of haemorrhagic complications, including intracranial haemorrhage in some cases. Early use of aspirin is relatively safe and helpful for secondary

CASE FIG. 24.4.1 MRI scan showing recent infarction in left middle cerebral artery territory, due, in this case, to embolism from a stenosed internal carotid artery.

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CASE STUDY 24.4 CONTINUED prevention, but confers only marginal benefit for the acute lesion. Investigations should include full blood count, ESR, electrolytes and creatinine, blood glucose, and fasting lipids done either acutely or several weeks after the event. An ECG and chest X-ray would be advisable, particularly if surgery is planned. A CT or MRI scan would exclude the unlikely possibility of a primary intracerebral haemorrhage as the basis of the stroke, as well as showing the small infarct if it was performed after an interval of 2 or 3 days. An MRI scan in this patient showed an infarct in the left middle cerebral arterial territory, as anticipated (Case Fig. 24.4.1). Carotid Doppler studies will establish whether there is significant atheromatous disease on the appropriate left side. If carotid stenosis of greater than 70% is found and the patient maintains a good recovery, he would be a good

candidate for carotid endarterectomy within a few weeks of this minor stroke (or sooner if the presenting symptom had been TIAs alone). If no carotid lesion was found, consideration of embolism from the heart would require echocardiography, preferably via the transoesophageal approach to give adequate views of the left atrium. Treatment would include reinstatement of regular low-dose aspirin as soon as the CT scan has excluded a cerebral haemorrhage (75mg, 150mg or 300mg daily, depending on personal preference). In patients allergic to aspirin or already taking it regularly when symptoms occur, the addition of dipyridamole 200 mg b.d. or the substitution of clopidogrel 75 mg daily are both of proven value for secondary prevention of stroke on the basis of large clinical trials. Full anticoagulation with heparin and then warfarin is the treatment of

choice for proven or suspected cardiogenic embolism, postponing the start of treatment by 2 or 3 weeks if the patient has a large cerebral infarct that might be at risk of undergoing haemorrhagic transformation in response to earlier anticoagulation. Haemorrhagic change may occur spontaneously during reperfusion after an embolic cerebral infarct (Case Fig. 24.4.2). Severe symptomatic carotid stenosis justifies endarterectomy as long as the risks of surgery are not considered to be unacceptably high on the basis of other factors, such as a major stroke with poor recovery, very advanced age, severe hypertension, coronary artery disease or other coexisting disorders. In all patients the appropriate management of longer-term risk factors such as hypertension, hyperlipidaemia, diabetes and smoking is very important.

CASE FIG. 24.4.2 Haemorrhagic cerebral infarction CT scan 7 days after the acute stroke, showing patchy areas of high density (blood, within a recent infarct in middle cerebral artery territory). This patient had not been treated with aspirin, heparin or rTPA.

Differential diagnosis of stroke The abrupt onset of a neurological deficit, often with a distribution corresponding to a single vessel territory, and 1

1340

Figs 24.7

with a tendency to improve slowly, usually leaves little doubt about the diagnosis of a stroke. Other diagnoses should be considered when the history is atypical, inadequate or unreliable. These include: • • • •

Subdural haematoma, sometimes bilateral Cerebral abscess Encephalitis (particularly due to herpes simplex) Cerebral tumour.

TABLE 24.40 Causes of spontaneous intracerebral haemorrhage

24

• • • •

FIG. 24.33 Multiple bilateral cerebral infarcts in a middle-aged man with a history of coronary artery and peripheral vascular disease

Other conditions may occasionally produce stroke-like presentations, including demyelinating disease, cerebral venous thrombosis and acute hypoglycaemia.

Complications of stroke The complications of a disabling cerebral infarct or haemorrhage are listed in Table 24.41. Death from the stroke itself usually occurs within the first 2 weeks. Pneumonia is an early and sometimes fatal complication. Incontinence, a poor prognostic feature, is associated with recurrent urinary tract infections.

Investigation of acute stroke Because 80-90% of strokes are ischaemic rather than haemorrhagic, the basic approach to investigation is the same as for patients with TIAs (Table 24.38, p. 1334). Screening for the more obscure causes of stroke is performed selectively, depending on the age of the patient and the type of lesion. CT scanning Not all patients require a CT scan to establish the diagnosis, but when performed, it usually provides more precise diagnostic and prognostic information. In practice, most patients admitted to hospital with a stroke do now undergo CT or MR scanning, but in certain circumstances imaging is absolutely essential: • Uncertainty about the diagnosis. Particularly when the history is inadequate or the patient is deteriorating, a scan is required to exclude a subdural haematoma, expanding intracranial haematoma, tumour or focal intracranial infection. • Distinction between infarction and haemorrhage. When there is doubt on clinical grounds and active intervention is planned with anticoagulants or even aspirin, it is important to exclude a haemorrhagic lesion.

Hypertension Cerebrovascular disease without hypertension Subarachnoid haemorrhage, with intracerebral extension Arteriovenous malformations (alone, or as part of Sturge-Weber syndrome*) • Other cerebrovascular disease: Mycotic aneurysms Cortical thrombophlebitis Capillary haemangiomas Haemorrhagic telangiectasia** Cavernous haemangiomas Haemangioblastomas*** Congophilic (amyloid) angiopathy • Bleeding into cerebral tumours (rare) • Haematological disease: Thrombocytopenia from any cause Haemophilia Sickle cell disease latrogenic - anticoagulants - cytotoxic drugs Common causes are shown in bold type. * Sturge-Weber syndrome - AVM with ipsilateral trigeminal cutaneous capillary angioma ('port-wine' stain). ** Osler-Rendu-Weber syndrome - haemorrhagic telangiectasia in brain and retina. ***Von Hippel-Lindau disease - CNS haemangioblastomas, particularly in cerebellum, brainstem and spinal cord, with retinal haemangioblastomas, renal or pancreatic cysts, hypernephroma and adrenal tumours.

• Young patients. Those with vascular events at an unexpectedly early age require full investigation to exclude unusual causes of stroke, including unsuspected multiple lesions or a vascular malformation. • Cerebellar stroke. Expanding cerebellar haematomas or acute hydrocephalus due to swelling of a cerebellar infarct are rare but life-threatening vascular events that may require immediate surgical intervention. O It is apparent that rigorous application of these guidelines will require almost all patients with stroke to have a CT scan, in order to avoid overlooking an unsuspected haemorrhage in a very small proportion of cases prior to starting long-term aspirin. This is becoming a more widespread practice, although not all physicians and neurologists agree that it is strictly necessary. Although CT scanning is usually adequate to clarify the diagnosis - certainly to rule out haemorrhage as the underlying mechanism - there are some situations in which MRI is preferable as the primary imaging procedure, if available. These are listed in Table 24.42 lumbar puncture This is rarely indicated in the acute phase, but CSF examination may be necessary if there is suspicion of an

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TABLE 24.42 Use of MRI in preference to CT for cerebrovascular disease

TABLE 24.41 Complications of stroke Neurological Cerebral oedema (early) Epilepsy Spasticity Contractures, frozen shoulder, shoulder subluxation Depression Incontinence Respiratory and cardiovascular Neurogenic pulmonary oedema (early) Cardiac arrhythmias (early) Pneumonia DVT Pulmonary embolism

Renal and metabolic Urinary infection Renal failure Dehydration Electrolyte abnormalities SIADH (early) Hyperglycaemia/diabetes (early) Skin Pressure sores General Weight loss Weight gain Malnutrition Dependent oedema

underlying inflammatory disorder causing the stroke, e.g. low-grade meningitis (especially TB and fungi), neurosyphilis, cerebral arteritis, SLE or HIV infection.

Angiography Development of tomographic imaging (both CT and MRI) has left relatively few indications for cerebral angiography in stroke patients. The following are fairly clear-cut, however: • In patients with continuing carotid ischaemic events (despite aspirin) being considered for endarterectomy, cervical angiography is necessary unless Doppler studies (a) are available, and (b) have shown that there is definitely no potentially operable lesion. Digital subtraction angiography with venous contrast injection is usually adequate for visualization of the carotid and other neck vessels. • To identify a suspected intracerebral arteriovenous malformation or aneurysm in patients with intracerebral haemorrhage for whom active surgical management or interventional radiological treatment (p. 1345) is contemplated. • To identify features of macroscopic cerebral arteritis or other rare arteriopathies such as dissection or fibromuscular dysplasia (Table 24.30). • Investigation of primary subarachnoid haemorrhage (see p. 1344). • Occasional cases of suspected cerebral vein or venous sinus thrombosis. 1 Magnetic resonance angiography

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1

Fig. 24.8

0 Fig. 24.7 3

4

Fig. 24.9

0 Fig. 24.10

MCQ 24.10

Confirmation of brainstem or cerebellar infarction Diagnosis of carotid or vertebral dissection Detection of small AVM or cavernous angioma Suspected cerebral venous thrombosis Late distinction of haemorrhage from infarction (weeks after the event)

(MRA) has largely superseded conventional contrast angiography for the diagnosis of this disorder. Echocardiography This is indicated in selected cases in which ischaemic episodes are likely to have been embolic and a cardiogenic source is to be screened for or confirmed. It is not justifiable to perform echocardiography unselectively on all patients with stroke or TIA.

Management of stroke Acute phase Cerebral infarction Many medical treatments, including anticoagulants, putative cerebral vasodilators, haemodilution, dextran, hyperbaric oxygen, hypercapnia and hypocapnia, have been advocated as measures that may improve the prognosis of acute cerebral infarction. However, none has been proved to be of benefit by adequate clinical trials. Dexamethasone. There is some evidence that reducing cerebral oedema with dexamethasone may enable some patients to survive. However, life-threatening cerebral oedema is associated with large infarcts, so that the quality of survival in the few patients who may be saved in this way is poor. Anticoagulation. There is no place for routine anticoagulation in stroke, except in patients in whom a cardiac source for emboli is certain or strongly suspected. For patients with a cerebral infarct who have a cardiac lesion likely to be the source of an embolus, the timing of anticoagulation is problematical. Immediate anticoagulation carries a risk of turning a soft cerebral infarct into a haemorrhagic one, but against this is the possibility of further cerebral embolisms. This issue has not yet been the subject of a proper clinical trial. A reasonable course is to delay anticoagulation for a few days after a minor ischaemic stroke and for at least 2 weeks after a more extensive embolic infarct. The duration of anticoagulant therapy will vary, from a few weeks after an embolus from a mural thrombus, to lifelong treatment for an embolus due to rheumatic mitral or aortic valve disease. Cerebral emboli occurring during the course of acute bacterial endocarditis or subacute endocarditis are usually considered to be a contraindication to anticoagulants; this is because of the high risk of haemorrhage from mycotic

aneurysms, which are formed from the spread of infection from the embolus into the vessel wall. Thrombolysis. Carefully conducted trials have shown that thrombolytic therapy with tissue plasminogen activator (tPA) may improve the functional outcome of ischaemic stroke in patients treated within 3 hours of the onset. Later treatment carries an unacceptably high risk of haemorrhagic complications. This intervention could be used only in a small number of specialist units with the facilities to get patients into hospital and imaged by CT or MRI very soon after the onset of symptoms. It is at present still under evaluation. Hypotensive treatment. Many patients presenting with stroke have transient high blood pressures on admission. However, a sustained diastolic pressure of 110mmHg or more is an indication for hypotensive treatment. Surgery. All the available evidence indicates that surgical revascularization procedures have no place in the management of acute stroke, mainly because of the high incidence of reperfusion haemorrhage and oedema within the infarcted tissue treated in this way.

SUMMARY 6 Stroke • Cerebral infarction causes about eight times as many strokes as cerebral haemorrhage. • Most patients with TIA or ischaemic stroke require long-term prophylactic treatment with aspirin. • Cerebral infarcts caused by emboli from the heart require secondary preventive treatment with anticoagulants. • Atrial fibrillation is the most common identifiable risk factor for cardiogenic embolism. • Primary intracerebral haemorrhage may cause strokes which are clinically indistinguishable from cerebral infarction, but impairment of conscious level, vomiting and signs of raised intracranial pressure are more common with large haemorrhages. • Secondary prevention of cerebral infarction includes treatment of hypertension, diabetes and severe hyperlipidaemia if present, weight loss, cessation of smoking and low-dose aspirin. • Carotid surgery should be considered in patients with recent symptoms due to a severe internal carotid stenosis. • Unusual causes of stroke are more common in younger patients.

Intracerebral haemorrhage As with large infarcts, dexamethasone may improve the number of patients surviving but not the quality of survival. Expanding haematomas in the cerebellum constitute an acute neurosurgical emergency, and immediate evacuation may return a moribund patient to a good quality of life. 0 Surgical evacuation of large supratentorial haematomas is of doubtful value, however, as surviving patients are usually left profoundly disabled. Systematic trials are in progress to answer this question. The early management of most patients with acute stroke, irrespective of the pathology, therefore consists mainly of the provision of good supportive medical and nursing care, directed towards the prevention and early treatment of secondary complications (Table 24.41, p. 1342).

general, the more severe the initial deficit the less complete will be the eventual recovery. Certain features are of poor prognostic significance: these include impaired consciousness, incontinence, and sustained lateral deviation of gaze. About 20% of all patients with strokes due to cerebral infarction die within the first month, and the long-term death rate is about 5-10% per annum. These late deaths are as likely to be due to myocardial infarction as to further stroke. The recovery from spontaneous intracerebral haemorrhage (excluding subarachnoid haemorrhage) is not as good as from infarction. Mortality during the first few weeks is considerably greater than for infarction. ©

Rehabilitation The mainstay of treatment after strokes from all causes is rehabilitation. This involves nursing and medical staff, physiotherapists, occupational therapists and speech therapists. Even in patients with considerable residual deficit, a return home is often possible with sufficient support. The long-term efficacy and cost-effectiveness of specialized stroke units is still debated. However, it is likely that a multidisciplinary team working together in a dedicated ward will shorten hospital stay and improve the quality of care for many stroke patients.

SUBARACHNOID HAEMORRHAGE

Secondary prevention As for TIAs, secondary prevention after stroke involves minimizing exposure to risk factors, by following the procedures outlined on page 1333.

Prognosis Most patients show some recovery after cerebral infarction, but this is very variable and difficult to predict. In

24

The majority of spontaneous subarachnoid haemorrhages are caused by berry aneurysms which develop at proximal branch points in the major cerebral vessels at the base of the brain. The common sites are the bifurcation of the middle cerebral artery, O the terminal carotid, the anterior cerebral artery and the posterior communicating artery. Basilar artery aneurysms are less common. 0 Aneurysms are sometimes multiple. Most are idiopathic and probably congenital, although the age incidence of diagnosis suggests that they enlarge with time. A higher than expected incidence of aneurysms has been found in association with polycystic kidney disease (even in the absence of hypertension), coarctation of the aorta and Ehlers-Danlos syndrome. Other predisposing causes may include fibromuscular dysplasia and pseudoxanthoma elasticum. Subarachnoid haemorrhage can occur at any age, but is a particularly important cause of death and disability in the 20-40-year age group. In a minority of cases the predisposing causes listed for intracerebral haemorrhage

1343

RECENT ADVANCES IN CEREBROVASCULAR

DISEASE • Diagnostic accuracy has been improved by more widespread access to CT scanning and, more recently, MRI. • MR angiography offers a non-invasive means of investigating extracranial arterial disease, proximal intracranial arteries, and thrombosis in major cerebral veins and venous sinuses. • MR angiography reliably detects large intracranial aneurysms, and with continuing technical refinements, greater sensitivity in identifying small aneurysms is anticipated. • Completion of the large both American and European trials of cartoid endarterectomy has confirmed a role for this operation in carefully selected patients. • Large trials have confirmed the excess risk of embolic stroke in patients with atrial fibrillation, and the substantial reduction of this risk with anticoagulant treatment, except in the very elderly. • A combination of aspirin with dipyridamole was more effective than aspirin alone in one large multicentre trial. • The new antiplatelet agent clopidogrel is at least as effective as aspirin for the prevention of stroke. • Thrombolysis with tPA is potentially helpful in acute ischaemic stroke, but only if given within 3 hours of onset.

Investigation If tested within 8 hours of the haemorrhage the CSF may not contain blood, although the pressure is usually raised. Xanthochromia - the yellowish discoloration of the supernatant CSF in a spun sample, due to haemoglobin breakdown products - does not develop for at least 24 hours. The CSF in subarachnoid haemorrhage is often obviously uniformly bloodstained. Cell counts of CSF in three separate bottles distinguish a traumatic tap from true subarachnoid haemorrhage. It is potentially hazardous to perform a lumbar puncture in an unconscious patient or one with focal hemisphere signs. In each case, it is possible that there is an intracerebral haematoma, with an increased supratentorial intracranial pressure. CT scanning demonstrates even quite small quantities of subarachnoid blood (Fig. 24.34), and also intracerebral blood if present. Angiography is contraindicated in stuporose or comatose patients, but should be done at an early stage if the patient is fit enough because of the risk of rebleeding (maximal between 7 and 14 days). Many of those not fit enough initially will improve over a few days, and angiography can then be undertaken with reasonable safety. Patients may deteriorate after subarachnoid haemorrhage, owing to rebleeding, vasospasm or hydrocephalus. CT scanning will often identify the cause. Management and prognosis Many aneurysms are amenable to surgical treatment by clipping, or sometimes by wrapping the lesion. Early angiography and surgery carry a higher risk of cerebral

(Table 24.41) may be responsible. In about 10% of patients with subarachnoid haemorrhage no cause can be found. Clinical features The typical history of subarachnoid haemorrhage is severe headache of abrupt onset accompanied by neck pain and stiffness, and vomiting. Drowsiness is common, and there is often confusion and impairment of consciousness. Some patients will be deeply unconscious at presentation. In such patients neck stiffness may be absent. Focal hemisphere signs may be present, due to either intracerebral bleeding or vasospasm, which may affect the aneurysm-bearing vessel or other vessels. A third cranial nerve palsy (due to direct compression) often occurs with posterior communicating artery aneurysms and, less commonly, with carotid and middle cerebral artery aneurysms. There may be papilloedema and subhyaloid haemorrhages, the latter being seen only in subarachnoid haemorrhage.

1

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MCQ 24.11

FIG. 24.34 Extensive subarachnoid haemorrhage from an anterior communicating artery aneurysm In the unenhanced scan, blood (showing as a dense white image) is present in the interhemispheric fissure anteriorly, the Sylvian fissures, the third ventricle and the posterior parts of the right lateral ventricle.

ischaemic complications due to arterial spasm, but this must be balanced against the risk of rebleeding if surgery is delayed. There is no clear consensus of opinion, but in the UK the majority of patients in good clinical condition after a subarachnoid haemorrhage are investigated during the first week and operated upon 7-10 days after the event. The mortality of this condition remains high. Approximately 40% of patients die as a direct result of a first haemorrhage, 10% of these before reaching hospital. Of those that are admitted alive, mortality is about 25% at the end of the first week, 50% at 2 months and 70% at 5 years. If the aneurysm cannot be safely clipped, the overall risk of subsequent recurrent haemorrhage is about 35% in the first year and 3% per year thereafter. Recent advances in interventional neuroradiology have enabled some surgically inaccessible aneurysms to be occluded by insertion of thrombogenic platinum coils at the time of angiography. Results with this technique are comparable to those following surgery for more difficult aneurysms in the posterior fossa, and it seems likely that endovascular occlusion of aneurysms (and other cerebral vascular lesions) will be more widely practised in the future.

Arteriovenous malformations Arteriovenous malformations (AVM) (Fig. 24.35) tend to bleed from the venous side. Haemorrhage terminates at an earlier stage, probably because the pressure is lower, and the clinical effects are often less severe than bleeding from aneurysms. There can be episodes of bleeding over a period of many years, causing a relatively mild neurological deficit. Epilepsy is common with AVM. The diagnosis can be made on an enhanced CT scan, but MRI is superior, particularly for the detection of small lesions. The definitive test is an angiogram (Fig. 24.36). Many AVM, because of their deep situation and extent, are best left alone. Others are amenable to partial, or sometimes

total, excision. Embolization of feeding vessels offers an alternative method of treatment but, as with surgery, this often carries an unacceptable risk of producing a major deficit owing to infarction of the surrounding normal brain. O

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FURTHER READING ON CEREBROVASCULAR DISEASE Bamford J 1992 Clinical examination in diagnosis and subclassification of stroke. Lancet 339:400-402. Barnett H M, Taylor D W, Eliasziw M et al. 1998 Benefit of carotid endarterectomy in patients with asymptomatic moderate or severe stenosis N Engl J Med 339:1415-1425. CAPRIE Steering Committee 1996 A randomised blinded trial of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE) Lancet 348:1329-1339. CAST (Chinese Acute Stroke Trial) Collaborative Group 1997 CAST: randomised placebo-controlled trial of early aspirin use in 20000 patients with acute ischaemic stroke. Lancet 349:1641-1649. Davenport R, Dennis M 2000 Neurological emergencies: acute stroke. J Neurol Neurosurg Psychiatry 68:277-288. Dennis M, Langhorne P 1994 So stroke units save lives: where do we go from here? Br Med J 309:1273-1276. International Stroke Trial Collaborative Group 1997 The International Stroke Trial: a randomised trial of aspirin, heparin, both or neither among 19435 patients with acute ischaemic stroke. Lancet 349:69-81. Kopitnik T A, Samson D S 1993 Management of subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry 56:947-959. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group 1995 Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 333:1581-1587.

DEMENTIA Dementia is broadly defined as a deterioration of previously acquired intellectual capacity sufficient to interfere with social or occupational functioning. Diagnosis requires

FIG. 24.35 T2 weighted axial MRI showing a large parieto-occipital arteriovenous malformation The flow void in arterial and draining venous channels is clearly visible, and the high signal adjacent to the lesion is haemosiderin, indicating previous haemorrhage from the AVM. This woman presented at the age of 17 with partial and secondary generalized seizures.

1345

other neurological disorders or, very rarely, a demonstrable general medical cause (Table 24.43). The majority of cases fall into the 'primary degenerative' category and the most common of these is Alzheimer's disease, particularly in the elderly population. With progressive advances in our understanding of the genetic, ultrastructural and metabolic factors contributing to these degenerative syndromes, subclassification of dementias in the future is likely to become more specific and scientific.

Clinical diagnosis Assessment of intellectual function is discussed on pages 1286 and 1287. Amnesia or dysphasia in isolation do not constitute a state of dementia, although they may be presenting features of a more global disorder. Severe language dysfunction makes more general assessment very difficult. The mode of onset and rate of progression of symptoms may give some indication about the underlying cause of dementia. Alzheimer's disease and other degenerative disorders typically progress slowly over years; more rapid deterioration should raise the possibility of spongiform encephalopathy (Creutzfeldt-Jakob disease), paraneoplastic encephalitis, communicating hydrocephalus or cerebral arteritis. Vascular dementia may have a fluctuating or stepwise course, punctuated by acute focal symptoms, but this is by no means invariable. B

FIG. 24.36 Arteriovenous malformation A CT scan showing an acute left frontal cerebral haemorrhage, with surrounding oedema. B Left carotid angiogram in the same patient, showing an extensive arteriovenous malformation.

that there should be impairment of memory and involvement of at least one other aspect of cognitive function. The typical components of this generalized process may include focal cortical deficits (dysphasia, dyspraxia or agnosia), change of personality, and impairment of judgement and abstract thinking. Distinction must be made from the clouding of intellect that results from disturbance of consciousness and arousal: this is the defining characteristic of an acute or subacute confusional state (delirium). Deterioration of cognitive performance may also be a major presenting feature of psychiatric disorders, particularly depression; the impairment of function is no less real, but the term 'pseudodementia' is generally used in this setting, and recovery occurs with effective treatment of the depressive illness.

Investigation of dementia Brain imaging is important and often contributes to the diagnosis, but it may show no abnormality in the early stages of the degenerative syndromes. MRI is more sensitive than CT for the detection of multifocal inflammatory or vascular lesions, small metastases and subtle meningeal disease. The use of CT is adequate to show generalized cortical atrophy (the most common finding), more obvious strokes, large tumours or hydrocephalus. The range of other possible screening tests is shown in Table 24.44: these are used selectively, depending on the clinical features and, to some extent, on the results of brain imaging. Examination of the CSF is helpful mainly in the detection of inflammatory disorders, infective or otherwise. Suspected vasculitis may justify cerebral angiography. Biopsy of the brain is occasionally performed when the diagnostic possibilities include a potentially treatable vasculitic, inflammatory or neoplastic process that has not become apparent from the results of the less invasive investigations.

ALZHEIMER'S DISEASE

Classification and causes of dementia 1346

The practical classification of dementia is traditionally heterogeneous and based on presumed degenerative pathology, the presence of vascular disease, occasionally

The great majority of patients over the age of 60 with progressive dementia have Alzheimer's disease. It has been estimated that approximately 7-8% of all people over the age of 65 have this disease.

TABLE 24.44 Investigation of dementia

TABLE 24.43 Causes of dementia Cause

Examples

Blood tests

Radiology

'Primary degenerative'

Alzheimer's disease Lewy body dementia Pick's disease Frontal lobe dementia

• • • •

• Brain CT or MRI scan • Chest X-ray • Screen for primary cancer

Dementia as a feature of other degenerative neurological disorders

Huntington's disease Multiple system atrophy Steele-Richardson syndrome Parkinson's disease Inherited ataxias Rarely MND

• Thyroid function

Vascular

Multiple cerebral infarcts Diffuse small vessel disease Arteritis

Inflammatory

Multiple sclerosis Sarcoidosis, SLE

Infection

Postencephalitic (viral) TB, syphilis, HIV-related SSPE, PML, Whipple's

Prion-mediated encephalopathy

Creutzfeldt-Jakob disease, sporadic and new variant

Neoplastic

Metastases Large frontal tumours Multifocal cerebral lymphoma

Paraneoplastic

'Limbic encephalitis', usually with small-cell lung cancer

Endocrine

Hypothyroidism

Metabolic

Uraemia, hepatic failure Prolonged hypoglycaemia Wilson's disease Lipidoses etc

Nutritional

Vitamin B12 deficiency

Toxic

Alcohol; other drug misuse Solvents, heavy metals Prescribed drugs

Trauma

Post head injury Multiple trauma (e.g. boxers) Chronic subdural haematoma

Hydrocephalus

'Normal-pressure' syndrome Obstructive (usually tumour)

Psychiatric 'pseudodementia'

Depression; anxiety Schizophrenia Conversion syndrome

MND = motor neuron disease; SLE = systemic lupus erythematosus; HIV = human immunodeficiency virus (p. 1427); SSPE = subacute sclerosing panencephalitis (p. 1426); PML = progressive multifocal leukoencephalopatny (p. 1427).

• • • • • •

FBC, ESR Autoantibody screen Renal function Liver function

Calcium Glucose Vitamin B12 Toxicology screen Treponemal serology HIV serology

24

Specialized neurological • EEG

• CSF examination • Cerebral angiography • Brain biopsy

Aetiology Alois Alzheimer described the histological abnormalities in the atrophied brains of patients dying with dementia, and these changes remain the defining characteristics of the condition; however, none of the histological changes is, in itself, unique to Alzheimer's disease. In addition to atrophy (Fig. 24.37) and reduced numbers of cortical neurons in all areas, many surviving neurons contain neurofibrillary tangles. Senile plaques (amyloid plaques) structures of about 50 um diameter - are invariably present. Both changes are found to some extent in the brains of elderly non-demented patients, and so may be considered normal ageing changes. With the growth of our understanding of brain histochemistry, a number of theories based on altered chemistry have been proposed. Much attention has focused on the degenerative changes in the subcorticocortical cholinergic projections from the frontal regions and the corticocortical association pyramidal neurons, which are glutamatergic. Recent studies have suggested that Alzheimer's disease is familial in about 15% of cases, usually inherited as an autosomal dominant trait. Specific genetic markers have been reported in some kindreds: mutations of the amyloid precursor protein (APP) gene on chromosome 21 in earlyonset cases, and the apolipoprotein E4 genotype in families with later-onset disease.

Clinical features Loss of recent memory with a complaint of forgetfulness is the most common presenting symptom. Loss of interest in life and personality change, sometimes with antisocial and disinhibited behaviour, are also common early symptoms. Dysphasia, dyslexia, dysgraphia and dyscalculia are sometimes particularly marked. Dyspraxic symptoms, such as topographagnosia (inability to find one's way about in familiar surroundings) and dressing apraxia, are frequent. Loss of bladder and bowel sphincter control may be an early or late feature. Sleep disturbance is common. Wandering

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FIG. 24.37 CT scan showing generalized cerebral atrophy in a patient with degenerative dementia of Alzheimer type Note the very large Sylvian fissures and cortical sulci, with normal-sized lateral and third ventricles, consistent with the predominantly cortical nature of this disease.

may become a serious problem. Increasing confusion and complete social disintegration eventually occur. The most common physical complaint in Alzheimer's disease is unsteadiness of gait. The gait may appear ataxic or parkinsonian, and a combination of cerebellar, extrapyramidal and pyramidal signs may be found later in the disease. Myoclonus is common in the advanced stages. The course of Alzheimer's disease is very variable, average survival being between 5 and 10 years.

Investigation and management There is no single diagnostic test for Alzheimer's disease. The finding of diffuse cerebral atrophy on CT scanning (Fig. 24.37) and exclusion of other treatable causes of dementia usually leave little doubt about the diagnosis. Management is largely supportive, though there is much current interest in a possible therapeutic effect of cholinergic drugs. Proposed treatments have included centrally acting cholinergic agents such as physostigmine (too toxic), tetrahydroaminoacridine (Tacrine), donepezil and rivastigmine. The latter two agents have been licensed in the UK for prescription by suitably qualified specialists to selected patients with 'mild to moderate' Alzheimer's

1

1348

MCQ24.12

disease, although the evidence for their efficacy is not compelling. Progressive deterioration of the dementia imposes a considerable strain on families and other carers, and many patients eventually require institutional care. O

LEWY BODY DEMENTIA Diffuse Lewy body disease is a more common cause of dementia in later life than was previously recognized. Pathological changes similar to those of the nigrostriatal degeneration in Parkinson's disease are more diffusely present in the cerebral hemispheres. The clinical syndrome is characterized by striking fluctuations of the degree of dementia and confusion, with visual hallucinations and sometimes paranoid ideation. Features of parkinsonism support the diagnosis, but these may develop later in some cases. Unfortunately, treatment with dopaminergic medication, even in small doses, tends to exacerbate confusion and hallucinations.

PICK'S DISEASE Pick's disease is rare. It consists of tive impairment of speech function atrophy of the frontal and temporal inherited as an autosomal dominant

dementia with selecassociated with focal lobes. It is frequently condition.

CASE STUDY 24.5 POOR MEMORY AND REDUCED JOB PERFORMANCE IN A 67-YEAR-OLD MAN A 67-year-old man presented with impairment of memory and difficulty coping with his job as a shop manager. The symptoms had come on gradually and progressively over a period of 2 or 3 years. His wife commented that he spoke less fluently and was forgetful and absentminded around the house. He had twice been unable to find his car after an afternoon's shopping. There had been some comments from colleagues about his deteriorating performance at work. For several months he had seemed anxious and preoccupied. His sleep was disturbed, he was eating less well, and he had lost interest in most of the things that he usually enjoyed. His previous medical history was unremarkable except that he had required treatment for hypertension for 5 years. There had been no focal neurological symptoms and no angina or other cardiac problems. He had given up smoking in his late 50s. On examination he seemed both anxious and depressed, and was easily flustered during testing of cognitive function. He gave a fairly clear account of his symptoms but there were occasional hesitations in his spontaneous speech. On specific testing his comprehension of complex instructions and questions was not perfect and he had difficulty naming more obscure objects. He performed less well than expected on tests of verbal fluency and mental arithmetic. On a simple test of short-term memory he could recall only four out of nine items after 5 minutes. Errors on simple drawing tasks suggested mild constructional dyspraxia. There were no abnormal findings in the physical examination, in particular no disorder of speech or gait, and no focal neurological signs in the limbs. His blood pressure was slightly raised at 180/95.

Questions 1. What is the clinical syndrome? 2. Are there any locallzing

features? 3. What is the most likely underlying pathology? 4. What further investigations should be done? 5. Is there any effective treatment? ;

Discussion The history suggests a slowly progressive dementing process characterized by impairment of memory, mild dysphasia, dyscalculia and early constructional dyspraxia. There is likely to be involvement of both cerebral hemispheres, particularly temporal and parietal areas, but also frontal speech areas in the dominant hemisphere. Early dysphasia and dyspraxia are more likely to result from cortical pathology than subcortical disease. The diagnosis is likely to be Alzheimer's disease. The other relatively common cause of 'primary degenerative' dementia in later life is cortical Lewy body disease, but this typically presents with a more fluctuating course that includes episodes of confusion, visual hallucinations, and often associated physical symptoms and signs of parkinsonism. The much less common syndromes of frontal or frontotemporal dementia (which include Pick's disease) typically present with a disorder of judgement and behaviour, associated language dysfunction, but relative preservation of perception, spatial skills, praxis and memory. Depressive illness can present with a complaint of deterioration of memory and other aspects of intellectual performance, and this patient has definite features of depression, but the history as a whole suggests that the mood disorder is a

24

secondary reaction to the primary problem of dementia. Although hypertension is a risk factor for multi-infarct disease or dittuse subcortical vascular encephalopathy, there are no features in the history or examination to suggest a vascular basis for the dementia. The slow steady progression and pattern of cerebral dysfunction are in keeping with a degenerative process, with its main impact on the cortical areas discussed above. Other than a careful history and examination, including a detailed assessment of cognitive function, the most important investigation of patients with dementia is brain imaging with CT or preferably MRI. This will usually show nothing more than cortical or generalized cerebral atrophy, or occasionally a more focal or asymmetric pattern of atrophy that helps to refine the diagnosis, but imaging is important to rule out other conditions. Rare structural causes of dementia which are treatable include communicating hydrocephalus, chronic subdural haematoma or a benign frontal tumour. Extensive multifocal vascular disease is visible on CT but is better shown by MRI. Rarely an MRI scan will show unexpected evidence of an inflammatory or neoplastic process. Investigation of dementia traditionally includes routine blood tests to screen for potentially treatable medical disorders such as hypothyroidism, vitamin B12 deficiency and neurosyphilis, but in practice these conditions do not present with the clinical picture described in this patient and the yield from such tests is extremely low. In selected cases the investigation process must be extended to rule out prion disease, HIV-related dementia, other rare low-grade infective disorders within the CNS, cerebral vasculitis, sarcoidosis, toxic causes or paraneoplastic encephalopathy. In these circumstances, useful

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CASE STUDY 24.5 CONTINUED information will occasionally emerge from CSF examination, EEG, cerebral angiography or, rarely, brain and meningeal biopsy. However, it should be emphasized that most cases of dementia are diagnosed on the basis of the clinical features, with or without some supplementary information from brain imaging. The diagnosis is presumptive, as specific pathologies such as Alzheimer's or Pick's diseases can be identified only at necropsy, or in rare instances from brain biopsy material. In this patient a CT scan showed mild generalized enlargement of cortical sulci which was thought to be

slightly more pronounced than expected for the patient's age. There was no evidence of vascular disease in the brain. Routine blood tests were all normal. There is no established treatment for Alzheimer's disease and management of the condition is largely supportive, practical and nonmedical. Trials of medication with centrally acting cholinergic drugs (originally tacrine, more recently donepezil, rivastigmine and galantamine) have shown a modest improvement in cognitive function in some patients with 'mild to moderate' symptoms of presumed Alzheimer's disease. There is continuing debate as

SUMMARY 7 Dementia • Alzheimer's disease (AD) is the commonest cause of dementia in people over 60 years of age. • In the elderly, depression may closely mimic dementia. • AD nearly always presents at over 55 years of age. • Dementia in younger patients must always be thoroughly investigated. • Dementia with abnormal neurological signs as an early feature is unlikely to be AD.

HUNTINGTON'S CHOREA Huntington's chorea is a dominantly inherited condition consisting of chorea and progressive dementia of unknown cause. It is not common, with an estimated prevalence of 1 in 20000.

to whether this translates into an effect that is useful in everyday life for patients and their carers, and so far the use of these drugs has not been sanctioned for general prescription in the UK. Recent interest has focused on the possibility of preventing the relentless accumulation of amyloid plaques in the brain by the use of a vaccine technique. This has shown promising results in an animal model of Alzheimer's disease, possibly even improving performance in some affected mice, but studies in humans have yet to be carried out.

times suicide. The average duration of the disease from onset of symptoms to death is about 15 years. In the advanced stages there is increasing dementia, akinesia and rigidity. O

Management Treatment is purely symptomatic. Neuroleptic drugs such as sulpiride, pimozide or haloperidol may help the chorea to some extent. Genetic counselling is vital. The children of a parent with Huntington's chorea have a 1 in 2 risk of developing the disease, and their children have a 1 in 4 risk. A recent advance has been the identification of a specific genetic mutation on the short arm of chromosome 4, which allows confirmation of the diagnosis in affected individuals, and also presymptomatic diagnosis in their siblings and children. This is clearly an advance, but it also adds to the complexity and ethical difficulties of the counselling process in families with the disease.

Clinical features The onset of symptoms is gradual, usually between 30 and 50 years, beginning with either chorea or early symptoms of dementia, often taking the form of a change in personality. Chorea gradually becomes more marked, and eventually interferes with all voluntary movements. A feature of the early stages of the dementia is some retention of insight which, associated with a knowledge of the family history, can lead to severe depression, and some-

NORMAL PRESSURE HYDROCEPHALUS This disorder is relatively rare but important because of its potential reversibility by surgical treatment with a ventriculoperitoneal shunt. Patients classically present with dementia, bladder disturbance and a disorder of gait (p. 1360).

DEMENTIA DUE TO VASCULAR DISEASE 1

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Fig. 24.11

2

MCQ 24.13

This condition is probably overdiagnosed, as autopsy studies show many suspected cases to have degenerative

pathology of Alzheimer type as well as the vascular lesions recognized during life. However, dementia can result from various patterns of cerebral vascular disease (see p. 1337): • Multiple large cortical infarcts, typically embolic from the heart; • Multiple subcortical lacunar infarcts, typically due to hypertensive small vessel disease, but possibly embolic in some cases; • Diffuse subcortical small vessel disease ('Binswanger encephalopathy'), also seen most often in hypertensive subjects; • Diffuse patchy ischaemic damage following cardiac arrest or profound hypotension; • Cerebral arteritis (very rare). The diagnosis of vascular dementia is likely to be made on the basis of the CT scan appearances and other evidence of vascular disease. Investigation and management involve attention to all vascular risk factors (Table 24.35, p. 1332), particularly hypertension and potential sources of cardiac embolism.

CREUTZFELDT-JAKOB DISEASE (CJD) CJD is a very rare disease which is now known to be associated with the acquisition of an abnormal form of the naturally occurring prion protein, a membrane-based glycoprotein present in most tissues. The transformation of the normal to abnormal form of the protein involves only an alteration of its tertiary structure from predominantly a-helix to B-pleated sheets, with no change of amino-acid sequence, but the dissemination of this process within the nervous system is sufficient to cause rapidly progressive degenerative pathology. The abnormal prion protein can be acquired in at least four ways: • Somatic mutation, the presumed mechanism in the very rare sporadic CJD (1 per million per year), usually arising in later life (average age 65); • Inherited via a point mutation or repeat insertion involving the amyloid precursor protein gene on chromosome 20p. About 15% of all cases; • latrogenic via infected human material on surgical instruments or in transplanted tissues (corneal and dural grafts, pituitary material); • From ingestion of infected animal tissue (BSE to other animals and probably also to humans). The incubation period in infected cases ranges from 2 to 40 years, depending on the entry site and genetic predisposition. The pathology of CJD and other prion-mediated diseases, such as kuru in Papua New Guinea, scrapie in sheep and goats, and bovine spongiform encephalopathy (BSE) in cattle, is a non-inflammatory spongiform vacuolation in grey matter, with neuronal loss, astrocytic proliferation, and sometimes amyloid plaques. The typical clinical picture in classic CJD is of rapidly

progressive dementia with myoclonus and unsteadiness. Other features may include prominent ataxia, parkinsonism, anterior horn cell degeneration, exaggerated startle responses or cortical blindness. Death follows within less than 6 months in 70% of cases. Since 1995 there have been about 40 reported cases of a new variant of CJD which typically affects young people in their teens or 20s. This usually presents with behavioural and psychiatric symptoms, progresses less rapidly than classic CJD, and only later includes ataxia, dementia and myoclonus. Survival may extend over 2 or 3 years. Immunostaining of lymphoreticular tissue from tonsillar or splenic biopsy may provide a useful diagnostic test. The cerebral pathology includes extensive amyloid plaques which stain for prion protein; innoculation studies with transgenic mice have provided strong evidence to suggest a direct link between this new variant syndrome and BSE in cattle. 0

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FURTHER READING ON DEMENTIA Bowler J V 2000 Criteria for vascular dementia: replacing dogma with data. Arch Neurol 57:170-171. Holmes C, Cairns N, Lantos P, Mann A 1999 The validity of current clinical criteria for Alzheimer's disease, vascular dementia and dementia with Lewy bodies. Br J Psychiatry 174:45-50. Mayeux R, Saunders A M, Shea S et al. 1998 Utility of the apolipoprotein E genotype in the diagnosis of Alzheimer's disease. N Engl J Med 338:506-511. Post S, Whitehouse P, Binstock R et al. 1997 The clinical introduction of genetic testing for Alzheimer's disease. JAMA 277:832-836. Rossor M N 1994 Management of neurological disorders: dementia. J Neurol Neurosurg Psychiatry 57:1451-1456. Small G W, Rabins P B et al. 1997 Diagnosis and treatment of Alzheimer disease and related disorders; consensus statement of the American Association of Geriatric Psychiatry, The Alzheimer's Association and the American Geriatric Society. JAMA 278:1363-1371. van Duijn C M 1996 Epidemiology of the dementias: recent developments and new approaches. J Neurol Neurosurg Psychiatry 60:478-488.

CEREBRAL TUMOURS Primary cerebral tumours account for about 10% of all tumours, and about 40% of all intracranial tumours are metastatic; 60% of those are of bronchial origin. Some primary tumours are much more common than others (Table 24.45 and Fig. 24.38). There are considerable differences between tumours in children and those in adults. In children most tumours arise in the posterior fossa, whereas in adults most are supratentorial. Gliomas and meningiomas are rare in children.

Clinical features Cerebral tumours present in four main ways:

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TABLE 24.45 Classification of cerebral tumours Tumour

Origin

Site

Age

Astrocytoma grades I-V

Astrocytes

20 years or more, occasionally in children

Oligodendroglioma Ependymoma Medulloblastoma Ganglioneuroma Primary lymphoma/microglioma Pinealoma Haemangioblastoma Pituitary adenoma Craniopharyngioma Chordoma Meningioma Schwannoma Glomus tumour Cholesteatoma

Oligodendrocytes Ependyma Neurons Neurons Lymphoid Pineal Uncertain Adenohypophyseal cells Epithelial cell rests in Rathke's pouch Notochord remnants Arachnoid Schwann cells Nodose ganglion of vagus Uncertain

Mainly cerebral hemisphere. Also cerebellum and optic nerves Cerebral hemisphere Ventricles Fourth ventricle and cerebellum Fourth ventricle Hemisphere or cerebellum Pineal gland Cerebellum Pituitary gland Hypothalamus Clivus and pituitary fossa Any site of meninges Eighth nerve Jugular foramen Cerebellopontine angle/petrous temporal bone Any part of skull

Hemisphere or cerebellum

Mainly adults

Skull tumours Osteoma Osteosarcoma Myeloma Metastatic carcinoma Metastases

Lung, breast, kidney, colon, thyroid etc.

FIG. 24.38 Approximate relative frequencies of cerebral tumours

• With symptoms and signs of focal neurological deficit • With epilepsy, either focal or generalized (when supratentorial) • With symptoms and signs of raised intracranial pressure • With endocrinological effects (pituitary tumours).

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Cerebral hemisphere tumours A tumour arising in one cerebral hemisphere will eventually cause symptoms and signs of focal neurological deficit. Surrounding cerebral oedema often leads to focal deficit,

20 years or more Mainly children Children Mainly children Mainly adults, particularly in HIV infection Mainly children Children and young adults Mainly adults Children and adults Young adults Adults (40-50 years) Mainly adults Adults Adults Mainly adults

which is greater than that caused by the tumour itself. Epilepsy is a common manifestation, whereas headache is a very variable symptom. Local invasion of the meninges by tumour may cause localized headache. A large hemisphere tumour may cause hydrocephalus, which may occasionally be accompanied by an abrupt clinical deterioration. In general, the deficit produced by tumours is contralateral to the lesion, but a swollen hemisphere may compress the contralateral cerebral peduncle against the free edge of the tentorium, causing a hemiparesis ipsilateral to the tumour. The ipsilateral third nerve may be compressed. These signs of tentorial coning occur as a late feature of a cerebral hemisphere tumour. Papilloedema may or may not accompany raised intracranial pressure and, when present, is often more marked on the ipsilateral side. Posterior fossa tumours Tumours arising in the cerebellum cause gait ataxia if situated medially in the vermis, or of the ipsilateral limbs if situated in one cerebellar hemisphere. Later, compression of the brainstem produces local effects and involvement of the long tracts, Tumours within the brainstem itself (usually gliomas) are rare. Midbrain and pontine tumours lead to ocular gaze palsies, internuclear and upper cranial nerve palsies, and long tract signs. Lower cranial nerve palsies

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FIG. 24.39 Magnetic resonance scan showing a large pituitary tumour in sagittal section The tumour, an adenoma, has extended upwards, out of the pituitary fossa, and is compressing the optic chiasm. (Reproduced by permission of Dr J Stevens and Dr A Valentine.)

occur with intrinsic medullary tumours, but are commoner with extrinsic tumours, such as glomus tumour or meningeal infiltration by carcinoma or lymphoma. Enlarging posterior fossa tumours of any type may obstruct the aqueduct of Sylvius and cause hydrocephalus, with abrupt clinical deterioration. Coning at the foramen magnum may occur with large posterior fossa tumours. The cerebellar tonsils are pushed downwards through the foramen magnum, with accompanying compression of the medulla. Pituitary tumours Pituitary tumours rarely increase intracranial pressure, but may cause headache owing to expansion within the pituitary fossa. Pituitary adenomas may be secretory, presenting with endocrine effects (Ch. 17). Pituitary tumours which expand out of the pituitary fossa impinge on the optic chiasm (Fig. 24.39). The characteristic visual field defect is a bitemporal hemianopia, but temporal field loss in one eye only may occur. Occasionally pituitary tumours expand laterally into the cavernous sinus, involving the oculomotor and trigeminal nerves. Craniopharyngiomas may impinge on the optic chiasm, producing visual field loss identical to that of a pituitary tumour. Cerebellopontine angle tumours The commonest cerebellopontine angle (CPA) tumour is the acoustic neuroma (Fig. 24.40), but meningiomas and, less frequently, other tumours (e.g. epidermoids) also occur at this site. An enlarging extrinsic CPA mass produces progressive deafness (eighth nerve), facial sensory loss (trigeminal nerve), facial weakness (facial nerve) and

FIG. 24.40 Acoustic neuroma Gadolinium-enhanced MRI showing a large, partly cystic mass arising in the left cerebellopontine angle and compressing the brainstem and cerebellum.

then ipsilateral cerebellar signs (see Figs 24.12 and 24.13, p. 1294). Eventually, brainstem compression leads to brainstem and long tract symptoms and signs, and hydrocephalus develops.

Investigation Clinical suspicion of cerebral tumour comes from a history of insidious onset and gradual progression. The absence of neurological signs does not exclude a cerebral tumour. Raised intracranial pressure may give rise to subtle intellectual impairments, and careful assessment of the mental state is an important part of the examination. Skull X-ray. The skull X-ray is of limited value but may be diagnostic in pituitary tumours, in which the pituitary fossa is often enlarged, or in CPA tumours, in which views of the internal auditory meati may demonstrate unilateral enlargement due to bony erosion from an acoustic neuroma. In meningiomas, the skull vault overlying the tumour may become thickened (hyperostosis) and the impression of large draining veins may be apparent. Chronically raised intracranial pressure causes erosion of the skull vault, giving rise to a 'beaten copper' appearance, and there may also be erosion of the posterior clinoid processes. In adults, in whom the pineal gland may become calcified, shift from the midline by an expanding hemisphere tumour may be seen. Certain tumours, particularly oligodendrogliomas and slowly growing astrocytomas, may become calcified, and this is sometimes visible as speckled calcification on a plain skull X-ray. MR scanning, with and without intravenous gadolinium contrast enhancement, is the definitive investigation in patients suspected of having a cerebral tumour (Figs 24.40-24.43), although CT scanning is often an adequate investigation in many patients. Early gliomas and small tumours, particularly in the posterior fossa, may be

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CASE STUDY 24.6 A 64-YEAR-OLD WOMAN WITH DIFFICULTY IN DRESSING, INABILITY TO FIND HER WAY HOME FROM SHOPPING, AND A WITNESSED FIT A 64-year-old woman previously in excellent health was brought to the A&E department by ambulance, following a fit at home witnessed by her husband. While sitting she had lost consciousness without warning, and a generalized convulsion occurred. There was postictal drowsiness but no focal symptoms. Examination in the A&E department revealed no abnormal signs and she was discharged home and told that she would be receiving an urgent appointment for the neurology clinic. Over the next 4 weeks she had several episodes of pins and needles sensation in the left arm, each lasting about 30 seconds. Following these she complained that her left arm felt weak for about 12 hours. She also had difficulty dressing herself and required her husband's help. Finally, on a short trip to the local shops on her own, she became lost and was unable to find her way home. Following this her husband took her to the GP and she was admitted to hospital. On examination she was alert and orientated. She was found to have left-sided visual and sensory inattention and there was mild bilateral papilloedema. The left plantar response was extensor. She was unable to localize stimuli accurately on the left side of the body and was unable to dress without assistance. The remainder of the examination was normal.

Questions 1. What is the anatomical localzation of the lesion? 2. What is the most likely diagnosis? 3. What investigation is needed and what immediate treatment is likely to be given? Discussion The symptoms and signs strongly indicate a lesion in the right parietal lobe. The generalized convulsion was followed by focal sensory fits, then dressing apraxia and topographagnosia, the last two symptoms being particularly associated with non-dominant hemisphere parietal disturbances. Examination, showing left visual and sensory inattention, supports this and the extensor left plantar response indicates a wider disturbance of right hemisphere function, indicated by the bilateral papilloedema.

CASE FIG. 24.5.1 MRI showing large parietal tumour

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1

Figs 24.12

3

Case 24.5

2

Fig. 24.13-24.15

Epileptic fits developing for the first time at this age should always raise the suspicion of an underlying structural lesion. Acute cerebral infarction rarely causes fits, although fits may occur with intracerebral haemorrhage. Fits develop as a late consequence of cerebral infarction in a small minority of patients. In the patient described here there is no history of a stroke-like episode and the initial generalized fit was followed by progressive symptoms. The finding of bilateral papilloedema indicates raised intracranial pressure, and so a tumour is by far the most likely diagnosis. Although not usually presenting with fits as the first symptom, a chronic subdural haematoma should be included in the differential diagnosis. Other diagnoses, such as cerebral abscess or encephalitis, are unlikely with no focus of infection and the normal conscious level at second presentation to the A&E department. Investigation with MRI or CT is urgently required. In this case a large tumour was found, centred in the right parietal lobe and extending into the frontal lobe, with marked mass effect and midline shift (Case Fig. 24.5.1). There was no evidence of a primary tumour elsewhere and the cerebral lesion was solitary. The appearances were consistent with a malignant primary cerebral tumour and the short history, associated with such a large tumour, suggested that this was likely to be a highly malignant astrocytoma. Biopsy and histology revealed a grade IV astrocytoma (glioblastoma multiforme). Radiotherapy was given but there was relentless progression and the patient died 4 months later.

missed on CT scans. MR scanning may demonstrate these lesions. Angiography. Although vascular tumours such as meningiomas can usually be confidently identified on CT scans, neurosurgeons may require detailed information about blood supply only obtainable from angiography.

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FIG. 24.41 Astrocytoma: CT scan A A highly malignant astrocytoma, grade IV (glioblastoma multiforme), showing marked mass effect and irregular contrast enhancement. IT] Low-grade astrocytoma. MRI showing a very large lesion in the left hemisphere, involving the thalamus, basal ganglia, parietal and occipital lobes, with midline shift and extension of the tumour across the midline. There is associated hydrocephalus, caused by obstruction of the cerebral aqueduct by tumour extending down to the brainstem. Histology showed a grade II astrocytoma.

FIG. 24.42 An enhanced CT scan showing a right-sided parasagittal meningioma, arising from the falx This tumour had produced a slowly progressive left hemiparesis developing over 5 years.

Individual cerebral tumours Astrocytomas Astrocytomas are the commonest primary malignant cerebral tumours. They are of variable malignancy, grade I being the least and grade IV being the most malignant. Grade IV astrocytomas are known as glioblastoma multiforme (Fig. 24,41). Survival times of 20-30 years are possible with a grade I astrocytoma, but only about one patient in five will survive longer than 1 year with a glioblastoma multiforme. In adults, the great majority of astrocytomas arise in the cerebral hemispheres, brainstem astrocytomas being rare. A relatively benign form of astrocytoma occasionally occurs in the cerebellum in adults. In children, cerebellar gliomas are often cystic, and long survivals have been reported after resection of these tumours. The optic nerve and hypothalamus are other preferential sites of astrocytoma formation in children. Most astrocytomas remain unilateral in the cerebral hemisphere, but some grow through the corpus callosum to the contralateral hemisphere. These tend to be the histologically more malignant tumours. Slowly growing tumours are associated with less surrounding oedema than rapidly growing ones. Partial relief of oedema with dexamethasone may produce considerable clinical improvement, but the effect is usually short-lived. Oligodendrogliomas Oligodendrogliomas are slowly growing tumours, often partly calcified, arising in the cerebral hemispheres in adults. They carry a relatively good prognosis.

Ependymomas Ependymomas arise from the ependymal cells lining the fourth and lateral ventricles. O They usually present in childhood or adolescence, and tend to run a fairly malignant course. Spread of these tumours may occur via the CSF; thus, wide dissemination sometimes results. Medulloblastoma Medulloblastoma is the commonest CNS tumour in children. The tumour arises in the roof of the fourth ventricle, causing ataxia, local brainstem signs, long tract signs and, eventually, hydrocephalus. They are of variable malignancy. The overall 5-years survival rate with radiation and chemotherapy is 50%. Primary cerebral lymphoma/microglioma These are rare tumours which only arise in the cerebral hemispheres in adults. They are diffusely spreading, highly malignant. There is an increased incidence in AIDS. They respond to treatment with chemotherapy and radiation but relapse is frequent. Meningioma Meningiomas arise from the arachnoid and are benign. The most common sites are the parasagittal region arising from the falx, the meninges of the convexity over the hemispheres, the olfactory groove, and the wing of the sphenoid (Fig. 24.42). 23 They are more common in women, and tend to present over the age of 40 years. Involvement of bone is common in meningioma, with erosion and

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hyperostosis. These slowly growing tumours are extremely vascular and often calcify. Surgical resection may be technically difficult, and the tumours tend to regrow if incompletely removed. Occasionally, malignant change to meningosarcoma occurs. Pituitary tumours The endocrinological aspects of pituitary tumours are discussed in Chapter 17. Prolactinomas are associated with weight gain, amenorrhoea and galactorrhoea. Growthhormone-secreting tumours produce gigantism in childhood and acromegaly in adults. ACTH-secreting tumours cause Cushing's syndrome. Symptoms and signs of hypopituitarism are frequent. Schwannoma Schwannomas arise from the Schwann cells of the peripheral nerves and nerve roots. Within the cranium, acoustic neuromas are by far the most common (p. 1353), but Schwannomas may occasionally arise on other cranial nerves.

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Less common primary cerebral tumours Pinealomas are rare tumours seen mainly in children. They affect the dorsal midbrain, causing a characteristic failure of upward gaze, pupillary abnormalities and, sometimes, other ocular palsies. Ganglioneuromas are uncommon tumours of relatively low malignancy. They occur in children and arise from the floor of the third ventricle. Haemangioblastomas arise in the cerebellum in children or young adults. They may be either solitary or occur as part of the rare Von Hippel-Lindau syndrome (haemangioblastoma in CNS and retina, with renal or pancreatic cysts, hypernephroma and adrenal tumours). Haemangioblastomas are often cystic, with a vascular enhancing area of solid tissue seen on CT scanning. They present with ataxia and then symptoms of brainstem compression and hydrocephalus. Occasionally they secrete erythropoietin, causing polycythaemia. Many are amenable to surgery. Chordomas arise from the primitive notochord structures, the sella and clivus. They cause multiple lower cranial nerve palsies and sometimes invade the brainstem. Craniopharyngiomas arise from epithelial cells in the pituitary stalk. They are slowly growing and often calcify. They cause optic chiasmal compression and compression of the third ventricle, leading to hydrocephalus. Glomus jugulare tumours are highly vascular tumours, the precise cellular origin of which is uncertain. They may arise from the nodose ganglion of the vagus nerve. They give rise to the characteristic jugular foramen syndrome, which includes ninth, tenth, eleventh and twelfth cranial nerve palsies on one side, accompanied by an ipsilateral Homer's syndrome, owing to involvement of the cervical

sympathetic fibres travelling with the carotid artery. Extension into the petrous temporal bone and middle ear causes conductive deafness, and the tumour is often visible through the tympanic membrane. With intracranial extension, brainstem and cerebellar compression may occur. Occasionally these tumours extend into the upper part of the neck, where they may form a visible mass. Bruits over these vascular tumours are common. Cholesteatomas within the petrous temporal bone probably arise from epithelial elements. Their relationship to middle ear disease remains uncertain. They usually present as a CPA syndrome and may involve the middle ear, producing conductive deafness. Cerebral and cerebellar metastases Although metastases commonly cause symptoms, many clinically silent metastases are found at postmortem. Many are multiple (Fig. 24.43) and the cerebellum seems to be a preferential site. The commonest primary tumours are of the bronchus, breast, kidney, colon and thyroid; leukaemia and lymphoma are also common tumours, leading to intracranial metastases. Secondary spread may also occur to other intracranial structures, particularly the meninges, producing a malignant meningitis.

FIG. 24.43 Multiple cerebral metastases These four contrast-enhanced scans show a cerebellar metastasis and multiple hemisphere metastases, in a patient with primary bronchogenic carcinoma.

The neurological non-metastatic effects of systemic malignancy are considered on page 1434.

Differential diagnosis The differential diagnosis of cerebral hemisphere tumours is wide, and includes cerebral abscess, tuberculoma, chronic subdural haematoma, vascular disease and, occasionally, encephalitis. In the posterior fossa, demyelinating disease needs to be considered, together with structural abnormalities such as an Arnold-Chiari malformation (p. 1385).

Management The urgency of treatment of cerebral tumours depends on whether there is raised intracranial pressure, due either to the mass effect of the tumour itself, or to associated hydrocephalus. Fits require anticonvulsants but sometimes prove resistant to therapy. Raised intracranial pressure leading to impairment of consciousness is an indication for urgent treatment to reduce cerebral oedema. Dexamethasone (10 mg immediately, followed by 4mg 4-hourly) is usually effective, an alternative being mannitol (200 mg of a 20% solution given intravenously over 15-30 minutes). Dexamethasone is used pre- and postoperatively to protect against the development of excessive cerebral oedema induced by surgery. Surgery Whenever possible, the aim of treatment for benign cerebral tumours is complete surgical resection. However, inac-

SUMMARY 8 Presentation and investigation of cerebral tumours • Cerebral hemisphere tumours may present with epilepsy, progressive tocal neurological deficit, or signs of raised intracranial pressure (ICP). • Posterior fossa tumours often present with ataxia, with or without focal brainstem and long tract signs. Raised ICP is common with larger lesions, owing to hydrocephalus. • Raised ICP may not be associated with either symptoms or papilloedema. • Pituitary tumours present with a variety of endocrine effects and, characteristically, a bitemporal hemianopia. • Cerebellopontine angle tumours present with unilateral deafness (VIII), facial sensory loss or pain (V), facial weakness (VII), and later, ataxia and long tract signs due to brainstem and cerebellar compression; eventually, hydrocephalus occurs. • If a cerebral tumour is suspected, a CT scan is the investigation of choice. • Lumbar puncture should never be done if a focal cerebral lesion or raised ICP is suspected. • Cerebral metastases are single or multiple and may be indistinguishable on CT from primary tumours. • Stroke, cerebral abscess, tuberculoma or chronic subdural haematoma may mimic cerebral tumour.

cessibility and potential damage to normal tissue often dictates a less ambitious surgical approach. Some benign tumours may recur, but very slowly, and many patients with residual meningioma tissue will have no further problems after the main bulk of the tumour has been resected. The role of surgery for malignant primary cerebral tumours remains uncertain. Biopsy of the tumour to establish the diagnosis and plan further treatment is often advisable. Hydrocephalus should be relieved as soon as possible by ventriculoperitoneal shunting. Although malignant primary cerebral tumours are not curable by surgery, removal of a large part of a tumour may produce improvement and relieve the effects of raised intracranial pressure. Surgery is not without risk of damaging normal cerebral tissue. The usual practice with probable malignant primary cerebral tumours presenting with epilepsy and/or a mild neurological deficit is to delay craniotomy and biopsy until a significant neurological deficit develops. In most cases a definite early diagnosis is unlikely to lead to any change in management. Metastases, both cerebral hemisphere and cerebellar, are often separable from surrounding brain tissue and can, occasionally, be completely surgically removed. Radiotherapy The role of radiotherapy in the management of malignant gliomas remains limited. Recent studies have shown only modest prolongation of survival in patients with any type of adult glioma, and the morbidity of the treatment has to be weighed against the marginal benefits. Radiotherapy is particularly upsetting in older patients, producing headache, nausea, vomiting, malaise and, sometimes, exacerbation of the neurological deficit. At the start of treatment there is often an increase in cerebral oedema, necessitating the use of large doses of dexamethasone. Radiotherapy is usually advised for the more malignant histological types of astrocytoma, but not for astrocytomas grade I. The effect in glioblastoma multiforme (grade IV) is, however, disappointing, and the prognosis is probably not significantly altered (20% survival at 1 year). For grade II astrocytoma the prognosis is marginally improved by radiotherapy. The overall prognosis for astrocytomas grades I-III is about 50% survival at 5 years (Fig. 24.44). However, some lowgrade tumours remain clinically static for many years. Survival for 20-30 years is possible with such tumours. Whole neuraxis radiotherapy for childhood medulloblastoma in conjunction with combination chemotherapy has greatly improved the prognosis. Ependymomas are variably radiosensitive. Radiotherapy is sometimes recommended after surgery for pituitary adenomas and craniopharyngiomas. Multiple metastases are often palliated with a combination of radiotherapy and dexamethasone. The newer techniques of stereotactically directed focal radiotherapy ('radiosurgery') may prove to be more effective than conventional external beam treatment, but controlled trials have yet to be completed. The alternatives at

24

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is not clear why hydrocephalus does not develop if this is the major abnormality.

Clinical features and investigation

FIG. 24.44 Survival curves for astrocytoma grades I-IV

present include tomographically focused external beam radiation, as also used for obliteration of small vascular malformations, or the more invasive photoradiosurgery, in which the radioactive source is directed into the tumour with a stereotactic probe. Chemotherapy The role of chemotherapy for most primary cerebral tumours remains uncertain. Nitrosoureas are the most frequently used agents and confer a small survival benefit. Intracerebral and meningeal leukaemia and lymphoma are treated with a combination of radiotherapy and intrathecal methotrexate (p. 1435). O

BENIGN INTRACRANIAL HYPERTENSION Benign intracranial hypertension (BIH) is also known as pseudotumour cerebri, as it may mimic a cerebral tumour. There is raised intracranial pressure without a demonstrable mass or hydrocephalus.

Aetiology and pathology The cause of BIH is unknown. There is a strong association with obesity and an empty sella. Occasionally, there is a history of a preceding episode of dural sinus thrombosis. Hypervitaminosis A in children may cause BIH, and the prescription of certain antibiotics (including tetracycline and nitrofurantoin) and, occasionally, corticosteroids may precede the development of the condition. Cerebral blood volume is increased in BIH and a disorder of autoregulation has been proposed. There is no evidence that vasogenic oedema occurs in BIH, and the syndrome is probably not due to overproduction of CSF. Reduced absorption of CSF has been demonstrated, but it

BIH is a rare condition most commonly affecting young women. There is headache, with associated malaise and nausea. Visual obscurations are frequent, resulting from papilloedema. Visual acuity may be impaired when papilloedema is severe, with enlarged blind spots and, sometimes, constriction of the visual fields. Reduced colour vision is common. About a third of patients develop diplopia, due to an associated sixth-nerve palsy. Many patients are grossly obese. Patients require a CT scan to investigate a possible mass lesion. The CT scan is either normal or shows small ventricles. When CT scan has excluded a mass lesion lumbar puncture is safe, and the diagnosis is confirmed if an opening pressure of more than 200-250mmHg is recorded. The CSF is normal. Angiography is often needed to exclude venous sinus thrombosis.

Management and prognosis The most important complication of BIH is permanent loss of vision. To prevent this, treatment is directed at reducing intracranial pressure. This can be achieved by repeated lumbar puncture, with removal of 20-30 mL of CSF several times a week, which may induce a remission. Some patients respond to a few weeks of high doses of prednisolone. Diuretics and carbonic anhydrase inhibitors (acetazolamide) may reduce the pressure in some patients. In obese patients there is usually a reduction in pressure with weight loss. In a few patients resistant to all other treatment, lumboperitoneal shunting may be necessary, or optic nerve sheath decompression to protect vision. Spontaneous remission usually occurs after a few months or years, but a small proportion of patients develop recurrent symptoms.

FURTHER READING ON CEREBRAL TUMOURS Kleihnes P, Burger P C, Scheithauer B W 1993 The new WHO classification of brain tumours. Brain Pathol 3:255-268. Patchell R A 1991 Brain metastases. Neurol Clin 9:817-824. Patchell R A, Posner J B 1985 Neurologic complications of systemic cancer. Neurol Clin 3:729-750. Surawicz T S, McCarthy B J, Kupelian V et al. 1999 Descriptive epidemiology of primary CNS tumours: results from the Central Brain Tumor Registry of the United States, 1990-1994. J NeuroOncol 1:14-25. Whittle I R 1996 Management of primary malignant brain tumours. J Neurol Neurosurg Psychiatry 60:2-5.

HYDROCEPHALUS 1

1358

MCQ 24.14

Hydrocephalus is an excess of CSF within the ventricles. The normal production and flow of CSF is detailed in

24

FIG. 24.45 The normal production and flow of CSF The fluid is secreted by the choroid plexus within the lateral, third and fourth ventricles. The direction of flow is from the lateral ventricles into the third ventricle, then via the cerebral aqueduct into the fourth ventricle; from there it passes down the central canal of the spinal cord and (via the foramina of Magendie and Lushka) into the subarachnoid spaces of the basal cisterns; CSF flows within the subarachnoid space downwards around the spinal cord and upwards over the whole surface of the brain before being absorbed into the dural venous sinuses via the arachnoid granulations.

Figure 24.45. Most CSF is absorbed through the arachnoid villi into the dural sinuses, although some is absorbed through the veins of the arachnoid. When there is obstruction to the flow of CSF, and CSF pressure rises, fluid may be forced through the ependymal lining of the ventricles directly into the brain substance. This oedema, most evident in the periventricular white matter of the lateral ventricles on CT scanning (Fig. 24.46), is characteristic of acute obstructive hydrocephalus.

Causes of hydrocephalus The causes of hydrocephalus are listed in Table 24.46. Cerebral dysgenesis Maldevelopment or absence of any part of the brain will lead to a compensatory excess of CSF.

FIG. 24.46 Acute hydrocephalus, showing grossly dilated lateral ventricles, with periventricular lucency, particularly anteriorly, indicating periventricular white matter oedema From a patient with obstruction at the level of the third ventricle.

TABLE 24.46 Causes of hydrocephalus Cerebral dysgenesis Obstruction to flow of CSF At level of third ventricle Hemisphere tumour Tumour involving third ventricle At level of aqueduct Aqueduct stenosis Posterior fossa tumour At level of fourth ventricle Atresia of exit foramina Dandy-Walker syndrome Arnold-Chiari malformation

Impaired CSF absorption Subarachnoid haemorrhage Meningitis Excess production of CSF Choroid plexus papilloma Secondary to cerebral atrophy

Obstruction to CSF flow This may occur within the ventricular system (noncommunicating hydrocephalus) or within the subarachnoid space as a result of failure of absorption or flow through the subarachnoid space (communicating hydrocephalus). A large cerebral hemisphere lesion may compress the third ventricle and obstruct the flow of CSF, producing hydrocephalus in one, or both, lateral ventricles. Very often, a mass lesion in one hemisphere will produce compression of the ipsilateral lateral ventricle and an obstructive hydrocephalus of the contralateral lateral ventricle. Any mass lesion in the posterior fossa may obstruct the flow through the cerebral aqueduct, causing enlargement of the lateral and third ventricles (Fig. 24.47).

impairment of reabsorption of CSF. However, in many cases of communicating hydrocephalus the CSF pressure is found to be normal (normal pressure hydrocephalus, see p. 1360). Communicating hydrocephalus may occur in acute meningitis, and is seen particularly with tuberculous meningitis. It may also occur after subarachnoid haemorrhage, and in diseases in which the CSF protein remains greatly elevated over long periods of time.

Impaired CSF absorption Dilatation of the lateral third and fourth ventricles indicates a communicating hydrocephalus and may result from

Excess production of CSF This occurs very rarely and usually indicates a papilloma of the choroid plexus.

Unknown cause Includes normal pressure hydrocephalus

1359

ventricle, which occupies most of the posterior fossa. In the Arnold-Chiari malformation there is elongation of the medulla, with herniation of the cerebellar tonsils through the foramen magnum, associated with obstruction of the outflow of CSF from the fourth ventricle (see also p. 1383). Very occasionally a posterior fossa tumour in infancy may be the cause of hydrocephalus. Trauma leading to subarachnoid haemorrhage and subsequent hydrocephalus is probably a fairly common cause of infantile hydrocephalus, as is meningitis. In many children, however, the cause of the hydrocephalus cannot be identified with certainty.

FIG. 24.47 CT scans from a patient with an acute cerebellar haemorrhage Blood has a high attenuation and appears as a white mass in the cerebellum. The haemorrhage and surrounding oedema are obstructing the cerebral aqueduct, causing acute hydrocephalus with well-marked periventricular lucencies.

Atrophic Any acquired disease leading to loss of brain volume will result in a compensatory increase in CSF volume, and often ventricular size. However, this is pathophysiologically distinct from hydrocephalus as discussed above. By far the commonest cause is the atrophy associated with Alzheimer's disease (presenile dementia). In this disease, there is both ventricular dilatation and cortical atrophy, giving characteristic CT scan appearances in most cases (Fig. 24.37, p. 1348). Diagnostic difficulties arise when the degree of ventricular enlargement is out of proportion to the extent of cortical atrophy, raising the possibility of an obstructive hydrocephalus.

INFANTILE HYDROCEPHALUS Most infants with hydrocephalus appear normal at birth.

Occasionally hydrocephalus leading to enlargement of the head may be present in utero and cause birth difficulties. About half of those affected have associated malformations of the brain. Congenital cerebral aqueduct stenosis, atresia of the exit foramina of the fourth ventricle and the Dandy-Walker syndrome are the commonest abnormalities. In the Dandy-Walker syndrome there is atresia of the foramen of Magendie, with a failure of development of the vermis of the cerebellum, and a grossly enlarged fourth

1360

Progressive enlargement of the head is the earliest clinical feature, with delayed development, mental retardation, fits, spastic limb weakness (particularly in the legs), optic atrophy and limitation of upward gaze. The condition is often fatal if untreated, but, occasionally, children may survive with a state of arrested hydrocephalus into adult life. They are almost invariably physically and mentally retarded. Investigation of infantile hydrocephalus includes the sequential measurement of head circumference. In suspected cases, investigations include skull X-rays (which show cranial enlargement and separation of the sutures), CT scanning and, in selected cases, contrast radiology. Treatment is with a shunt, which usually arrests further hydrocephalus and neurological deficit.

NORMAL PRESSURE HYDROCEPHALUS The term normal pressure hydrocephalus refers to the presence of ventricular enlargement affecting all the ventricles without cortical atrophy (Fig. 24.48), and with normal CSF pressure (as measured at lumbar puncture).

Clinical features, investigation and management

Aetiology

1

Clinical features, investigation and management

Case 24.6

2

MCQ 24.15

Patients present in adult life with dementia, and, usually, an associated physical neurological deficit, comprising ataxia of gait, pyramidal signs in the limbs and incontinence of urine. In patients with presenile dementia, but without physical abnormalities, diagnostic difficulties may arise in distinguishing normal pressure hydrocephalus from Alzheimer's disease (p. 1346). There may be similar difficulties distinguishing normal pressure hydrocephalus from diffuse small vessel cerebrovascular disease (p. 1337). 1 The pathogenesis of normal pressure hydrocephalus is unknown in most patients. A single measurement of CSF pressure at lumbar puncture is likely to be normal, but monitoring of intracranial pressure over 24-48 hours reveals intermittent periods of raised pressure.

24 FIG. 24.48 Normal pressure hydrocephalus There is gross enlargement of the entire ventricular system. This patient has been treated with a ventriculoperitoneal shunt; the shunt tube can be seen in the right lateral ventricle.

TABLE 24.47 Clinical features of extrapyramidal disease Akinetic-rigid syndrome (Parkinsonism) Akinesia/hypokinesia Bradykinesia Hypertonia: rigidity Distinctive gait

Other disorders of movement and posture (Dyskinesias) Tremor Chorea Athetosis Dystonia Tics

In patients shown to have periods of sustained increased intracranial pressure, the results of ventriculoperitoneal shunting are fair; about half of the patients show some improvement in both intellectual and physical deficits. Occasionally this improvement is dramatic and occurs within days of shunting. 2 FURTHER READING ON HYDROCEPHALUS Vannest J A L 1994 Three decades of normal pressure hydrocephalus: are we wiser now? J Neurol Neurosurg Psychiatry 57:1021-1025.

EXTRAPYRAMIDAL DISEASE The term extrapyramidal disease refers to disorders of motor pathways connecting the subcortical nuclei of the basal ganglia (corpus striatum) with important structures in the upper brainstem, particularly the pigmented neurons of the substantia nigra: hence this system is also referred to as the striatonigral tract. Parkinson's disease and the other less common extrapyramidal syndromes are predominantly degenerative disorders, but potentially reversible movement disorders may also result from subcortical vascular lesions and disturbance of dopaminergic pathways by drugs and toxins. The clinical features of extrapyramidal disease can be broadly divided into states of diminished movement with increased muscle tone (akinetic-rigid syndromes) and

various types of involuntary movement (dyskinesias) (Table 24.47).

Major symptoms of extrapyramidal disease Akinesia means a loss or poverty of movement and is usually the most striking and disabling feature of Parkinson's disease. The terms hypokinesia and akinesia are used interchangeably. Bradykinesia refers to the slowness of movement seen in patients with parkinsonism. Rigidity refers to the increase in tone in the limbs and trunk that frequently accompanies akinesia. It is typically of a cogwheeling type, and may be increased in a limb by asking the patient to clench the fist or tense the leg on the opposite side (reinforcement, or synkinesis). Dyskinesia includes a number of different types of involuntary movement. Tremor is a rhythmical movement of variable amplitude and frequency. The main causes are noted in Table 24.50 (p. 1367). Chorea refers to irregular jerky movements of variable amplitude, usually involving all limbs, the trunk and sometimes the facial muscles, though not simultaneously. In its mild forms chorea may be a discrete physical sign mimicking fidgeting movements. In its severe form, e.g. as in Huntington's chorea (p. 1350), it is readily recognizable. The causes of chorea are listed in Table 24.51. Dystonia refers to the adoption of an abnormal posture of any part of the body of variable duration. Dystonia is often not static, but associated with slow writhing movements of the affected part (athetosis). The term dystonia is now preferred to describe such dynamic abnormal movements in the setting of an abnormal posture. The causes of dystonia are listed in Table 24.52. Tics are rapid repetitive, sometimes semipurposeful movements, usually affecting the face, head or neck. They may resemble myoclonic jerks, but the movement is stereotyped and usually more complex. Unlike other involuntary movements, it is usually possible for patients voluntarily to control tics, but this leads to increasing anxiety and, eventually, resumption of the tic.

PARKINSON'S DISEASE Parkinson's disease is the most common extrapyramidal disease, affecting about 1 in 1000 adults and about 1 in 200

1361

TABLE 24.48 Akinetic-rigid syndromes Parkinson's disease Pure parkinsonism Postencephalitic parkinsonism Neuroleptic drugs MPTP toxicity

Parkinsonism with other neurological features Multiple system atrophy (MSA) Progressive supranuclear palsy (Steele-Richardson syndrome) Lewy body dementia Juvenile Huntington's disease Wilson's disease Bilateral subcortical vascular disease Hydrocephalus (rarely) Some types of cerebral palsy Post anoxic brain damage Toxins (e.g. manganese)

over the age of 65. First described as the 'shaking palsy' by James Parkinson in 1817, this is a slowly progressive condition in which there is akinesia, a rest tremor, cogwheel rigidity and postural abnormalities. Several other disease processes may present with a similar (but not identical) akinetic-rigid state, with or without tremor, and this syndrome is referred to as parkinsonism. The causes are listed in Table 24.48.

Aetiology The cause of Parkinson's disease is unknown. Pathology shows degeneration of the substantia nigra and other brainstem pigmented nuclei. It is currently thought that about 85% of substantia nigra neurons must be lost, with a corresponding decrease in dopamine, before symptoms and signs of Parkinson's disease develop. The search for possible environmental factors has increased following the discovery that a synthetic opiate analogue, MPTP, mistakenly synthesized by opiate addicts a few years ago, can cause an illness identical to Parkinson's disease.

Clinical features

1362

The mean age of onset of Parkinson's disease is 55 years. The symptoms virtually always start on one side and remain worse on that side for the duration of the disease. Tremor is the most common early symptom. Akinesia is often not noticed by the patient in the early stages, but may be commented on by relatives. The clinical features are summarized in Table 24.49. Tremor is initially only present at rest, disappearing transiently on voluntary action. It is a slow (4-6 Hz) tremor, and usually affects the hands first, producing a characteristic 'pill-rolling' movement. It may involve the whole limb, the legs, and sometimes the trunk. It is exacerbated by stress and anxiety and is worse in company. The tremor is often also present on maintained posture, and may thus cause increasing difficulty with everyday tasks, such as

TABLE 24.49 Clinical features of Parkinson's disease Tremor Present at rest or with maintained posture No tremor in minority of patients Akinesia Difficulty initiating ail voluntary movements, together with poverty of movement, leading to: facial masking dysarthria difficulty turning when walking festinant, small-paced gait difficulty turning in bed dysphagia, dribbling of saliva impaired manipulative tasks - dressing, writing Rigidity Cogwheeling type (may be elicited by reinforcement) Postural abnormalities Stooped, flexed posture Poor maintenance of standing posture Tendency to fall when standing still General Symptoms and signs asymmetrical at presentation and throughout illness. (If signs are symmetrized and there is no tremor, consider alternative causes of parkinsonism, particularly if there is no response to drug treatment) Majority of patients show response to dopamine therapy Prognosis: average survival from diagnosis about 10 years Later features 'Freezing', severe akinesia, on-off phenomenon Respiratory problems: aspiration, reduced cough Dysphasia Autonomic dysfunction: urinary incontinence, constipation, orthostatic hypotension (may also be related to treatment), impotence Drug induced dyskinesias, loss of drug effect Confusional states, produced or exacerbated by therapy Psychosis, often with paranoid features Treatment intolerance: side-effects common Dementia develops in some patients: frontal lobe dysfunction common

eating and drinking. The increase in tone causing rigidity is usually cogwheeling in type. Akinesia is frequently the most disabling feature of Parkinson's disease. There is slowness and difficulty in initiating movement, which affects all voluntary activity. Postural abnormalities are common in Parkinson's disease, a stooped flexed posture being typical. There is loss of postural control, leading to falls, both standing and while walking. The abnormalities of motor control outlined above combine to produce all the clinical features of Parkin-

son's disease. These include the abnormal posture, with facial masking, dribbling because of reduced swallowing ability, dysphonia, dysphagia and dysarthria. The combination of dysphonia and dysarthria produces the typical quiet monotonous speech, with a tendency to peter out with continued effort. Difficulty initiating movement leads to pausing before walking (start hesitation), and sudden freezing when attempting to change direction. Difficulty in stopping walking, once started, may lead to festination. There is an increased incidence of dementia in patients with Parkinson's disease. Natural history The course of Parkinson's disease is very variable. Quality of survival has undoubtedly been improved by levodopa treatment, but the drug has probably not greatly altered average survival, which is in the region of 10 years from the onset of symptoms. With initial treatment at the time of diagnosis, about one-third of patients with Parkinson's disease improve markedly, one-third show some improvement and onethird show no significant improvement in terms of regaining function. When there are no signs of improvement at all, the diagnosis should be reassessed and one of the other, less common causes of parkinsonism should be considered (Table 24.50). As a rule, parkinsonism which is not Parkinson's disease does not respond at all well to drug treatment.

Management The pharmacological approach recognizes both that there is a deficiency of dopamine in the corpus striatum and that a balance exists between dopaminergic and cholinergic activity. Levodopa. The introduction of levodopa (L-dopa) revolutionized the treatment of Parkinson's disease. The drug exerts its greatest effect on akinesia. It is now given in combination with an extracerebral decarboxylase inhibitor, either as Sinemet (levodopa plus carbidopa) or Madopar (levodopa plus benserazide), which prevents systemic metabolism of levodopa, thereby promoting higher CNS levels. Much smaller doses of levodopa can thus be given, leading to a reduction in the systemic side-effects of the drug, which include nausea and vomiting, postural hypotension and cardiac arrhythmias. Nausea and vomiting can be further reduced by taking levodopa after food. The drug may produce agitation, poor concentration, hallucinations and a frank psychosis. These effects frequently limit or prevent the use of the drug and are more common in elderly patients, and in those with long-standing Parkinson's disease or coexistent dementia. Excessive levodopa treatment often leads to dyskinetic movements. Controlled-release preparations of Sinemet or Madopar theoretically prolong the duration of action of levodopa and reduce the likelihood of unpredictable motor fluctua-

tions, but this effect is often disappointing in patients with advanced disease.

24

Anticholinergic drugs These agents (e.g. benzhexol and orphenadrine) probably have more effect on tremor than on bradykinesia and rigidity, but they are sometimes useful in early disease. Side-effects of the anticholinergic drugs include blurred vision due to impairment of accommodation (these drugs should not be used in glaucoma), a dry mouth, constipation and urinary hesitancy. Injudicious use in men with prostatic enlargement may precipitate urinary retention. The cerebral side-effects of these drugs include mental agitation, a toxic confusional state, psychosis and occasionally fits. Amantadine which increases the synthesis and release of dopamine, has a week antiparkinsonian effect and is occasionally helpful when there is intolerance to anticholinergic or levodopa therapy. In the early stages Parkinson's disease does not merit drug treatment. If tremor is the major disability, without symptomatic akinesia, either benzhexol (2mg t.d.s.) or orphenadrine (50mg t.d.s.) are recommended. Amantadine (100 mg b.d.) is an alternative. Dopamine agonists These agents act by direct stimulation of central dopamine receptors. The first drugs in this group were bromocriptine and pergolide; more recently licensed agents are ropinirole, cabergoline and pramipexole. These differ in their relative degree of activity at various dopamine receptor sites (Dl, D2 and D3), but their efficacy and side-effect profiles are broadly similar. The agonists are less effective than levodopa in relieving the symptoms of Parkinson's disease and many of their dopaminergic side-effects are predictably similar. They do have an important theoretical advantage as an initial treatment, which is the possibility of postponing the onset of the motor fluctuations and druginduced dyskinesia that almost invariably develop within a few years of starting treatment with levodopa. One trial with ropinirole has demonstrated this effect fairly convincingly. A potential disadvantage of the dopamine ago-

RECENT ADVANCES IN PARKINSON'S DISEASE For patients with intractable motor fluctuations, apomorphine, by intermittent injection or continuous infusion, is being more widely used to control symptoms in advanced disease. Implantation of thalamic stimulators will probably supersede ablative stereotactic surgery (pallidotomy) as a last resort for patients with severe unstable disease. Implantation of fetal midbrain tissue is an alternative surgical approach but remains controversial and is less widely available. 1363

nists is their tendency to cause drowsiness, which may rarely be acute and overwhelming. In severe and very unstable cases, oral dopaminergic therapy can be supplemented or completely replaced by subcutaneous injections of apomorphine. This is a potent dopamine agonist which can only be given by the parental route. Like insulin for diabetes, it can be given by intermittent bolus doses or (more effectively) by a continuous infusion pump. Motor fluctuations often improve and nausea can be controlled with regular domperidone. Enzyme blockade to delay breakdown of levodopa The duration of action of endogenous and administered dopamine may be prolonged by the use of the monoamine oxidase B inhibitor selegiline or the more recently available catechol-O-methyl transferase inhibitor entacapone. These agents can theoretically reduce the incidence of motor fluctuations resulting from abrupt wearing-off of levodopa in more advanced cases. The use of selegiline alone as an initial treatment has also been shown to delay the need for starting dopaminergic therapy. This is probably due to a direct symptomatic effect rather than a delay of progression of the underlying disease via a 'neuroprelective' mechanism, although this point is still debated. A single trial has suggested that the use of selegiline in advanced disease may be associated with increased mortality, possibly due to a higher risk of cardiac arrhythmias and severe postural hypotension, but this observation has not been supported by other studies. Surgical techniques Direct implantation of dopamine-producing cells into the basal ganglia has been shown to produce moderate improvement in patients with advanced disease. Grafts of fetal midbrain tissue (of an appropriate age) are more effective than implants of the patients' own adrenal medullary cells. Stereotactic ablative surgery can also be of some help in carefully selected patients with severe disease which is not responding to medication. The most effective lesioning procedure has been posteroventral pallidotomy, but interest has recently been directed more towards the use of implanted thalamic stimulators rather than Stereotactic ablation within the basal ganglia. In long-standing Parkinson's disease there is often decreasing responsiveness and increasing intolerance to treatment. However, many patients do relatively well and eventually die of causes unrelated to Parkinson's disease. O

1

1364

MCQ 24.16

OTHER AKINETIC-RIGID SYNDROMES Encephalitis lethargica (postencephalitic parkinsonism) Encephalitis lethargica is now a rare illness. It is a parkinsonian syndrome which may occasionally follow encephalitis. The great flu epidemics of the 1920s resulted in many cases of encephalitis lethargica. All the features of Parkinson's disease may be present, but there is a limited response to drug treatment.

Multiple system atrophy The term multiple system atrophy (MSA) is now used to refer to three overlapping degenerative conditions in which parkinsonism is an important feature. Progressive autonomic failure In progressive autonomic failure (Shy-Drager syndrome) there are degenerative changes in the basal ganglia, cerebellum, brainstem and the intermediolateral column of the spinal cord (producing sympathetic dysfunction). Patients often present initially with a syndrome indistinguishable from Parkinson's disease, although tremor is uncommon. Incontinence and impotence are early symptoms and, later, an obvious widespread autonomic disturbance develops, with postural hypotension, failure of sweating and respiratory problems, including sleep apnoea. Olivopontocerebellar degeneration In Olivopontocerebellar degeneration there are severe degenerative changes in the cerebellum, pons and medulla.

SUMMARY 9 Management of Parkinson's disease • When symptoms and disability are mild, in the early stages, drug treatment may not be required. • It tremor is the main problem consider an anticholinergic drug, unless contraindicated (glaucoma, prostatic hypertrophy). • It akinesia is the main problem, start L-dopa with a decarboxylase inhibitor or use a dopamine agonist and introduce L-dopa later. • Aim to alleviate, rather than abolish, the symptoms and signs. • Be aware of the major side-ettects of the drugs, which become much more common in the later stages of the disease. • Intolerance to the drugs, particularly L-dopa, is common later in the disease, and often necessitates reduction of dose and sometimes withdrawal. • Dose-related motor oscillations may be reduced in some patients by giving frequent small doses or by using controlled released Ldopa preparations. • In later stages, motor oscillations are frequently not related to dosage. • Selegiline is useful in some patients with motor fluctuation, but it probably does not slow progression of the underlying disease as previously thought. • Severe motor fluctuations unresponsive to oral therapy may improve with apomorphine treatment. • In severe disease surgery should be considered.

CASE STUDY 24.7 SLOWLY PROGRESSIVE CLUMSINESS AND STIFFNESS OF THE RIGHT HAND IN A 62-YEAR-OLD WOMAN A 62-year-old woman complained of clumsiness and stiffness in her right hand which had become slowly worse over a period of 18 months. This affected her handwriting and her ability to perform other fine manual tasks. She had not noticed any tremor. On specific questioning she also mentioned that her walking seemed slower and she felt awkward moving her body in bed or in the bath. Her family thought that her speech had become quieter and a little less clear. For many years she had been aware of some difficulty with bladder control, but this had been attributed to two difficult childbirths in her early 30s. She had otherwise been physically well in the past. She had been treated on three occasions for depressive illness, once as an inpatient. She was still taking paroxetine 20 mg daily, but could not recall all the other medications used in the past. On examination she had a parkinsonian facial appearance, with infrequent blinking and a diminished range of expression. Her speech seemed slightly dysarthric, although she herself felt that it was unchanged. Eye movements were unremarkable apart from some limitation of full upward gaze. There was increased tone in the neck muscles and in both upper limbs, more obviously so in the right wrist than the left. Dexterity was impaired in both hands, again much more so on the right. There was no tremor. Power and coordination were normal in all four limbs. The tendon reflexes were generally brisk, particularly in the legs, but both plantar responses were flexor. Sensation was normal. She walked rather stiffly, with smaller than normal steps, and there was no swinging of the right arm. General examination was unremarkable apart from a slight postural drop of the blood pressure from 140/85 lying to 130/80 standing.

Questions 1. What is the likely diagnosis? 2. Is any further investigation required? 3. How should the patient be managed?

Discussion She has asymmetrical parkinsonism without tremor, mainly affecting the right hand. By far the most common cause of this presentation is idiopathic Parkinson's disease (PD), which is unaccompanied by tremor in up to 30% of cases. However, absence of tremor, early bilateral limb involvement and the presence of any additional atypical features should always raise the suspicion of other extrapyramidal disorders, of which parkinsonism may be a part. The most important of these is multiple system atrophy (MSA), which may present with parkinsonism, cerebellar ataxia or autonomic dysfunction, or often a combination of some or all of these. Early dysarthria, the history of bladder disturbance and borderline postural hypotension in this patient are other features that might occur in MSA rather than classic PD. Drug-induced parkinsonism is bilateral and in most cases symmetrical, often also without tremor. This patient may have been treated previously with dopamineblocking drugs for her severe depressive illness, but these are unlikely to have any long-term effect (other than the clinically quite distinct syndromes of tardive dyskinesia or dystonia). Paroxetine and other SSRI antidepressants may cause tremor and rarely exacerbate the symptoms of PD, but this is not likely to account for all the present findings. Other conditions which may be mistaken for PD include Steele-Richardson-Olzewski

24

syndrome ('progressive supranuclear palsy'), multifocal subcortical vascular disease and, occasionally, communicating hydrocephalus, although each of these has distinctive features which usually enable the correct diagnosis to be made. The diagnosis of idiopathic PD is based on clinical features alone. Further investigations are therefore performed only when necessary to rule out or support alternative possible diagnoses, namely MSA in this case. It would be reasonable to consider brain imaging, which in established MSA may show focal atrophy of the brainstem and cerebellum. Urodynamic studies might clarify whether the bladder symptoms are due to a central neurogenic mechanism rather than the after-effects of obstetric trauma in the past. Formal autonomic function tests, particularly of the cardiovascular reflexes, may provide evidence of subclinical autonomic involvement. Denervation of the anal sphincter shown by EMG sampling may provide additional collateral evidence in support of a diagnosis of MSA. However, the results of all of these investigations would be normal in PD and possibly inconclusive in the early stages of MSA. The alternative strategy would be to try appropriate medication, which will be necessary anyway, assess the response to treatment, and pursue to further investigation later if the diagnosis remains in doubt. In idiopathic PD mild early symptoms do not necessarily require treatment. When medication is clearly justifiable, as in this case, most neurologists would start treatment with one of the dopamine agonists (pergolide, ropinirole, pramipexole or cabergoline). This is to defer the risk of motor complications of prolonged treatment with L-dopa. Nevertheless, if dopamine agonists were ineffective or poorly tolerated, L-dopa would

1365

CASE STUDY 24.7 CONTINUED then be tried in combination with a dopa-decarboxylase inhibitor (carbidopa or benserazide). A very good response to L-dopa is a further point in favour of a diagnosis of idiopathic PD, but some patients with MSA derive benefit as well, particularly in the early stages. Early use of the MAOI-B inhibitor selegiline may delay the need for Ldopa but there is no convincing

evidence that it slows the progression a physiotherapist and of PD by a 'neuroprotective' occupational therapist would also mechanism. If this woman responded be important. In advanced cases of poorly to both dopamine agonists MSA there may also be severe and L-dopa, and subsequent evolution dysarthria and difficulties with of her illness confirmed a diagnosis of swallowing, requiring help from a MSA rather than PD, other speech therapist and dietitian. A symptomatic treatments may become more serious late complication is respiratory obstruction, particularly at necessary for the management of postural hypotension and bladder night. dysfunction. Practical help from

Clinically, a progressive cerebellar, limb and gait ataxia, with dysarthria and nystagmus, overshadows parkinsonism. Pyramidal signs are also present. Striatonigral degeneration In Striatonigral degeneration there are extensive degenerative changes in the basal ganglia. This is the akinetic syndrome most likely to be confused with Parkinson's disease. All three syndromes comprising MSA are essentially untreatable, there being little or no response to levodopa therapy. Syndromes are relentlessly progressive and survival is much shorter than in Parkinson's disease. Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy) Steele-Richardson-Olszewski syndrome is characterized by parkinsonism without tremor, and a progressive supranuclear ocular (gaze) palsy, widespread pyramidal signs and, sometimes, dementia. Patients present with difficulty in walking or visual symptoms, particularly with reading or looking downwards. The syndrome is rarely helped by levodopa or other drug treatment.

Cerebral anoxia Diffuse cerebral anoxia (usually resulting from cardiorespiratory arrest) occasionally leads to parkinsonism, owing to bilateral basal ganglia infarction with relative preservation of other parts of the CNS. In younger people, carbon monoxide poisoning and severe hypotension with hypoxia in opiate overdosage are the usual causes of this syndrome. The parkinsonism is unresponsive to drug treatment and is sometimes progressive.

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Wilson's disease (hepatolenticular degeneration) Behavioural changes and dyskinesias are the common neurological manifestations of Wilson's disease in childhood, but parkinsonism, often with dyskinesias, is the more common adolescent and early adult presentation (p. 869). The presentation of Wilson's disease in adult life is almost invariably with the neurological manifestations, and patients may present as late as the fifth decade. Although

the basal ganglia bear the brunt of neurological damage in Wilson's disease, copper deposition in the CNS is widespread, with dementia developing in untreated patients. Wilson's disease must be considered in any child or young adult presenting with an extrapyramidal syndrome. Copper deposition in Descemet's membrane at the margin of the cornea may produce a Kayser-Fleischer ring. Copper deposition in the lens may cause a cataract, and deposits in the nailbeds a bluish discoloration. The crucial importance of making an early diagnosis of Wilson's disease is the prevention of further deterioration, and sometimes improvement of symptoms with effective treatment: the options include chelation with penicillamine or trientine. Liver transplantation is also effective for both hepatic and neurological symptoms in selected cases.

DYSKINESIAS: ABNORMAL MOVEMENTS Dyskinesias arising from extrapyramidal disease include certain tremors, chorea, ballismus, dystonia and tics. Many tremors are due to physiological or general medical causes or lesions in other parts of the nervous system. The muscle jerks and twitches of myoclonus, the other important type of involuntary movement, usually result from pathology affecting motor pathways in the cerebral cortex, brainstem or spinal cord.

Tremor Tremor (see also p. 1362) may be classified as: • Postural tremor, when it is maximal with maintained posture • Rest tremor, characteristic of extrapyramidal diseases • Action tremor, due to diseases affecting the cerebellum directly or its connections in the brainstem (Table 24.50). Normal physiological tremor may be exaggerated by anxiety, and is also enhanced in thyrotoxicosis, by sympathomimetic drugs and by alcohol.

Tremor Postural tremor Exaggerated physiological tremor

Cause

Anxiety Alcohol Thyrotoxicosis Drugs (Table 24.79, p. 1440)

Benign essential tremor

Uncertain

Severe brainstem and cerebellar disease

Usually MS Others as for action tremor

Sensory neuropathy (impaired proprioreception)

Usually chronic inflammatory neuropathy (CIDP)

Rest tremor Action tremor

Parkinson's disease Causes of parkinsonism (see p. 1362)

Cerebellar and brainstem disease

MS Infarction or haemorrhage Tumours Hereditary ataxias and spinocerebellar degenerations

Benign essential tremor Sensory neuropathy

24

TABLE 24.51 Causes of chorea

TABLE 24.50 Causes of tremor

Uncertain As above for postural tremor

Essential tremor Essential tremor (also known as benign essential tremor, familial tremor and senile tremor) is the commonest of the dyskinesias. It is usually mild and confined to the hands, but may also affect the head and, very rarely, the legs. The cause remains uncertain. It is a postural tremor which is also present on, but not exacerbated by, action. This differentiates it from cerebellar or parkinsonian tremor. There are no other neurological abnormalities. Emotional circumstances increase the tremor, and unlike with other forms of tremor, small amounts of alcohol have a therapeutic effect. There is a positive family history in at least 50% of cases, and the condition is thought to be dominantly inherited with variable penetrance. B-Receptor blockers such as propranolol help about one-third of patients. Judicious use of alcohol can be recommended in certain patients, and benzodiazepines are occasionally helpful.

Drug-induced Levodopa Dopamine agonists Neuroleptic agents Phenytoin Huntington's disease Sydenham's chorea Chorea gravidarum Chorea with oral contraceptive pill

With systemic disease Thyrotoxicosis Polycythaemia rubra vera Encephalitis lethargica SLE Hypocalcaemia Hypernatraemia Hemichorea or hemiballismus Subthalamic infarction Rarely tumour

now rare. The onset is usually gradual, most cases occurring between 7 and 12 years of age. In only 30% of cases is there a clear preceding history of a streptococcal infection with rheumatic fever. More widespread cerebral disturbance occurs in some patients, who may develop a confusional state or behavioural changes. The pathogenesis of these neurological complications of streptococcal infection is uncertain, but immune complex deposition is likely. Chorea is of variable severity. All the neurological manifestations resolve gradually over 1-6 months. Symptomatic treatment with neuroleptics, such as chlorpromazine or tetrabenazine, may be necessary. A history of Sydenham's chorea predisposes to the later development of chorea gravidarum, or chorea with the oral contraceptive pill or other drugs, such as phenytoin.

Hemiballismus Hemiballismus, or hemichorea, is a dramatic type of involuntary movement in which there are large-amplitude throwing movements of the limbs on one side. It usually occurs acutely in elderly patients, and is the result of infarction involving the contralateral subthalamic nucleus. It very occasionally occurs with a tumour or after head injury. Hemiballismus may rarely be accompanied by a hemiparesis or hemisensory impairment. It usually resolves spontaneously within a few months, but symptomatic treatment with neuroleptic drugs is necessary when the movements are severe.

Dysto.nia Chorea Chorea (see also p. 1362) has a number of causes, listed in Table 24.51. Huntington's chorea Huntington's chorea is discussed on page 1350. Sydenham's chorea Sydenham's chorea, a complication of rheumatic fever, is

The causes of dystonia are listed in Table 24.52. Acute drug-induced dystonia is the most common type; it is usually mild, and is reversible on stopping the offending drug. Cervical dystonia (spasmodic torticollis) Cervical dystonia may occur as an isolated phenomenon or as part of a generalized dystonia. There is involuntary turning of the head to one side, which may be a maintained

1367

TABLE 24.52 Causes of dystonia Focal dystonia Writer's cramp Cervical dystonia ('spasmodic torticollis') Cranial dystonia Hemidystonia (unilateral, due to stroke, tumour etc.)

Generalized dystonia Drug-induced acute and tardive dystonias Antiemetics; prochlorperazine, metaclopromide Neuroleptics Levodopa and dopamine agonists Torsion dystonia Dystonia with other cerebral diseases Hereditary-Gangliosidoses Metachromatic leukodystrophy Wilson's disease Huntington's disease Homocystinuria Acquired - Cerebral palsy Encephalitis lethargica Mitochondrial disease

posture or a rhythmical movement, and there is frequently associated extension of the neck (retrocollis). Onset is usually in adult life without obvious provocation, although occasionally there is a history of trauma to the neck. It may last a few weeks or months, remit and not recur. However, recurrent episodes are common, and in some patients there is no remission. Drug treatment is rarely helpful, but some response may be seen with diazepam, high doses of benzhexol, or propranolol if the dystonia is markedly tremulous. The treatment of choice in most cases is local injection of botulinum toxin into the sternomastoid and sometimes other affected muscles. This produces prolonged neuromuscular blockade, which may last several months. Torsion dystonia (dystonia musculorum deformans) Torsion dystonia is a rare and disabling generalized dystonia of unknown cause. When it presents in childhood there is often a family history, or examination of other family members may reveal milder forms of the condition. Inheritance as an autosomal dominant or recessive trait has been reported. The disease tends to be more severe in children than in the adult-onset group. Typically, dystonic posturing of the trunk and limbs is provoked or exacerbated by voluntary actions.

1

1368

MCQ 24.17

Large doses of benzhexol (up to 120mg a day), sometimes combined with diazepam, offer the best chance of improvement. Attempts at stereotactic surgery may have to be considered, but bilateral thalamotomy necessarily carries substantial risks. Cranial dystonia Cranial dystonia includes blepharospasm, an involuntary closure of the eyelids due to spasm of the orbicularis oculi muscles; and oromandibular dystonia, which refers to involuntary dystonic movements of the tongue, jaw and face which may seriously interfere with speech and eating. The cause of these dystonias is unknown. Cranial dystonia usually starts in middle-age and does not remit. Treatment, as in other dystonias, is unsatisfactory. Neuroleptic drugs are rarely helpful and the best combination is high-dose benzhexol and diazepam. Injection of botulinum toxin into the orbicularis oculi muscles is the treatment of choice for isolated blepharospasm. Writer's cramp Some cases of writer's cramp may be psychogenic, but the condition is widely regarded as being a focal dystonia with an organic basis, albeit of unknown nature. It almost always occurs as an isolated abnormality. Observation of the patient writing demonstrates the problem. The pen is usually gripped awkwardly and/or too tightly, with an abnormal posture of the hand and arm and sometimes of the trunk and head. Writing is slow and laborious, and becomes increasingly illegible with continued effort. The condition may also affect other repetitive, fine manipulative tasks, e.g. musicians often present with a similar difficulty in playing their instruments.

Myoclonus The causes of myoclonus are listed in Table 24.53. Myoclonus may be divided into two major categories, generalized and focal or segmental. Generalized myoclonus may be divided into three subgroups: • Essential myoclonus refers to myoclonus which is not associated with any other neurological abnormality. It is often familial and runs a benign course. • Myoclonic encephalopathies are generalized progressive or static encephalopathies in which myoclonus is a frequent or recognized feature. • Myoclonus associated with epilepsy (see page 1323). Focal myoclonus is rare. Lesions of the cortex or cerebral hemisphere may occasionally be the cause. Palatal myoclonus is indicative of a brainstem lesion involving olivodentatorubral pathways. Myoclonus occurs very rarely with spinal cord lesions. Asterixis The term asterixis is used to refer to the flapping tremor seen in the severe metabolic disturbances of respiratory,

TABLE 24.53 Causes of myoclonus Type of myoclonus Generalized myoclonus Acquired metabolic encephalopathies

Post anoxic

Cause

Uraemia Hepatic failure Respiratory failure Cardiorespiratory arrest Carbon monoxide poisoning

Priori encephalopathy

Creutzfeldt-Jakob disease

Infections

Viral encephalitis Post-measles SSPE

Degenerative disorders

Alzheimer's disease Corticobasal degeneration

Essential familial myoclonus Rare inherited metabolic encephalopathies

Gangliosidoses Lafora body disease

Associated with epilepsy

'Malignant' infantile epilepsies Juvenile myoclonic epilepsy Other generalized epilepsies

Focal myoclonus

Cortical hemisphere lesions Brainstem infarction or tumour Rarely spinal cord lesions

renal and hepatic failure. The same patients may also have multifocal myoclonus of metabolic origin. Asterixis is an irregular lapse of postural stability, best seen in the outstretched hands with the wrists and fingers fully extended. The brief flexion movements, of the hands are sometimes referred to as 'negative myoclonus'.

Drug-induced extrapyramidal disease Chlorpromazine and related drugs (the neuroleptics) may produce a number of extrapyramidal side-effects, including parkinsonism, acute dyskinesias, tremor and tardive dyskinesia. The antiemetics metaclopramide and prochlorperazine also have neuroleptic properties, and may produce acute and chronic extrapyramidal syndromes. Most tremors and dystonias resolve on withdrawal of the offending drug, and involuntary movements can often be acutely stopped by intravenous anticholinergic drugs, such as benztropine. Tardive dyskinesias are the exception. Excessive levodopa or dopamine agonist therapy is a common cause of dyskinesia and dystonia in patients with Parkinson's disease (see also Table 24.78 on page 1436). Tardive dyskinesia Tardive dyskinesia is the most serious side-effect of neuroleptic treatment; it requires at least 6 months of continuous neuroleptic administration. The usual manifestations

are orofacial dyskinesias with a variety of chewing, pouting and lip-smacking movements, combined with a discrete dystonia, or choreiform limb movements and, sometimes, rocking trunk movements. Occasionally the dyskinesias may be incapacitating. Withdrawing the drug responsible leads to a gradual improvement in about half the patients, with resolution over a period of up to 3 years. However, in other patients there is no improvement and in a small minority the dyskinesia is progressive and resistant to all treatment, despite stopping the neuroleptic drug. The frequent prescription of drugs with neuroleptic properties, such as prochlorperazine and metaclopramide, emphasizes the need to take a careful and detailed drug history in all patients presenting with symptoms and signs of extrapyramidal disease.

24

Involuntary movements of the face Abnormal facial movements can arise from disorders at almost every anatomical level within the motor system, as shown in Table 24.54. Focal motor seizures are paroxysmal and distinctive, often also involving the arm and hand on the affected side. Myoclonus is usually bilateral and multifocal, apparent in the limbs as well, typically with other features of an encephalopathic state (Table 24.54). The various extrapyramidal movement disorders have already been discussed above. Facial myokymia is a unilateral rippling movement of the cheek that occurs most often as a symptom of multiple sclerosis affecting the brainstem. Hemifacial spasm is a syndrome of brief irregular twitches affecting the muscles around the eye and mouth on one side. The most common cause is irritation of the facial nerve by an adjacent small blood vessel, often a slightly tortuous branch of one of the cerebellar arteries. The treatment options include carbamazepine, local injections of botulinum toxin into the affected muscles, or (rarely) neurosurgical exploration to decompress the facial nerve. Recovery from a Bell's palsy is often complicated by aberrant reinnervation, which results in inappropriate muscle contraction in one part of the face during movement of another. Partial closure of the eye when smiling is a typical example of this type of synkinesis. O FURTHER READING ON EXTRAPYRAMIDAL DISEASE Calne D B 1993 Treatment of Parkinson's disease. N Engl J Med 329:1021-1027. Marsden C D 1994 Parkinson's disease. J Neurol Neurosurg Psychiatry 57:672-681.

HEAD INJURY In the UK approximately 5000 people die each year as a result of head injury; many others survive, but with some

1369

TABLE 24.54 Movement disorders affecting the face Motor cortex

Focal motor seizures Myoclonus

Extrapyramidal

Chorea (esp. drug-induced) Dystonia (often due to drugs) Isolated blepharospasm Tics Parkinsonian tremor

Brainstem

Myoclonus Facial myokymia Tonic seizures in MS

Facial nerve

Hemifaciai spasm Synkinesis after Bell's palsy

Neuromuscular

Tetany (low Ca2+, Mg2+, K+) Tetanus

FIG. 24.49 Multiple bilateral intracerebral haematomas in a young man with a severe closed head injury In the right hemisphere there is massive oedema, causing midline shift and obstruction of CSF flow, leading to hydrocephalus of the left lateral ventricle.

disability. Road traffic accidents are the commonest single cause, and alcohol can be implicated both in many of these and in other causes of severe head injuries. Fracture of the skull occurs in only a small proportion of head injuries. Its absence does not imply a mild head injury, but the presence of a skull fracture is associated with a greatly increased incidence of intracranial haemorrhage.

Effects of head injury Immediate Severe blows to the head cause shearing forces within the brain, causing diffuse axonal injury, particularly to the white matter, and also focal areas of damage in the cortex and deeper parts of the brain. O Haematomas may develop deep within the hemispheres, often distant from the site of impact. The inferior surfaces of the frontal and temporal lobes are particularly common sites of haematoma formation, because of their rough bony surfaces. Lacerations of the cortex may be produced by depressed skull fractures. Secondary Haematoma formation Haematomas may form at the time of the head injury, but often develop during the first 24 hours and sometimes over longer periods. Their maximum effect on cerebral function may occur at much longer intervals, the most extreme example being chronic subdural haematomas. Intracerebral haematomas may be multiple and are very variable in size (Fig. 24.49). Oedema developing around

1

1370

Figs 24.16, 24.17

2

Fig. 24.17

FIG. 24.50 Right-sided extradural haematoma, associated with a skull fracture There is acute severe cerebral compression.

haematomas will further contribute to a rise in intracranial pressure. Extradural haematomas (Fig. 24.50) develop within hours of head injury in which the skull vault is fractured. They are due to bleeding from torn meningeal arteries, commonly the middle meningeal artery. On arrival at hospital the patient may be alert and orientated, but the conscious level then rapidly deteriorates. Unless promptly treated extradural haematomas may be fatal, or lead to permanent brain damage. Large acute subdural haematomas may produce similar effects, but are less likely than extradural haematomas to lead to a rapid early deterioration of cerebral function. Acute subdural haematomas are relatively uncommon, O probably because bleeding is

due to rupture of cortical veins crossing the subdural space, which occurs more slowly than arterial bleeding. Bleeding into the subdural space usually presents later as a chronic subdural haematoma (p. 1372). Cerebral oedema and raised intracranial pressure Cerebral oedema may result from diffuse cerebral injury without haematoma formation; it also develops around haematomas. The effect is a rise in intracranial pressure which may be life-threatening. Infection There is a risk of meningitis or cerebral abscess with any penetrating injury of the skull. Leakage of CSF through the nose (rhinorrhoea) or the ear (otorrhoea) indicates a basal skull fracture and the potential for meningitis to develop. Fractures involving the nasal sinuses may also lead to infection. Extracranial factors complicating the effects of head injury A compromised airway, chest injury or infection and, rarely, the adult respiratory distress syndrome may all lead to hypoxia. Together with hypotension - usually the result of bleeding in the abdomen or associated with other injury - hypoxia intensifies cerebral ischaemia.

Management Early management The first consideration in the management of head injury is resuscitation (Ch. 14). The airway must be cleared. Intubation and artificial ventilation may be necessary. Shock in head-injured patients is almost always the result of other major injury, and requires immediate correction. Having resuscitated the patient, an initial neurological examination is undertaken. This includes a thorough examination of the skull and scalp, determining any CSF leaks, and assessing the conscious level; it is particularly important to monitor subsequent improvement or deterioration. The Glasgow Coma Scale (p. 1283) provides a simple means of assessment. Neck injuries are a common accompaniment of head injury. The neck must therefore be handled with care until cervical spine X-rays have excluded major bony injury. Definite indications for CT scanning following head injury are a history of loss of consciousness at any time, the presence of scalp bruising or swelling, any neurological signs, a CSF leak or evidence of a penetrating injury. The increasing availability of CT scanning in recent years has resulted in fewer patients having skull X-rays. However, it is still common practice for patients with mild head injury to have a skull X-ray. All patients with a skull fracture demonstrated on X-ray should have a CT scan. However, absence of a skull fracture does not exclude serious intracranial problems in an individual patient, but for patients with a fracture whose conscious level is impaired there is a 1 in 4 risk of intracranial haemorrhage. This compares with a 1 in 30 risk of haemorrhage in patients with a fracture but with a normal conscious level; a 1 in 120

chance in patients without a skull fracture, but with impairment of conscious level; and a 1 in 6000 chance in patients without skull fracture or impairment of conscious level. It is important to know what the conscious level was immediately after the head injury; a history of a lucid interval of consciousness suggests the possibility of an extradural haemorrhage, for which urgent CT scanning and treatment is necessary.

24

Neurosurgical referral Many patients with minor head injury can be rapidly discharged if there is no history of loss of consciousness, no evidence of skull fracture and no abnormal neurological signs. Any patient in whom there has been loss of consciousness for any period must be admitted and observed for 24 hours. Neurosurgical referral in obvious severe head injury is clearly essential. Neurosurgical advice should also be sought for any patient who has suffered a period of unconsciousness lasting for more than an hour, who has abnormal neurological signs persisting for more than a few hours, or who has a skull fracture. Referral is particularly important if there is a basal skull fracture, a compound depressed fracture, or evidence of a penetrating injury. When in doubt, the patient and CT scan should always be discussed with a neurosurgeon. Treatment of intracranial haematomas Extradural haematomas often increase in size during the first few hours after head injury, and prompt evacuation is crucial. Acute subdural haemorrhage is less common, and deterioration in the hours following head injury is not characteristic of this type of bleeding. Large subdural collections need to be evacuated. Large intracerebral haematomas are evacuated, particularly if associated with neurological deterioration or a very poor initial neurological state. Multiple small haematomas are best managed conservatively. CSF leaks usually resolve within a few days and surgical treatment is not necessary. Prophylactic antibiotics should be given. Depressed skull fractures alone do not necessarily require treatment, but if there is cortical damage reduction is necessary, and open fractures require surgical closure of the dura and skin. Cerebral oedema frequently develops after major brain injury, compounding the neurological deficit. Mannitol and frusemide are effective in reducing this, but the use of dexamethasone in the treatment of cerebral oedema resulting from head injury is controversial. Artificial ventilation is often necessary in severe head injury, and ventilation is sometimes used electively to reduce arterial CO2 levels in order to reduce intracranial pressure (see Ch. 14). Whether or not this alters the outcome of brain damage due to head injury is uncertain. Late complications of head injury Persistent physical neurological deficit is the rule after severe head injury. In addition to hemiparesis or quadra-

1371

CASE STUDY 24.8 EPISODES DF EXPRESSIVE DYSPHASIA IN A 69-YEAR-OLD MAN A 69-year-old right-handed man was taken urgently to his GP by his wife. Seven days earlier, while abroad on holiday, he had become unable to express himself but could understand what was being said to him. This episode had lasted about an hour. The next day he had another attack of expressive dysphasia, associated with clumsiness of the right hand, noticed when dressing. These symptoms lasted several hours but had resolved completely. He subsequently attended an A&E department, where he was told that he had had two transient ischaemic attacks. He was advised to stop smoking and to take aspirin 75 mg daily. Over the next few days he had further episodes of expressive dysphasia, some associated with weakness of the right arm, and he also complained of mild headache. He became unusually drowsy at times during the day and his wife thought that he was slow in his thinking, unrelated to the episodic expressive dysphasia.

His past medical history included an inferior myocardial infarct at the age of 60, with uneventful recovery, and he had had a cholecystectomy at the age of 62. There was no history of recent or past head injury. On examination he had a very mild expressive dysphasia but the remainder of the neurological examination was normal. His pulse was regular, blood pressure 170/100, and there were no other abnormal signs.

Questions 1. What is the differential diagnosis? 2. What immediate investigation is needed? Discussion Although the initial symptoms indicated that he was probably having left carotid TIAs, the development of persistent dysphasia, together with headache and drowsiness, was not in keeping with this diagnosis and raised

paresis, dysphasia and visual field defects are common. Cranial nerves are commonly affected (e.g. diplopia is a common and troublesome post head-injury symptom). Cerebellar deficits are fairly common. Brain injury may eventually lead to focal or generalized cerebral atrophy, as well as hydrocephalus. 1 Epilepsy may develop shortly after brain injury or later, sometimes years afterwards. Chronic subdural haematoma Chronic subdural haematoma is more common in older patients. In at least 50% of cases there is no history of any preceding head injury, and in others the injury recalled is usually trivial and not associated with loss of consciousness or other immediate neurological sequelae. Degradation of the subdural blood produces smaller molecules with greater osmotic effect, and the subdural haematoma

1

1372

Fig. 24.18

2

MCQ 24.18

the possibility of alternative pathologies. Top of the list in this age group is a chronic subdural haematoma, suggested particularly by the fluctuating symptoms, though a space-occupying lesion such as a tumour could not be excluded. Chronic subdural haematoma (see below) occurs as a result of previous minor trauma, often not later recalled by the patient, as in this case. Imaging with CT or MRI is the urgent investigation needed in a patient with this history. Patients admitted to hospital with a presumptive diagnosis of stroke, unable to give a clear history either because of drowsiness, confusion or dysphasia, should always be scanned and not assumed to have had a stroke. Chronic subdural haematoma is common in middle-aged and elderly patients. Failure to make the diagnosis may prove fatal, and most patients will make an excellent recovery following burr-hole evacuation of the subdural haematoma.

increases in size over weeks or months, changing into a straw-coloured fluid. This may present with hemisphere symptoms and signs, together with symptoms and signs of raised intracranial pressure. A mild hemiparesis with intellectual deterioration and a fluctuating level of consciousness is the classic, but by no means the only, presentation of chronic subdural haematoma. Papilloedema is often present. Chronic subdural haematomas are bilateral in a proportion of cases (Fig. 24.51). The differential diagnosis includes cerebral tumour or abscess, and chronic subdural haematoma is often misdiagnosed as cerebrovascular disease. Treatment by drainage of the haematoma through burr holes often produces a marked improvement, regardless of the age of the patient. Boxing encephalopathy A combination of progressive cognitive impairment, dysarthria, ataxia, extrapyramidal and pyramidal signs may develop in some boxers. This 'punch drunk' syndrome is the result of repeated blows to the head, and a similar syndrome may result from repeated minor head injury in

24

SUMMARY 10 Acute management of head injury • All patients with head injury must be neurologically examined • All patients with more than very brief loss of consciousness should be admitted and observed for 24 hours • All patients with loss of consciousness after head injury should have a skull X-ray • Patients with scalp bruising or swelling should have a skull X-ray • Patients with a skull fracture, CSF leak, abnormal neurological signs, or suspicion of penetrating injury must have a CT scan, whether or not there was initial loss of consciousness at the time of injury • Patients with prolonged loss of consciousness must have a CT scan • Neurosurgical advice should be sought if: there has been a loss of consciousness of more than 1 hour there are any abnormal neurological signs there is a CSF leak an intracranial haematoma is shown on CT there has been a penetrating injury there is a depressed or compound skull fracture

other sports, e.g. rugby football or diving. The cerebral damage is irreversible. Scans usually show diffuse atrophy. Psychological effects of head injury and the post-traumatic syndrome Amnesia for events after the injury (post-traumatic amnesia) is always longer than that before the event (pretraumatic or retrograde amnesia). The period of posttraumatic amnesia is related to the severity of the head injury. Some intellectual impairment after severe head injury is inevitable. Most improvement occurs within the first few months, but can occur for up to 2 years. Multidisciplinary rehabilitation units are adapting to the needs of increasing numbers of head-injured patients, many of whom are young. Some patients develop a variety of persistent and disabling symptoms after apparently minor head injuries. These usually include headache, positional vertigo, irritability, poor memory and concentration, and a general failure to cope with their usual activities. There are often associated depressive symptoms, and there has been much unproductive debate as to whether such symptoms are due to 'organic' brain damage or psychological factors. In practice the distinction is not possible or helpful. Certainly there are demonstrable neuropsychological deficits in many such patients, and these may result from microscopic shearing lesions affecting axonal fibres in the subcortical white matter and brainstem, attributable to the distortion of brain substance by linear and torsional forces during sudden acceleration and deceleration. This view is supported by the occurrence of very similar symptoms in many patients with whiplash injuries, in whom there has been no direct trauma to the head at all. In some patients with prolonged post-traumatic symptoms there seems little doubt that the degree and duration of disability are determined

FIG. 24.51 Chronic bilateral subdural haematomas On the left hemisphere there is a clear line of demarcation between compressed brain and the subdural collection. The attenuation of the subdural is mainly low, indicating that it is chronic, but there is fresh blood, producing a fluid level in the posterior part of the subdural. There is a smaller right chronic subdural haematoma.

to some extent by the patient's personality and the circumstances under which the injury occurred. Legal proceedings may complicate the issue further, but more often by perpetuating anxiety and uncertainty than by inducing a state of frank malingering. In helping the patient to return to a more normal life, explanation and reassurance about residual symptoms are generally more effective than a dismissive approach. The term post-traumatic syndrome is used to refer to the persistent symptoms that may follow mild to moderate head injury. These include headache (post-traumatic type, see p. 1311) dizziness and vertigo, mild cognitive impairment, usually of memory and concentration, and psychological symptoms of irritability, personality change, anxiety, reduced libido, depression, sleep disturbance and fatigue. Uncontrolled studies suggest that antidepressant treatment is helpful. ©

FURTHER READING ON HEAD INJURY Jennett B 1996 Epidemiology of head injury. J Neurol Neurosurg Psychiatry 60:362-369. Teasdale G M 1995 Head injury. J Neurol Neurosurg Psychiatry 58:526-529.

CEREBRAL PALSY The term cerebral palsy refers to a variety of neurological deficits, mainly affecting motor function, which arise as a result of prenatal insult, birth injury or some illness in early infancy. Implicit in the diagnosis is the assumption that the deficit is static, but it is usually impossible in early life to

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establish the extent of the cerebral injury, which only becomes fully manifest in late childhood. In addition to motor deficits, intellectual impairment and behavioural problems are common. The majority of children with cerebral palsy survive into adult life.

Incidence and aetiology The incidence of cerebral palsy varies from country to country, but is of the order of 2-5 per 1000 liveborn children surviving to school age in the UK. Table 24.55 summarizes the many factors known to be important in the development of cerebral palsy.

Major types of cerebral palsy The classification of the cerebral palsies is descriptive, and is based on the major motor deficit (Table 24.56). Spastic hemiplegia is the commonest type of cerebral palsy. In addition to the hemiplegia there may be a hemisensory and hemianopic visual field defect, and sometimes dysphasia. There are often bilateral lesions, and up to half of these children have learning difficulties. Some have associated choreoathetosis and many develop epilepsy. Spastic paraplegia causes difficulty in walking; the legs often do not develop properly and are short. The upper limbs are relatively spared, although the reflexes are brisk, and there is sometimes clumsiness of the hands. Learning difficulties, fits and squints are all common. Tetraplegia is the result of extensive bilateral cortical damage, which leads to mental retardation and, often, visual and sensory deficits, in addition to a spastic tetraplegia. The visual defect may be cortical in origin, or due to optic nerve atrophy. Squints are common, as is epilepsy. The bilateral upper motor neuron deficit leads to a pseudobulbar palsy. Many children do not survive for more than a few years. In choreoathetosis and dystonia, choreoathetoid movements may not develop for some months postnatally. The early brief choreiform movements may be subtle, and athetosis may not develop until the child is about 2 years old. The involuntary movements often lead to dysarthria, but these children are usually of normal intelligence. In the past, kernicterus was a common cause of this type of palsy. Ataxia, a form of pure cerebellar ataxia thought to be usually due to maldevelopment of the cerebellum, is occasionally seen; it is often associated with mental retardation. Mixed syndromes are common, the most frequent being a combination of a spastic paraplegia and ataxia. There is often associated hydrocephalus, possibly the result of intraventricular haemorrhage prenatally, or birth trauma.

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MCQ 24.19

TABLE 24.55 Factors important in causation of cerebril palsy Antenatal Developmental abnormalities Infections, e.g. CMV, rubella, toxoplasma, syphilis Hypoxia, e.g. placenta praevia, placental haemorrhage, maternal hypotension Pre-eclamptic toxaemia Irradiation Maternal age <20 or >35 years Twins Natal Trauma Breech delivery Prolonged or precipitous delivery

Intracerebral haemorrhage Subdural haemorrhage Intraventricular haemorrhage Subarachnoid haemorrhage

Prematurity Postmaturity Postnatal in preterm infants Cerebral ischaemia Cerebral haemorrhage Hypoxia secondary to respiratory distress syndrome Acidosis Hypothermia Hypoglycaemia Postnatal in children with normal CNS at birth Encephalitis Meningitis Hypoxia, e.g. during cardiac surgery Kernicterus Trauma, including non-accidental injury

TABLE 24.56 Classification of cerebral palsy Spasticity Hemiplegia Paraplegia (diplegia) Tetraplegia Involuntary movements Choreoathetosis Dystonia

Cerebellar ataxia Mixed syndromes

Management The full extent of disability in children with cerebral palsy may not be evident for some years, and it is important from an early stage to recognize potentially treatable additional deficits such as squints, epilepsy and deafness. Physiotherapy has a large role to play, but contractures and other deformities inevitably develop in some children and

may require surgical treatment. Dislocation of the hip is common in spastic legs. The combined efforts of therapists from various disciplines are necessary, together with family counselling and social support. Many children require special education. Specially adapted equipment, such as typewriters and communicators, may be needed to enable the child with severe disability but normal intelligence to communicate. Lack of mobility is a major problem, threatening to deprive children of many educational and recreational opportunities, and special wheelchairs may be needed. Many less severely affected patients with cerebral palsy are able to lead reasonably independent lives.

FURTHER READING ON CEREBRAL PALSY Brett E M (ed) 1991 Paediatric neurology, 2nd edn. Edinburgh: Churchill Livingstone.

CEREBELLAR ATAXIAS The cerebellum is responsible for coordination of all motor activity. Impairment of its function is common in neurological disease, and this may be evident in the control of the eyes, speech, trunk or limbs. Afferents to the cerebellum arise from muscle and joint receptors via fibres travelling in the spinocerebellar tracts; there is also some input from cutaneous afferents, the vestibular system and some visual afferents. For clinical purposes, the cerebellum may be divided into the two hemispheres and the midline vermis. Lesions of one hemisphere produce ipsilateral limb incoordination (ataxia), hypotonia and, sometimes, nystagmus. Vermis lesions cause disturbance of control of truncal movement, leading to the characteristic wide-based unsteady gait. It is also important to recognize that cerebellar signs may be caused either by lesions of the cerebellum itself, or its connections within the brainstem. Thus, lesions confined to the brainstem often produce cerebellar signs. Limb or gait ataxia may also be caused by weakness or sensory impairment, particularly proprioceptive loss.

Hereditary ataxias, spinocerebellar degenerations and hereditary spastic paraparesis The neurological deficit in cerebellar ataxias ranges from a pure cerebellar ataxia (as in autosomal dominant inherited, late-onset cerebellar ataxia), through mixed syndromes, involving spinal as well as cerebellar features (spinocerebellar degenerations), to a pure spastic paraplegia. There are often other neurological and nonneurological associated features.

The hereditary ataxias' Most hereditary ataxias are rare; many are of concern

TABLE 24.57 Causes of cerebellar ataxia in children Congenital malformations Cerebellar agenesis/hypoplasia Dandy-Walker syndrome* Arnold-Chiari malformation**

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Infectious Secondary to bacterial meningitis Secondary to encephalitis Hydrocephalus*

Hereditary ataxias Friedreich's ataxia

Tumours Medulloblastoma

Trauma Birth trauma* Head injury in childhood*

Astrocytoma Haemangioblastoma

*May persist into adult life. **May present in adult life.

principally to the paediatric neurologist, as those affected usually fail to survive into adult life (see Table 24.57). Early-onset hereditary ataxias Friedreich's ataxia, an autosomal recessive condition, is much the most common type of hereditary ataxia. Progressive ataxia of gait and limbs usually develops in childhood and always before the age of 25 years, and is associated with dysarthria, nystagmus, a spastic paraparesis and extensor plantars, but with areflexia due to an axonal sensory neuropathy. A cardiomyopathy is present in about two-thirds of patients, and diabetes in about 10%; some patients are of low intelligence. The ataxia is relentlessly progressive and death usually occurs during the fourth decade from cardiac failure. A similar, but more benign, autosomal recessive condition (also arising in childhood) occurs in which there is no evidence of neuropathy. O Ataxia telangiectasia - an autosomal recessive syndrome of progressive cerebellar ataxia with onset in childhood - is associated with conjunctival and cutaneous telangiectasia. Two important and treatable disorders which include ataxia among other presenting neurological symptoms are Wilson's disease (p. 1366) and Refsum's disease (p. 1399). Late-onset hereditary ataxias A number of hereditary ataxias do not develop until the patient is more than 20 years of age. A pure cerebellar ataxia of onset at over 50 years is occasionally seen. In most patients with dominantly inherited late-onset ataxias the major feature is a slowly progressive gait and limb ataxia, with dysarthria and nystagmus associated with marked cerebellar atrophy (Fig. 24.52). The spinocerebellar ataxias (SCAs) are now being reclassified according to their genetic basis, which does not always correlate closely with the clinical features. At least six numbered SCA syndromes are now recognized, and with the rapid rate of

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SUMMARY 11 Causes of adult onset cerebellar ataxia Inherited Congenital Inflammatory

Neoplastic

Paraneoplastic Vascular Trauma

FIG. 24.52 Cerebellar atrophy CT scan in a patient with a hereditary ataxia, showing severe cerebellar atrophy. The patient had marked ataxia of gait, dysarthria and milder limb ataxia.

progress in molecular genetic research this subclassification is still evolving. Specific genetic tests are now available to establish the diagnosis in these cases. Cerebellar ataxia also occurs as a minor feature of many other inherited metabolic defects, most of which produce widespread neurological deficits, e.g. mitochondrial cytopathy.

Toxic Endocrine Degenerative

Later onset SCA syndromes Rarely Friedreich's ataxia Arnold-Chiari malformation (cerebellar ectopia) Multiple sclerosis Sarcoidoisis Infections (TB, viral) Often metastatic in adults Meningioma, neurofibroma Haemangioblastoma Usually with small-cell bronchial carcinoma Infarction, haemorrhage Arteriovenous malformations Head injury Postsurgical Alcohol, phenytoin, solvent abuse Hypothyroidism (very rare) Multiple system atrophy (MSA)

Wood N W, Harding A E 2000 Cerebellar and spinocerebellar disorders In: Bradley W G, Daroff R B, Fenichel G M, Marsden C D eds Neurology in clinical practice. Oxford: Butterworth-Heinemann, 1931-1951.

DISEASES OF THE SPINAL CORD

Acquired ataxias Mild unsteadiness of gait is extremely common in elderly patients and is often multifactorial in origin. A degree of cerebellar degeneration is common in old age. Iatrogenic drug-induced ataxia is also common, particularly in the elderly, the offending drugs including phenytoin, carbamazepine and benzodiazepines. An acute reversible ataxia is produced by alcohol, but chronic alcohol abuse may lead to a predominantly midline vermis degeneration which is largely irreversible (p. 1438). Cerebellar involvement is common in multiple sclerosis (MS). Mild ataxia may occur in hypothyroidism, and may occasionally be the presenting factor. Cerebellar tumours and some paraneoplastic syndromes can cause ataxia. Pyogenic abscesses and tuberculomas occasionally develop in the cerebellum. Encephalitis may produce a cerebellar ataxia, particularly in children, in whom a pure syndrome of cerebellar ataxia is now recognized. Other causes of ataxia in childhood are listed in Table 24.56. Ataxia arising as a result of foramen magnum and posterior fossa congenital malformations, particularly Arnold-Chiari type I malformations (p. 1385), may present in adult life, without any neurological deficit in early life.

FURTHER READING ON CEREBELLAR ATAXIAS 1376

Harding A E 1984 The hereditary ataxias and related disorders. Edinburgh: Churchill Livingstone.

Anatomy and physiology The spinal cord extends from the foramen magnum to the level of the lower border of the first lumbar vertebra (see Fig. 24.19). The essential features of spinal cord lesions are bilateral symptoms and/or signs, together with impairment of bladder and bowel control, impairment of sexual function in men and, sometimes, a sensory level on the trunk. Partial spinal cord lesions do not produce all these effects; when the signs are unilateral, they may be difficult to distinguish from lesions at higher levels in the nervous system. The major motor pathways in the spinal cord are the corticospinal tracts. These decussate at the level of the lower medulla and descend in the anterolateral columns of the spinal cord, ending on anterior horn cells. The two major sensory pathways are the dorsal columns and the spinothalamic tracts. Dorsal column fibres convey joint position and vibration sensation and some touch. Spinothalamic tract fibres convey information about pain, temperature and some touch. Some spinal cord lesions produce selective sensory tract damage, giving rise to dissociated sensory loss on the trunk and in the limbs. A sensory level on the trunk is a hallmark of spinal cord disturbances, but is present only in a minority of lesions. The sensory level is often several segments below the actual level of the lesion in the spinal cord. The abdominal reflexes are occasionally helpful in determining the level of a thoracic cord lesion. However, the

abdominal reflexes are lost with increasing age and are absent in obese patients. The segmental level of the upper abdominal reflexes is T9, and of the lower T11. It is often not possible to localize the precise level of a spinal cord disturbance on clinical grounds: in most cases special investigation is necessary. Compressive spinal cord lesions may be complicated by disturbances of blood supply that cause additional damage to the cord. Any acute spinal cord lesion may give rise to a flaccid paraplegia with areflexia and non-reactive plantar responses, rather than a spastic paraparesis. It can be difficult to distinguish a spinal cord lesion from a peripheral lesion causing widespread weakness, e.g. an acute Guillain-Barre syndrome. However, involvement of the bladder and the presence of a sensory level will clearly indicate that the lesion is within the spinal cord in most cases. Clinical differentiation of extradural, intradural, extramedullary and intramedullary lesions is often not possible. Some intramedullary lesions, e.g. syringomyelia, give rise to a highly characteristic evolution of symptoms and signs.

Patterns of spinal cord deficit Cervical lesions The cardinal features of spinal cord lesions are listed in Table 24.15, page 1306. The two most common causes of cervical cord lesions are demyelinating disease and cervical spondylosis. Degenerative change is usually most pronounced in the midcervical region at C5-6, and the myelopathy that may be associated with cervical spondylosis is often maximal at this level. Any cervical cord lesion may produce a combination of root signs (leading to lower motor neuron signs in the upper limbs), radicular sensory impairment and a spastic paraparesis. A lesion at C5 or 6 results in sluggish or absent biceps and supinator reflexes, with brisk reflexes below this, including the triceps jerk and lower limb reflexes. The occurrence of a finger jerk when eliciting the biceps or supinator reflexes is referred to as an inverted supinator reflex. Cervical cord compression may give rise to dorsal column sensory impairment in the legs, whereas intrinsic lesions tend to produce spinothalamic disturbances more often than do compressive lesions. Bladder symptoms usually consist of urgency and frequency, eventually with incontinence. Acute cervical cord lesions may result in retention with overflow. Impotence in males is common in cervical cord disturbances. Lesions at C3 or above affect the phrenic nerve outflow and cause respiratory paralysis. Many cervical lesions produce minor symptoms in the upper limbs, such as reflex asymmetry, but the major problem is a spastic paraparesis. Careful examination of the upper limbs is essential in all patients presenting with a paraparesis, as there may be signs helpful in localizing the lesion to the cervical region.

Thoracic cord lesions Thoracic cord lesions cause a spastic paraparesis, with bladder, bowel and sexual impairment, and sensory loss as with cervical lesions. A sensory level on the trunk is particularly helpful in establishing the level of the lesion but, as mentioned above, a level on the trunk may be caused by a lesion in the cervical region.

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Brown-Sequard syndrome The clinical features of hemisection of the spinal cord were first described by Brown-Sequard (Fig. 24.53). This syndrome may be produced by compression or inflammatory disease of the spinal cord and, occasionally, with vascular lesions. There is ipsilateral sensory loss over one or several segments at the level of the lesion, and also ipsilateral dorsal column sensory impairment. Ipsilateral pyramidal signs occur and, sometimes, bilateral pyramidal signs, but these are always worse on the ipsilateral side; there is also contralateral spinothalamic sensory impairment. Bladder and bowel involvement is variable. Conus medullaris Lesions at the conus produce a mixture of upper and lower motor neuron lumbosacral root signs, and are usually caused by a tumour, such as an ependymoma or Schwannoma. The bladder disturbance is usually retention and overflow in a large atonic bladder.

FIG. 24.53 The features of hemisection of the spinal cord, the Brown-Sequard sydrome In addition to the signs shown there is sometimes border zone hyperaesthesia, either at the upper limit of the contralateral spinothalamic sensory loss or in the territory of the ipsilateral root sensory loss, or both.

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TABLE 24.58 Causes of acute or subacute paraparesis

TABLE 24.50 Causes of chronic progressive paraparesis

Trauma to a previously normal spine Infection Vertebral disease Epidural abscess Metastatic carcinoma TB abscess Cervical spondylosis Syphilitic myelitis Dorsal disc prolapse HIV infection Paget's disease Vascular myelopathy Rheumatoid arthritis Pott's disease of spine Vascular Tumours Anterior spinal artery occlusion Infarction secondary to hypotension Extradural or intradural carcinoma, lymphoma, myeloma, Embolic infarction leukaemia Infarction secondary to Dorsal meningioma aortic dissection Neurofibroma Arteriovenous malformation: infarction or haemorrhage Primary intramedullary haemorrhage Haematological disease Vasculitis-PAN Any cause of thrombocytopenia Epidural or Inflammatory Other clotting intraMyelitis of unknown cause disorders medullary haemorrhage Multiple sclerosis Leukaemia SLE Anticoagulant treatment Sarcoidosis Metabolic Subacute degeneration of the cord

Vertebral disease Cervical spondylosis Dorsal disc prolapse Rheumatoid arthritis Pott's disease of spine Ankylosing spondylitis

Investigation and management of spinal cord lesions It is essential in any patient presenting with a spinal cord syndrome - particularly when acute or subacute in onset to exclude spinal cord compression, as this is potentially surgically remediable. Complete loss of bladder function for more than 24 hours cannot be reversed, even if a compressive lesion is relieved, though there may be partial recovery of complete motor and sensory deficits after this time. Table 24.58 lists the many causes of acute and subacute spinal cord lesions, and Table 24.59 lists the causes of chronic progressive paraplegia. Initial investigations include a chest X-ray, which may demonstrate a primary carcinoma or metastases. Plain Xrays of the cervical and thoracic spines may show spondylotic change, lytic change or collapse of a vertebra. Plain CT scans of the spine may be helpful, but patients presenting with an acute or subacute paraplegia will require MR scanning. MRI is the definitive test in establishing spinal cord

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MCQ 24.20

Tumours Meningioma Neurofibroma Glioma Ependymoma Chordoma Lipoma Syringomyelia With Arnold-Chiari malformation With tumour Post-traumatic

Vascular Arteriovenous malformation Inflammatory Multiple sclerosis Sarcoidosis Radiation myelopathy Arachnoiditis Metabolic Subacute combine degeneration of the cord Paget's disease Degenerative Motor neuron disease Hereditary Hereditary spastic paraplegia

Infection Tropical spastic paraparesis (HTLV1 infection) Syphilitic myelitis

compression (Fig. 24.54). In patients in whom no structural lesion is demonstrated, examination of the CSF is particularly important. A raised lymphocyte count and protein content suggest an inflammatory cord lesion. Management. Where there is substantial loss of cord function, and in particular when there is bladder or bowel disturbance, surgical decompression is usually necessary. In the case of destructive malignant disease surgical decompression may need to be accompanied by procedures to stabilize the spine, which may be difficult to achieve in the presence of extensive metastatic disease. The results of surgery are often poor, and urgent radiotherapy alone is increasingly being used in this situation. Dexamethasone in addition may be helpful. O

CAUSES OF SPINAL CORD LESIONS Spinal cord injury Many spinal cord injuries are the result of road traffic accidents and sports injuries. A spinal cord injury may not be suspected initially, particularly when there is associated head injury. All patients with severe head injury require cervical spine X-rays to investigate an associated spinal injury. If cervical spine X-rays show no bony displacement or fracture, the patient can be managed conservatively. If X-rays demonstrate a fracture or displacement indicating

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FIG. 24.54 T2 weighted MRI of the cervical spine in a 68-year-old man with a 9-month progressive history of difficulty in walking; examination revealed a spastic tetraparesis A Sagittal section, showing a prolapsed disc at C3/4, causing cord compression, with signal change visible within the cord. B Axial section at the same level, showing marked narrowing of the spinal cord.

SUMMARY 12 Spinal cord compression • Progressive weakness of the legs and bladder symptoms should be considered to be due to spinal cord compression until proved otherwise. • Total loss of bladder control for more than 24 hours, due to spinal cord compression, is likely to be permanent, even if the compression is subsequently relieved. • Urgency of investigation of cord compression will depend on the speed of progression of symptoms, but is always urgent when bladder function is threatened. • Minimum investigation includes chest X-ray, plain X-rays of the spine, full blood count and ESR and then a spinal MRI. • Investigation of suspected cord compression should always be performed in close consultation with a neurosurgeon.

instability, great care is necessary when moving the patient. Surgical reduction of fractures may be necessary, but many patients are treated with traction in the hope that some neurological recovery will occur. In the elderly with associated cervical spondylosis, spinal cord injury is likely to occur with relatively minor trauma. Hyperextension injuries lead to contusion of the cord in a canal narrowed by spondylotic change. When examining a patient suspected of having a cervical spine injury, it is

important not to move the neck excessively. Neck X-rays must be obtained urgently and neurosurgical advice taken. The management of severe paraplegia due to spinal cord injury is best undertaken in spinal injury units. The condition often results in permanent paralysis. Spinal cord injury in the dorsal region is less common than in the cervical region.

Degenerative cervical spine disease Degenerative cervical spine disease may present with local neck pain, symptoms and signs of a radiculopathy, or evidence of a myelopathy. Neck pain due to a cervical degenerative arthritis is extremely common in middle-aged and elderly people, but in most cases there is no associated neurological deficit. Cervical radiculopathy is caused by narrowing of the exit foramina by osteophyte encroachment combined with disc degeneration and loss of disc space height. The most common level for cervical radiculopathy in degenerative cervical spine disease is at C5 and C6. This causes pain which radiates over the shoulder and into the upper arm, and sometimes diffusely throughout the arm. Signs include wasting, weakness and sometimes fasciculation in deltoid, spinati and biceps, with loss of the biceps and supinator reflexes and sometimes sensory impairment in a root dis-

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tribution. If there are no signs of an associated myelopathy, it is best to treat initially with a firm cervical collar by day, and a soft cervical collar at night. Root pain often settles within a few weeks with this treatment, and motor signs may also improve. In a few patients with evidence of a persistent or progressive radiculopathy, investigation with myelography may be necessary, followed by surgical treatment to decompress the root. Myelopathy. In patients with a myelopathy, with progressive paraparesis, MRI is necessary. With a disc prolapse, surgery is by an anterior approach in which the degenerative disc material is removed and a bone graft inserted (Cloward procedure). For diffuse cervical canal stenosis, which usually occurs in old people, it is often not possible to perform the Cloward procedure at multiple levels and, when indicated, a posterior decompression is preferred.

Thoracic disc Prolapse of a thoracic disc is relatively rare. It may present as a progressive paraparesis. Following investigation with MRI, decompression is necessary, usually via an anterior approach.

Paget's disease

usually all that is required. When there is neurological involvement decompression may be necessary, followed by antituberculous chemotherapy.

Rheumatoid arthritis Rheumatoid arthritis (Ch. 22) may produce diffuse cervical arthritis, but the characteristic lesion is atlantoaxial subluxation. Narrowing of the upper cervical canal is produced by subluxation of the odontoid process. This may present as a chronic progressive tetraparesis. Occipital neuralgia, caused by compression of the upper cervical sensory roots (C2), is a common early symptom. Occasionally the onset of symptoms is abrupt and provoked by minor head trauma. There may also be symptoms of brainstem dysfunction - dysarthria and dysphagia being the commonest - owing to compression of the anterior spinal artery or vertebral arteries by upward displacement of the odontoid process. MRI demonstrates the abnormality (Fig. 24.55). Elderly, very disabled patients with atlantoaxial subluxation can be managed conservatively with a firm cervical collar, but if there is a progressive myelopathy surgery is usually recommended. This involves removal of the odontoid process and posterior stabilization of the upper cervical spine.

Paget's disease occasionally produces localized vertebral involvement in one or several adjacent vertebrae in the thoracic region, which can cause compression. Surgical decompression may be necessary, followed by treatment for the underlying disease.

Pott's disease of the spine Tuberculosis affecting the spine usually occurs in the thoracic region of children or young adults. A single vertebra, or several adjacent vertebrae, may be affected and the onset is insidious. The first symptom is usually back pain, and this is sometimes severe. With gradual destruction of one or more vertebrae a kyphosis may develop. Infection by tuberculosis starts in an adjacent disc and then involves the vertebral body. This leads to collapse of the vertebra, with eventual wedge collapse of one or several adjacent vertebrae and the development of a paravertebral cold abscess. A slowly progressive paraparesis is the usual neurological presentation. X-rays demonstrate rarefaction of the bones and loss of disc space height. The differential diagnosis includes pyogenic infection (which may produce similar X-ray changes) and malignancy. When Pott's disease of the spine is not associated with neurological involvement, antituberculous drugs are

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Case 24.7

FIG. 24.55 Atlantoaxial subluxation MRI showing erosion of the odontoid process, with retro-odontoid soft tissue mass compressing the spinal cord at the level of C1.

Metastases Metastatic deposits of cancer or lymphoma are common causes of acute or subacute paraplegia. Cord compression usually results from extradural deposits, and there is often associated vertebral collapse (Fig. 24.56). Urgent radiotherapy is performed with careful neurological observation, and surgery may be required. O

Primary spinal cord tumours Meningiomas occasionally occur in the thoracic region, usually in middle-aged or elderly women (Fig. 24.57). They present with a gradually progressive paraparesis. The results of surgical removal are usually good. Neurofibromas may develop on spinal roots at any level (Fig. 24.58). These gradually enlarge, producing bony erosion of the exit foramina, and then spread into the spinal canal, compressing the theca and spinal cord. The history is usually of a gradually progressive paraparesis or tetraparesis. Plain X-rays of the spine will often suggest the diagnosis of neurofibromatosis, showing extensive bony erosion (Fig. 24.58A). Intramedullary tumours are rare. Gliomas usually occur in the cervical region in young adults. Some are amenable to partial surgical resection. When an intrinsic tumour causes enlargement of the cord, bony decompression of the spinal canal by laminectomy may be helpful. Some spinal cord gliomas are radiosensitive, so that prolonged survival,

with slow progression, can occur; other tumours run a much more aggressive course. Ependymomas may arise at any level of the spinal cord and are often associated with cysts. Although these tumours are histologically benign, they are often difficult to remove surgically. A lipoma may occur anywhere in the cervical or thoracic spinal cord, as well as the cauda equina, where they are associated with spina bifida and spinal dysraphism. When they cause neurological deficit, partial surgical resection is usually necessary. Chordomas are rare tumours derived from remnants of the embryonic notochord. In the head they arise in the region of the clivus, and in the spinal canal, usually in the sacrococcygeal area.

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Myelitis Acute inflammation of the spinal cord may occur at any level and is usually of unknown cause. In some patients there is a history of preceding viral infection, and myelitis commonly occurs as part of MS. There is usually a history of weakness and sensory loss in the legs progressing over a few days, sometimes leading to a severe paraparesis with a clear sensory level on the trunk. A Brown-Sequard syndrome may result from myelitis. Bladder and bowel involvement are common, and back pain at the level of the lesion is also a common feature.

FIG. 24.56 MRI showing tuberculosis of the spine (Pott's disease) The AP A and lateral B scans show destructive change in the bodies of D5 and D6, with resulting angulation of the spine at these levels. A large collection of tuberculous material (cold abscess) is visible anterior to the spine, extending into both sides of the chest. The scans are from a 22-year-old man, presenting with a 3 month history of thoracic back pain. Although the spinal cord is angulated, it is not yet compressed, though this would be an inevitable consequence if the disease progressed untreated.

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FIG. 24.57 Myelogram showing the midthoracic region in an elderly woman presenting with a slowly progressive spastic paraparesis and a sensory level on the trunk at T10 A large rounded mass is compressing the spinal cord. At operation a meningioma was removed. Myelography is now rarely performed, as MRI provides superior quality non-invasive imaging. However, in patients with cardiac pacemakers, and sometimes other metallic implants, MRI is centralndicated and myelography is then necessary.

Investigation and management MRI is needed to exclude spinal cord compression. The CSF shows a raised lymphocyte count and protein level. Treatment is with steroids or ACTH. In myelitis due to MS there is usually partial recovery of function. In idiopathic myelitis, when severe paralysis occurs, many patients are left with a severe residual deficit.

Epidural abscess Epidural abscesses are usually pyogenic and most often due to staphylococcal infection, usually bloodborne from another site of infection. The history is of a rapidly progressive paraparesis, with local back pain and tenderness, and there is often fever. Urgent surgical decompression and antibiotic treatment are necessary.

FIG. 24.58 Cervical neurofibroma A Plain oblique view of the cervical spine in a woman of 63 years with a spastic tetraparesis. A grossly enlarged exit foramen is present at C3/4. B Axial MRI with gadolinium contrast, showing an enhancing lesion at C3 level on the left side (arrowed). This is widening the neural foramen at this level and extends both intraspinally and extraspinally, the appearances being typical of a dumbbell tumour.

Vascular disease 1

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Figs 24.19, 24.20

2

Fig. 24.21

Vascular disease affecting the spinal cord is relatively uncommon, although some of the neurological deficit seen with compressive lesions may be due in part to inter-

ruption of the blood supply to the cord. Anterior spinal artery occlusion produces an acute paraparesis, often with predominantly spinothalamic sensory impairment. Recovery is variable. Generalized hypotension, embolism and dissection of the aorta can all impair spinal cord blood supply. Arteriovenous malformations may present acutely as a result of infarction or haemorrhage, or there is sometimes a stepwise or gradually progressive paraparesis. The diagnosis is usually apparent on MRI, confirmed by spinal angiography. Some are treatable with interventional radiological techniques, using coils or glue to occlude the abnormal vessels; others are amenable to surgical treatment. Vasculitis occasionally leads to acute spinal cord lesions; this occurs most commonly in polyarteritis nodosa.

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Syringomyelia In syringomyelia a large fluid-filled cavity develops within the spinal cord; it is in communication with the central canal and contains CSF. Syrinxes may be long cysts extending over the whole length of the spinal cord, but are often more localized. They are most common in the cervical region, where they are often associated with Arnold-Chiari malformations (p. 1376). Syrinxes may also be associated with spinal cord tumours and can occur as a late sequel of trauma. The pathogenesis of most syrinxes remains uncertain. However, the fact that there is a frequent association with Arnold-Chiari malformations suggests that partial obstruction to the flow of CSF from the foramina in the roof of the fourth ventricle may play some part. Clinical features The developing cyst impinges on anterior horn cells and produces unilateral or bilateral (often asymmetrical) wasting, affecting particularly the small hand muscles, O but eventually also other muscles in the upper limbs. Interruption of the decussating spinothalamic fibres centrally in the spinal cord leads to a dissociated sensory impairment in the upper limbs involving pain and temperature sensation, with preservation of other modalities. Because the spinothalamic fibres from the lower limbs have decussated lower down in the cord and their fibres lie laterally in the spinothalamic tracts, there is no impairment of spinothalamic sensation in the lower limbs. Eventually, the corticospinal tracts become involved, producing a spastic paraparesis; a late feature is involvement of dorsal column sensation (joint position and vibration sensation). The dissociated sensory impairment in the hands leads to painless traumatic lesions of the fingers. The upper limb reflexes are usually absent. In the legs, a mild paraparesis develops. Syringomyelia is usually slowly progressive and the chronic loss of pain sensation may lead to the development of Charcot joints in the hand, elbow or, occasionally, shoulder joints.

FIG. 24.59 Syringomyelia MRI showing a large syrinx which extends the whole length of the spinal cord, associated with elongation of the medulla and cerebellar tonsils, which descend through the foramen magnum.

Occasionally, cervical syrinxes may extend into the brainstem (syringobulbia), affecting the lower cranial nerve nuclei and producing dysphagia and dysarthria. There may be sensory loss of spinothalamic type on the face, owing to the involvement of the spinal nucleus and tract of the trigeminal nerve. Investigation MRI demonstrates syrinxes clearly (Fig. 24.59). O Management and prognosis When there is an associated Arnold-Chiari malformation, foramen magnum decompression may arrest the further progression of the syrinx in some (but not all) patients. The more recent operation of syringoperitoneal shunting is now preferred by some neurosurgeons. The prognosis is variable. In some patients the neurological deficit arrests after a time, whereas in others there is relentless progression.

Subacute combined degeneration of the cord Long-standing B12 deficiency in pernicious anaemia may lead to degeneration of the lateral and posterior columns of the spinal cord, together with a peripheral neuropathy. This produces the clinical syndrome known as subacute combined degeneration of the cord. There may be an associated

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mild dementia and optic atrophy. Patients with subacute combined degeneration are usually middle-aged or elderly. Paraesthesiae or pain in the hands and feet are frequent presenting complaints; there are often few signs in the early stages, but a progressive paraparesis soon develops. Only some patients are anaemic; a normal haemoglobin does not exclude this diagnosis, but a macrocytosis is invariably present (Ch. 23). Treatment with parenteral B12 is usually beneficial, but an established severe paraparesis and peripheral neuropathy may not respond well. O

Motor neuron disease Motor neuron disease (MND) may present as a slowly progressive spastic paraparesis. MND is considered further on page 1388.

Radiation myelopathy Occasionally, damage to the cervical spinal cord occurs following radiotherapy to the neck for conditions such as Hodgkin's disease. Symptoms of a progressive myelopathy usually develop between 6 months and 5 years after radiotherapy. The myelopathy may be mild, but in some cases it is steadily progressive and leads to a severe deficit.

Sarcoidosis Sarcoidosis has many neurological manifestations (p. 1431) and is a rare cause of myelopathy.

Hereditary spastic paraplegia Hereditary spastic paraplegia - of dominant inheritance, often with variable penetrance - takes the form of a slowly progressive paraplegia without sensory deficit. Bladder and bowel involvement is often a late feature and may be absent. Onset is usually in the second or third decade. Paraparesis associated with the spinocerebellar degenerations is considered on page 1375.

Tropical spastic paraparesis A slowly progressive paraparesis caused by HTLV1 infection is seen in the tropics and migrants from these countries. There is sometimes an associated mild peripheral neuropathy. The condition was previously known as Jamaican neuropathy, but the spinal cord disturbance tends to dominate the clinical picture. Occasionally other lesions, such as optic atrophy and ataxia, are present. The paraparesis is usually slowly progressive and may remain mild.

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MCQ 24.21

2

Figs 24.21, 24.22

3

Case 24.8

The infection is sexually transmitted and maternofetal transmission is recognized.

DEVELOPMENTAL ANOMALIES AFFECTING THE SPINAL CORD Spina bifida Spina bifida refers to defective fusion of the vertebral arches. Aetiology The cause of spina bifida in most patients is unknown, but there is an association with trisomy 13 or 18 in a few infants. The condition is commoner in girls. There has been a decrease in the incidence of spina bifida in recent years, the reason for which is uncertain. There is now evidence that folic acid deficiency early in pregnancy causes spina bifida. The anticonvulsant drugs sodium valproate and carbamazepine are also associated with a slightly increased incidence of spina bifida. Clinical features Defective fusion of the vertebral arches is most common in the lumbar region. It is extremely common in a single lumbar vertebra and is an incidental radiological finding of no significance in many normal people. However, when the defect of the vertebral arches extends over several segments, there may be associated abnormalities. These include: • A tuft of hair overlying the defect • A low, tethered spinal cord extending below the lower border of L1 • A dermal sinus extending towards the spinal canal • Intraspinal lipoma • Sometimes, diastematomyelia (splitting of the spinal cord). Neurological problems associated with this type of bony abnormality are collectively known as spina bifida occulta. However, an extensive bony abnormality may be present without any neurological deficit. Spina bifida cystica Spina bifida cystica is a more severe defect in which the meninges prolapse through the bony defect of the vertebral arches. They may prolapse without including neural tissue (a meningocele), or may include neural elements (a meningomyelocele). In its most severe form, spina bifida leads to a wide-open defect without covering of the cauda equina; this is known as rhachischisis. With meningocele and meningomyelocele there is nearly always an associated Arnold-Chiari type II malformation (see below), with hydrocephalus and a kyphosis. Management. Meningoceles require closure, but following this, some infants develop hydrocephalus and will require shunting. Spina bifida cystica is associated with obvious cauda equina problems at birth, with paralysis of

the legs. The decision on whether or not to treat some of these infants remains controversial. If nothing is done, death from meningitis is almost inevitable. Treatment consists of closure of the defect and shunting for hydrocephalus. With such measures many of these children will survive. However, most will be severely handicapped and will require further operations later for contractures and other problems resulting from their severe neurological deficit.

ondary hydrocephalus. This malformation is often associated with other major brain and spinal cord malformations. The abnormality is usually obvious at birth, though it occasionally presents later in childhood, with ataxia. Shunting of the hydrocephalus is necessary, sometimes together with posterior fossa surgery.

Spina bifida occulta Spina bifida occulta may present in childhood, adolescence, or adult life. Many of these patients have a partial cauda equina syndrome. There is often a long-standing history of bladder difficulties, with enuresis, frequency and, sometimes, incontinence during the day. The signs of cauda equina deficit in the legs may be relatively mild or be fairly obvious, with underdeveloped, short legs and muscle wasting. Investigation and management. Patients whose symptoms (particularly bladder symptoms) are progressing warrant investigation with myelography. This may demonstrate a low tethered cord, some degree of spinal dysraphism and, occasionally, a lipoma or haemangioma. Surgical intervention seldom produces improvement; the aim is to prevent further progression. This may be achieved when a lipoma or haemangioma is present, and in some cases of spinal dysraphism, but release of a tethered cord alone does not usually produce any benefit.

The Klippel-Feil deformity consists of fusion of two or more cervical vertebrae, sometimes involving most of the cervical spine. There may be abnormal and unstable joints in the cervical spine. The neck is short and the posterior hairline is low. There is often associated platybasia and other abnormalities of the petrous temporal bone, which lead to conductive deafness in some patients. There is also an association with syringomyelia. The presence of incomplete decussation of the pyramidal tracts often produces the curious physical sign of mirror movements. Patients with the Klippel-Feil deformity may present with a gradually progressive tetraparesis or a cervical radiculopathy, but occasionally with a sudden onset of tetraplegia following minor neck trauma, as a result of instability in the cervical spine. They may also present with symptoms and signs of syringomyelia.

Arnold-Chiari malformations Arnold-Chiari malformations are of two types. In type I malformations there is cerebellar tonsilar herniation through the foramen magnum, often associated with syringomyelia (Fig. 24.59). O Most patients present in adult life, either with symptoms and signs attributable to the syringomyelia, or with ataxia, lower cranial nerve palsies, nystagmus and a mild spastic tetraparesis. Treatment is initially by foramen magnum decompression, and sometimes later shunting of the syrinx. O In type II malformations there is herniation of the cerebellar vermis and tonsils, and of the lower part of the brainstem through the foramen magnum. There is associated hydrocephalus, and, as mentioned above, there is a strong association of the type II malformation with meningomyeloceles. The type II malformation usually presents in infancy, with dysphagia causing feeding difficulties. There may be associated platybasia, an upward displacement of the skull base. The treatment is to shunt the hydrocephalus and perform a foramen magnum decompression.

Dandy-Walker syndrome Dandy-Walker syndrome is a severe congenital abnormality in which there is hypoplasia of the vermis of the cerebellum, with massive cystic dilatation of the fourth ventricle and expansion of the posterior fossa; there is sec-

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Klippel-Feil deformity

FURTHER READING ON SPINAL CORD DISEASE Byrne T N, Waxman S G 2000 Paraplegia and spinal cord syndromes. In: Bradley W G, Daroff R B, Fenichel G M, Marsden C D, eds Neurology in clinical practice. Oxford: ButterworthHeinemann, 367-380. Grundy D, Swain A 1993 ABC of spinal cord injury, 2nd edn. London: BMJ Books.

DISEASES AFFECTING SPINAL ROOTS

Anatomy and physiology Dorsal and ventral spinal roots are given off by every segment of the spinal cord; thus, there are eight cervical, 12 thoracic, five lumbar, five sacral and one coccygeal pair(s). The dorsal and ventral roots join in the intervertebral foramina. The lumbar and sacral roots pass downwards, below the lower end of the spinal cord, which terminates at the lower border of the L1 vertebral body (conus medullaris); the lower lumbosacral roots form the cauda equina below this level. The sympathetic outflow from the spinal cord travels in the Tl to L1 roots; the caudal parasympathetic outflow is localized to the S2-S4 roots. An important part of the blood supply to two watershed regions of the spinal cord enters via roots, one in the lower cervical region, one at the thoracolumbar junction, the artery of Adamkiewicz. Interruption of the arteries travelling on these roots may critically impair the blood supply of the cord, causing infarction.

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TABLE 24.60 Clinical features of spinal nerve root lesions • Motor Wasting Fasciculation (acute or subacute lesions) Segmental Weakness distribution Reduced or absent reflex, in appropriate segment • Sensory Pain Numbness Segmental Paraesthesiae distribution Sensory loss • Spinal pain • Myelopathy may be an associated feature, depending on the nature and extent of lesion

Effects of root lesions The clinical effects of root lesions may be both negative and positive (Table 24.60). Negative effects include segmental wasting and weakness, sometimes with reflex loss if an appropriate root is affected, and a dermatomal sensory impairment. Positive effects are sensory - root pain which may or may not be clearly localized, paraesthesiae and hyperaesthesiae. Root pain due to structural lesions which tether the root and inhibit movement may be exacerbated by spinal movement and by manoeuvres that increase intraspinal pressure, such as coughing, sneezing and straining. The commonest cause of root lesions is degenerative spine disease affecting the middle and lower cervical discs and vertebrae (C4/5, C5/6 and C6/7), and the lumbar region, especially L4/5 and L5/S1.

Cervical spondylosis Spondylosis is the term used loosely to describe the degenerative changes that often occur in the cervical and lumbar regions (Ch. 22). The spinal canal is narrowed by these degenerative changes which, in the cervical spine, are usually most marked at C4-5, C5-6 and C6-7. Clinical features Cervical spondylosis presents in three ways: • With local pain related to the degenerative changes, but without neurological involvement; • With root compression, either motor, sensory or both; • With spinal cord compression.

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MCQ 24.22

Root or cord compression may develop gradually over long periods of time, or may present acutely, usually as the result of a disc prolapse. If a root is compressed by the disc protrusion, pain and paraesthesiae in a radicular distribution are usually the first symptoms, sometimes followed by motor symptoms and signs appropriate to the root involved. Acute disc protrusions may also cause symptoms and signs of cord compression. Diagnosis In many patients the signs indicating a root (rather than a peripheral nerve or brachial plexus) basis for the symptoms are not clear-cut. EMG and nerve conduction studies can be helpful. Plain cervical spine X-rays with oblique views to show the intervertebral foramina may provide indirect evidence of nerve root compression. The lesions are shown definitively by MRI (Fig. 24.60). Although root pain is usually due to a disc protrusion there are a number of other causes, including compression in malignant vertebral body collapse, and other spinal tumours. Malignant invasion of the brachial plexus must also be considered (p. 1399). Management In patients with minor symptoms of cervical root compression a period of rest in a firm cervical collar, together with analgesia, will often help the pain and aid the spontaneous resolution of the signs over several weeks. Continuing severe pain, the failure of signs (particularly motor) to improve and progression of signs are indications to investigate further with MRI. MRI is also indicated if there are signs of cord compression (p. 1378). A disc causing continuing pain and neurological deficit may be surgically removed via facetectomy or foraminotomy from a posterior approach, or anteriorly through the disc with vertebral body fusion, using a bone graft (Cloward's procedure). O

Lumbar spondylosis Low back pain is experienced by virtually all adults at some time (Ch. 22). In most cases the cause cannot be identified with confidence. Pain radiating down one leg is not always due to root compression: musculoskeletal pain may radiate in a similar way. The two roots most commonly compressed by prolapsed lumbar discs are the L5 root (by a prolapsed L4-5 disc) and the S1 root (by an L5-S1 prolapse) (see Table 24.61). L5 root pain is felt on the lateral aspect of the leg and dorsum of the foot, while S1 pain tends to radiate down the back of the leg to the sole of the foot. However, many patients are unable to clearly localize their pain. With L5 root compression, there is partial weakness of dorsiflexion and eversion of the foot. As extensor hallucis longus is supplied by L5 alone it is relatively weaker, and this is helpful in distinguishing a root

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FIG. 24.60 Lumbar disc prolapse causing root compression A Sagittal MRI showing a degenerate disc at L5/S1, which has prolapsed posteriorly into the spinal canal. B Axial MRI in the same patient, showing that the prolapsed disc is causing compression of the exiting left SI root (arrow).

TABLE 24.61 Lumbar spondylosis: common signs of disc prolapse Root (disc)

Symptoms

Motor signs

Sensory signs

L5 (L4/5 disc prolapse)

Pain in lateral aspect of leg, dorsum of foot and hallux*

Wasting of tibialis anterior

Reduced sensation in L5 distribution

Numbness and paraesthesiae in dorsum of foot and hallux

Weakness in dorsiflexion of foot; more marked weakness of extensor hallucis longus

Limited SLR with pain

Lumbar back pain S1 (L5/S1 disc prolapse)

Pain in buttock, posterior thigh and calf, sole of foot1

Wasting of gastrocnemius/ soleus

Reduced sensation in S1 distribution*

Numbness and paraesthesiae in lateral border and sole of foot

Weakness in plantar flexion and toe flexion

Limited SLR with pain

Absent ankle jerk Lumbar back pain *Pain often described as 'sciatica'; see Fig. 24.20, SLR = straight leg raising.

lesion from a peroneal nerve lesion. Sensory loss will be within an L5 distribution. With S1 lesions it is difficult to detect minor degrees of weakness of gastrocnemius soleus because of its strength. However, there may be reduction or loss of the ankle jerk and, on sensory testing, impairment of sensation on the lateral border of the foot and on the sole. In either L5 or S1 lesions due to compression by a disc, the tethering of the root by the disc may cause a

positive root stretch test; straight leg raising is the standard test for this. Back and/or leg pain with focal neurological signs may settle with a period of bed rest, and traction is sometimes helpful. However, the continuing presence of focal signs is an indication for investigation with MRI, with a view to decompressive surgery.

Lumbar canal stenosis The combination of a congenitally narrow lumbar canal with subsequent degenerative change leads to canal stenosis. This may cause low back pain, together with focal signs, sometimes indicating a lesion of more than one root. The syndrome of cauda equina claudication is almost always associated with lumbar canal stenosis; its symptoms are thought to be due to impairment of the blood supply of the roots of the cauda equina, secondary to the canal stenosis. The history is pain, numbness, paraesthesiae or weakness in the legs or buttocks, provoked by exertion and relieved by resting; symptoms often resolve more rapidly when the lumbar spine is flexed, i.e. in a sitting posture. The symptoms may mimic vascular claudication in the legs, but numbness and paraesthesiae (when present) are a helpful clue to the diagnosis. There may be no abnormal neurological signs at rest, but sometimes, immediately after exertion, focal signs may develop. Foot pulses are normal. MRI confirms the stenosis, which is often pronounced at several disc levels, presenting a formidable surgical challenge.

Cauda equina lesions Cauda equina lesions usually cause bilateral symptoms and

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signs involving the buttocks, perineum and legs, together with bladder and rectal involvement. The bladder symptoms comprise reduced sensation, both of bladder filling and of urethral sensation, with difficulty voiding, a poor stream, and incomplete emptying. Eventually, painless retention with overflow incontinence develops. Constipation and faecal soiling may occur. It is essential to examine sensation on the buttocks and perineum in any patient with unexplained loss of bladder or rectal sphincter control. The development of bladder symptoms is an indication for urgent MRI. Acute cauda equina compression can result from a central (directly posterior as opposed to posterolateral) disc protrusion. Another common cause is metastatic carcinoma or malignant infiltration. Other lesions occasionally affecting the cauda equina include neurofibromas, Schwannomas, lipomas, meningiomas and ependymomas. Spina bifida is considered on page 1384.

Thoracic disc prolapse Thoracic disc prolapse is relatively rare and usually causes cord compression rather than root symptoms. The diagnosis is confirmed by MRI. Surgical treatment is hazardous, and a lateral or anterior approach is necessary.

MOTOR NEURON DISEASES

Upper and lower motor neurons may be affected in a wide variety of ways, either separately or in combination. Table 24.62, provides a classification and list of causes. Many causes are rare. Of the diseases that primarily affect motor neurons, the most common is acquired motor neuron disease (amyotrophic lateral sclerosis - ALS). Spinal muscular atrophy (SMA) comprises a rare group of hereditary diseases in which there is slow degeneration of anterior horn cells. The polio virus shows a highly selective tropism for anterior horn cells: the disease is considered on p. 1426.

TABLE 24.62 Diseases affecting motor neurons Upper motor neuron syndromes Inherited: *hereditary spastic paraparesis (p. 1375) pure form (Strumpell) complex multisystem forms adrenomyeloneuropathy (usually with sensory loss) hexosaminidase deficiency Acquired: *primary lateral sclerosis progressive pseudobulbar palsy tropical spastic paraparesis (HTLV1 infection) tumours trauma vascular lesions usually with sensory loss inflammatory cord lesions cord compression toxins (cycad, lathyrism, lead, mercury, lithium) Lower motor neuron syndromes Inherited: *spinal muscular atrophy type I infantile (Werdnig-Hoffman) type II juvenile (Kugelberg-Weiander) type III adult - various phenotypes hexosaminidase deficiency Acquired: acute - polio Coxsackie and other enteroviruses chronic - post-polio syndrome focal or segmental amyotrophy anterior horn ceil degeneration in Creutzfeld-Jakob disease, Shy-Drager syndrome, paraneoplastic - lymphoma, post radiation Combined upper and lower motor neuron syndromes Inherited: *familial ALS hexosaminidase deficiency Acquired: *ALS (motor neuron disease) probable toxic ALS: Guam ALS-like syndrome in thyrotoxicosis, hyperparathyroidism, dysproteinaemia (IgG and IgM), post radiation ALS = amyotrophic lateral sclerosis; * = the primary motor neuron diseases.

MOTOR NEURON DISEASE MND is a progressive degenerative disease of unknown cause which affects upper and lower motor neurons in the brain and spinal cord. It is rare, with a prevalence of about 4-6 per 100000, and usually affects middle-aged or elderly people. The disease is usually rapidly progressive, death resulting within 3-4 years of onset of symptoms.

Pathology 1388

The pathology of MND is degeneration of anterior horn cells in the spinal cord, and lower motor neurons in the cranial nerves; the upper cranial nerves controlling eye

movements, and the motor neurons to the bladder and bowel sphincters are spared. Cortical upper motor neurons supplying both cranial nerves and spinal motor neurons also degenerate, leading to the characteristic combination of widespread upper and lower motor neuron signs. In most patients there is no intellectual impairment. Sensory tracts and nuclei remain normal.

Aetiology and pathogenesis The cause of MND is unknown. Interest has focused

on familial cases, in which genetic studies have shown a mutation on chromosome 21 encoding superoxide dismutase (SOD). It is thought this mutation may underlie 20% of familial cases, and possibly 2% of all cases of MND. SOD facilitates the conversion of intracellular superoxide radicals to hydrogen peroxide. It is ubiquitous, but there is high expression in the cell bodies and axons of motor neurons, which have a high metabolic rate and high mitochondrial activity. It is proposed that abnormal SOD may generate damaging hydroxyl radicals and nitrotyrosine residues on intracellular proteins, which lead eventually to cell death. There is also evidence that motor neurons may be particularly susceptible to calcium-mediated toxic processes after activation of glutamate receptors, and that the expression and function of glutamate reuptake transporter protein may be impaired in MND, causing an increase in extracellular glutamate, leading in turn to glutamate excitoxicity. The aetiopathogenesis of MND is a topic of current research, but the cause of the majority of sporadic cases remains uncertain.

Clinical features MND may present with almost any combination of upper and lower motor neuron symptoms and signs, and is often asymmetrical in the early stages. As the disease progresses, however, a common pattern emerges. Patients present with bulbar problems or limb symptoms, or a combination of both. Early bulbar symptoms are dysarthria and dysphonia, dysphagia and difficulty in chewing, with nasal regurgitation of fluids. There may be recurrent chest infections, and respiratory muscle weakness may cause dyspnoea. In the limbs the common presentations are weakness of a hand or a whole arm, often with wasting which the patient has noticed, or, in the leg, progressive foot drop. Cramps are common. Examination often reveals wasting, fasciculation and weakness in the muscles innervated by the cranial nerve nuclei. A particularly important sign is fasciculation in a wasted tongue. In the limbs, a combination of fasciculation and weakness, with brisk reflexes in wasted muscles, in the

SUMMARY 13 Diagnosis of motor neuron disease (MND) Never make a diagnosis of MND in the presence of sensory loss or bladder symptoms. Upper motor neuron (UMN) and lower motor neuron (LMN) signs in the upper and lower limbs may be produced by a combination of cervical and lumbar spondylosis. Do not make a definite diagnosis of MND until there are UMN and LMN signs in the same muscle groups in the limbs, and similar signs affecting cranial nerve-innervated muscles. If there is any doubt that a spinal cord lesion is present, MRI is essential.

absence of any sensory abnormality, is strongly suggestive of MND.

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Differential diagnosis In many patients a confident diagnosis can be made at the initial presentation, but in some, particularly those without cranial nerve signs, diagnostic difficulties may arise. A progressive bulbar palsy without limb signs may resemble myasthenia gravis. Multiple bilateral cerebral hemisphere infarcts or diffuse subcortical small vessel disease can produce bulbar problems similar to those of MND. When there are no cranial nerve signs, a cervical lesion producing a combination of motor root signs in the upper limbs with myelopathic upper motor neuron signs in both upper and lower limbs must be considered. This is the presentation of the amyotrophic lateral sclerosis variant of MND. Any sensory deficit or the presence of bladder symptoms suggests that the diagnosis is not MND. When limb signs are entirely lower motor neuron, a pure motor neuropathy is a possibility. The rare condition of multifocal motor neuropathy with conduction block (MMN) may mimic MND, with widespread lower motor neuron signs. Diagnosis of MMN depends on the demonstration of multiple sites of motor neuron conduction block, away from the common sites of nerve compression. MMN is an inflammatory condition, which may respond to intravenous immunoglobulin treatment. In cases with predominantly proximal weakness and wasting, diabetic amyotrophy may be considered, and in occasional patients with signs confined to the legs, a cauda equina lesion may require exclusion.

Investigation The diagnosis of MND is essentially a clinical one. Needle EMG shows denervation but not its cause. Motor and sensory nerve conduction studies are normal. Muscle biopsy is seldom necessary.

Prognosis and management There is relentless progression. In older patients, and particularly those presenting with limb rather than bulbar problems, the disease may last for 5-10 years from onset of symptoms to death. In others, death may result in less than a year. A few patients become demented. There may be emotional lability. There is no cure for MND, which is invariably fatal. Riluzole, which has sodium channel blocking activity, and which inhibits glutamate release, has been shown to have a weak effect in delaying disease progression. Treatment remains largely supportive. For patients with dysarthria and dysphonia a range of communicators are now available. In the earlier stages these symptoms, together with dysphagia, may be considerably ameliorated by speech therapy. Dysphagia requires careful attention to consistency of the food. Thin liquids and solids often lead to choking, but

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CASE STUDY 24.9 DIFFICULTY IN SWALLOWING IN A 71-YEAR-OLD WOMAN A 71-year-old woman presented to her GP complaining of difficulty with swallowing. This had started 2 months earlier and had gradually worsened. Initially she had noticed a tendency to choke on liquids, and then difficulty swallowing chunks of meat. She had also noticed that her jaw felt tired towards the end of a meal. She had no other symptoms, but her husband remarked that her voice had changed, becoming quieter and slightly altered in quality. Her past medical history included hypothyroidism, treated for 20 years (presenting with weight gain and fatigue), an episode of pyelonephritis aged 35, and mild hypertension, treated for the past 8 years. Her medication included bendrofluazide, thyroxine and vitamins. She smoked 10 cigarettes a day and drank about 5 units of alcohol per week. There was a strong family history of hypertension, strokes and myocardial infarction. On examination the GP found mild dysphonia and no other signs. The patient was referred to an ENT surgeon who observed by indirect laryngoscopy that both vocal cords moved normally and there appeared to be no other laryngeal abnormality. A video swallow showed mild pharyngeal incoordination without aspiration. She was referred to a speech therapist without a clear diagnosis. Over the following weeks her symptoms deteriorated considerably. She was choking on all food and drink and had noticed liquid coming down her nose when drinking, particularly if she was simultaneously coughing. Her voice had worsened and she developed mild slurring of her speech. She had also noticed that

1

1390

MCQ 24.23

some muscles in her right hand had thinned, though there had been no loss of function in the hand. She had lost over 1 stone in weight, which she attributed to her inability to eat properly. She was referred urgently by her GP to a neurologist. At the consultation, some 7 months after the onset of her symptoms, further enquiry revealed that she had no sensory symptoms and there had been no sphincter disturbance. On examination, in the cranial nerves there was bilateral wasting and weakness of the masticatory and facial muscles. The jaw jerk was brisk. There was reduced palatal movement bilaterally, pharyngeal sensation was normal, and there was obvious dysphagia with choking when she attempted to drink some water. The tongue was wasted and fasciculating, with reduced range and speed of movement. Sternomastoids and neck flexion were weak. The cranial nerves were otherwise normal. In the motor system there was asymmetrical wasting of the shoulder girdle and upper limb muscles, fasciculation in several proximal muscles, and weakness of most muscle groups, being most marked in the deltoid and triceps on the left. In the legs there was no wasting but there was some fasciculation in the right quadriceps. Tone was increased in both legs and there was mild weakness in a pyramidal distribution. Upper and lower limb reflexes were very brisk and both plantar responses were extensor. Sensory examination was entirely normal and her gait appeared mildly spastic. Examination of other systems was normal, except for a vital capacity of 1.6 and a blood pressure of 155/100.

Questions 1. What is the diagnosis? 2. Which investigations should be done? 3. What is the prognosis? 4. What should be the further management? Discussion When this woman presented with dysphagia and mild dysphonia it was clearly important to exclude localized pharyngeal and laryngeal pathology, and a referral for an ENT opinion was appropriate. However, in the absence of any demonstrable structural cause the probability of a neurological basis for her symptoms should have been considered at an earlier stage. By the time she was seen by the neurologist, the clinical picture was characteristic for motor neuron disease (MND), with widespread weakness, wasted fasciculating muscles, brisk reflexes in wasted muscles in the upper limbs (i.e. a combination of upper and lower motor neuron signs in the same muscles), a normal sensory examination and absence of bladder and bowel involvement. Motor neuron disease may present with limb symptoms or symptoms indicative of cranial nerve-innervated muscle involvement, or a combination. When there are isolated bulbar problems it is essential to exclude structural brainstem lesions such as tumour or a Chiari malformation (which may present even in late middle age) and consider the possibility of myasthenia gravis. If there is any doubt about the diagnosis of myasthenia, a tensilon test and appropriate

a blended diet may cause fewer problems. None the less, eating usually imposes increasingly severe problems. A nasogastric tube or gastrostomy may be helpful in many patients. Dribbling of saliva may be helped by oral atropine or a tricyclic antidepressant, the latter also sometimes having a beneficial effect on mood. Progressive

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CASE STUDY 24.9 CONTINUED neurophysiological testing are essential. In patients presenting with limb symptoms alone, the commonest patterns are wasting in the upper limbs with a spastic paraparesis (ALS) or, initially, mono limb weakness, a progressive footdrop being a fairly frequent mode of onset in older people with the disease. In either situation, structural cervical or lumbar pathology must be excluded with MRI, even in the absence of obvious sensory loss. In widespread disease such as in the patient described here, there can be little doubt about the diagnosis from clinical assessment. At this age and with this pattern of deficit there really is no differential diagnosis, but the rare multifocal motor neuropathy with conduction block, an inflammatory condition that responds

to intravenous immunoglobulin treatment, should always be considered as it is potentially treatable. Investigation in this case included EMG, which showed widespread denervation in the upper and lower limb muscles, with some evidence of reinnervation, and nerve conduction was normal without evidence of conduction block. MRI was not performed. The prognosis in motor neuron disease with prominent bulbar involvement is very poor - usually less than 1 year in a patient like the one described here. The combination of dysphagia and reduced vital capacity results in repeated chest infections, which are usually the cause of death. As respiratory failure progresses patients often develop

respiratory paralysis with aspiration pneumonia is the usual cause of death. Some patients with ventilatory failure and sleep disturbance can be helped by non-invasive ventilation, but artificial ventilation via an endotracheal tube may merely prolong suffering. Most patients become immobile and eventually require full nursing care. Patients remain alert to the end, and drug treatment to alleviate distress is often indicated. O

HEREDITARY SPINAL MUSCULAR ATROPHY Several rare disorders are described, but the two most common are Werdnig-Hoffman disease and Kugelberg-Welander syndrome. Werdnig-Hoffman disease Werdnig-Hoffman disease is an autosomal recessive condition that presents either neonatally as a floppy baby, or with progressive weakness and wasting within the first year of life, owing to widespread lower motor neuron degeneration. Death occurs within the first 4 years of life. Kugelberg-Welander syndrome Kugelberg-Welander syndrome is a progressive spinal muscular atrophy of either autosomal dominant or recessive inheritance. The disease sometimes affects children over the age of 2, but onset is usually in adolescence or early adult life, when there is degeneration of lower motor

orthopnoea, which markedly disturbs sleep. Assisted ventilation at night is often helpful, improving the quality of remaining life. As patients with MND become increasingly disabled, full nursing care is needed. Many hospices are involved in the care of these patients. Riluzole has a weak effect in MND, prolonging survival by an average of 3 months. Careful counselling of the patient and their family as soon as the diagnosis is made is essential. With more slowly progressive disease the diagnosis may only become definite after many months or even years, and patients require considerable support through such periods of diagnostic uncertainty. In many countries there are support groups which provide an essential component of care for these unfortunate patients.

neurons, with relative sparing of cranial nerve nuclei. Kugelberg-Welander syndrome often presents with a predominantly proximal weakness, which may give a similar picture to a limb girdle dystrophy. This form of spinal muscular atrophy is relatively benign, but most patients eventually become disabled.

FURTHER READING ON MOTOR NEURON DISEASE Leigh P N, Chaudhuri R 1994 Motor neurone disease J Neurol Neurosurg Psychiatry 57:886-896. Shaw P J 1999 Motor neurone disease Br Med J 318:1118-1121.

DISEASES OF PERIPHERAL NERVES AND PLEXUSES PERIPHERAL NEUROPATHY Peripheral nerves contain motor, sensory and autonomic fibres, with their cell bodies in the anterior horn, dorsal root ganglia and autonomic ganglia, respectively. Nerve fascicles are surrounded by connective tissue, the perineurium, which forms a blood-nerve barrier maintaining a special environment in the endoneurium, the intrafascicular compartment in which the fibres lie. Myelinated nerve fibres are of varying size, the largest in diameter conducting at velocities of up to 70 metres per second (m/s), the

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smallest at about 5 m/s. Unmyelinated axons conduct at less than 1 m/s. The Schwann cells provide axons with a certain amount of physical support, form the myelin of myelinated fibres, and probably act in a nutritional capacity to axons. Most of the synthesis in nerve fibres occurs in the cell bodies, with subsequent transport down axons.

Pathophysiology The principal pathology in diseases affecting peripheral nerves is either axonal degeneration or demyelination. Axonal degeneration may take the form of a neuronopathy in which the cell body and the whole axon are affected, or an axonopathy, in which the part of the axon furthest from the cell body is first affected. In demyelinating neuropathies the primary pathological process is demyelination. This may lead to conduction block, with consequent loss of function. Severe demyelination may lead to secondary axonal degeneration. Regeneration in axonal neuropathies may occur after a period of Wallerian degeneration. Regeneration proceeds at only 1-2 mm per day. Remyelination in demyelinating neuropathies initially leads to short internodes and thin myelin sheaths, causing greatly reduced conduction velocities. A severely reduced nerve conduction velocity on electrophysiological testing indicates a demyelinating neuropathy; this may be generalized, e.g. as in Guillain-Barre syndrome (acute inflammatory polyneuropathy), or focal, as in an entrapment neuropathy such as the carpal tunnel syndrome. The fibres in peripheral nerves are occasionally damaged by diseases which primarily affect the connective tissue, particularly the blood vessels of the nerve. Examples are the neuropathies due to vasculitis seen in polyarteritis nodosa, or SLE.

Clinical classification Neuropathies may be divided into: • Mononeuropathy, when a single nerve is involved; • Multiple mononeuropathy (mononeuritis multiplex or multifocal neuropathy), in which more than one, and sometimes many, individual nerves are affected in a patchy distribution. Multifocal neuropathy is typical of some diseases (Table 24.63); • Polyneuropathy, in which there is a diffuse symmetrical involvement of the peripheral nerves. Some diseases, notably diabetes, may also produce a multifocal neuropathy. Some polyneuropathies (e.g. Guillain-Barre syndrome) also affect the spinal roots, and in such cases the terms polyradiculoneuropathy or polyradiculopathy are more accurate.

Clinical features 1392

Neuropathies may affect motor and sensory fibres, or each differentially. Autonomic involvement is prominent in certain neuropathies, the commonest being diabetes.

TABLE 24.63 Causes of multifocal neuropathy ('mononeuritis multiplex') • • • • • •

Diabetes Connective tissue disease, e.g. SLE, RA, PAN Inflammatory, e.g. sarcoid Infective, e.g. leprosy, herpes zoster (usually a mononeuritis) Familial disposition to entrapment neuropathy (tomaculous neuropathy) Other physical injury, e.g. radiotherapy, electrical injury, thermal injury, ischaemia • Neoplastic, e.g. carcinomatous or lymphomatous infiltration, neurofibromatosis, malignant nerve tumours, related to paraproteinaemia

Motor nerve involvement The major symptom of motor nerve involvement is weakness (Fig. 24.61). Examination reveals wasting and weakness which, in the case of mononeuropathies, are appropriate to the distribution of a particular nerve; in the case of polyneuropathy, this is usually most marked distally in the limbs. Most peripheral neuropathies involve the lower limbs before the upper. Occasionally a predominantly proximal weakness may result from peripheral neuropathy, e.g. as in Guillain-Barre syndrome. Fasciculation is sometimes seen in peripheral neuropathy, usually in patients with rapidly progressive denervation. Tendon reflexes are often absent, usually as a result of sensory loss rather than motor impairment. Loss of the ankle jerks is common in normal elderly people. Sensory nerve involvement Sensory involvement includes the negative symptom of numbness and the positive symptoms of paraesthesiae and pain. Some neuropathies differentially affect large and small fibres. Those selectively affecting large fibres (e.g. uraemic neuropathy) impair touch, pressure, two-point discrimination and joint position sense; pain and temperature sensation are unaffected. Neuropathies selectively affecting small fibres (e.g. small fibre diabetic neuropathy or amyloid neuropathy) produce loss of pain and temperature sensation, with relative preservation of other modalities. All the tendon reflexes may be present, as they depend on large fibre function. Substantial loss of pain and temperature sensation may lead to neuropathic feet ulcers. In mononeuropathy, sensory impairment is within the distribution of a single nerve. In polyneuropathy a stocking and glove, distal sensory impairment is typical. Autonomic involvement A severe type of burning pain (causalgia) occurs after injury to major limb peripheral nerves, e.g. the median, ulnar and sciatic nerves, and occasionally with injury to smaller nerves. Causalgia is often associated with evidence of local or regional reflex sympathetic disturbance, including vascular and sweating changes, and trophic changes in

times a feature of polyneuropathy, most notably alcoholic neuropathy. In a minority of patients autonomic involvement is sufficiently severe to cause symptoms. Loss of blood pressure control leads to syncope. There may be impairment of sweating, sometimes severe enough to cause hyperpyrexia in hot weather; impairment of bladder and bowel sphincter function may lead to incontinence.

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Diagnosis and investigation In cases where the history and examination leave doubt about the presence of a neuropathy, motor and sensory nerve conduction studies are valuable. Small fibre neuropathies pose particular diagnostic difficulties in that, with large fibre preservation, tendon reflexes are not lost and sensory loss is selective and often discrete. Recording of thermal thresholds for warming and cooling offers a simple way of assessing small fibre sensory function. Nerve biopsy is only occasionally helpful in establishing the cause of a neuropathy. It is most often useful in patients with multifocal neuropathy, in those suspected of having amyloid, and in a number of the rare inherited metabolic disorders that lead to abnormal depositions in peripheral nerves, such as metachromatic leukodystrophy.

Mononeuropathy

FIG. 24.61 Neuropathy A Symmetrical wasting of the lower legs in a patient with severe motor neuropathy, in this case due to diabetes. Note prominent edge of tibiae exposed by thinning of tibialis anterior muscles. B and C Wasting of the hands due to peripheral motor neuropathy. Note thinning of the first dorsal interosseous muscle between thumb and index finger (especially the right hand) and flattening of the thenar eminences (also worse on right). •

the skin and nails. Causalgia may be partly or completely relieved by sympathetic blockade, indicating the role of sympathetic activity in maintaining such pain. Similar burning pain, together with sympathetic changes, is some-

The more common entrapment neuropathies are described below and Table 24.64 lists the main features of a number of less common traumatic mononeuropathies. Brief periods of nerve compression cause focal demyelination, leading to conduction block, but without loss of axonal continuity (neurapraxia). Remyelination will restore both conduction and function over days or weeks. With more severe compression, which often occurs over a longer period, axonal interruption may result; this leads to Wallerian degeneration of the axons distal to the site of compression, but with continuity of the connective tissue elements of the nerve. Axonal regeneration and remyelination with relief of compression occur over a much longer period after such injury, but good restoration of function is possible. With severe, penetrating injuries causing division of the nerve, connective tissue continuity is also lost and regeneration is always incomplete, even with the most careful surgical apposition of nerve ends. Median nerve Carpal tunnel syndrome Compression of the median nerve at the wrist beneath the flexor retinaculum gives rise to the carpal tunnel syndrome. This is most common in middle-aged women, and more likely to occur after wrist fracture, in pregnancy, in rheumatoid arthritis with involvement of the wrist joint, in myxoedema and in acromegaly. The medium nerve may also be damanged by penetrating trauma at the wrist.

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TABLE 24.64 Causes and features of individual nerve lesions (see also Fig. 24.62) Nerve (root)

Site and cause of lesion

Clinical features

(Median, ulnar and radial nerves: see text and Fig. 24.62*) Axillary (C5, 6) Brachial plexus. Crutches Sleeping partner's head - 'honeymoon palsy' Musculocutaneous (C5, 6) Humeral fracture with brachial plexus injury Femoral (L2-4)*

Lateral cutaneous nerve of thigh (L2, 3)* Obturator (L-4) Sciatic (L4, 5, S1-3)*

Common peroneal/lateral popliteal (L4, 5, S1, 2) Tibial (L4, 5, S1-3)*

Sural (L5, S1-2)

Paralysis of shoulder abduction, deltoid Paralysis of biceps, brachialis. Sensory loss on lateral aspect of forearm Paralysis of iliacus, quadriceps, sartorius Sensory loss over anterolateral thigh and saphenous distribution Absent knee jerk

Fracture of pelvis or femur Dislocation of hip Hip operations Psoas abscess or psoas haematoma in haemophilia Pressure of inguinal ligament Obesity. 'Meralgia paraesthetica' Neoplastic or radiotherapy damage in pelvis Fetal head pressure, or forceps injury Pelvic mass. Fracture/dislocation of femur Penetrating trauma Baker's cyst in popliteal fossa Pressure palsy in drug addicts and alcoholics Compression at neck of fibula: squatting, sitting cross-legged, pressure under anaesthesia Fibular fracture Trauma in thigh and popliteal fossa Distal injury in tarsal tunnel

Sensory loss over anterolateral thigh. Often with burning pain and paraesthesiae Weakness of hip adductors. Sensory loss over lower medial thigh Paralysis of all lower leg and foot muscles Absent ankle jerk. Sensory loss of whole foot, extending up lateral aspect of lower leg Often painful Foot-drop and weakness of eversion. Sensory loss over lateral aspect of lower leg and dorsum of foot Paralysis of plantar flexion and inversion Sensory loss on sole. Pain common. In tarsal tunnel syndrome, paralysis of medial foot muscles and sensory loss on sole Sensory loss over lateral border of foot

Pressure in lower calf and at ankle, e.g. from tight boots

* These are the most important lesions.

Symptoms may be provoked by occupational use of the hands. The symptoms of carpal tunnel syndrome are pain, numbness and paraesthesiae in the hand. The symptoms are often diffuse, affecting the whole hand. Pain may radiate through the forearm, and occasionally may involve the whole arm. Typically, pain is most troublesome at night or first thing in the morning. Sensory symptoms are more common than motor symptoms, but some patients notice weakness of the thumb. On examination there is weakness of abductor pollicis brevis (APB), with or without wasting, and also weakness of opponens. There is sensory impairment in a median distribution (Fig. 24.62). The Tinel sign is positive when gentle tapping over the carpal tunnel causes paraesthesiae in part of the cutaneous distribution of the nerve. In mild cases a wrist splint to reduce movement at the wrist may help, and an injection of hydrocortisone into the carpal tunnel may give temporary relief. In cases where there is sensory loss or weakness, surgical decompression of the carpal tunnel is required. Mild carpal tunnel syndrome symptoms often resolve spontaneously.

Motor supply

MEDIAN

Sensory territory

Thenar muscles: • abductor pollicis brevis • flexor pollicis brevis (with ulnar) • opponens pollicis • lumbricals to index and middle fingers Flexor carpi ulnaris Flexors of distal phalanx of ring and little fingers

ULNAR

RADIAL

All intrinsic hand muscles except the thenar group above Triceps Brachioradialis Supinator All extensors of wrist, thumb and fingers

FIG. 24.62 Mononeuropathies in the hand

1

1394

MCQ 24.24

Proximal lesions More proximal injuries of the median nerve are unusual. A lesion at the elbow causes weakness of the long finger flexors (except the ulnar half of flexor digitorum pro-

SUMMARY 14 Peripheral neuropathy • Peripheral neuropathy is classified clinically into mononeuropathy, multifocal neuropathy and polyneuropathy. • Polyneuropathies may be motor or sensory, but are usually mixed (sensorimotor). • The clinical type of the neuropathy may be helpful in identifying the cause. • In polyneuropathies, legs are affected before the arms. • Tendon reflexes may be partly preserved in a polyneuropathy in the early stages, or when the neuropathy predominantly affects the legs, or is predominantly motor rather than sensory. • Autonomic involvement characteristically occurs with some neuropathies. • Some neuropathies (e.g. Guillain-Barre) may affect respiratory function.

fundus), together with weakness of flexor carpi radialis, pronator teres, most of the thenar muscles and the two radial lumbricals. There is weakness of flexion of the index and middle fingers and distal phalanx of the thumb, in addition to weakness of APB and opponens. Sensory loss is the same as in carpal tunnel syndrome. Ulnar nerve Ulnar nerve lesions usually follow entrapment at the elbow. Above the elbow the nerve gives rise to branches supplying the medial part of the deep finger flexors and flexor carpi ulnaris. In the forearm the nerve gives off the dorsal branch, which supplies the skin over the medial part of the dorsal aspect of the hand, the medial one-and-a-half digits, and the medial part of the palm over the hypothenar eminence (Fig. 24.62). The deep branch of the nerve supplies the hypothenar muscles, the interossei, adductor pollicis, the third and fourth lumbricals and part of flexor pollicis brevis. Sensory symptoms from ulnar nerve lesions include pain, paraesthesiae and numbness in the hand; as with carpal tunnel syndrome, these symptoms may not be confined to the anatomical distribution of the nerve. Weakness is often asymptomatic. A lesion of the nerve in the region of the elbow may lead to palpable thickening of the nerve in the ulnar groove. The muscles in the forearm are spared. In the hand, there is wasting of the first dorsal interosseus and abductor digiti minimi, and wasting of the other interossei, causing guttering between the metacarpals and weakness of finger abduction. In severe lesions a claw-hand posture develops. This is due to paralysis of the interossei and medial two lumbricals, which normally flex the fingers at the metacarpophalangeal joints and extend the fingers at the interphalangeal joints. In claw-hand there is extension at the metacarpophalangeal joints owing to the unopposed action of the long extensors of the fingers, and flexion at the interphalangeal joints owing to the action of the flexor

digitorum superficialis. The posture mainly affects the little and ring fingers, because, although all the interossei are weak, the radial lumbricals supplied by the median nerve prevent extension of the lateral metacarpophalangeal joints. Lesions of the ulnar nerve above the elbow produce weakness of finger flexion and flexor carpi ulnaris. Lesions at the wrist and in the hand spare the dorsal branch, so that sensation on the dorsum of the hand and fingers is preserved. Lesions at the wrist involve the superficial branch, so that sensory loss occurs on the medial palm and palmar aspects of the ring and little fingers; lesions within the hand usually spare this branch.

24

Radial nerve The radial nerve lies on the posterior surface of the humerus in the radial groove, and supplies triceps in the upper arm and the skin on the back of the upper arm. In the forearm the nerve gives branches to brachioradialis, and extensor carpi radialis longus and brevis. The deep branch supplies supinator, extensor digitorum, extensor carpi ulnaris and extensor digiti minimi. The extension of the deep branch is the posterior interosseous nerve, which supplies abductor pollicis longus, extensor pollicis longus and brevis, and extensor indicis. The terminal superficial radial nerve innervates the skin over the lateral part of the dorsum of the hand and thumb, index and middle fingers. When the radial nerve is injured in the axilla or in fractures of the humerus, there is paralysis of all these muscles, including triceps. 'Saturday night palsy' is a neurapraxia in which the nerve is damaged in the upper arm when compressed over the arm of a chair, the result of going to sleep in this position when drunk. Triceps is spared, but there is weakness of all other muscles supplied by the nerve, producing a wrist-drop, together with sensory loss over the dorsum of the hand (Fig. 24.62). Recovery takes place over several weeks; function in the hand is improved by a splint to correct the wrist-drop. O

Multifocal neuropathy ('Mononeuritis multiplex') Compared with polyneuropathy, mononeuritis multiplex has relatively few causes (Table 24.63). Biopsy of an affected sensory nerve may reveal specific pathological changes much more often than in polyneuropathy.

Polyneuropathy The many possible causes of polyneuropathy are shown in Table 24.65. Despite extensive investigation, the cause of some neuropathies is never established. In such cases it is particularly important to examine family members, both clinically and electrophysiologically, as this may establish the diagnosis of a hereditary neuropathy.

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COMMON CAUSES OF NEUROPATHY

TABLE 24.65 Causes of polyneuropathy

Endocrine and metabolic neuropathies

Inflammatory Acute inflammatory polyneuropathy: Guillain-Barre syndrome Chronic inflammatory demyelinating polyneuropathy (CIDP)

Serum sickness Sarcoidosis SLE PAN

Metabolic Diabetes Uraemia Porphyria

Myxoedema Amyloid Metachromatic leucodystrophy

Nutritional Beri-beri (thiamine deficiency) Pellagra (niacin deficiency) Vitamin B12 deficiency

Burning feet syndrome Sprue Malabsorption

Neoplastic Non-metastatic Myeloma

Paraproteinaemia Macroglobulinaemia

Diabetic neuropathy In many countries diabetes is the commonest cause of neuropathy. Mononeuropathy and multifocal neuropathy Entrapment neuropathies, e.g. carpal tunnel syndrome, are much more likely to develop in diabetes. In additional, peripheral nerves may be affected by the small vessel disease of diabetes. This microangiopathic pathology underlies the third cranial nerve palsy which typically produces an ophthalmoplegia but spares the pupil. This is because the fibres to the pupil are distributed in the outer part of the nerve, and the ischaemia produced by small vessel occlusion affects predominantly central parts of the nerve. Other cranial nerves may be affected. A multifocal neuropathy in the limbs is occasionally seen, and is presumed to have a microangiopathic basis. Diabetic amyotrophy Diabetic amyotrophy is a proximal multifocal neuropathy which affects the femoral nerve and, to a lesser extent, other nerves supplying proximal muscles in the leg. It occurs in middle-aged or elderly diabetics, commonly in those with poor diabetic control. The condition is usually unilateral. The first symptom is pain in the thigh lasting for weeks or months. Weakness rapidly develops; this is most marked for hip flexion and knee extension, but usually also involves other muscles at the hip and the hamstrings (see Fig. 24.61 A). Distal power is normal. The knee jerk is absent. Recovery begins within weeks or months and is usually good. Poly neuropathy Polyneuropathy is the commonest type of diabetic neuropathy. It is a sensory motor neuropathy, but in many patients it remains predominantly sensory. Numbness and paraesthesiae are the main symptoms, occasionally with hyperaesthesiae on the soles of the feet. Pain, either a continuous aching or burning, or of a shock-like stabbing nature, may occur. The onset is usually insidious over weeks or months. A much rarer type of painful polyneuropathy affects predominantly the small myelinated and unmyelinated fibres, leading to impaired pain and temperature sensation. Tendon reflexes, which depend on large fibre afferents, are preserved. Patients with this type of neuropathy complain of severe pain in the feet, often associated with hyperaesthesia. Another type of acute peripheral polyneuropathy

1

1396

MCQ 24.25

Infections Leprosy Diphtheria Measles

Toxic Alcohol Lead Arsenic Gold Mercury Drugs Isoniazid Nitrofurantoin Vincristine Metronidazole Disulphiram Clioquinol Dapsone

Hereditary HMSN type I HMSN type II HMSN type III Hereditary sensory neuropathy Friedreich's ataxia Familial dysautonomia (Riley-Day)

Mumps Infectious mononucleosis Brucellosis HIV

Thallium Triorthocresyl phosphate (TOCP) Insecticides Acrylamide N-hexane

Sulphonamide Emetine Phenytoin Pyridoxine Griseofulvin Cisplatinum Amiodarone Tricyclic antidepressants

Porphyria Metachromatic leukodystrophy Fabry's disease - angiokeratoma corporis diffusum

in diabetes affects all fibre types. The onset is preceded by rapid weight loss. This neuropathy, which is very painful, resolves after 9 months to a year in most patients. Autonomic neuropathy Autonomic neuropathy is common in diabetes and is nearly always seen in association with a sensory motor polyneuropathy. The pupils may be affected, with reduced response to light. There may be dysphagia if the oesophagus is involved. Gastric atony causes vomiting, and denervation of the lower bowel leads to diarrhoea. Postural hypotension with syncope is the commonest early symptom. Diagnostically, postural hypotension and the absence of the normal cardiac beat-to-beat interval variation are useful observations. Erectile impotence, retrograde ejaculation, retention of urine and incontinence may all be troublesome features. Management The mainstay of treatment of diabetic neuropathy is good control of the diabetes (Ch. 19). This particularly helps the mononeuritis and multifocal neuropathies. Symptomatic treatment for neuropathic pain is often unsatisfactory. Simple analgesics, anticonvulsants and benzodiazepines may all help occasionally. Treatment of autonomic neuropathy is always difficult. Usually, the most troublesome symptom is postural hypotension. Tight stockings to prevent venous pooling in the legs rarely have a major effect. The blood pressure tends to be at its lowest in the morning and rises gradually during the day. Patients with autonomic failure tend to lose excess sodium and water during the night. This can be counteracted to some extent by sleeping with the head of the bed raised. This lowers the recumbent blood pressure, leading to renin release and a reduction in the nocturnal sodium and water loss. Fludrocortisone, which causes sodium and water retention, is also effective. A dose of 0.1-0.2 mg daily is usually sufficient, but excessive sodium and water retention, particularly in elderly patients, may lead to heart failure. Pressor drugs are seldom useful. Other neurological complications of diabetes are listed in Table 24.77 (p. 1433). Other endocrine and metabolic neuropathies Uraemic neuropathy is described on page 1432. Myxoedema causes an axonal, predominantly sensory polyneuropathy, but this is a much less common manifestation than either the proximal myopathy (p. 1407) or cerebellar ataxia (p. 1375) that occur in hypothyroidism. Amyloid, either hereditary or acquired, may cause a peripheral sensory motor neuropathy which particularly affects small fibres and is characteristically painful. A helpful diagnostic sign in this type of neuropathy is palpable thickening of the peripheral nerves. Long-standing lower limb ischaemia may lead to peripheral nerve damage, giving rise to signs of a peripheral polyneuropathy in the legs. O

Inflammatory polyneuropathies Guillain-Barre syndrome (GBS) GBS (acute inflammatory polyneuropathy) is an acute demyelinating, predominantly motor polyradiculoneuropathy which affects people of all ages.

24

Aetiology In some patients there is a history of a viral illness, often an upper respiratory infection. A number of specific preceding infections have been identified, including enterovirus and mycoplasma. It is thought that infection or some other immune stimulus may trigger a mainly cellmediated process, causing demyelination of spinal roots and peripheral nerves. There is little evidence that circulating antibodies are involved in this process. Clinical features Maximum weakness usually occurs between 10 and 14 days after the onset of the neuropathy. Occasionally, profound paralysis may develop within 24 hours. The first symptoms are usually sensory, with distal paraesthesiae, numbness, and sometimes pain. Cranial nerve involvement occurs in 30-40% of patients, with bilateral facial weakness being the common manifestation. Bulbar weakness predisposes to aspiration pneumonia. The autonomic nervous system is sometimes involved, causing lability of blood pressure and arrhythmias. Bladder dysfunction is rare. The CSF protein is sometimes raised to very high levels, causing impaired reabsorption in the arachnoid granulations, leading to papilloedema. Examination reveals weakness, with variable cranial nerve involvement. There is no wasting, as the neuropathy is acute in onset. Reflexes are nearly always all absent. Despite prominent sensory symptoms, objective signs of sensory loss are slight. Occasionally, there is an ascending dense sensory loss affecting first the limbs and then the trunk. Investigation The CSF is under normal pressure and shows a normal cell count, or slight pleocytosis of lymphocytes, and a markedly elevated protein of between 1 and lOg/L. Demyelination quickly spreads distally, and by the time electrodiagnostic tests are done there is usually some slowing of conduction, which later may become severe. The vital capacity must be measured regularly. Differential diagnosis The diagnosis is obvious in the majority of cases. Acute cervical spinal cord lesions, acute myaesthenia gravis and poliomyelitis all require consideration. In acute poliomyelitis weakness is often asymmetrical and, in contrast to Guillain-Barre syndrome, the CSF always shows a raised cell count of 10-200 cells/mm3. Management and prognosis During the period of progressive weakness, which may continue for up to 3 weeks after onset, it is essential to

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monitor respiratory function by measuring the vital capacity. It is important to note that patients with respiratory failure due to neuromuscular disease may not appear breathless until the vital capacity has reached a dangerously low volume, in contrast to patients suffering from pulmonary disease resulting in obstructive or restrictive defects. The peak flow rate is not an appropriate measure in patients with respiratory failure due to neuromuscular disease. A falling vital capacity in GBS is an indication for the patient to be housed in an intensive care setting, and for regular review of the need for effective ventilation. With supportive treatment alone, 85-90% of all patients with GBS recover completely over several months. Others are left with some residual deficit, usually mild. A few patients show a slowly progressive course (chronic inflammatory demyelinating polyneuropathy, CIDP), which may respond to corticosteroid or other anti-inflammatory treatments, or to plasma exchange or human immunoglobulin infusions. The last of these has now become the preferred treatment for CIDP. There is no evidence that corticosteroids improve the outcome in GBS. However, human immunoglobulin (ivlg) infusions and plasma exchange have both been shown to improve prognosis, if used early in the course of the disease, and ivIg has become the treatment of choice. Even those severely affected patients who require ventilation may make a complete recovery. 1 2 Miller Fisher syndrome Miller Fisher syndrome is a variant of acute inflammatory polyneuropathy in which there is an ophthalmoplegia, probably of peripheral origin, causes by demyelination of any or all of the third, fourth and sixth cranial nerves, together with ataxia and areflexia, with little or no weakness in the limbs. The prognosis is good; no treatment has been found to have an effect.

Nutritional neuropathies The neurological consequences of vitamin B12 deficiency are discussed on page 1383. In addition, a number of other nutritional deficiencies may cause polyneuropathies which are characteristically painful. The burning feet syndrome, described in Japanese prisoners of war, was probably the result of multiple nutritional deficits. Peripheral neuropathy - one of the neurological manifestations of pellagra due to niacin deficiency - is a sensory motor polyneuropathy in which severe burning of the feet with tenderness and hyperaesthesia of the lower legs and feet is prominent. A painful neuropathy also occurs in beri-beri due to thiamine deficiency.

O Case 24.9

1398

0

MCQ 24.26

Neoplastic neuropathies The neoplastic neuropathies are described on page 1434. Paraproteinaemic neuropathy Myeloma and other malignancies, such as some types of lymphoma and Waldenstrom's macroglobulinaemia, which produce a monoclonal gammopathy may be associated with a demyelinating neuropathy. In addition, a benign IgM gammopathy associated with a chronic, slowly progressive demyelinating neuropathy is now recognized; there is evidence that the neuropathy is caused by the abnormal IgM. Some patients respond to immunosuppression or plasma exchange.

Infective neuropathies Worldwide, leprosy (p. 325) is the most frequent infective cause of peripheral neuropathy. It produces a multifocal neuropathy and there is marked nerve thickening. Both brucellosis and infectious mononucleosis are rarely associated with an acute, predominantly motor, polyneuropathy, similar to acute inflammatory polyneuropathy. The neuropathy occurring with infectious mononucleosis may respond to steroid treatment. A mononeuritis or multifocal neuropathy may also develop with either of these infections. Mumps and measles are very rarely complicated by a transient polyneuropathy. Diphtheria (p. 312) may cause a profound demyelinating peripheral neuropathy, owing to the action of the exotoxin. The first symptom is palatal weakness, usually occurring about 2 weeks after pharyngeal infection. Weakness of the external ocular muscles may develop after about 4 weeks, and a generalized polyneuropathy after about 7 or 8 weeks. This may include respiratory weakness, for which ventilation is necessary. Remyelination with gradual recovery occurs over several months, but the commonly associated myocarditis may prove fatal. Neuropathies occurring with HIV infection are considered on page 448.

Toxic neuropathies Alcoholic neuropathy, described on page 1441, is the most important of the toxic neuropathies. Other toxic causes of neuropathy are listed in Table 24.65. These produce axonal neuropathies and many cause widespread CNS damage in addition.

Drug-induced neuropathy Certain drugs almost inevitably cause a neuropathy if given in sufficiently large dosages for long enough. Examples include vincristine and metronidazole. Other drugs show a strong tendency to produce neuropathy but depend on host susceptibility. For example, isoniazid neuropathy (preventable with small doses of pyridoxine) is much more likely to develop in patients whose liver is only capable of slow acetylation of the drug.

Hereditary neuropathies HMSN types I and II (peroneal muscular atrophy, Charcot-Marie-Tooth disease) Peroneal muscular atrophy (Charcot-Marie-Tooth disease) is the commonest of the hereditary neuropathies and is subdivided into hereditary motor and sensory neuropathy (HMSN) types I and II, on the basis of motor nerve conduction velocity. Type I HMSN tends to present in the first decade of life, with difficulty in walking and pes cavus or equinovarus foot deformity. Associated kyphoscoliosis is common. There is severe distal wasting in the legs and, later, in the upper limbs. The wasting in the legs sometimes spares the upper part of the thighs, producing the so-called 'inverted champagne bottle legs'; however, a diffuse pattern of wasting in the legs is as common. In the upper limbs, in addition to wasting, weakness and generalized areflexia, there is frequently tremor and a cerebellar type of ataxia. Respiratory muscle weakness can occur. Peripheral nerves are sometimes thickened. Nerve conduction velocity is reduced to less than 38m/s, and is often severely slowed, indicating a severe demyelinating type of neuropathy. Type II HMSN is primarily an axonal neuropathy with a peak onset in the second decade, but with many cases presenting much later than this. Weakness and wasting are less marked than in type I, and tend to be confined to the lower limbs. Foot and spinal deformity is less common than in type I and there is no palpable nerve thickening. The tendon reflexes in the legs are absent, but are often preserved in the arms. Motor conduction velocities are reduced, but not below 38m/s. In both types of HMSN the inheritance is usually autosomal dominant, although sporadic cases occur of both types and a few cases probably have an autosomal recessive mode of inheritance. In both types men tend to be more severely affected than women. Porphyria An axonal neuropathy may develop in attacks of acute intermittent porphyria (p. 1027). The neuropathy is unusual in distribution, in that a predominantly proximal weakness may develop together with a proximally distributed sensory impairment. Refsum's disease Refsum's disease is a condition with autosomal inheritance which results from defective metabolism of the long-chain aliphatic alcohol phytol. Metabolism cannot proceed past the stage of phytanic acid, owing to deficiency of the enzyme phytanic acid a-hydroxylase. Phytanic acid thus collects throughout the body and affects the nervous system, producing a demyelinating sensory motor polyneuropathy, cerebellar ataxia, sensory neural deafness, retinal pigmentary degeneration and anosmia. A cardiomyopathy is also common. Presentation is usually in the second decade, but occasionally patients present much later.

Phytol is derived from chlorophyll in the diet and the condition may be alleviated by a chlorophyll-free diet.

24

DISEASES AFFECTING BRACHIAL AND LUMBOSACRAL PLEXUSES

Brachial plexus lesions The brachial plexus is a relatively infrequent site of peripheral nerve damage. Trauma Lesions involving the upper part of the brachial plexus (C5 and C6, upper trunk) result from downward traction of the arm or forceful downward trauma on the shoulder. Severe trauma may avulse the C5 and C6 roots completely, causing extensive proximal weakness at the shoulder and sensory loss involving the outer aspect of the arm and the thumb, index and middle fingers. Trauma causing damage to the lower part of the plexus (C8 and Tl) usually occurs with upward traction on the arm. There is paralysis of the small hand muscles and weakness of wrist and finger flexors, with sensory loss on the medial aspect of the arm and the little and ring fingers. Horner's syndrome is often present. Birth injuries exemplify these two types of damage. In Erb's palsy, causes by excessive traction on the head or a breech delivery, there is an upper brachial plexus lesion in which paralysis of abduction occurs with the arm internally rotated at the shoulder, the elbow extended, and the forearm pronated in the 'waiter's tip' posture. In Klumpke's paralysis, due to traction with the arm abducted and extended, a lower brachial plexus lesion occurs. In adult life, trauma to the brachial plexus most commonly occurs as a result of motorcycle accidents. Cervical rib Cervical rib is either a bony rib or a fibrous band arising from the seventh cervical vertebra and attached anteriorly to the first rib. The C8 and Tl roots and the subclavian artery may be distorted as they pass over the cervical rib. Symptoms arise in adult life and may be either vascular or neurological, but rarely both together. Neurological symptoms are pain in the arm along the medial border and on the ulnar aspect of the hand, with weakness of grip. Very often symptoms are provoked by carrying heavy objects. Examination shows wasting and weakness of the small hand muscles and the medial finger and wrist flexors, with sensory loss affecting the little and ring fingers extending along the ulnar border of the forearm. Vascular symptoms comprise ischaemia in the hand, sometimes embolic symptoms, and Raynaud's phenomenon. Treatment is surgical resection of the rib or band. Neuralgic amyotrophy Neuralgic amyotrophy, also called cryptogenic brachial plexus neuropathy, is an acute patchy lesion of the brachial

1399

plexus, usually involving mainly C5 and C6 innervated muscles. Occasionally the condition may follow immunizations or be associated with a connective tissue disorder. The first symptom is severe pain around one shoulder. Weakness develops within a few days of onset of the pain, and most often affects the deltoid, spinati and serratus anterior, less commonly biceps and triceps, and rarely forearm and hand muscles. There is sometimes sensory loss, but this is usually mild. Demyelination is the likely underlying pathology. The prognosis is good. Occasionally phrenic nerve involvement causes diaphragm weakness and breathlessness. Phrenic nerve damage may not recover. Malignant invasion of the brachial plexus The commonest tumours invading the brachial plexus are carcinomas of the lung and breast. Lymphoma, spreading from cervical glands, is occasionally responsible. Virtually complete brachial plexus lesions may be seen with malignant invasion, and pain is a common and usually very troublesome symptom. Benign nerve tumours, such as neurofibromas, occasionally arise in the brachial plexus; very occasionally, primary malignant tumours involve the plexus.

Neurophysiological investigation is often helpful in demonstrating that the extent of denervation is greater than would be found with a single root. CT scanning and MRI are used to visualize the posterior pelvic region if a lumbosacral plexus lesion is suspected.

FURTHER READING ON DISEASES OF PERIPHERAL NERVES AND PLEXUSES Asbury A K, Gilliatt R W 1984 Peripheral nerve disorders. A practical approach. London: Butterworths. Dyck P J, Thomas P K, Griffin J G, Low P A, Podulso J F (eds) 1993 Peripheral neuropathy, 3rd edn. Philadelphia: W B Saunders. McLeod J G 1995 Investigation of peripheral neuropathy. J Neurol Neurosurg Psychiatry 58:274-283. O'Brien M D 2000 Aids to the examination of the peripheral nervous system. Edinburgh: W B Saunders. Schaumburg H H, Berger A T, Thomas P K 1991 Disorders of peripheral nerves, 2nd edn. Philadelphia: F A Davis.

DISEASES AFFECTING THE NEUROMUSCULAR JUNCTION

Radiation brachial plexus lesions Radiation may cause delayed damage to the brachial plexus, and considerable diagnostic difficulties arise when it is difficult to distinguish malignant invasion from radiation damage. MRI may be particularly helpful in some patients. Radiation lesions usually develop several years after treatment.

These are rare disorders in which there is defective transmission at the neuromuscular junction. The commonest is myasthenia gravis, with a prevalence of approximately 4 in 100000.

Lumbosacral plexus lesions

Myasthenia gravis (MG) is a disease characterized by fatiguable weakness of striated muscle. This may be localized or generalized and is due to a defect of transmission at the neuromuscular junction. Women are affected twice as often as men, with the onset usually in early adult life. However, it may appear at any age. Neonatal MG, which occurs in one in eight babies born to mothers with MG, resolves over a few weeks. There is an association of MG with the presence of thymic hyperplasia in younger patients and thymoma in older patients. Such tumours may be benign or malignant. MG also shows a strong association with thyrotoxicosis, and associations also exist with diabetes mellitus, rheumatoid arthritis and SLE, suggesting an autoimmune basis. There are antibodies to the acetylcholine receptor, and although the antibody titre does not correlate well with disease severity, the presence of a raised titre of acetylcholine receptor antibody is a useful diagnostic test.

A wide variety of lesions may affect the lumbosacral plexus. The main diagnostic problem is confirming that the lesion is of the lumbosacral plexus rather than an intraspinal lesion causing a lumbosacral radiculopathy. The two commonest lumbar root lesions due to discs are at L5 and S1 (p. 1385). Lumbosacral plexus lesions will often affect root levels higher than L5, and the presentation of an atypical lumbar radiculopathy syndrome should always raise the possibility of a plexus lesion. The commonest cause is malignant invasion from carcinoma of the cervix, rectum, uterus, bladder or prostate, and occasionally lymphoma. As with malignant invasion of the brachial plexus pain is a prominent symptom, with progressive wasting and weakness, and sensory impairment. The lumbosacral plexus may be involved in pelvic fractures. The fetal head is occasionally responsible for damage during parturition.

MYASTHENIA GRAVIS

Clinical features 1

1400

Fig. 24.23

2

Case 24-10

3

MCQ 24.27

The commonest initial presentation is weakness, often affecting only the external ocular muscles, and usually with ptosis (ocular myasthenia). However, any muscle may be involved, including bulbar and neck muscles, respiratory,

shoulder girdle and pelvic girdle muscles. MG may be very localized at the onset but usually becomes generalized with time. It remains confined to the ocular muscles in 10% of patients. There is a tendency for the condition to relapse and remit, and intercurrent illness, particularly infection, may provoke severe exacerbations. Initially, diplopia may only be noticeable at the end of the day. Bulbar weakness causes difficulty in chewing, weakness of the facial muscles, dysarthria, palatal weakness leading to regurgitation of fluids, and dysphagia and dysphonia. Neck weakness is common when there is bulbar weakness. In the limbs, symptomatic weakness is usually proximal and affects shoulder girdle more than pelvic girdle muscles. The hallmark of myasthenic weakness is fatiguability, and this must therefore be tested in the physical examination. Ptosis tends to appear more rapidly on sustained upward gaze. Eye movements should be tested with maintained gaze in different directions, and the patient questioned for the appearance of diplopia. Repetitive counting may reveal bulbar weakness. In the limbs, power is tested before and after repetitive proximal limb movements. In early MG, muscle bulk is normal. However, in advanced MG permanent, often non-fatiguable, weakness with wasting sometimes develops. Even in wasted, weak muscles reflexes are present and may be brisk.

Diagnosis The diagnosis can usually be made with confidence on clinical grounds, but can be confirmed or established in cases of doubt by the intravenous edrophonium (Tensilon) test. O This anticholinesterase drug has a duration of action of only a few minutes. A test dose of 1-2 mg is given to ensure no major adverse effects, followed by 5-10mg as an intravenous bolus. Myasthenic weakness is usually improved with this drug, but the success of the tests depends on timing and a degree of clinical expertise. Eye movements in ocular MG may appear not to be improved even when this is the correct diagnosis, as the improvement may be limited. EMG can be helpful, showing a decremental response to supramaximal repetitive stimulation of a muscle nerve. Acetylcholine receptor antibody titres are raised in about 90% of patients with generalized MG, and about 55% of patients with ocular MG. A chest X-ray and thoracic CT should be done to investigate the possibility of thymic enlargement. There is a strong association of thymoma with striated muscle antibody.

Management Initial treatment is with the long-acting anticholinesterase pyridostigmine, a usual starting dose being 60 mg three or four times a day. Atropine is given if muscarinic side-effects are troublesome. Larger doses of pyridostigmine are given if there is deterioration. Large doses of pyridostigmine (more than 12-15 doses of 60 mg daily) are capable of pro-

SUMMARY 15 Myasthenia gravis

24

• Weakness and fatigability of any muscle group, but especially eyes, face and proximal limbs • Diagnosis usually confirmed by edrophonium (Tensilon) test • Acetylcholine receptor antibodies present in 85% of cases • Treatment initially with pyridostigmine, then immunosuppression with steroids with or without azathioprine • Plasma exchange and ITU management may be necessary in severe cases with respiratory muscle involvement

ducing a cholinergic block at the neuromuscular junction; this leads to weakness which may be indistinguishable from myasthenic weakness. When there is uncertainty as to whether weakness is due to a cholinergic or myasthenic crisis, a test dose of Tensilon should be given, with an anaesthetist and full resuscitation equipment on hand. Thymectomy in MG is likely to benefit most patients if it is undertaken relatively early in the course of the disease. It is nearly always done in patients suspected of having a thymoma, the exceptions being old age and other associated illness. Thymectomy may produce a long period of remission, particularly in younger patients. Immunosuppression with prednisolone and azathioprine is beneficial in patients with a limited response to pyridostigmine. The use of these drugs at an early stage of the disease remains controversial. Many patients are maintained in reasonable health for long periods with a combination of these drugs. Plasma exchange improves weakness in MG, probably by removing circulating acetylcholine receptor antibody. It is extremely helpful as an immediate life-saving measure in severe MG with respiratory involvement. A number of drugs with membrane-stabilizing properties may profoundly worsen the weakness of MG. These drugs include suxamethonium (the initial diagnosis of MG may be made after prolonged paralysis with this anaesthetic drug), B-blockers, the aminoglycoside antibiotics and anticonvulsant drugs. Penicillamine occasionally induces MG. This is usually mild, and often confined to ocular muscles. Acetylcholine receptor antibodies are positive, and the condition remits within 1 year of stopping penicillamine. 2

Prognosis The prognosis is variable. Some patients, young or old, run a progressive downhill course despite all treatments, and die within a few years. Others remit for variable periods. The prognosis is much worse for patients with a thymoma (usually those in the older age group). 3

LAMBERT-EATON MYASTHENIC SYNDROME In the rare Lambert-Eaton myasthenic syndrome (LEMS) the defect at the neuromuscular junction is prejunctional,

1401

owing to failure of release of acetylcholine. Typical fatiguable weakness develops proximally in the limbs and trunk, and there is occasionally ptosis. Bulbar muscles are unaffected. In some patients there is no clear history of fatiguable weakness. In contrast to MG, tendon reflexes are usually absent but can be reinforced by a brief maintained isometric contraction. This is the so-called post-tetanic potentiation, a useful sign in diagnosis. Autonomic symptoms, owing to failure of acetylcholine release in the parasympathetic nervous system, are common, and include a dry mouth, sphincter dysfunction and erectile impotence. About half the cases of LEMS arise in patients with small cell cancer of the lung, but half are not associated with any disease. Both types appear to have an autoimmune basis and may be helped by prednisolone and azathioprine. Guanidine and 3,4-aminopyridine have both been used to increase release of acetylcholine at the neuromuscular junction.

Sensory action potentials and conduction velocities are normal, and there is a reduced compound motor action potential to stimulation of motor nerves. However, as with LEMS, in which a similar prejunctional defect occurs, tetanic stimulation of the nerve gives rise to an increase in the amplitude of the muscle action potential (post-tetanic potentiation). Injection of the patient's serum into mice will reproduce the weakness. Treatment involves intensive supportive measures with ventilation in many patients. Botulinum antitoxin is given to neutralize any remaining circulating unbound toxin, and benzyl penicillin to destroy any Cl. botulinum in the gut. With these measures, the mortality is low. Small doses of botulinum toxin, injected into appropriate muscles, are now used therapeutically in a variety of conditions, including blepharospasm, hemifacial spasm, cervical dystonia, limb dystonia, and spasticity, particularly leg adductor spasm.

FURTHER READING ON DISEASES AFFECTING THE NEUROMUSCULAR JUNCTION BOTULISM The exotoxin of Clostridium botulinum binds irreversibly to the presynaptic terminals of nerves whose impulse transmission is mediated by acetylcholine. Those include neuromuscular junctions, autonomic ganglia and parasympathetic nerve terminals. The toxin acts by preventing the release of acetylcholine. Antitoxin has no effect once the toxin has become bound, but recovery of transmission is achieved by terminal axonal sprouting and the formation of new synaptic contacts. Botulism results from eating food contaminated with Cl. botulinum, which produces the toxin under anaerobic conditions. The toxin is neutralized within 60 seconds by heating to above 85°, and botulism thus usually results from eating home-made food preserves, small outbreaks being the rule. It is a rare disease in the UK, but is more frequent in other parts of the world where preparation of uncooked food preserves is common.

Clinical features The first symptoms, which occur 12-72 hours after ingestion, are a dry mouth, abdominal distension with constipation, hesitancy of micturition, blurred vision (due to failure of accommodation), nausea and vomiting. Weakness of cranial nerve innervated muscles occurs early, so that diplopia is often the first symptom of weakness. Widespread weakness, including respiratory paralysis, then develops.

Diagnosis and management

1402

The symptoms and signs of autonomic cholinergic dysfunction distinguish botulism from Guillain-Barre syndrome, MG and diphtheria. EMG may also be helpful.

Critchley E M R, Hayes P J, Isaacs P E T 1989 Outbreak of botulism in north west England and Wales, June 1989. Lancet ii, 849-853. Newsom-Davis J 1992 Diseases of the neuromuscular junction. In: Asbury A K, McKhann G M, McDonald W I, Diseases of the neryous system. Philadelphia: W B Saunders pp 197212. Thomas C E, Mayer S A, Gungon Y et al 1997 Myasthenic crisis: clinical features, mortality, complications, and risk factors for prolonged intubation. Neurology 48:1253-1260. Tim R W, Massey J M, Sanders D B 1998 Lambert-Eaton myasthenic syndrome (LEMS). Clinical and electrodiagnostic features and response to therapy in 59 patients. Ann N Y Acad Sci 841:823-826.

MUSCLE DISEASE The term myopathy refers to any condition that primarily affects muscle physiology, structure or biochemistry. The functional unit of muscle is the motor unit, which comprises a variable number of muscle fibres all innervated by a single anterior horn cell via a motor axon. Muscle fibres are of three types, subdivided on the basis of histology and enzyme content (Fig. 24.63): • Type I fibres are smaller than type II and contain larger numbers of mitochondria and oxidative enzymes, and a larger amount of fat. They are relatively slow contracting and relaxing, and are important in postural control. • Type II fibres have a higher content of glycogen and certain enzymes, including phosphorylase, necessary for anaerobic metabolism. These fibres are rapidly contracting, so-called fast twitch muscle fibres. Type II fibres are further subdivided into types IIa and IIb on the basis of oxidative enzyme content.

TABLE 24.66 Classification of muscle disease

24

• Muscular dystrophies Duchenne Becker Limb girdle Childhood Facioscapulohumeral • Myotonic disorders Dystrophia myotonica Myotonia congenita

FIG. 24.63 Transverse frozen section through a biopsy sample of human vastus lateralis, stained for myosin ATPase The black fibres are type I, the intermediate staining fibres type lIb, and the remainder of varying paler shades type Ila. Scale bar = 100 um. (Photomicrograph courtesy of Prof D N Landon.)

Histochemical and biochemical techniques are increasingly used in the recognition and diagnosis of metabolic defects that affect muscle function. Dystrophy is the term used to describe inherited degenerative muscle diseases.

Clinical features The major categories of muscle disease (Table 24.66) are: • • • •

The dystrophies (hereditary) The myotonic disorders (hereditary) Inflammatory muscle disease A number of endocrine and metabolic disorders (some hereditary).

Symptoms The main symptoms of muscle disease are weakness, wasting (often a symptom as well as a sign), pain and fatiguability. Less common symptoms are cramps and muscle twitching. Weakness. The distribution of wasting and weakness is characteristic for many myopathies, particularly the dystrophies. The time course of development of weakness is also diagnostically helpful. Muscle pain. Pain is particularly a symptom of inflammatory muscle disease and may be present at rest as well as on exertion. Metabolic disorders often lead to exertional pain. Other muscle diseases are less likely to cause pain. Fatiguability. Fatiguability is a leading symptom of the myasthenic syndromes (p. 1400). Cramps. Cramps usually occur at night and are only rarely a symptom of myopathy. They may be relieved by a small dose of quinine sulphate. Other important points in the history are details of any current or past systemic illnesses that might be associated

• Inflammatory Infective: bacterial, viral, parasitic (see Table 24.68) Unknown cause: polymyositis, dermatomyositis, sarcoidosis • Endocrine Thyroid disease - hyper- and hypothyroidism Cushing's disease Addison's disease Hyperparathyroidism • Metabolic Glycogen storage diseases Periodic paralyses Mitochondrial diseases • Drug-induced Corticosteroids Chloroquine Amiodarone Penicillamine Alcohol Zidovudine Clofibrate • Other Inclusion body myositis

with myopathy and - in view of the many inherited disorders of muscle - a family history. Signs Wasting and weakness are the major signs of muscle disease. The distribution is characteristic for the various dystrophies. Most acquired myopathies have a proximal limb girdle type of distribution. Muscle hypertrophy is an occasional feature of muscle disease. Muscle tone is usually reduced in wasted muscles, though this is not specific for muscle disease. Myotonia is a delayed muscular relaxation following voluntary contraction seen in dystrophia myotonica and myotonia congenita. Tenderness of the muscles is usually seen only in inflammatory disorders. Tendon reflexes are preserved in myopathies until wasting is severe. In some dystrophies, reflexes in affected muscle groups are absent from an early stage.

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TABLE 24,67 Classification of the muscular dystrophies X-linked Duchenne Becker

Autosomal dominant Facioscapulohumeral Scapuloperoneal Oculopharyngeal Ocular

Autosomal recessive Limb-girdle Childhood dystrophy

FIG. 24.64 Vital capacity in Duchenne dystrophy

Investigation Nerve conduction tests and EMG will distinguish neurogenic and myopathic electrical changes, and are the most reliable quick methods of identifying the underlying cause of wasting and weakness when there is clinical doubt. Diseased muscle fibres tend to release the enzyme creatine kinase (CK). In Duchenne dystrophy and polymyositis very high serum levels may be found; in other myopathies the CK may be raised to a lesser degree. However, it is important to recognize that any generalized denervating process may cause a modest rise in CK; MND is the commonest cause of this. Other enzymes, including aminotransferases and aldolase, are also released from diseased muscles, but are not specific for muscle. Tests of thyroid and adrenal function are appropriate in some patients, whereas in those with the periodic paralyses investigation of potassium levels and balance may be necessary. The complex mitochondrial myopathies and the glycogen storage diseases require special investigation. Muscle biopsy is only occasionally needed to settle diagnostic doubt as to whether a myopathy is present. A combination of histology and histochemistry in muscle biopsy now permits characterization of the disease process in many patients with muscle disease. O

THE MUSCULAR DYSTROPHIES

The muscular dystrophies can be classified according to the mode of inheritance (Table 24.67). The Duchenne type is the commonest of all; the rest are much rarer. The symptoms, signs and rate of progression are extremely variable in the different dystrophies. Skeletal deformities and contractures are common in some types.

Duchenne muscular dystrophy Duchenne muscular dystrophy (DMD) has an incidence of 13-33 per 100000 live births.

1404

1

Figs 24.24-24.27

4

MCQ 24.29

2

MCQ 24.28

0 Fig. 24.26

Clinical features DMD usually presents in the third year of life with weakness of the pelvic girdle muscles, leading to delay and difficulty in walking, falls, difficulty in rising from the floor and climbing stairs. Hypertrophy of the calf muscles, and sometimes the deltoids, occurs. This is probably a true hypertrophy resulting from relative sparing of these muscles. Exaggeration of the normal lumbar lordosis develops, together with an equinovarus deformity due to weakness of the tibialis anterior and peroneal muscles, with relative sparing of the calf muscles; this leads to a tendency to walk on tiptoe. When rising from the floor a characteristic method of climbing up the legs is adopted (Gowers' sign). Contractures at the knees and elbows are common. The condition is relentlessly progressive, so that most boys are in a wheelchair by 10 years of age, and have died before the age of 20. Cardiac failure, due to cardiac muscle involvement, and respiratory failure are the commonest causes of death (Fig. 24.64). In selected children ventilatory failure can be controlled, and quality of life improved, by nocturnal non-invasive nasal ventilation (Ch. 13, p. 667). Some boys with DMD are of low intelligence. Diagnosis of DMD over the age of 3 is usually not difficult on clinical grounds, though it can be difficult in the early stages. The condition must always be suspected in boys with delayed walking past the age of 18 months. The CK is raised from birth. 0 Genetics of DMD Much recent research has been devoted to the genetics of DMD and the gene has been localized on the short arm of the X chromosome, in a region designated Xp21. With a number of DNA probes (p. 58), it is now possible to identify the gene in carriers and affected fetuses. However, accuracy of identification depends on the availability of DNA samples from many members of a particular family, because in DMD different mutations may occur over a long stretch of the gene. A number of cases result from spontaneous mutations in maternal ovarian cells, the exact proportion of all cases of DMD being uncertain. Thus,

the risk of the sister of a DMD boy being a carrier of the abnormal gene is less than the 50:50 expected if half the mother's X chromosomes carry the DMD gene inherited from her mother. The identification of carriers does enable the incidence of DMD to be reduced in families with a known history of the condition, but not when DMD occurs as a result of spontaneous mutation. Affected boys can be identified in utero and aborted, but this tends to lead to an increased number of female children, many of whom will be carriers of the DMD gene.

abduction of the arms. There is associated wasting of pectoralis major and other shoulder girdle muscles. Later, weakness of the anterolateral muscles in the lower legs develops, causing foot drop and weakness of eversion. Other muscles in the legs are sometimes affected. There is no cardiac muscle involvement and many patients have a normal lifespan.

Other dystrophies

Myotonia - the continuing contraction of a muscle after voluntary contraction ceases - is usually seen as a feature of dystrophia myotonica, but also occurs in the rarer myotonia congenita.

Becker dystrophy Becker dystrophy is an X-linked dystrophy similar in its distribution of weakness to DMD, but more benign. Onset of symptoms occurs between 5 and 25 years, with inability to walk occurring about 20 years after the onset of symptoms. Muscle hypertrophy is a common prelude to the development of weakness. Cardiac muscle is not involved in this type of dystrophy. As Becker patients survive into adult life they may pass on the abnormal gene to their daughters, who may then have affected sons. Limb girdle dystrophy Limb girdle dystrophy - an autosomal recessively inherited condition - begins in the second or third decade of life and affects the sexes equally. Initially, the onset of weakness may be in either the shoulder girdle or pelvic girdle muscles. Severe disability usually results within 20 years of onset, though benign forms do occur. ©Wasting and weakness may become widespread in the limbs, and the condition can be confused with spinal muscular atrophy (p. 1391). It is now recognized that many patients with the clinical syndrome of limb girdle dystrophy have an underlying defect of mitochondrial metabolism (p. 1407). Childhood dystrophy The term childhood dystrophy refers to dystrophy in children of autosomal recessive inheritance. Occasionally, a Duchenne-like dystrophy is seen in girls, often when the parents are consanguinous. The disease is more benign than DMD in boys. Congenital muscular dystrophy is a rare condition presenting at birth with severe generalized hypotonia, and then progressive wasting and weakness. The condition mimics the infantile form of anterior horn cell degeneration, Werdnig-Hoffman disease. The prognosis is very poor. Facioscapulohumeral dystrophy Facioscapulohumeral dystrophy is an autosomal dominant condition affecting boys and girls, with onset during childhood or early adult life. Facial muscle weakness leads to a typical drooping appearance around the mouth, with difficulty closing the eyes. Weakness around the scapula causes winging and riding up of the scapulae on the chest wall on

24

MYOTONIC DISEASES

Dystrophia myotonica Dystrophia myotonica is an autosomal dominant condition, and the gene locus is now known to be on chromosome 19. The features are initially a distal muscle dystrophy with myotonia, with later involvement of proximal muscles, causing respiratory failure, facial muscle weakness and ptosis. Other features of the condition are low intelligence or progressive dementia, cataracts, frontal balding in males, cardiomyopathy, diabetes and gonadal atrophy. Dysphagia is common due to dystrophic change and incoordination of contraction caused by the myotonia. Occasionally, external ophthalmoplegia occurs. Somnolence, either centrally mediated or due to respiratory insufficiency, or both, is common, and sleep apnoea occurs. The condition usually presents in the third and fourth decades. The degree of myotonia is variable. Most men are infertile. Survival is usually not beyond middle age, death usually resulting from cardiorespiratory failure. Myotonia may be helped by procainamide (250-500 mg t.d.s) or phenytoin (300mg daily), but these drugs should only be given when myotonia impairs functional ability. O

Myotonia congenita (Thomsen's disease) Myotonia congenita is a dominantly inherited condition in which myotonia is present from birth, when it may cause feeding difficulties. There is no dystrophy; indeed, in some children there is muscular hypertrophy. Myotonia tends to improve with age. It is usually worst at rest and in the cold, and is relieved to some extent by exercise.

INFLAMMATORY MUSCLE DISEASE Inflammatory diseases of muscle can be divided into those in which a causative infective organism can be identified, and those in which the cause is unknown (Table 24.68). In the UK, all types of infective myositis are uncommon.

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TABLE 24.68 Inflammatory myopathies Infective Bacterial

Clostridial myositis (gas gangrene) Staphylococcal myositis

Viral

Postviral myalgia Influenza myositis Coxsackie A & B Echo

Parasitic

Cysticercosis Trichinosis Toxoplasmosis Trypanosomiasis

Unknown cause

Polymyositis Dermatomyositis Polymyositis with connective tissue disease Sarcoidosis Other granulomatous myositis Eosinophilic polymyositis

Parasitic myositis Myositis may occur as part of a number of parasitic infections, none of them common in the UK. In cysticercosis, ingested larvae spread from the gut to all parts of the body. Their presence in muscles and the nervous system may be asymptomatic at the time of infestation. In the muscles an acute painful myositis may result or, as the encysted larvae gradually enlarge, a diffuse hypertrophic myopathy may occur. In the brain, epilepsy may result. In trichinosis, larvae of the nematode Trichinella spiralis, eaten in inadequately cooked pork, spread widely via the blood, including to muscles. There, they cause an acute, painful myositis, together with conjunctivitis, periorbital oedema and, often, a generalized rash. Toxoplasma gondii occasionally causes a myositis. Collections of parasites (pseudocysts) are found in the muscles. Trypanosomiasis causes an acute polymyositis, often with encephalomyelitis and myocarditis. The treatment of all these diseases is considered in Chapter 9.

Myositis of unknown cause Infective causes Bacterial myositis In the UK clostridial myositis develops in dirty wounds under anaerobic conditions. Clostridium welchii produces a toxin and enzymes which cause necrosis of muscle with inflammation and haemorrhage. Urgent treatment with surgical debridement and penicillin is necessary. In tropical countries acute suppurative tropical myositis is relatively common (it is rarely seen in temperate zones). The initiating lesion may be a penetrating or crush injury, or it may be secondary to a Staphylococcal arthritis. Staphylococcus is the usual infecting organism. Proximal lower limb muscles are usually most affected. Viral myositis A number of viruses regularly produce myositis. Myalgia with a bad cold (adenovirus or rhinovirus) is a non-specific effect. A more severe polymyalgia may arise after influenza infections. It affects the thigh or calf muscles, which may swell, and the CK is raised. Two of the Coxsackie viruses occasionally cause myositis. Bornholm disease and epidemic myositis affecting muscles in the trunk, particularly the chest, are now known to be caused by Coxsackie B5. Polymyositis with myoglobinuria may be caused by Coxsackie B6. Other viruses, notably the echoviruses, have occasionally been associated with myositis.

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1

Figs 24.24, 24.28-24.29

3

Fig. 24.25

4

2

MCQ 24.30

Case 24.11

Polymyositis refers to a group of conditions the cardinal feature of which is a myopathy, usually proximal in distribution, and of acute, subacute or chronic presentation, in which the CK is variably raised, myopathic changes are present on EMG, and muscle biopsy shows an inflammatory infiltrate with varying degrees of muscle necrosis. Polymyositis and dermatomyositis are discussed in Chapter 22, page 1180. GO Sarcoidosis may cause a proximal myopathy, usually subacute in onset, in which typical non-caseating granulomas are found on muscle biopsy. Other conditions which occasionally produce an inflammatory proximal myopathy are polyarteritis nodosa and Wegener's granulomatosis. In eosinophilic polymyositis, muscle involvement is only one part of a multisystem disease associated with eosinophilia, which includes heart and lung involvement, peripheral neuropathy, encephalopathy, skin changes and hypergammaglobulinaemia. Prognosis of polymyositis and related disorders The prognosis for polymyositis not associated with other disease at presentation is good. Childhood, adolescent and early adult dermatomyositis similarly has a good prognosis. However, in later-onset dermatomyositis, particularly in men, the prognosis is poor, owing to the 50% incidence of underlying cancer. The outlook is also worse for polymyositis associated with collagen disease. The prognosis for polymyositis with sarcoidosis is variable.

Inclusion body myositis Inclusion body myositis is an increasingly recognized cause of myopathy in later life. It is most common in middle-aged

and elderly men, who present with slowly progressive painless proximal wasting and weakness. The cause is unknown. EMG shows mild myopathic changes, and muscle biopsy shows characteristic inclusion bodies, comprising autophagic vacuoles and filamentous inclusions. © The condition is unresponsive to immunosuppressive treatment. O

of reported chronic alcoholic myopathy probably have a neuropathic rather than a myopathic basis (p. 1441). An acute reaction to halothane anaesthesia, malignant hyperpyrexia, is now known to have a muscular basis, though the mechanism remains unclear. The condition is familial and is rare. Dantrolene has been used to prevent the reaction but, if suspected from a family history, it is best to use alternative anaesthetic agents.

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ENDOCRINE MYOPATHIES Thyroid disease In some patients with uncontrolled thyrotoxicosis a symptomatic proximal myopathy develops, and mild degrees of asymptomatic proximal weakness can be demonstrated in many thyrotoxic patients. This resolves with treatment of the thyrotoxicosis. About 5% of all patients with MG also have thyrotoxicosis. A normokalaemic periodic paralysis is occasionally seen in thyrotoxicosis (see below). Hypothyroidism is occasionally associated with a proximal myopathy, typically leading to pain in the muscles after exertion. Myopathy with adrenal and pituitary disease In Cushing's syndrome there is usually some evidence of a proximal myopathy, with wasting and weakness. Steroids given therapeutically for any reason may lead to a similar proximal myopathy. The rate at which this appears in different people is extremely variable. Patients who have had adrenalectomy for Cushing's disease may develop a proximal myopathy, thought to be caused by raised levels of circulating corticotrophin. In acromegaly and pituitary gigantism, generalized weakness, particularly proximally, is common. In Addison's disease and hypopituitarism, weakness is a leading symptom, usually secondary to salt and water abnormalities. Parathyroid disease In hyperparathyroidism a painful proximal myopathy may develop. A particularly painful myopathy characteristically occurs in osteomalacia, often without much wasting or weakness.

TOXIC MYOPATHIES Various drugs may cause a myopathy, of which the most important are the corticosteroids. Steroid myopathy is usually reversible if the drug is withdrawn. Other drugs that occasionally cause myopathy include vincristine, chloroquine and amiodarone, all of which also cause a neuropathy. Emetine and e-aminocaproic acid also cause a myopathy. Penicillamine leads to the development of a myasthenic syndrome indistinguishable from MG. This is sometimes reversible on withdrawal of the drug, but in many patients it is permanent. Alcohol may produce an acute myopathy with myoglobinuria, usually following an alcoholic binge. Many cases

METABOLIC MYOPATHIES Glycogen storage diseases of muscle The most important of the glycogen storage diseases of muscle is McArdle's disease, caused by a deficiency of myophosphorylase in muscle, leading to impaired utilization of muscle glucose. The disease presents with muscle pain and stiffness which is made worse by exertion. The condition usually comes on in early adult life and, although it is usually non-progressive, some patients develop increasing wasting and weakness. Many other biochemical abnormalities affecting muscle glucose utilization have been described, most leading to multiple system disorders and disability and death in children. Acid maltase deficiency is one important exception, which may present with a limb-girdle dystrophic picture. The specific underlying metabolic defect is suspected when biopsy shows characteristic glycogen-containing vacuoles. None of the glycogen storage diseases affecting muscle is yet treatable. The periodic paralyses These are dominantly inherited conditions in which episodic weakness is associated with a change in plasma and muscle potassium concentrations. There are two major types: the commoner hypokalaemic periodic paralysis and the less severe hyperkalaemic variety. In the hypokalaemic type, episodes of weakness are provoked by exertion but usually occur on the following day during a period of rest. In some patients attacks are provoked by large carbohydrate meals. Each attack may last several hours. During the episodes of weakness, plasma potassium is below 3.0mmol/L, with some accumulation of potassium within muscle cells. Acetazolamide or a thiazide diuretic usually prevents attacks, and some patients respond to oral potassium. The disease usually starts in the second or third decade, and attacks tend to improve gradually during adult life. In the hyperkalaemic type, attacks of generalized weakness of about 30 minutes' duration are also provoked by exertion, but the weakness immediately follows the exercise. During the attack the plasma potassium concentration increases. Acetazolamide helps this type of attack. Mitochondrial myopathies (cytopathies) The mitochondrial myopathies are rare and their numerous clinical manifestations have only recently been recog-

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nized. Because tissues and organs other than muscle (notably the CNS) may also be affected, producing multisystem diseases, the broader term mitochondrial cytopathy is now used. Some of the disorders are confined to muscle, but clinical syndromes also include dementia, fits, ataxia, pigmentary retinopathy, stroke-like episodes, extrapyramidal syndromes, deafness, and peripheral neuropathy without clinically obvious myopathy. A number of underlying mitochondrial defects are responsible for these disorders. In muscle biopsies the common feature is the so-called ragged red fibre, in which there are accumulations of abnormal mitochondria at the periphery of the muscle fibres. O Ultrastructurally, mitochondria are abnormal in size and shape, and often contain paracrystalline inclusions. These mitochondrial abnormalities, however, are not always present. Many different biochemical abnormalities have now been described.

CHRONIC FATIGUE SYNDROME Pathological fatigue is a well recognized feature of certain neurological disorders, notably myasthenia, certain myopathies and MS, and is also encountered in some types of peripheral neuropathy. However, some patients with a primary complaint of chronic fatigue have no identifiable neurological disease. Their condition is sometimes referred to as 'myalgic encephalomyelitis' (ME) or 'postviral fatigue', but there is no rational basis for the use of either of these diagnostic labels. The available evidence suggests that as many as 70% of such patients have a treatable depressive disorder, although this explanation may be resisted. A few may eventually be found to have MS or other specific disorders; in others there may indeed have been an unidentified viral myositis, in which case the prognosis is good. Some patients, however, remain persistently and severely incapacitated by their symptoms. As in the case of the post-traumatic disorder following head injury (p. 1373), it seems likely that the degree of long-term disability reflects the complex interaction between a relatively minor illness and the patient's personality and individual circumstances at the time.

FURTHER READING ON MUSCLE DISEASE Mastaglia F L, Laing N G 1996 Investigation of muscle disease. J Neurol Neurosurg Psychiatry 60: 256-274. Walton J 1994 (ed) Disorders of voluntary muscle, 6th edn. Edinburgh: Churchill Livingstone.

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Fig. 24.27

DEMYELINATING DISEASES Demyelinating diseases are a group of CNS disorders in which the primary pathological process is demyelination without axonal degeneration. By far the most important of these is multiple sclerosis (MS). Demyelination is also the result of a number of rare inherited disorders of sphingolipid metabolism; these include the leukodystrophies and some lipid storage diseases.

MULTIPLE SCLEROSIS MS is a disease of unknown cause in which discrete areas of demyelination develop at many sites in the brain and spinal cord. Lesions develop in different sites at different times, usually with some capacity for regeneration and restoration of function. This leads to a characteristic relapsing and remitting history in many patients; in others, a slowly progressive deficit occurs. Although demyelination is the primary pathology in MS, extensive areas of demyelination are associated with axonal loss, and in most patients there is a slowly cumulative neurological deficit.

Epidemiology The prevalence of MS shows a strong geographical variation, being essentially a disease of temperate climates. Even within the UK there are considerable variations in prevalence, e.g. around 30 per 10000 in Shetland and Orkney, compared to 6 per 10000 in England. MS is very rare in childhood and uncommon in early adolescence. There is an increasing incidence with age, with a peak at about 30 years. It is uncommon over the age of 50. In late presentations it is often possible to obtain a history of a previous minor neurological episode in earlier life which was likely to have been due to MS. This emphasizes the relatively benign course of the disease in some patients. Slightly more women than men are affected by MS.

Pathology Acute demyelination occurs in discrete areas known as plaques, which may be single or multiple. The lesions may occur anywhere in central white matter, but common sites are the optic nerve, the brainstem and cerebellum, the periventricular regions and the cervical spinal cord. Later, glial scarring results in the whitish appearance of the chronic plaque. Some remyelination is possible, but this is limited. Resolution of oedema in and around plaques reverses conduction block and improves function. Axonal loss occurs, leading to permanent disability. Even without symptoms or signs, slowing of conduction can often be demonstrated in visual, auditory and somatosensory pathways by electrophysiological testing.

Aetiology There have been many hypotheses about the cause of MS. Acute demyelination is an inflammatory process and the most favoured explanation at present is that acute demyelination is the result of an abnormal immune response to an antigen, perhaps of viral origin. Recent studies have suggested that herpes simplex viruses types II and VI may be of particular importance in pathogenesis. Genetic factors may be important in some instances, as there is an association of MS with HLA-A3 and DR2 antigens. Studies of migrants show that if migration occurs before the age of 15, the risk of developing MS becomes that of the country to which the patient has migrated. This evidence emphasizes the importance of an environmental factor or factors. Studies in a model of MS, experimental allergic encephalomyelitis (EAE), suggest that there is an autoimmune response to myelin antigens, triggered by a nonself, perhaps viral, antigen. Myelin basic protein and myelin oligodendrocyte glycoprotein become major antigens in EAE, though this has not been demonstrated in MS. These antigens cause T-cell activation, leading to the production of proinflammatory cytokines, and there are other, unknown, factors causing T-cell migration and adhesion. It is postulated that activated T cells promote an immunological cascade, involving the recruitment and stimulation of macrophages and B lymphocytes, and the release of nitric oxide (NO) and free oxygen radicals (FOR). Antibodies, NO and FOR mediate myelin destruction and disrupt the blood-brain barrier.

Clinical features Because plaques may occur at any site in central white matter, the clinical manifestations of MS are extremely variable. However, early in the disease a number of presentations are characteristic (Table 24.69). Optic neuritis Inflammation of the optic nerve may be symptomatic or asymptomatic. When it affects the optic nerve head, it is sometimes termed papillitis; when inflammation occurs in the optic nerve further behind the eye, it may be called retrobulbar neuritis. Symptoms. In acute optic neuritis (which is nearly always unilateral) there is dimming of vision, blurring, loss of acuity and reduced colour vision. These symptoms usually progress over hours or a few days. Rarely, vision may be lost altogether. Patients may be aware of the central or paracentral scotoma characteristic of this condition. Pain in and around the eye, particularly with movement of the eye, is common. The symptoms may be mild and transient, lasting only a few days, and may not cause patients to present to their doctors. Signs. Examination during acute symptomatic optic neuritis will usually show impaired visual acuity, but formal visual field mapping may be necessary to detect small sco-

TABLE 24.69 Common sites of focal demyelination and corresponding symptoms Site

Clinical features

Optic nerve

Transient monocular visual impairment with local pain Good prognosis Rarely bilateral or progressive

Spinal cord

Sensory symptoms in all four limbs L'Hermitte phenomenon (see text) Spastic paraparesis or tetraparesis Bladder and sexual dysfunction

Brainstem

Diplopia Facial numbness or neuralgia Vertigo Dysarthria, dysphagia Ataxia

Cerebellum

Ataxia Dysarthria Nystagmus

Cerebral hemispheres

Altered mood (euphoria or depression) Dementia Seizures (rare)

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tomas. The pupillary reaction to light shone in the affected eye will be sluggish in both affected and unaffected eyes; a brisker response is obtained in both eyes when the same light is shone into the unaffected eye, indicating an afferent pupillary defect. On fundoscopy there may be no abnormality if inflammation is located proximally in the optic nerve, but with inflammation near to the optic nerve head there may be papilloedema. Optic neuritis usually resolves within a few weeks, often without residual symptoms. However, a degree of optic atrophy is often detectable as pallor of the optic disc, a useful diagnostic sign in MS: Some patients will be aware of continuing impairment of visual acuity and colour vision and, rarely, there is severe visual impairment after a single episode. Repeated acute episodes of optic neuritis during the course of MS are common. Sometimes, a slowly progressive visual impairment results from indolent optic neuritis. Other rare causes of optic neuritis include sarcoidosis, syphilis, herpes zoster and SLE. About 30% of patients presenting with optic neuritis have no other evidence of MS, and do not develop the disease. Cervical cord Involvement of the cervical spinal cord is very common early in the course of MS (Fig. 24.65), presenting with motor, sensory or bladder, bowel and sexual disturbances. Symptoms may be unilateral, but pyramidal signs are usually bilateral. Although there are usually no symptoms

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FIG. 24.65 Sagittal MR scan (T1-weighted image) of the cervical region and brainstem of a young woman with fluctuating sensory symptoms of a spinal cord lesion The scan shows several focal hyperintense lesions within the cervical cord, some of which are associated with swelling of the cord. The appearances are typical of demyelinating disease and the patient's subsequent clinical course left no remaining doubt about a diagnosis of multiple sclerosis.

in the upper limbs in the early stages, brisk reflexes are often found. 1 Sensory symptoms include tingling paraesthesiae and numbness. Examination reveals disturbance of dorsal column function (impaired joint position and vibration sensation) and, less often, of spinothalamic sensation. A common early manifestation of MS is L'Hermitte symptom, in which the patient notices brief tingling in the legs, and sometimes the trunk and upper limbs, on flexing the neck. This is probably due to mechanical sensitivity of dorsal column fibres in an area in, or surrounding, a plaque of demyelination. It may occasionally occur after cervical cord trauma, with cervical tumours, and in subacute combined degeneration due to vitamin B12 deficiency. Bladder disturbances are common in MS and are occasionally the presenting complaint. Urgency and frequency of micturition, and then incontinence, are characteristic. Constipation is the main bowel disturbance early in MS, but urgency of defaecation with soiling may occur. Erectile impotence and ejaculatory failure are common symptoms. Brainstem and cerebellum Visual disturbances other than optic neuritis are frequent, and include diplopia due to either sixth-nerve palsy or an

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Case 24.12

0 Figs 24.30, 24.31

internuclear ophthalmoplegia (INO). In INO, which is caused by a lesion of the medial longitudinal fasciculus, eye movements are dysconjugate on lateral gaze; thus, on right lateral gaze there is incomplete adduction of the left eye, and there may be associated nystagmus, which is of greater amplitude in the abducting right eye: so-called ataxic nystagmus. Nystagmus without ocular palsy is a common manifestation of brainstem demyelination, and may be horizontal, vertical or rotatory. Vertigo is a fairly common early symptom of MS, owing to plaque formation involving the vestibular nuclear complex. Ataxia involving limbs and/or trunk is also frequent early in the disease, and is due to plaque formation within the cerebellum or affecting its connections in the brainstem. Long motor and sensory tracts may also be involved in the brainstem; this produces symptoms and signs similar to those of cervical cord demyelination. Paroxysmal symptoms Brief episodic symptoms, lasting only 30-60 seconds, may occur in clusters, sometimes very frequently throughout the day. These can take the form of diplopia, facial numbness, typical trigeminal neuralgia, vertigo, dysarthria, ataxia, disturbance of sensation or power in the limbs, or brief tonic spasms affecting one or both extremities on one side. These various paroxysmal phenomena are virtually pathognomonic of MS and are believed to result from spontaneous discharges within areas of demyelination in the brainstem. The attacks may respond dramatically to carbamazepine in relatively low dosage, a further point in favour of the diagnosis.

Later features Depression in long-standing MS is common and requires vigorous treatment. Widespread cerebral hemisphere demyelination leads to intellectual impairment. Often, there is a predominantly frontal impairment, producing disinhibition and other frontal features (p. 1287). Brainstem demyelination leads to complex ocular palsies, ataxia and long tract signs. Rubral tremor is a particularly disabling type of cerebellar tremor; it is postural and large in amplitude, preventing purposeful actions in the arms. Myokymia refers to a continuous rippling twitching of the facial muscles on one side. It is probably due to irritation of the facial nucleus. Progressive bulbar involvement producing dysarthria, dysphagia and dysphonia indicates a particularly poor prognosis. Lower motor neurons are rarely affected in MS. Other factors Patients with MS frequently remark that their symptoms are worse in hot weather, after a hot bath, during fever or after exertion, all of which raise body temperature. Conduction in demyelinated axons is blocked by small rises in body temperature. The risk of relapse is reduced during pregnancy, but then slightly increased during the first 3 months of the postpartum period.

Course and prognosis MS can be a remarkably benign disease with long periods of remission and relatively little neurological deficit. However, in most patients an increasing neurological deficit accumulates. The end stage of severe progressive MS is characterized by dementia, quadriplegia, incontinence, blindness, pressure sores and recurrent respiratory and urinary tract infections. In about three-quarters of patients the disease has a relapsing and remitting course, and in the remainder a chronic progressive course. In about 20% of patients there is no significant disability after 5 years, and the average life expectancy overall from the onset of symptoms is 20-30 years. In about 5% of patients the disease is rapidly progressive and fatal within 5 years. Poor prognostic factors are an older age at onset, the development of dementia and the early development of ataxia.

Diagnosis In many patients the diagnosis is straightforward and established on clinical evidence of more than one lesion in the nervous system, together with a characteristic relapsing and remitting history. The finding of optic atrophy in a patient presenting with a brainstem or cervical cord lesion is particularly helpful diagnostically. MRI is the investigation of first choice. Characteristic lesions are seen in the brain (or cervical cord) in the majority of cases (Fig. 24.66), 0 but a normal MRI does not rule

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FIG. 24.66 Magnetic resonance scan in multiple sclerosis Multiple areas of abnormal signal, here shown in white, are visible in the cerebral hemisphere white matter, particularly adjacent to the lateral ventricles.

out the diagnosis. CT scanning is much less sensitive and rarely helpful diagnostically. Evoked potentials, either visual, auditory or somatosensory from the limbs, are sensitive measures of damage in these sensory pathways. Visual evoked potentials are recorded from the scalp over the occipital cortex. A flash or regular pattern reversal stimulus produces a small visual evoked potential, which can be averaged. The latency is prolonged if there has been significant demyelination at any time in the past. Similar information can be obtained concerning brainstem auditory pathways and large fibre, dorsal column somatosensory pathways from the limbs. In the absence of any present or past symptoms the evoked potentials are often delayed. CSF protein content may be raised. The IgG fraction of this may be greater than 10%, and CSF electrophoresis may show discrete bands in the gamma 4 and gamma 5 regions (oligoclonal bands). These immunoglobulins are synthesized locally within the CNS. Oligoclonal bands are not unique to MS and occur occasionally in other conditions, including neurosyphilis and neurosarcoidosis. However, the finding of oligoclonal bands in the clinical setting of suspected MS lends support to this diagnosis.

Management There is no specific treatment for MS. Corticosteroids may accelerate remission in relapse, probably by reducing inflammation and oedema in acute plaques. High-dose methylprednisolone is given in a dose of 1 g daily for 3 days, or 500 mg daily for 5 days. Steroids have no effect on the outcome of a particular relapse and do not protect against

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further relapses. Long-term immunosuppression with traditional drugs is of very limited benefit, although there is some evidence to suggest that azathioprine or low-dose methotrexate may modify the course of the illness in a minority of cases. Results with B-interferons have been more encouraging. In patients with active relapsing and remitting disease, regular injections of B-interferon 1b or la have been shown to reduce the incidence of new attacks by about 30%, at least during the first 2 or 3 years of treatment. These agents probably also have a modest effect in slowing down the underlying accumulation of disability, although the practical value of this is still the subject of debate. The drug is more widely used in the USA and other European countries than in the UK, where its cost-effectiveness is questioned in comparison with other possible uses of NHS funds. The synthetic immunosuppressant copolymer-1 has been shown to reduce relapse rate to an extent very similar to that of (3-interferon, possibly with a more favourable sideeffect profile. This agent is now licensed under the name glatiramer acetate (Copaxone) and can be prescribed as an alternative to B-interferons. Its cost is similarly high. Dietary restrictions or supplements are frequently recommended, but there is no evidence of their efficacy. Hyperbaric oxygen has also had a vogue in recent years. Carefully controlled clinical trials have not shown any benefit. The treatment of MS remains symptomatic and supportive. Physiotherapy and occupational therapy have a large role to play. Spasticity may be relieved by antispastic drugs, such as baclofen, dantrolene, diazepam and tizanidine, but these may cause drowsiness and exacerbation of weakness. Urinary urgency and frequency are often partly relieved by anticholinergics. Other patients will require urinary devices, such as sheaths and pads, and some patients eventually need permanent catheterization. An alternative, increasingly used and suitable for many patients, is intermittent self-catheterization.

OTHER ACQUIRED DEMYELINATING DISEASE Postviral and postvaccinial encephalomyelitis In postviral and postvaccinial encephalomyelitis, widespread acute inflammation with demyelination in the brain and spinal cord follows a viral illness - either one of the exanthemata or an intercurrent viral infection. The syndrome is also referred to as acute demyelinating encephalomyelitis (ADEM). Occasionally, a similar disease follows smallpox vaccination and other inoculations, particularly for rabies. Because of the frequency of the exanthemata in childhood, children are affected by this type of encephalomyelitis more often than adults. Occasionally there is no preceding history of infection or inoculation. The illness is characterized by subacute onset of malaise, headache, vomiting, drowsiness, convulsions and fever, together with focal symptoms and signs. A hemiparesis, brainstem and cerebellar signs, and evidence of a myelitis are the principal focal features. Occasionally, optic neuritis occurs. Coma and death may ensue, but the majority of patients recover, some with residual intellectual and physical deficit, including epilepsy. Occasionally there are recurrent episodes. Rarely, an initial severe episode of MS presents in this way. The acute illness resembles an encephalitis due to direct viral infection and, clinically, it can be impossible to distinguish the two (p. 1423). Acute haemorrhagic leukoencephalopathy, in which there are accompanying multiple areas of haemorrhage, probably represents a particularly severe form of encephalomyelitis. The demyelinating condition of central pontine myelinolysis is discussed on page 1441.

Counselling in MS

SUMMARY 16 Multiple sclerosis (MS)

MS is a common neurological disorder, and patients with a wide variety of symptoms think - often incorrectly - they have MS. The lay view of MS and its prognosis is often more gloomy than the reality. In patients with a single neurological episode possibly due to MS, it is usually ill-advised to discuss the possibility of MS unless directly asked by the patient. When the diagnosis is definite, however, it is best to inform the patient. Time must be set aside to discuss the disease, its effects and its prognosis with both patient and

• MS is the commonest progressive disabling neurological disease affecting young adults in the UK. • Common sites of symptomatic demyelination are the optic nerves, cervical cord, brainstem, cerebellum and, usually later in the course of the disease, the cerebral hemispheres. • MS may run a relapsing-remitting or chronic progressive course. The former is more likely to occur with younger age of onset. • Prognosis is better with young onset and a relapsing-remitting course, but is very variable. • Corticosteroids may accelerate recovery from an acute exacerbation. • Other immunosuppressive agents have little effect on the longterm course of the disease, but B-interferons 1a and 1b show some promise in this respect. • There is no clear-cut evidence that dietary restrictions or supplements, or hyperbaric oxygen, alter the cause of the disease.

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relatives. Open discussion and allaying fears, which are often misguided or ill-founded, are usually helpful. 1

MCQ 24.31

24

TABLE 24.70 Disorders of sphingolipid metabolism Disease

Biochemical defect

Clinical features

Aryl sulphatase A deficiency Unknown Galactocerebroside B-galactosidase deficiency

See text X-linked dementia, spasticity, neuropathy, hypoadrenalism Onset in infancy Irritability, motor regression, nystagmus, spasticity or hypotonia, optic atrophy, fits. Death within 1 year

Motor regression in infancy. Optic atrophy. Death within 2 years

Gaucher's disease Niemann-Pick disease

p-acetyl hexosaminidase deficiency causing accumulation of GM2 ganglipside Glucocerebrosidase deficiency Sphingomyelinase deficiency

Fabry's disease

Ceramide trihexosidase deficiency

The leukodystrophies Metachromatic leukodystrophy Adrenoleukodystrophy Globoid cell leukodystrophy

Lipid storage diseases Gangliosidoses, e.g. Tay-Sachs disease

Disorders of sphingolipid metabolism Many rare disorders of myelin metabolism exist. These fall into two broad groups, the leukodystrophies and the lipid storage diseases (Table 24.70). Demyelination is common to both groups. They are primarily of relevance to paediatric practice. Most lead to progressive mental deterioration and a multiplicity of neurological signs, often including spasticity in the limbs, fits, ataxia and optic atrophy. Death within months or 1-2 years occurs in many of these disorders; metachromatic leukodystrophy, adrenoleukodystrophy and Fabry's disease are exceptions. There is no specific therapy for these conditions. Metachromatic leukodystrophy Metachromatic leukodystrophy is an autosomal recessive condition caused by a deficiency of aryl sulphatase A, in which there is tissue accumulation of metachromatic lipids in the white matter of the CNS and in peripheral nerves. The effects are widespread, with onset of symptoms usually in early childhood but sometimes as late as adolescence.

Progressive neurological deterioration after birth. Death within 1 year Onset at 6 months. Progressive mental and neurological deterioration May survive many years Cardiac, renal and nervous system involvement

There is weakness, ataxia, dementia and fits. Examination shows signs of peripheral neuropathy, in addition to pyramidal weakness, ataxia and dementia, and there is often optic atrophy. The diagnosis is made by assay of the enzyme in leukocytes, and metachromatic material can be seen on rectal or peripheral nerve biopsy.

FURTHER READING ON DEMYELINATING DISEASES Hughes R A C 1994 Immunotherapy for multiple sclerosis. J Neurol Neurosurg Psychiatry 57:3-6. Matthews W B 1991 McAlpine's multiple sclerosis, 2nd edn. Edinburgh: Churchill Livingstone. Mcdonald W I 1995 New treatments for multiple sclerosis. Br Med J 310:345-346.

BACTERIAL INFECTIONS OF THE NERVOUS SYSTEM ACUTE BACTERIAL MENINGITIS

RECENT ADVANCES IN MULTIPLE SCLEROSIS • In the appropriate clinical context, MRI of the brain and spinal cord is now the most sensitive investigation providing support for the diagnosis of MS. • MRI also allows more confident diagnosis of MS at an earlier stage of the disease in many patients. • Treatment with B-interferon has been shown to reduce the risk of new attacks in patients in a relapsing and remitting phase. Its value for longer-term treatment has yet to be established. • More effective control of bladder symptoms, with intermittent self-catheterization, has improved the quality of life for many patients with MS.

Bacterial meningitis is infection of the leptomeninges and the CSF which diffusely affects the whole meninges and subarachnoid space and, sometimes, the ventricles (ventriculitis). The three bacteria most commonly causing meningitis, Neisseria meningitidis, Haemophilus influenzae and Streptococcus pneumoniae, gain access to the meninges and subarachnoid space via the bloodstream from the nasopharynx, through the walls of the intracranial venous sinuses. Once in the CSF, bacteria rapidly multiply. Other bacteria may also cause meningitis (Table 24.71; see also Ch. 9); any bacterium causing septicaemia may enter the CSF and cause meningitis. Haematogenous spread may also occur from infective endocarditis, osteomyelitis and pyelonephritis.

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TABLE 24.71 Treatment of bacterial meningitis in adults Organism

Treatment

Neisseria meningitidis

Benzyl penicillin (2.4g, 4-hourly) or chloramphenicol (20mg/kg 6-hourly) in hypersensitivity to penicillin Cefotaxime or benzylpenicillin or chloramphenicol, doses as for N. meningitidis Cefotaxime or ceftriaxone (3g, 8-hourly) or chloramphenicol (20mg/kg, 6-hourly) or ampicillin (2g, 6-hourly for 2 days, then 1 g 6-hourly) or co-trimoxazole (160mg trimethoprim and 800 mg sulfamethoxazole, 12-hourly) Flucloxacillin (3g, 6-hourly) or vancomycin (500 mg, 6-hourly) or gentamicin (5mg/kg per day*) in penicillin hypersensitivity Piperacillin (4g, 6-hourly) with tobramycin (3-5mg/kg per day) or ticarciliin (5g, 6-hourly) with gentamicin (5mg/kg per day*)

Streptococcus pneumoniae Haemophilus influenzae

Staphylococcus aureus Staphylococcus epidermidis Pseudomonas aeruginosa

pressure from downward displacement of an oedematous brain, with raised intracranial pressure. The major arteries at the base of the brain may occasionally become occluded by the purulent arteritis, leading to major strokes, affecting either the cerebral hemispheres or the brainstem. Cortical veins may also become occluded, which may lead to areas of infarction. Infection may also spread into the subdural space, causing a subdural empyema. Localized epidural abscesses may occur over the cerebral hemispheres, and epidural abscesses may develop secondary to meningitis in the spinal cord, leading to spinal cord compression. Late sequelae of acute bacterial meningitis include persistent cranial nerve palsies, although the acute palsies usually improve to some extent. Deafness, due to eighthnerve damage, is often bilateral, severe and permanent. This has been estimated to occur in 5-40% of all patients. In young children, diffuse cerebral damage with mental retardation often results from acute meningitis, particularly with H. influenzae infection.

*Gentamicin blood levels necessary.

Clinical features Mechanisms of infection Direct infection occurs from penetrating trauma, including compound skull fractures and gunshot wounds. Fractures of the skull with CSF leaks are common causes of meningitis. Septic foci closely adjacent to the meninges (and thus potential causes of meningitis) include sinusitis, middle ear and mastoid infection, and osteomyelitis of the skull bones. Lymphatic spread of infection to the spinal cord occurs from retropharyngeal, retroperitoneal and psoas abscesses. Congenital abnormalities, particularly meningomyeloceles, provide a further route of infection. Despite the most careful aseptic precautions, meningitis still remains a serious complication of neurosurgical procedures. Shunts are particularly likely to lead to infection. Meningitis is a much more common illness in immunocompromised patients; these include patients undergoing organ transplantation and those with HIV infection.

Complications of meningitis

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Meningitis may be complicated by ventriculitis or intracerebral abscess. There may be obstruction of CSF flow through the foramina between the ventricles and cerebral aqueduct, causing hydrocephalus. Purulent exudate may cause reduced reabsorption of CSF in the arachnoid granulations, also leading to hydrocephalus; and septic thrombosis of the venous sinuses can occur, leading to an increase in intracranial pressure with a communicating hydrocephalus. The purulent exudate in the basal meninges may affect the cranial nerves and arteries that cross the subarachnoid space; cranial nerve palsies are thus common complications of bacterial meningitis. The third and sixth cranial nerves may also be affected by direct

In adults the main symptoms of meningitis are headache, vomiting, irritability, photophobia and drowsiness. Fits are usually a later symptom. In meningococcal meningitis the progression of symptoms may be extremely rapid, the patient presenting in coma within hours of the onset of symptoms. The signs are fever, neck stiffness, drowsiness, stupor or coma; sometimes, there is neurological deficit - cranial nerve palsies, hemiparesis or other focal signs - which results from occlusion of the basal cerebral arteries. Focal deficit is more common in advanced, untreated cases of meningitis. Neck stiffness may be mild or absent in deeply comatose patients. Meningeal irritation may cause a positive Kernig's sign, and Brudzinski's sign, in which neck flexion causes flexion of the legs. Later, there may be a posture of extension of the neck and spine. The typical rash of meningococcal septicaemia may be present (p. 274 and Fig. 9.16, p. 310). In neonates and young children the symptoms and signs of meningitis may be minimal. Fits are a much more common presenting feature in the young, and irritability, fever and drowsiness may be the only signs. Likewise, in the elderly there may be few signs and, in some cases, a much more insidious onset.

Differential diagnosis The commonest alternative cause of severe headache, neck stiffness and vomiting, with or without focal signs, is subarachnoid haemorrhage. This is usually, but not always, abrupt in onset. CT scanning is helpful in demonstrating subarachnoid blood in such cases. Aseptic viral meningitis is the other main differential diagnosis. Other types of meningitis may cause an identical presentation to acute bacterial meningitis. The onset of tuberculous meningitis

CASE STUDY 24.10 HEADACHE, FEVER, CONFUSION AND DROWSINESS IN A 32-YEAR-OLD MAN A 32-year-old Caucasian man was referred to hospital with a 3-day history of headache, malaise, fever and then drowsiness. By the time of admission he seemed confused and irritable and was barely able to describe his symptoms. His wife said that he had previously been well apart from a minor upper respiratory infection 4 or 5 weeks before this illness. He had had a motor cycle accident in his early 20s and was unconscious for a few hours afterwards. He was kept in hospital for 2 days but then made a full recovery. His most recent travel was a holiday in Tunisia 4 months earlier. On examination he was drowsy and irritable, with a fever of 39 °C. There was marked neck stiffness. He was photophobic, to such an extent that examination of the pupils and optic fundi was extremely difficult. There were some faint red blotches over his upper chest area but no skin lesions elsewhere. His posterior pharynx looked red, but there was no exudate or tonsillar enlargement. There were no enlarged lymph nodes and general examination was otherwise unrevealing. Brief glimpses of the fundi were thought to show normal appearances. The right pupil was larger than the left, but both reacted briskly to light. Eye movements appeared full and conjugate, as far as examination was possible. The left eardrum was obscured by wax. The cranial nerves were otherwise intact and there were no signs in the limbs apart from generally brisk tendon reflexes, which were symmetrical. Both plantar responses were ambiguous but probably flexor.

Questions What is the likely diagnosis? What causative of ganisms should be considered? How should the patient be investigated and managed?

Discussion The clinical picture is that of acute meningitis or meningoencephalitis. If the mode of onset and rate of progression was sudden or unknown, then subarachnoid haemorrhage should also be considered, but the time course and high fever in this case is much more suggestive of infection. There are no clear clinical clues. The vague rash on his chest is not typical of meningococcal septicaemia, but this is nevertheless the most likely organism in a previously fit young man with a short history. The previous head injury, although more than 10 years ago, could conceivably have left him with an unrecognized CSF leak, so pneumococcal infection should also be considered. Other bacterial agents are less likely unless there is an unknown history of immunological compromise. There are no overt risk factors for HIV infection in this patient, but this possibility should always be kept in mind if meningitis pursues an atypical course and is poorly responsive to standard treatment. Viral meningitis remains possible in the absence of any positive clinical features of bacterial infection. Herpes simplex encephalitis would not typically present with intense photophobia and marked neck stiffness, but this diagnosis cannot be excluded completely on clinical grounds. 'Atypical' organisms causing meningoencephalitis include Mycoplasma, Legionella and Borrelia burgdorferi. A cerebral illness developing a few weeks after a viral respiratory infection raises the possibility of acute postinfective demyelinating encephalomyelitis (ADEM), but this would not usually be associated with marked meningism. Immediate investigations should include routine haematology and biochemistry, blood cultures, chest Xray and, if possible, urine examination. In seriously ill patients

24

or those deteriorating very rapidly, particularly children, it is reasonable to start intravenous antibiotics immediately after taking the blood cultures, without waiting until after CSF examination. A GP seeing a sick child at home with probable meningococcal meningitis should give a first dose of penicillin, cefotaxime or ceftriaxone intravenously or intramuscularly before summoning an ambulance or driving the patient to hospital. This patient's blood picture showed a white cell count of 17.6 x 10/mm3, 85% neutrophils, a finding strongly in favour of acute bacterial infection rather than viral meningitis. Biochemistry and chest X-ray were normal. The value of urgent CT scanning in patients with acute meningitis is limited, and brain imaging should not delay CSF examination and the start of appropriate therapy unless there is a strong likelihood that the findings will alter the management plan. Such findings would include focal infection (cerebral abscess, subdural empyema, cerebritis with local mass effect), hydrocephalus sufficient to require shunting or external drainage, or evidence of venous sinus thrombosis complicating the infection. None of these complications is likely during the first 48 hours of an acute meningitic illness. The main clinical indications for scanning are therefore the presence of focal symptoms or signs, including focal seizures, or a severely depressed or rapidly deteriorating conscious level. In this patient, with a short history typical of acute meningitis, modest deterioration of his conscious level, no focal signs and normal optic fundi, it would be more appropriate to proceed to an immediate lumbar puncture. Most clinicians would start appropriate antibiotics to cover meningococcal and pneumococcal infection without waiting for the CSF results, particularly if the patient appears to be deteriorating rapidly. Immediate treatment is mandatory if a characteristic petechial rash begins to appear, whether or not the lumbar puncture has been done.

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CASE STUDY 24.10 CONTINUED The CSF was under raised pressure (210mmH2O) and contained 950 white cells/mm3, predominantly neutrophils, with a raised protein of 1.6 g/L and glucose of 1.8mmol/L (blood glucose 6.8mm/L). The Gram stain was not confidently interpreted by the duty microbiologist, but it was thought to show the presence of Gram-positive rods. Screening for bacterial antigens was also requested, but the results were not immediately available. Treatment was started immediately after the lumbar puncture with intravenous ceftriaxone, and this was continued after obtaining the results,

which were consistent with meningococcal infection. Other possible antibiotic regimens would be cefotaxime, chloramphenicol or benzylpenicillin, although penicillin is not optimal for a patient who might have pneumococcal infection, as many strains of this organism are penicillin resistant. In a seriously ill patient with possible pneumococcal meningitis the addition of vancomycin from the outset would also be appropriate. This patient improved steadily over the next 3 days. Meningococcus was eventually cultured from the blood but not the CSF, confirming the

can be acute, but is more often subacute and may be insidious. In immunocompromised patients fungal (cryptococcal or Candida) or amoebic meningitis must be considered and an India ink stain of the CSF performed. The opisthotonos of tetanus may mimic meningeal irritation. In children, acute fever is fairly often associated with neck stiffness as a non-specific sign.

Investigation Examination of the CSF is diagnostic but lumbar puncture can be a dangerous procedure in certain instances, e.g. in the presence of a developing cerebral abscess complicating the meningitis. Intracranial pressure is nearly always raised in meningitis, but in the presence of papilloedema, focal signs or coma it is safest to perform a CT scan to exclude hydrocephalus or a focal mass lesion prior to performing lumbar puncture. When scanning is not available, clearly a risk must be taken and the CSF examined. Initiation of treatment should not be delayed by either CT scanning or lumbar puncture in very ill patients with clinically obvious meningitis, particularly children with suspected meningococcal disease, who may die within hours. Blood cultures may be the only investigation possible prior to starting antibiotics in such cases. At lumbar puncture, the opening pressure should be measured before samples are taken for a Gram stain, culture, cell count, protein and glucose estimation. Typical findings in acute bacterial meningitis are a neutrophil count of more than 1000/mm3, a glucose which is less than

1 1416

MCQ 24.32

2

MCQ 24.33

bacteriological diagnosis. Intravenous antibiotics were continued for 7 days and he was then switched to an oral regimen for another 10 days. Immediate members of his family and other close contacts were treated with rifampicin. If primary treatment of the meningitis had been with penicillin, rifampicin should also be given to the patient for 48 hours to clear the organism from the nose. Treatment with ceftriaxone or cefotaxime would achieve that effect satisfactorily without the need for rifampicin.

SUMMARY 17 Lumbar puncture in meningitis • Lumbar puncture (LP) is safe in patients with meningitis without focal signs and whose conscious level is no worse than drowsy. • If there are focal signs or the patient is in coma, a complication of meningitis (e.g. cerebral abscess, hydrocephalus) may have supervened. There is a risk of coning with LP. Get a CT scan. • If in doubt, ask for neurological advice before doing an LP. • Minimum examination of the CSF in suspected meningitis includes cell count, protein, glucose, Gram stain and Z-N stain. • In any patient who may be immunocompromised, ask for special microbiological CSF tests for fungal, listerial, amoebic and other rare organisms. • Tuberculous meningitis rarely causes a white cell count of more than 1000/mm3, and a Z-N stain may be negative. If there is strong clinical evidence, treat for TB. • Never give intrathecal antibiotics.

40% of the blood glucose or below 1.7mmol/L, and a considerably raised protein concentration. Blood cultures, and any other relevant cultures, from suspected foci of infection should be taken. However, it cannot be overemphasized that prompt treatment of acute meningitis is essential for survival and the prevention of complications. Meningococcal meningitis may be fatal within 24 hours. In immunocompromised patients unusual pathogens must be looked for, such as Listeria monocytogenes, tuberculosis, amoeba and fungal infections, particularly Cryptococcus. Findings similar to those of acute bacterial meningitis may be found in viral meningitis. The pleocytosis in the CSF usually comprises lymphocytes but can be due to neutrophils, and the CSF glucose is occasionally low. CSF glucose may also be low in malignant meningitis, subarachnoid haemorrhage, tuberculous meningitis and malignant hypertension.

Failure of the patient's clinical state to improve within 24-36 hours of starting antibiotic treatment is an indication for further CSF examination. This is particularly important when there is microbiological doubt about the causative organism. A rise in cell count in the second CSF, with a persistently low glucose, implies an inadequate antibiotic treatment, which must therefore be changed. With correct treatment, the cell count rapidly falls. If signs indicate a spinal cord lesion in a patient with meningitis, a spinal epidural abscess should be suspected and, in consultation with a neurosurgeon, MRI should be urgently performed. O

Management Antibiotics Antibiotic treatment must be started immediately the CSF has been taken. In rare instances where there is likely to be a delay in performing a lumbar puncture, treatment must be started blind. Table 24.71 sets out the antibiotics used for different organisms; these are usually given intravenously. Chloramphenicol should not be used in neonates because of bone marrow and renal toxicity occurring as a result of inadequate metabolism by the liver. Chloramphenicol is effective against the rarer Listeria monocytogenes. For patients suspected of being immunosuppressed and who may thus be infected with one of the less common bacteria, an initial broad-spectrum antibiotic combination is given, such as gentamicin and cefuroxime. Bacterial culture is usually available within 24 hours, by which time some clinical improvement should have occurred. If not, the CSF must be re-examined. High-dose intravenous antibiotics should always be continued for at least a week. As meningeal inflammation decreases the blood-brain barrier is gradually restored, allowing less of the drug to gain access to the infected meninges. An identified focus of infection, e.g. sinusitis or suppurative otitis media, is an indication for a longer period of treatment, during which time the focus must be treated on its own merits. Immunosuppressed patients also require longer periods of treatment. Intrathecal penicillin makes no difference to outcome and is potentially dangerous. Large doses cause an encephalopathy with fits, which is usually fatal.

Fits Fits are common, particularly in children with meningitis. Treatment of status epilepticus or serial epilepsy is as described on page 1328. Regular oral anticonvulsant treatment should be started in all patients having fits. It can be given via a nasogastric tube, but phenytoin may also be given by slow intravenous injection, and phenobarbitone by intramuscular injection. Loading doses are necessary, followed by regular maintenance doses. Phenytoin competes with Chloramphenicol for glucuronation in the liver and so increases levels of this antibiotic.

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Raised introcranial pressure and hydrocephalus Generalized cerebral oedema may produce lifethreatening rises in intracranial pressure. This is treated urgently with mannitol and then dexamethasone. Hydrocephalus may develop after several days; in such cases there is typically a clinical improvement after the initiation of treatment, followed by a deterioration. The diagnosis is established by a CT scan. Some patients with progressive hydrocephalus will require treatment with a ventricular drain. Cerebral abscess Despite adequate treatment, some patients will develop cerebral abscesses. The development of fits and focal signs also raises the possibility of venous sinus thrombosis (p. 1419). Clinical deterioration, with or without focal signs or fits, is an indication for an urgent CT scan. If the scan is normal, the CSF must be re-examined. Prevention Treatment of close contacts (family, medical and nursing staff) of patients with Strep, pneumoniae meningitis is not necessary, but it is recommended with H. influenzae or N. meningitidis. Rifampicin (600 mg b.d. for adults or 20mg/kg per day for children for 2 days) is effective prophylaxis for both bacteria. Alternatives are sulphonamides (if the organism is known to be sensitive), ceftriaxone or one of the quinolones. Vaccines for N. meningitidis may be used in family members when the meningococcus occurs in small epidemics, and for contacts at particular risk, such as the immunocompromised, the very young and the elderly.

Prognosis Steroids The addition of steroids to the treatment of acute Haemophilus meningitis in children has been shown to reduce the risk of late complications such as permanent deafness. In adult practice there is no firm evidence, but steroids are sometimes given to critically ill patients, particularly those with CSF obstruction, mass lesions or focal ischaemic complications believed to be due to secondary endarteritis. This is usually in the context of pneumococcal or tuberculous disease.

Overall mortality for the three common pathogens ranges from as low as 3% for H. influenzae to as high as 60% for Strep, pneumoniae. Mortality is highest in the very young and the elderly. ©

INTRACRANIAL ABSCESS Intracranial abscesses are most commonly intracerebral, but pus may collect in the subdural space (subdural

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ing skull trauma accounting for a small proportion of cases; and, in about 10% of cerebral abscesses no source for the infection is found. Cerebral abscess is more likely to occur in patients with debilitating illness and in the immunocompromised. Subdural empyema usually results from frontal sinusitis or penetrating injury, and sometimes middle-ear infection. In infants it is often secondary to meningitis. In adults it is occasionally secondary to septicaemia. Extradural abscess has similar causes and may also be secondary to osteomyelitis of the skull, now a rare condition.

FIG. 24.67 Cerebral abscess Enhanced CT scan of a patient with a left frontal acute pyogenic abscess. Note the typical ring enhancing lesion with massive surrounding cerebral oedema, causing midline shift. There is also a small subdural collection of pus (subdural empyema). The intracranial abscess in this 21-year-old man was secondary to frontal sinusitis.

Bacteriology In contrast to meningitis, intracranial abscesses are often due to mixed infection. The organisms most frequently implicated are Strep, viridans, Staph. aureus, Klebsiella, and occasionally other Gram-negative bacteria. Infection with one of these is frequently associated with an anaerobe, either anaerobic streptococcus or bacteroides. In immunocompromised patients, a wide range of bacteria may be responsible, together with occasional amoebic or fungal abscesses.

Clinical features empyema) or in the extradural space. Subdural empyema or intracerebral abscesses may extend to the meninges and cause meningitis, or, conversely, infection may spread from the meninges. Intracerebral abscesses may rupture into the ventricles, causing a ventriculitis. An intracerebral abscess starts as an area of cerebritis which then develops into a pus-filled cavity surrounded by a wall of variable thickness, and, outside this, cerebral oedema. The oedema is often extensive and, together with the abscess itself, leads to increased intracranial pressure and a mass effect on surrounding structures. O Some abscesses are single, others multilocular or multiple (Fig. 24.67).

Aetiology Cerebral abscesses. Excluding cerebral abscesses occurring in AIDS (which are usually multiple and are most often caused by Toxoplasma gondii, p. 1428), about 60% of intracerebral abscesses are caused by middle-ear infection and are situated in the temporal lobe or cerebellum. About 20% are secondary to frontal sinusitis, which results in frontal lobe abscess; approximately 10% are due to bacteraemia or septicaemia from the lung (abscess, empyema or bronchiectasis), the heart (infective endocarditis), dental sepsis, or some other peripheral site, with penetrat-

O Figs 24.32-23.34

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0 Fig. 24.8

0 Figs 24.32-23.34

Intracerebral abscess. An acute pyogenic abscess is likely to cause symptoms that progress quickly over days rather than weeks. Multiple abscesses may cause a plethora of symptoms and signs. A combination of headache, rapidly progressive neurological deficit, symptoms of raised intracranial pressure with or without fever, and a deteriorating conscious level suggests the possibility of an intracerebral abscess. Fits are also very common. Fever is very variable in cerebral abscess. Meningism is quite common. A careful search for a systemic source of infection must be made in every case of suspected abscess. Subdural empyema. Patients with subdural empyema are usually very ill. The pus spreads rapidly over the surface of the hemisphere, producing hemiparesis, raised intracranial pressure, fits and meningism. Extradural abscess. Extradural abscesses are often well localized and may present less acutely. They usually cause localized severe headache and are associated with sinusitis, mastoiditis or penetrating trauma.

Investigation The most important immediate investigation is a CT or MRI scan. O Most acute pyogenic abscesses are rounded lesions of low attenuation with ring enhancement and much surrounding oedema, producing a mass effect (Fig. 24.67). However, these appearances are not specific to abscess and may occur with tumours. In the earlier stage of spreading cerebritis there is no ring enhancement. Plain radiology should include skull X-rays, to look particularly for evidence of sinusitis or mastoiditis and middle-

ear infection, and a chest X-ray. Culture of any possible source of infection, together with blood cultures, should be done. Lumbar puncture is contraindicated.

Management Rapidly rising intracranial pressure is usually the lifethreatening factor in pyogenic intracerebral abscess, and urgent drainage of the pus is necessary. Although Gram stain of the aspirated pus may give some guide to antibiotic treatment, the initial treatment must be guaranteed to be effective against a wide range of organisms. A combination of benzylpenicillin, cefuroxime, gentamicin and metronidazole is reasonable, until bacterial results are available. All patients with supratentorial abscess, with or without fits at presentation, should be given an anticonvulsant, because of the high incidence of fits. Cerebral oedema may require treatment with either mannitol or dexamethasone, and ventilation is sometimes necessary. Some abscesses only need to be drained on one occasion, but others may need several evacuations. Serial CT scanning permits frequent monitoring of abscess size. Surgical treatment for supratentorial abscesses is usually limited to regular aspiration. Eventual healing with antibiotic treatment is often good, with little or no neurological deficit. In cerebellar abscess many surgeons will attempt complete excision, both because of the dangers of hydrocephalus and because it is possible to excise sizeable lesions with relatively little risk of producing neurological deficit. Subdural empyema and extradural abscesses require surgical drainage and high doses of intravenous antibiotics.

Prognosis The prognosis is related to the clinical state at the time of presentation. The overall mortality of intracerebral abscess is in the region of 10%. In survivors, lasting neurological deficit is often not severe. Persistent fits are a problem in 30-50% of patients with supratentorial abscess.

CORTICAL VENOUS THROMBOPHLEBITIS AND VENOUS SINUS THROMBOSIS Thrombosis of cortical veins and thrombosis of the dural venous sinuses are relatively rare. Thrombosis of the dural sinuses is nearly always preceded by cortical vein thrombosis. The exception to this is cavernous sinus thrombosis.

Aetiology The causes of cortical thrombophlebitis and dural venous thrombosis are listed in Table 24.72. The commonest causes are infection and the hypercoagulable state that occurs postpartum.

TABLE 24.72 Causes of cortical vein and dural sinus thrombosis

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• Infection of scalp, skull, sinuses, face, middle ear, mastoiditis, Also secondary to meningitis and septicaemia • Postpartum (days or weeks following delivery) • Dehydration, e.g. dysentery, cholera • Diabetes mellitus • Trauma (open or closed head injury) • Catheterization of jugular veins • Prothrombotic disorders (e.g. antithrombin III, protein C or S deficiency, factor V Leiden) • Blood dyscrasias, particularly leukaemia • Postoperative hypercoagulability • Severe heart failure • Tumour invasion of sinuses • Rare non-metastatic effect of malignant disease • Contraceptive pill, particularly in smokers

Clinical features There is an acute or subacute onset of severe headache, fits, hemiparesis, drowsiness, and then a progressive impairment of conscious level due to cerebral oedema, together with an increase in intracranial pressure. Focal signs, such as aphasia or hemianopia, sometimes occur. A low-grade fever is often present, even in patients without a primary infective cause.

Investigation Skull X-ray may reveal evidence of sinus or middle-ear infection. CT scans may show patchy or confluent areas of cerebral cortical oedema, sometimes with haemorrhage. Magnetic resonance angiography (MRA) is now the investigation of choice for demonstrating the thrombosed veins and sinuses. 3 If the patient is too irritable and restless for this procedure, formal angiography may be necessary. Lumbar puncture should not be done in the presence of severe cerebral oedema, as judged from the CT or MRI scan. The CSF is under raised pressure and may be normal or, frequently, slightly bloodstained.

Management Fits must be urgently controlled, and raised intracranial pressure is treated with dexamethasone. In patients with an infective cause appropriate antibiotics should be given. The role of anticoagulants remains controversial and no adequate trials have been carried out, but the available literature supports the use of heparin in severe or progressive cases, and there is no convincing evidence that the risk of haemorrhagic transformation of ischaemic lesions is thereby increased. The prognosis is good, with resolution of all symptoms and signs in most cases.

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CAVERNOUS SINUS THROMBOSIS Cavernous sinus thrombosis is usually secondary to infective lesions originating on the face or to sinusitis of the frontal sphenoidal or ethmoidal sinuses. Untreated, unilateral thrombosis often spreads to become bilateral within a few days.

Clinical features The onset of the illness is with fever, then headache, severe malaise, pain in the eye and diplopia, and, eventually, loss of visual acuity in the affected eye. There is sometimes also nausea and vomiting. Examination reveals orbital oedema, sometimes with proptosis, normal or impaired visual acuity, and there may be papilloedema. There is a partial or complete ophthalmoplegia with ptosis. The pupil is not spared. The trigeminal nerve is sometimes involved, leading to sensory impairment on the face and cornea.

Differential diagnosis

Clinical features

Caroticocavernous fistula, either due to rupture of an intracavernous carotid aneurysm or occurring secondary to head injury, may produce a similar clinical picture. However, the degree of proptosis is often greater with a caroticocavernous fistula, and the proptosis is pulsatile. There is usually a loud bruit in the region of the eye which may be altered by ipsilateral carotid artery compression.

TBM usually presents subacutely. There is often a prodrome of general malaise, without specific symptoms, of up to 6 weeks, followed by headache, lethargy and vomiting. Examination may reveal no focal abnormal neurological signs, and even meningism may be mild or absent in the early stages. A low-grade fever is usual, but may be intermittent. Focal signs include cranial nerve palsies in about 25 % of patients. These may occur as single or multiple palsies, those most commonly affected being the third, fourth, sixth, second, seventh and eighth nerves. Fits, either focal or generalized, occur in about 25% of patients. Raised intracranial pressure, owing to generalized cerebral oedema or hydrocephalus, produces papilloedema. Hemiparesis, dysphasia or hemianopia may be caused by cortical infarction, major vessel occlusion at the base of the brain, or the development of a tuberculoma (Fig. 24.68). Many patients are drowsy or stuporose at the time of presentation, but coma during the course of TBM indicates a poor prognosis; only about 50% of patients survive from this state. Finally, inappropriate ADH secretion may develop. O

Investigation and management MRI, including venous angiographic sequences, may show indirect evidence of cavernous sinus thrombosis. Periorbital venography can be diagnostic but is now rarely performed. Treatment is with high-dose intravenous antibiotics and fluids, and sometimes by surgical treatment of associated sinusitis. O

TUBERCULOUS MENINGITIS Tuberculous meningitis (TBM) is now uncommon in the UK but is still a major problem in developing countries. In the past the peak incidence was in children, but nowadays a larger proportion of patients with TBM are adults.

Pathology TBM is nearly always due to infection with Mycobacterium

1

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tuberculosis and only rarely with the atypical mycobacterium. Infection reaches the meninges via haematogenous spread during miliary infection. A granulomatous inflammation develops, particularly affecting the basal meninges, where it involves the large arteries and the cranial nerves. The optic chiasm may also be affected, leading to a variety of visual field defects. Reabsorption of CSF may be impaired by granulomatous inflammation, leading to hydrocephalus, which may also be caused by obstruction of CSF outflow from the fourth ventricle. Granulomatous inflammation over the cerebral hemispheres may lead to cortical infarction. Fits are common in TBM. Tuberculomas may develop deep within the brain, behaving as tumours. Generalized cerebral oedema with raised intracranial pressure is common. TBM frequently leads to spinal arachnoiditis, which may cause root or cord lesions. These are often transient, but severe cord lesions with complete spinal block (as demonstrated at myelography) may develop.

MCQ 24.34

2

MCQ 24.35

Investigation The most important investigation is examination of the CSF. This is safe in patients without signs of raised intracranial pressure or focal signs (excluding cranial nerve palsies). In any patient suspected of having TBM with papilloedema or focal hemisphere signs, a CT scan should be done prior to lumbar puncture to exclude hydrocephalus or tuberculoma. In these patients CSF should be obtained for diagnostic purposes after consultation with a neurosurgeon. Likewise, in patients with signs of a myelopathy, spinal block and the possibility of exacerbat-

FIG. 24.68 Large left frontal tuberculoma Contrast-enhanced scan shows appearances indistinguishable trom an acute pyogenic cerebral abscess with mass effect, substantial cerebral oedema and ring enhancement. Although the tuberculoma in this patient was solitary, they are frequently smaller and multipe.

ing the cord lesion by lumbar puncture must be considered. Again, close collaboration with a neurosurgeon is necessary. The CSF in TBM usually contains 50-500 cells/mm3 and only rarely more than 1000mm3. In the early stages these are mainly neutrophils; later, lymphocytes predominate. The protein is raised, sometimes to very high levels. The glucose is nearly always low. This is helpful in differentiating TBM from viral meningitis. Ziehl-Neelsen staining of the CSF is not infrequently negative, even when tubercle bacilli are later cultured. A lengthy and careful search of a stained centrifuged deposit of CSF is necessary. The polymerase chain reaction (PCR) or immunological tests can be used to detect the presence of mycobacterial antigen in the CSF, but both false positive and false negative results are still a problem with these techniques.

Differential diagnosis Viral meningitis is excluded if the CSF glucose is low; however, malignant meningitis, whether carcinomatous, leukaemic or lymphomatous, may cause a similar picture. Fungal meningitis may also cause a similar clinical presentation and CSF findings. India ink staining is useful. Meningovascular syphilis and sarcoidosis are two rare causes of aseptic meningitis.

Management It is important in TBM to start treatment as soon as possible. Even with prompt chemotherapy, complications such as hydrocephalus, cerebral infarction, tuberculomas and cranial nerve palsies are common. Drugs normally given are isoniazid, rifampicin, pyrazinamide and, sometimes, ethambutol (see Ch. 13, p. 645).

Streptomycin is not commonly used; if it is used, there is no advantage in giving the drug intrathecally. The penetration of cycloserine, ethionamide and pyrazinamide is better than that of the other antituberculous drugs, but this is not an important factor when the meninges are inflamed. Second-line drugs are used only when sensitivities from culture indicate their use. Clinical improvement in TBM is slow. Clinical deterioration suggests the possibility of hydrocephalus, and the diagnosis is confirmed by CT scanning. Persistence of fever after 3 weeks is cause for concern, and the CSF should be re-examined after obtaining a CT scan, if possible. A minimum of 18 months of treatment is necessary, and 2 years is recommended by most authorities. Anticonvulsants are often needed but should not be given unless fits occur. Tuberculomas (Fig. 24.68) may arise during the course of treatment even when the organism is sensitive to the drugs being given. They may be solitary or multiple. Most resolve with continued medical treatment, but larger lesions may have to be surgically drained. The place of corticosteroids in treatment remains controversial. Claims have been made for lessening of the basal and spinal arachnoiditis, with prevention of hydrocephalus, cranial nerve palsies, strokes and spinal cord syndromes, but none of these claims has been substantiated by careful clinical trials. Steroids are often given when one of these complications arises, or in very sick patients, but as yet there is no clear indication for such treatment.

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Prognosis The mortality of TBM in the UK is still high (15-30%), and in developing countries it is higher. Adverse factors affecting prognosis are coma at presentation, pregnancy, and an age of less than 2 years or more than 65 years. Persistent problems in survivors include major cranial nerve palsies causing blindness, squints and deafness; strokes causing hemiparesis, dysphasia and other focal hemisphere signs; and a paraparesis from spinal arachnoiditis. In a small proportion of patients hydrocephalus develops as a late complication, sometimes years after successful treatment.

SUMMARY 18 TB meningitis • • • • • •

Usually subacute in onset Infection outside the CNS not always apparent Focal signs in 25%, most often cranial nerve lesions CSF often inconclusive, especially early on Initial treatment is usually with four antituberculous drugs Steroids are justifiable for selected patients with multiple tuberculomas, other progressing focal lesions, severe hydrocephalus or drug reactions • Secondary communicating hydrocephalus may require shunting

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FURTHER READING ON BACTERIAL INFECTIONS OF THE NERVOUS SYSTEM Anderson M 1993 Management of cerebral infection. J Neurol Neurosurg Psychiatry 56:1243-1258 Lambert H P 1994 Meningitis. J Neurol Neurosurg Psychiatry 57:405-415 Quagliarello V, Schell W M 1992 Bacterial meningitis: pathogenesis, pathophysiology and progress. N Engl J Med 327:864-872

VIRAL INFECTIONS OF THE NERVOUS SYSTEM Viral infection of the nervous system produces illness via two mechanisms: either by direct invasion or as a postinfectious illness, in which initial infection leads to an immunological reaction which itself causes damage soon after infection. This damage is usually predominantly demyelination, and it is likely that viruses cause some type of sensitization to CNS myelin. The clinical spectrum of viral diseases comprises meningitis, encephalitis and myelitis, occurring either alone or, quite frequently, in combination. In addition, it has recently been recognized that some progressive fatal encephalitides may be the result of persistent viral infection. These include subacute sclerosing panencephalitis (SSPE) and progressive multifocal leuko-encephalopathy (PML).

Viruses

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Some viruses are very selective in the regions and cell types within the nervous system that they affect. For example, the polio virus affects predominantly anterior horn cells, whereas others may produce a wide variety of illnesses; Coxsackie, for example, may cause either meningitis or a diffuse encephalitis. Viral meningitis is most often caused by Coxsackie, echo, measles, mumps, herpes simplex, herpes zoster, adenoviruses and EB virus. Direct HIV infection must now be added to this list, and is of increasing importance. The viruses causing encephalitis vary in different parts of the world. In the UK, mumps, echo, Coxsackie, measles, herpes simplex, herpes zoster, EB virus and adenoviruses are the commonest causes, in this order of frequency. HIV is now also recognized to produce encephalitis. In Asia, Japanese B virus is the commonest cause of encephalitis, whereas in North America herpes simplex is the leading pathogen. Myelitis is caused by Coxsackie, echo, herpes zoster, EB virus and, occasionally, polio and rabies viruses. Immediate identification of the virus causing many presumed viral meningitides and encephalitides is often difficult, retrospective diagnosis often resting on the result of antibody titres in paired sera. In postinfectious encephalomyelitis, diagnosis often depends entirely on serological testing, except when the cause is one of the

exanthemata. The common causes of postinfectious encephalomyelitis are measles, varicella, vaccinia, mumps, rubella, influenza and, occasionally, rabies vaccine.

Pathology of viral infection Most viruses reach the nervous system via blood spread from the initial site of infection, often the respiratory or gastrointestinal tracts. Some viruses spread centripetally via the nerves, e.g. the herpes viruses, which may lie dormant in sensory ganglia for many years. It is not clear why some viruses remain confined to the meninges and others invade the brain or spinal cord, nor why some show such a predilection for certain sites in the nervous system. Within the brain and spinal cord, viruses lead to destruction of neurons, followed by phagocytosis, demyelination, vascular inflammatory change with perivascular lymphocytic cuffing, diffuse inflammatory change with a predominantly lymphocytic infiltrate, and a variable amount of oedema. Oedema may cause life-threatening rises in intracranial pressure. These pathological changes occur both in direct viral invasion and in postinfectious encephalomyelitis, but in the latter, demyelination in association with oedema is the predominant pathological change. The various syndromes of viral invasion of the nervous system and their causative agents are summarized in Table 24.73.

VIRAL MENINGITIS Clinical features and investigation In a minority of cases of viral meningitis there is a history suggesting viral infection. The meningitis may be acute or subacute in onset, with headache, fever, neck stiffness, nausea and vomiting, and diagnosis is not usually difficult. It is indistinguishable clinically from bacterial meningitis. The crucial investigation is examination and subsequent culture of the CSE The pressure is usually raised, with a pleocytosis up to several 1000/mm3; this is usually of lymphocytes, but sometimes predominantly polymorphs. The protein is increased but, in contrast to bacterial meningitis, the glucose is only very occasionally low. No organisms are seen on Gram staining. These changes may be seen in other causes of aseptic meningitis, including partly treated bacterial meningitis. The blood count may show a lymphocytosis, and antibody titres on acute and convalescent sera may enable a retrospective aetiological diagnosis to be made.

Management and prognosis Treatment is symptomatic in the majority of cases. Herpes simplex or herpes zoster meningitis is treated with a 5-day course of intravenous aciclovir. A history of steroid or

TABLE 24.73 Summary of viral infections involving the nervous system Meningitis or meningoencephalitis

Herpes simplex* Varicella zoster* CMV* EBV Mumps Measles HIV* (Others)

Progressive diffuse encephalopathies

Subacute sclerosing panencephalitis following measles infection Progressive multifocal leukoencephalopathy in immunosuppressed individuals (AIDS, lymphoma, sarcoidosis), caused by human polyoma virus (JC agent)*

Retinitis

CMV in AIDS patients*

Myelopathy

Herpes zoster* Polio HIV* HTLV 1 ('tropical spastic paraparesis')

Motor neuronopathy

Polio HTLV 1 ?HIV

Lumbosacral polyradiculopathy

Herpes simplex (genital)* CMV in AIDS cases*

Monoradiculopathy or trigeminal ganglionitis

Herpes zoster*

* Treatable or at least partially responsive to treatment.

other immunosuppressive treatment, or of systemic disease likely to produce an immunocompromised host, should lead to a search for unusual pathogens. The prognosis of viral meningitis is excellent. However, HIV infection is an exception to this (p. 1428) and herpes simplex meningitis is sometimes recurrent.

VIRAL ENCEPHALITIS Clinical features As with meningitis, there is usually no prodromal illness in viral encephalitis. The symptoms and signs are drowsiness, headaches, nausea and vomiting, confusion, fits and, sometimes, focal signs. Occasionally, a predominantly brainstem encephalitis occurs. In severe cases, stupor and coma develop. A low-grade fever is usual. Raised intracranial pressure due to oedema is common. An associated menin-

gitis may cause neck stiffness. The onset can be rapid, with coma developing within 12-24 hours, but the onset usually occurs over 24-72 hours. In herpes simplex encephalitis (Fig. 24.69) focal temporal lobe lesions are common, in the setting of a diffuse encephalitis. This may be apparent both clinically with dysphasia, a visual field defect or temporal lobe epilepsy, and on investigation with EEG or CT scan. However, other viruses may cause a similar clinical picture. The differential diagnosis of viral encephalitis includes other infections, particularly cerebral abscess, cerebral malaria (p. 347), metabolic encephalopathies (p. 1432) and cerebral tumours, and occasionally the presentation may mimic subdural haematoma or stroke.

24

Investigation It is wise to do a CT scan before examining the CSF if there is an impaired consciousness level, signs of raised intracranial pressure or focal signs. Scanning may demonstrate an abscess. Focal low density in one or both temporal lobes suggests herpes simplex infection. Often, there is no abnormality on the CT scan, or else diffuse cerebral oedema. MRI is more sensitive than CT in detecting early changes. The CSF usually shows a modest rise in the cell count, usually lymphocytes; the protein is raised with a normal glucose, and the pressure is increased. Detection of viral antigen in CSF in herpes simplex encephalitis at an early stage of infection is now available in some centres. The EEG in encephalitis usually shows diffuse changes of encephalopathy, sometimes with focal features. Management and prognosis Treatment is largely supportive. Aciclovir is beneficial in herpes simplex and herpes zoster encephalitis, and it is reasonable practice to give a course of intravenous aciclovir to all patients with encephalitis in whom herpes simplex may be the cause. Commonly, it is not clinically possible to differentiate direct viral infection from postinfectious encephalomyelitis, unless there is a clear preceding history of an identifiable viral illness, or a preceding vaccination or immunization. The position of steroid treatment in postinfectious viral encephalitis is uncertain. A reasonable approach is to reserve steroids for very sick patients with encephalitis, and to give steroid with aciclovir. The prognosis of known causes of encephalitis is very variable. Rabies encephalitis is always fatal. Mortality rates for other viruses include 40-75% for herpes simplex, 10-20% for measles, and less than 1% for mumps. There may be permanent deficit after severe encephalitis due to any virus, whether direct viral or postinfectious. Physical deficits such as hemiparesis are less common than intellectual impairment and behavioural disturbances.

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CASE STUDY 24.11 HEADACHE, DROWSINESS, CONFUSION AND SEIZURE IN A 37-YEAR-OLD WOMAN A 37-year-old woman was admitted to hospital with a 48-hour history of headache, drowsiness and confusion, culminating in a generalized convulsive seizure. From her husband's observations, the onset of this attack may have included focal movements of her right arm and leg before she lost consciousness completely. He also commented that her speech had become abnormal earlier that day, with apparent difficulty finding words as well as impaired understanding of others. She had been vaguely unwell for a longer period of 7-10 days. Her previous health had been good apart from occasional migraine with classic visual symptoms. She was a nonsmoker and drank little alcohol. She was taking a 20 ug oestrogen contraceptive pill. On examination she was drowsy and at first responded only to painful stimuli, moving her limbs more on the left side than the right. She was febrile with a temperature of 38°C. There was mild photophobia and some resistance to passive neck flexion. Her conscious level later improved to the extent that she was opening her eyes spontaneously and making some attempt to talk, but her speech was inappropriate and nongrammatical, and her comprehension of simple questions and commands was clearly impaired. There was facial asymmetry (lower on the right) and possibly some weakness of the right arm, although limited cooperation made assessment of motor function difficult. The tendon reflexes were symmetrical and generally brisk. The plantar responses were both extensor. General examination revealed no other abnormalities, in particular no skin rash, enlarged lymph nodes or evidence of arthropathy. A second generalized seizure occurred while she was being assessed in the accident and emergency department.

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Questions 1. What is the differential diagnosis? 2. What investigations should be performed? 3. What immediate management is advisable?

Discussion The patient has a subacute encephalopathic illness with fever, features of meningeal irritation and seizures. Dysphasia and mild right hemiparesis indicate focal involvement of frontal and temporal regions in the left hemisphere. The differential diagnosis includes a wide variety of inflammatory disorders, infective or otherwise: • • • •

Viral encephalitis Cerebral abscess Cerebral venous thrombosis Meningoencephalitis due to an 'atypical' organism, including HIV-related infections • Tuberculous meningitis with focal ischaemic lesions or tuberculoma • Malaria or other tropical infections are unlikely unless there is a relevant travel history • Non-infective inflammatory disorders (acute demyelinating encephalomyelitis, sarcoid, SLE, Behcet's, CNS vasculitis etc.). A neoplastic process is unlikely with such a short history, but a subacute presentation can rarely occur with CNS involvement by lymphoma, leukaemia, disseminated metastases or malignant meningitis. Paraneoplastic encephalitis usually develops more slowly and insidiously. Immediate investigation should include appropriate blood screening tests for all the above disorders, a chest X-ray and imaging of the brain, preferably with MRI if the patient is sufficiently stable and cooperative to lie still in the scanner. This could

include venous angiographic sequences if the standard brain images show features suggestive of venous sinus or cerebral vein thrombosis. If MRI is not available or technically practicable, CT scanning before and after contrast injection is the alternative. If the scan is not diagnostic, shows no focal mass lesion, obstructive hydrocephalus or substantial cerebral oedema, CSF examination is also an urgent priority. As well as performing routine microscopy and staining for appropriate bacterial organisms, mycobacteria and fungi - and cytological examination to rule out a neoplastic meningitis - early detection of minute quantities of viral or mycobacterial DNA may be possible using the polymerase chain reaction (PCR). In this patient the immediate blood findings were non-specific (WBC 10.8, normal differential, ESR 22 mm/h, biochemistry all normal) and the chest X-ray clear. An urgent MRI scan showed an area of bright signal and slight swelling in the medial aspect of the left temporal lobe. The brain looked otherwise normal. Lumbar puncture showed CSF under raised pressure of 240mmH2O, with 78 white cells/mm3 (all lymphocytes) and a red cell count of 1900/mm3. The protein was 0.89g/L and CSF glucose 2.4, with a blood glucose of 7.1 mmol/L. No organisms were seen or subsequently cultured; PCR for herpes simplex was not available on the night of admission. The clinical history, MRI appearances and CSF findings were suggestive of herpes simplex encephalitis (see also example of HSE, Fig. 24.69, on p. 1425). Points in favour of the diagnosis were the brief prodromal illness, the focal temporal lobe involvement, and lymphocytic CSF with normal glucose, only modest elevation of the protein and some evidence of haemorrhage. Similar CSF changes might be found in

24

CASE STUDY 24.11 CONTINUED cerebral venous thrombosis, but the MRI did not support this diagnosis. Non-viral infective disorders seemed unlikely and it was decided that there was no clear indication for broadspectrum antibiotics or antituberculous therapy. Treatment was started immediately with intravenous aciclovir in a dose of l0mg/kg every 8 hours. Because

two seizures had occurred, the patient was also loaded with 1 g phenytoin by slow i.v. infusion, followed by 300 mg daily during the acute phase of the illness. An EEG was performed, but this showed only non-specific encephalopathic features without the distinctive focal temporal discharges sometimes seen in HSV encephalitis. The diagnosis was subsequently

confirmed by a positive PCR test on the CSF. Aciclovir was continued for 2 weeks and the patient gradually improved during that time. After several weeks she had recovered substantially, but there was persisting impairment of memory and also mild dysphasia.

FIG. 24.69 T2-weighted MRI from a patient with herpes simplex encephalitis who presented with drowsiness, dysphasia and fits Extensive abnormal signal is present in the left temporal lobe, with similar abnormality medially in both frontal lobes.

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POLIOMYELITIS Poliomyelitis remains a health problem in developing countries and sporadic cases of polio are still seen rarely in the UK. Following a viraemia, the virus spreads to the meninges and gains access to the CNS, where it shows an extraordinary tropism for anterior horn cells in the spinal cord and brainstem, with inflammation and cell destruction.

Clinical features Only in 1 % of those infected with the virus does a paralytic illness occur. The onset of this is 3-4 days after the initial febrile illness has resolved. However, the minor illness may be very mild in adults and may pass unnoticed. Predisposing factors to the development of the paralytic form of the illness are a history of recent tonsillectomy, recent inoculation and pregnancy. The site and severity of the paralysis is probably determined partly by physical exertion during the period between the minor illness and the onset of the paralysis (major illness). The major illness is heralded by fever and neck stiffness, and then paralysis with myalgia develops. In the spinal form there is involvement of spinal anterior horn cells only, and there is often temporary bladder paralysis. In the bulbar form there is paralysis of the muscles supplied by the ninth, tenth and twelfth cranial nerves, causing pharyngeal, laryngeal and lingual paralysis. Vasomotor centres in the brainstem are also involved, causing tachycardia and lability of the blood pressure. In the bulbospinal form there is a mixture of bulbar and spinal paralysis. Respiratory paralysis may result either from the spinal form, with paralysis of the diaphragm, intercostal and abdominal muscles, or from bulbar paralysis, which is usually complicated by a pharyngeal paralysis leading to severe dysphagia. Paralysis is generally worse in adults than in children, with less capacity for recovery.

Differential diagnosis Diagnosis of polio in epidemics is not difficult, but the diagnosis in isolated cases is often not suspected until paralysis develops. Occasionally, other viruses may lead to temporary paralysis, including Coxsackie, echo and arboviruses. Differential from Guillain-Barre syndrome is occasionally a problem, but the CSF in Guillain-Barre shows no increase in cell count, and the presence of sensory symptoms and signs in this syndrome usually leaves no doubt about the diagnosis.

1

1426

MCQ 24.36

Investigation and management The CSF in poliomyelitis shows normal or slightly increased pressure, a pleocytosis of 10-200 cells/mm3 (initially polymorphs, changing to lymphocytes within 24-36 hours), a moderate increase in protein and a normal glucose. Virus may be isolated from a throat swab for a few days only, but is present in the stool for many months. Treatment may be prophylactic if the minor illness can be recognized (in epidemics), by advising strict rest in order to reduce the risk of severe paralysis. Analgesia is often needed for the severe myalgia, and ventilation for respiratory paralysis. Regular measurement of vital capacity is essential. Pneumonia is a common complication. Many patients are left with severe paralysis and require the full resources of rehabilitation. Patients with severe respiratory paralysis require long-term respiratory support.

Post-polio syndrome Many years following acute paralytic poliomyelitis, patients may complain of the development of slowly progressive weakness. Such patients are usually middle-aged or older. Weakness predominantly affects the muscles involved in the acute paralytic illness, but may also affect those that were previously clinically spared. There is progressive muscle wasting, sometimes with fasciculation, leading to increasing disability, mainly affecting the limbs and trunk but sometimes also involving bulbar function. The condition is usually slowly progressive. It is unlike motor neuron disease in that there is no upper motor neuron component. The precise pathogenesis is unknown, but is thought to relate to a delayed effect of the viral infection on anterior horn cells. Patients with weakness due to old polio often complain of getting weaker, with deteriorating function, as they get older, without clinical evidence of a post-polio syndrome on examination. Such deterioration can, in most cases, be explained by ageing, weight gain, arthritis and other intercurrent illness, or a combination of these factors. O

UNUSUAL VIRAL INFECTIONS OF THE CNS Subacute sclerosing panencephalitis Subacute sclerosing panencephalitis (SSPE) is subacute encephalitis occurring in children, caused by persistent infection with measles virus. It is more common when there is a history of infection at an early age, often less than 2 years. After a latent period of months, or in some cases several years, there is an insidious onset of intellectual decline, behavioural change (particularly apathy), then ataxia, myoclonic jerking and, often, a hemiparesis or tetraparesis. Other features include a retinitis and choroiditis, papilloedema, optic atrophy and cortical blindness. The disease is relentlessly progressive, and death usually occurs within 2 years of onset.

CT scans in SSPE show patchy low-density lesions in the cerebral hemisphere white matter, and progressive cerebral and cerebellar atrophy. There is no effective treatment.

TABLE 24.74 Neurological complications of HIV infection Cerebral syndromes Diffuse

Progressive multifocal leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) is an illness that occurs only in immunocompromised patients, particularly those with lymphoma. It is now also being increasingly seen in AIDS. The causative viruses are the JC and SV40 papovaviruses. Oligodendrocytes are preferentially affected, producing wide-spread demyelination, spreading from many different foci in the white matter. Patients present with progressive dementia, and focal signs including hemiparesis, hemianopia, dysphasia and ataxia. The disease is progressive and death usually occurs within a few months. Brain imaging in PML (MRI is much more sensitive than CT) shows multiple lesions, mainly in the subcortical and cerebellar white matter. The CSF is normal. Treatment with cytosine arabinoside and interferon has been described but with inconsistent results; the long-term prognosis is poor.

PRION DISEASE OF THE CNS CREUTZFELDT-JAKOB DISEASE

Focal

FURTHER READING ON VIRAL INFECTIONS OF THE NERVOUS SYSTEM McGill J I, White J E 1994 Aciclovir and post herpetic neuralgia and ocular involvement. Br Med J 309:1124. Whitley R J 1990 Viral encephalitis. N Engl Med 323:242-250.

NEUROLOGICAL MANIFESTATIONS OF AIDS The human immunodeficiency virus (HIV) is highly neurotropic and has widespread effects on the central and peripheral nervous systems. Nervous system involvement is common both in established AIDS and as a result of acute infection at the preconversion stage, before antibodies to the virus are detectable. The full extent of nervous system involvement in HIV infection is still uncertain, with new syndromes currently being recognized. It has been estimated that about 75% of AIDS patients have evidence of nervous system involvement, as determined at necropsy. In about 10% of patients one of the neurologi-

HIV-related dementia Encephalitis/meningitis (HIV, other viruses, bacterial, tuberculous, fungal) Hydrocephalus secondary to tuberculous or cryptococcal meningitis Cerebral vasculitis Progressive multifocal leukoencephalopathy (PML) Abscess (pyogenic, tuberculous, fungal, toxoplasma) Lymphoma, primary or metastatic Infarction or haemorrhage (vasculitis or embolism)

Optic neuropathy

HIV itself, or demyelinating

Retinitis

CMV infection

Myelopathy

HIV itself Herpes zoster, ?CMV Compression by abscess, lymphoma, plasmacytoma

Radiculopathy

Herpes zoster Multiple lumbosacral, due to CMV

Peripheral neuropathy

Acute inflammatory (like Guillain-Barre) Chronic inflammatory Distal sensory neuropathy Multifocal pattern Mononeuropathies

Myopathy

Polymyositis/dermatomyositis Zidovudine-induced myopathy

This rare transmissable encephalopathy is discussed on p. 1351.

24

cal manifestations is the presenting illness of AIDS; the problems include encephalitis, meningitis, cerebral abscesses, cerebral tumours, myelopathy, peripheral neuropathy and retinitis. There is an increased incidence of syphilis in patients with AIDS. The neurological complications of HIV infection are summarized in Table 24.74.

Encephalitis Subacute. The subacute form of encephalitis is a major problem in about 30% of AIDS patients, but probably affects all those, to some extent, who survive long enough. In the majority the subacute encephalitis is thought to be caused by direct HIV infection, but other pathogens may produce a similar clinical picture, including CMV, herpes zoster, herpes simplex, atypical mycobacteria and diffuse lymphoma. It nearly always arises in patients who have already had other manifestations of AIDS, but there have been recent reports of subacute encephalitis being the presenting illness. It usually develops as an insidious onset of intellectual failure, but sometimes more acutely, with a confusional state provoked by another illness. Depression,

1427

itself common in AIDS, may initially be thought to be the explanation of the symptoms. There is progression to a severe dementia in many cases. The leading physical manifestation is ataxia, and pyramidal signs are also common. The CT scan may be normal in the early stages but later shows progressive atrophy. CSF usually shows a lymphocytic pleocytosis and a raised protein content. Acute. An acute, recoverable encephalitis is now recognized within 3 months of HIV infection, occurring at about the time antibodies are first detectable. This illness lasts about a week and is characterized by headache, fits, confusion and decreased level of consciousness.

Meningitis AIDS patients may develop a preconversion acute aseptic meningitis with typical or atypical features of meningitis, presenting with headache, neck stiffness, fever and, sometimes, cranial nerve lesions (the fifth, seventh and eighth being the most common), together with long tract signs. This type of meningitis may be recurrent or become chronic. Many pathogens may cause meningitis in established AIDS. These include all the common bacteria producing meningitis, as well as many less common organisms. Cryptococcus neoformans is particularly important (p. 333). Here, the CSF shows a modest increase in cells, an increase in protein and a reduced glucose, and the organism can be demonstrated with an India ink stain. The detection of cryptococcal antigen in the CSF (and blood) is diagnostically useful. The possibility of other types of fungal infection, and of amoebae and Listeria monocytogenes, has also to be considered when examining the CSF.

Cerebral abscess Cerebral abscess is common in AIDS. Multiple abscesses are more usual than single lesions, and are most often caused by Toxoplasma gondii (about 70%). Multiple tuberculomas, primary cerebral lymphoma and Candida albicans may all cause a similar clinical picture. Patients present with headache, focal deficits and fits. Because of the predominance of toxoplasma (and unless there is a lifethreatening increase in intracranial pressure) a reasonable approach is to give a 1-2-week trial of treatment for toxoplasma (p. 344) in the first instance. If there is no clinical improvement, biopsy of an easily accessible lesion is undertaken.

deficits, headache and fits. The CT appearances may be indistinguishable from multiple abscesses.

Myelopathy A myelopathy alone is uncommon in AIDS but may occur in association with subacute encephalitis. It is thought to be due to direct HIV infection. An acute preconversion myelopathy has also been described.

Peripheral neuropathy Acute preconversion neuropathies include a cranial neuropathy, most often involving the facial nerve, which usually recovers over several months; and a mononeuritis multiplex (multifocal neuropathy) affecting the limbs. An acute inflammatory neuropathy of Guillain-Barre type may occur at the time of seroconversion; chronic inflammatory demyelinating neuropathy has also been described. A painful sensory neuropathy occurs in more advanced cases. Commoner than either of these is a symmetrical painful sensory motor polyneuropathy. This is thought to be due to direct HIV infection, and is usually progressive.

Retinitis A retinitis caused by CMV occurs in AIDS patients. Blurred vision, loss of acuity and scotomas are early features. It may progress in some cases to complete blindness. Fundoscopy shows retinal vessel irregularity and narrowing, with perivascular exudates and haemorrhages, and later, arteriolar occlusion causing retinal infarction. Many patients respond to treatment with ganciclovir.

Myopathy A myopathy has been described in a few patients. In some, this is related to treatment with zidovudine. Polymyositis and dermatomyositis also complicate HIV infection, despite the impairment of cell-mediated immune response in this disease. O

FURTHER READING ON NEUROLOGICAL MANIFESTATIONS OF AIDS Everall I P 1995 Neuropsychiatric aspects of HIV infection. J Neurol Neurosurg Psychiatry 58:399-402. Weiner J B 1993 Neuropathies and HIV infection. J Neurol Neurosurg Psychiatry 56:739-741.

Tumour Primary cerebral lymphoma is not infrequent in AIDS, and may present either as a progressive dementia or with focal

NEUROSYPHILIS AND OTHER RARE INFECTIONS SYPHILIS

1

1428

MCQ 24.37

The major features of syphilis infection are described in Chapter 11. Treponema pallidum may invade the CNS

weeks or months after the initial infection, but only causes a meningitic illness in about a quarter of these cases. Occasionally the meningitis is severe, with transient cranial nerve palsies and convulsions; usually, however, it is mild or even asymptomatic. All the clinical manifestations of late or tertiary syphilis have a chronic meningitis as the underlying pathological process. This process leads to arterial involvement (syphilitic arteritis), affecting meningeal and parenchymal vessels. Tertiary syphilis may present as: • Chronic meningovascular syphilis • Parenchymatous involvement as general paralysis of the insane (GPI) or tabes dorsalis. Syphilitic amyotrophy is a rare form of parenchymatous involvement.

Diagnostic tests Details of the serological tests for syphilis are discussed in Chapter 11. In active neurosyphilis of any type the CSF is always abnormal, showing a raised cell count with positive antibody tests (VDRL,TPHA, FTA and TPI). The protein content is also usually raised, and there is evidence of local synthesis of IgG, with oligoclonal bands on electrophoresis. Difficulty arises when positive antibody tests are found, without a rise in the cell count, in a patient with a neurological presentation not typical for one of the syndromes of neurosyphilis. Under these circumstances it is important to give a full course of antibiotic treatment and to reexamine the CSF 6 months later.

Meningovascular syphilis In meningovascular syphilis there is a combination of chronic basal granulomatous meningitis and syphilitic arteritis. The condition presents within 10-12 years of primary infection, either with a generalized illness, including headache, neck stiffness, convulsions, and confusion or psychosis, usually without fever, or with focal neurological symptoms, often cranial nerve palsies and, sometimes, strokes affecting either the hemispheres or brainstem. Optic atrophy is a common feature. Although meningovascular syphilis is relatively uncommon, it is important to recognize it as it usually responds well to treatment in the earlier stages.

Syphilitic gumma Gummas are large granulomatous lesions arising in the meninges with central necrosis. They usually remain superficial over the hemisphere, and present with fits, hemiparesis, dysphasia and other focal deficits. Gummas occasionally occur in the spinal meninges and cause cord compression.

Parenchymatous syphilis In all three forms of parenchymatous syphilis - GPI, tabes dorsalis and syphilitic amyotrophy - the pathology is a

meningoencephalomyelitis. The meninges show changes of chronic granulomatous inflammation and thickening, and there are both degenerative changes within the brain with neuronal loss, and glial changes, together with endarteritis obliterans. In about 50% of cases Treponema pallidum can be demonstrated. There is generalized cerebral atrophy. In tabes dorsalis and amyotrophy there are usually diffuse pathological changes, but the spinal cord bears the brunt of the disease.

24

General paralysis of the insane GPI is characterized by progressive mental deterioration (dementia), which is usually insidious in onset but may be abrupt, together with a variety of physical deficits. The condition develops 15-20 years after initial infection. Younger patients presenting with dementia should have serological tests for syphilis. Dysarthria and tremor - either cerebellar or extrapyramidal in type, affecting limbs, trunk and tongue - are common, as are fits, brisk reflexes and extensor plantars. The tremor is frequently the most disabling of the physical manifestations. Occasional focal features, such as dysphasia or hemiparesis, occur. The Argyll Robertson (AR) pupil may occur with all forms of tertiary syphilis but is most often seen in GPI and tabes dorsalis. The AR pupil is usually, but not always, small. It fails to react to light, but does react normally to convergence. It is nearly always bilateral. The pupils are often irregular and unequal in size (anisocoria). Differential diagnosis. The differential diagnosis of GPI includes Alzheimer's disease, diffuse cerebrovascular disease or multi-infarct dementia, metabolic encephalopathy, chronic alcoholic cerebral degeneration, traumatic encephalopathy and subdural haematoma. Treatment. Prompt treatment in the early stages will arrest progression, and in some patients there is reversal of the deficits. Without treatment, death occurs within a few years. Tabes dorsalis Tabes dorsalis develops 10-25 years after initial infection and in some cases may be accompanied by GPI. There is degeneration, initially in the dorsal roots and then in the posterior columns of the spinal cord. Lightning pains are virtually pathognomic of tabes, and often occur for years before other manifestations of the condition. They are usually in the legs, but may also occur in a girdle distribution around the trunk and, very occasionally, in the face. They last only seconds, are lancinating and severe. Tabetic crises are sudden attacks of epigastric pain and vomiting, lasting hours to days. This may mimic an acute abdomen, but there is cutaneous hyperaesthesia without peritonism. Similar crises may rarely affect the bladder, uterus, rectum and genitalia. Ataxia with a slapping, steppage gait is characteristic, and is sensory in type owing to the dorsal column degenerative change. Examination shows loss of joint position and vibration sensation in the legs. Distal cutaneous numb-

1429

ness and paraesthesiae are common, and there is sometimes hyperaesthesia of the feet. Loss of deep pain sensation leads to the development of neuropathic (Charcot) joints, and severe loss of cutaneous sensation causes penetrating ulcers on the feet. There is often a breastplate area of sensory impairment on the thorax, with a butterfly distribution of sensory loss on the face. There is areflexia in the legs, and the plantars may be flexor or extensor. A neurogenic bladder is common. Syphilitic amyotrophy Syphilitic amyotrophy is an uncommon manifestation of spinal cord involvement in neurosyphilis. There is a progressive neuronal loss in the anterior horns of the spinal cord. The condition mimics amyotrophic lateral sclerosis (one form of motor neuron disease, see p. 1389).

(esp. CN VII), painful radiculopathies, myelopathy or meningoencephalitis.

LISTERIA Listeria is a rare cause of meningitis or meningoencephalitis, and is encountered most often in immunocompromised subjects (see below).

RICKETTSIA Rickettsial infections often produce pronounced headache and a non-specific encephalopathic state, but some are characterized by a frank encephalitis or immune-complex cerebral vasculitis.

Congenital syphilis The features of congenital syphilis are those of combined GPI and tabes dorsalis, so-called taboparesis. In addition there are other stigmata, including interstitial keratitis, sensory neural deafness, Hutchinson's teeth (widely spaced, notched teeth), a saddle nose deformity, and evidence of periostitis and osteochondritis on X-rays. Congenital syphilis is discussed in more detail in Chapter 11.

Management The management of syphilis is considered in detail in Chapter 11. The CSF must be re-examined 6-8 weeks after therapy and, if the cell count is still raised, a further course of penicillin is given. The CSF must then be re-examined at annual intervals for several years, to ensure eradication of infection. O

MYCOPLASMA Mycoplasma infection may be associated with neurological complications, including meningoencephalitis, cranial nerve palsies, myelopathy or peripheral neuropathy (see also p. 634).

FUNGAL INFECTION Fungal infections of the nervous system may take the form of low-grade meningitis (often with secondary communicating hydrocephalus), multiple abscesses, or localized sinus invasion with tissue destruction. Possible organisms include Cryptococcus, Nocardia, Aspergillus, mucormycosis, actinomycosis and coccidiomycosis. These infections usually arise in the context of AIDS, other immune deficiency states, steroid treatment or diabetes (see below).

FURTHER READING ON NEUROSYPHILIS AND OTHER RARE INFECTIONS Halperin J J, Volkman D J, Wu P 1991 Central nervous system abnormalities in Lyme neuroborreliosis. Neurology 41:1571-1582.

NEUROLOGICAL ASPECTS OF SYSTEMIC DISEASE, INCLUDING MALIGNANCY SYSTEMIC DISEASES THAT AFFECT THE NERVOUS SYSTEM Connective tissue disorders

LYME DISEASE This disorder, caused by the tick-borne spirochaete Borrelia burgdorferi, is characterized by skin lesions (erythema chronicum migrans), a systemic illness and various neurological features: these may include cranial nerve lesions

1

1430

MCQ 24.38

Systemic lupus erythematosus The microangiopathy of systemic lupus erythematosus (SLE, see Ch. 22) affects the CNS of at least 30% of patients at some stage during the illness. Mental changes, most commonly depression, but also psychosis and mania, occur. These can also be the result of high-dose steroid treatment. Other features of cerebral involvement include seizures, transient focal symptoms and cerebral infarcts. The pathological basis for these may be cerebritis and thrombotic microangiopathy rather than vasculitis. Infrequent spinal cord involvement is also acute or subacute,

suggesting an ischaemic myelopathy. In some cases abnormal CSF findings help to distinguish cerebral lupus from steroid psychosis. The peripheral nervous system may be affected by a neuropathy, either multifocal (presumed vasculitic) or distal and symmetrical. Neurological illness is rarely the presenting manifestation of lupus. Systemic sclerosis (scleroderma) Neurological involvement in systemic sclerosis (Ch. 22) is fairly common. It usually takes the form of a slowly progressive proximal myopathy, in which there is atrophy without inflammatory change. Occasionally a more rapidly progressive myopathy occurs, with increased creatine phosphokinase levels and inflammatory change on muscle biopsy, indistinguishable from isolated polymyositis. This latter form responds to anti-inflammatory and immunosuppressive treatment (p. 1180). Despite the often extensive skin and subcutaneous thickening, entrapment neuropathies are relatively infrequent. A cranial neuropathy may develop, most commonly affecting the trigeminal nerve and, occasionally, the facial nerve. Sensory loss on the face may be bilateral and severe. It is not certain whether the peripheral nerve lesions have a vasculitic basis or are simply due to sclerosis. Very occasionally, sclerotic change can affect the major neck vessels, causing strokes. Rheumatoid arthritis Peripheral nerve involvement Entrapment neuropathies, particularly carpal tunnel syndrome and ulnar neuropathy at the elbow, are common in rheumatoid arthritis (Ch. 22) and are simply related to the disorganization of the joints. A digital entrapment neuropathy also occurs. A multifocal neuropathy with a vasculitic basis is frequent; occasionally a symmetrical polyneuropathy develops. Both patterns of neuropathy are often associated with a cutaneous vasculitis. Muscle Muscle wasting and weakness due to atrophy are universal in advanced rheumatoid arthritis. Rarely, an inflammatory polymyositis occurs. Cervical myelopathy (p. 1380) is the most serious neurological complication of rheumatoid arthritis. Cerebral vasculitis is a very rare complication. Polyarteritis nodosa In polyarteritis nodosa (p. 1181), which affects many more men than women, medium- and small-sized arteries are patchily involved in an inflammatory process of unknown cause throughout the body. Peripheral nerve involvement is common, typically a vasculitic multifocal neuropathy. Myalgia is common and the finding of patchy vasculitic ischaemic necrosis on muscle biopsy is one way of making the diagnosis. Involvement of the CNS is less common, causing encephalopathy, seizures or strokes. Typically the ESR is very high and there are positive cytoplasmic antibodies (ANCA) against myeloperoxidase.

Churg-Strauss syndrome Although part of the same spectrum of systemic vasculitides, this condition is usually distinguished from PAN by the relative lack of renal involvement and the predominance of asthma, pulmonary lesions, and more marked eosinophilia. The neurological lesion is a painful multifocal neuropathy caused by vasculitic lesions very similar to those of classic PAN.

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Wegener's granulomatosis This is another variant of systemic vasculitis with involvement particularly of the sinuses, nasopharynx and lungs. Cranial neuropathies (I, II, III, IV and VI especially) are more common than peripheral nerve lesions. Positive ANCA directed against proteinase III are characteristic.

Diseases of unknown cause Sarcoidosis The many possible neurological complications of sarcoid are summarized in Table 24.75. These are all rare, but the diagnosis must be considered in any patient with multifocal pathology involving brain or spinal parenchyma, meninges or individual nerves. Appearances on enhanced MRI may be helpful and the CSF lymphocyte count and protein are often significantly raised. Systemic screening tests may be positive (e.g. CXR, serum ACE, gallium scan, liver biopsy) but the diagnosis is difficult to make in the absence of organ involvement outside the nervous system. Treatment with steroids appears to be more effective for active meningeal disease with mononeuropathies than for parenchymal granulomatous lesions. The addition of methotrexate or azathioprine may be necessary. Marked hydrocephalus requires shunting and, rarely, surgical removal of mass lesions is necessary. Behcet's disease Behcet's disease is characterized by a relapsing and remitting clinical picture over many years, with oral and genital

TABLE 24.75 Neurological complications of sarcoidosis Brain

Meninges

Granulomatous mass lesions MS-like white matter lesions Rarely granulomatous angiitis Chronic basal (and spinal) meningitis Communicating hydrocephalus

Cranial nerves

VII most common (may be bilateral) Optic neuropathy III, IV, VI, V, VIII (rarely others)

Spinal cord

Patchy inflammatory myelopathy

Peripheral nerves

Multifocal neuropathy Distal symmetrical sensory neuropathy Granulomatous myositis

Muscle

1431

ulceration, uveitis and, often, arthritis and rash. The cause of this disease is unknown. Nervous system involvement occurs in at least a quarter of patients at some time during the illness, and its relapsing and remitting nature may cause diagnostic confusion with MS. The pathology is a vasculitis causing small areas of infarction and demyelination. This often affects the brainstem, producing disorders of ocular movement, and cerebellar and long tract signs. With cerebral hemisphere involvement a hemiparesis may result. There are no diagnostic tests for Behcet's disease: diagnosis rests on the clinical combination of oral and genital ulceration and sometimes other systemic features, with a typical neurological presentation.

GENERAL METABOLIC DISTURBANCES Hypoxio and global cerebral ischaemia Severe hypoxia in isolation is rare, arising for instance from carbon monoxide poisoning or anaesthetic catastrophes in which oxygen delivery to the brain is curtailed but cerebral perfusion (glucose supply) is maintained. Most major medical crises involve simultaneous impairment of both oxygen and blood flow to the brain, hence the term hypoxic-ischaemic encephalopathy. Typical causes are listed in Table 24.76. The immediate effects of such an incident are loss of consciousness and of brainstem reflexes. The pupils are widely dilated and fixed, reflex eye movements are absent, there is no respiratory effort, and the limbs are flaccid with absent reflexes. If resuscitation is to prove successful, some clinical improvement should be evident within a short period. Pupillary reactions and spontaneous breathing are the earliest signs of improvement. If pupils remain fixed and there is still no ventilatory effort within an hour or so, the outlook is almost always very poor. Recovery to a state in which brainstem reflexes return to a variable extent, while the patient remains unconscious, is common, and recovery may become arrested at this stage. Further gradual recovery over weeks and months can occur from this state, but if consciousness is lost for 24 hours or longer after a diffuse hypoxic-ischaemic insult, some permanent

TABLE 24.76 Causes of diffuse cerebral hypoxia and ischaemia

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Cardiorespiratory arrest Profound hypotension (blood loss, drug overdose, cardiogenic) Cardiopulmonary bypass surgery Carbon monoxide poisoning Anaesthetic catastrophe Severe intracranial hypertension (trauma, subarachnoid haemorrhage (SAH), massive tumour) Fat or air embolism Diffuse microvascular occlusion (DIC or TTP, cerebral malaria)

intellectual and physical disability is inevitable. Rarely, an initial period of improvement after the event is followed by progressive deterioration over 2 or 3 weeks - the syndrome of delayed hypoxic-ischaemic encephalopathy. Hypoglycaemia Hypoglycaemia (Ch. 19) produces life-threatening coma, and the more profound and prolonged it is, the more likely it is that recovery will occur with neurological deficit. Hypoglycaemia may present as unexplained coma, confusion, with fits which may be partial or generalized, or with focal deficit of abrupt onset mimicking a stroke. Very rarely, a picture resembling MND is seen in patients with chronic hypoglycaemia due to insulinoma. In all cases of unexplained coma intravenous glucose should be given. In the Wernicke-Korsakoff syndrome (p. 1439) glucose given without thiamine may cause further deterioration, as glucose cannot be metabolized easily without thiamine. Given the increased incidence of Wernicke-Korsakoff syndrome in the UK, glucose and thiamine should now be given to all patients with unexplained coma. Respiratory failure Carbon dioxide retention (Ch. 13) causes headache, drowsiness, stupor, and eventually coma. A metabolic tremor (asterixis) is common, and myoclonic jerking and fits are occasional features. Papilloedema secondary to venous distension is present in a few patients. Uraemic encephalopathy Untreated acute and chronic renal failure (Ch. 20) lead to a progressive decrease in the consciousness level, associated with hyperventilation, asterixis, myoclonic jerking, tetany and convulsions. Rapid dialysis may lead to the socalled disequilibrium syndrome, in which plasma urea, electrolytes and osmolality are rapidly corrected but brain concentrations remain high. Water enters the hyperosmolar brain, producing a form of water intoxication. A predominantly sensory axonal peripheral neuropathy is a common complication of uraemia, and may be partially reversible with dialysis. Hepatic encephalopathy Hepatic encephalopathy is discussed on page 1439 and in Chapter 16. Hyponatraemia The neurological effects of hyponatraemia (p. 1104) are much more likely to appear if the latter develops rapidly; they comprise agitation, confusion, fits, myoclonus, asterixis, and then coma when the plasma sodium concentration falls below 110-115mmol/L. Central pontine myelinolysis (p. 1441) can rarely occur, typically after a rapid rise of the plasma sodium from a low level. Hypernatraemia Hypernatraemia (p. 1108) occurs in hyperosmolar diabetic

coma and in untreated diabetes insipidus, particularly when the hypothalamus is affected by the lesion producing the diabetes insipidus, abolishing thirst. Such lesions include large pituitary tumours, craniopharyngiomas, eosinophilic granulomas and sarcoidosis, together with hypothalamic tumours. A falling level of consciousness and convulsions develop when the plasma sodium concentration reaches 155-160 mmol/L. Hypokaloemia Hypokalaemia (p. 1111) produces muscle weakness and fatigue, followed by a decreasing level of consciousness with confusion and delirium. Death may occur from ventricular tachycardia. Hypomagnesaemia Hypomagnesaemia usually occurs with severe vomiting or diarrhoea, particularly if fluid replacement is given without adequate magnesium. It is commonly associated with hypocalcaemia. Symptoms of hypomagnesaemia include irritability, confusion, muscle twitching, tetany hallucinations, myoclonus, chorea, coma and fits. Hypermagnesaemia Hypermagnesaemia is rare, but may occur in renal failure caused by the administration of magnesium salts, usually inadvertently in the form of antacids. Magnesium is important in acetylcholine release at the neuromuscular junction, and hypermagnesaemia results in generalized weakness, lethargy, coma and death from respiratory paralysis. Hypercalcaemia The neurological symptoms of hypercalcaemia (p. 965) are agitation, confusion, hallucinations and, sometimes, delirium and fits. Papilloedema is occasionally a feature. Hypocalcaemia In chronic hypocalcaemia (p. 972) mental blunting is the rule and patients are often thought to be demented or retarded. Other features are fits and raised intracranial pressure. Tetany, which may be symptomatic, can be demonstrated as a positive Chvostek sign. Cataracts and basal ganglia calcification occur in long-standing hypocalcaemia. Porphyria Of the two types of porphyria (p. 1026), erythropoietic and hepatic, only the latter (acute intermittent porphyria) is associated with neurological consequences. Aminolaevulinic acid (ALA) binds to GABA receptor sites in the CNS, and the neurological complications are thought to be due in part to facilitation by ALA of transmission at GABA receptors. In acute intermittent porphyria mental changes are prominent, with agitation, mania, tremor, delirium, hallucination, fits, and eventually coma. Strokes and retinal ischaemia may occur, and are thought to be due to cerebral arterial spasm. An acute motor neuropathy may occur,

closely resembling Guillain-Barre syndrome. Rarely there are multiple cranial neuropathies, together with brainstem signs, in particular ocular movement abnormalities. These neurological manifestations are usually preceded and accompanied by abdominal symptoms.

24

NEUROLOGICAL MANIFESTATIONS OF ENDOCRINE DISEASE Diabetes Neurological complications are very common in diabetes, particularly a wide variety of neuropathies and an increased susceptibility to strokes and to some unusual infections. These are listed in Table 24.77 Note that hypoglycaemia can present with a range of cerebral symptoms, both generalized and focal. Depressed consciousness, focal symptoms and rarely seizures can also occur in diabetic ketoacidosis and non-ketotic lactic acidosis. The diabetic neuropathies are discussed in detail on page 1396. Thyrotoxicosis

The general neurological effects of thyrotoxicosis (p. 918) include anxiety and tremor. Proximal myopathy is common in untreated thyrotoxicosis (p. 918). Chorea is a rare sign of hyperthyroidism. Dysthyroid eye disease may occur while the hyperthyroid patient is thyrotoxic or euthyroid. In some cases the symptoms arise only after a euthyroid state has been achieved with treatment; in other patients the eye disease arises in the absence of any preceding toxicity. In dysthyroid eye disease there is an

TABLE 24.77 Neurological complications of diabetes Brain

Cranial nerves

Eyes

Spinal cord Peripheral nerves

Hypoglycaemic confusion, coma, seizures or transient hemiparesis TIAs and strokes of all types III or VI most common VII 'Pseudotabetic' pupils Ischaemic optic neuropathy Progressive retinopathy Retinal infarction Cataracts Orbital infection (e.g. mucormycosis) Epidural abscess Mononeuropathy Multifocal neuropathy Distal polyneuropathy (esp. sensory) Proximal motor neuropathy Thoracolumbar radiculopathy Autonomic neuropathy

1433

Apart from the mental slowing, a common neurological complication of hypothyroidism is unilateral or bilateral carpal tunnel syndrome, owing to compression of the median nerve by myxoedematous tissue.

Cushing's syndrome Mental changes in Cushing's syndrome can take the form of a mild euphoria associated with an increase in appetite or, occasionally, psychotic illnesses. A proximal myopathy is inevitable with large doses of steroids taken over a period of months, but the tendency to develop this complication is extremely variable.

Hypoadrenalism In Addison's disease hypoadrenalism causes hyponatraemia, hyperkalaemia and, often, hypotension; together, these factors cause lethargy and weakness. In severe Addisonian crises, coma develops and fits may occur.

FIG. 24.70 Coronal CT scan in a patient with dysthyroid eye disease There was marked proptosis, bilateral papilloedema and severe ophthalmoplegia. The scan shows gross enlargement of the extraocular muscles.

enlargement of the external ocular muscles owing to a lymphocytic infiltration, with oedema. The eye muscles can become enormously swollen (Fig. 24.70), causing impaired venous drainage from the orbit; this leads to papilloedema and reduced visual acuity. The pathogenesis of these changes remains uncertain (p. 919). The first symptom of the exophthalmic ophthalmoplegia is diplopia. The changes may be asymmetrical in the early stages. Examination reveals unilateral or bilateral proptosis, an ophthalmoplegia that usually affects all movements, with sparing of downward gaze and lid retraction; corneal ulceration may also occur. Treatment is urgent in patients with reduced visual acuity or papilloedema. Oral steroids usually relieve orbital pressure, with rapid recession of the exophthalmos. Failure to respond to steroids requires surgical decompression. Tarsorrhaphy may be necessary to protect the cornea. Dysthyroid eye disease usually runs a course of 1-2 years. Surgical measures to correct residual squint should be reserved until this stage.

Hypothyroidism

1434

The neurological manifestations of myxoedema include mental slowing and, sometimes, dementia. Alternatively, behavioural disturbances, psychosis and even mania may result ('myxoedema madness'). A predominantly sensory polyneuropathy is associated with hypothyroidism. Occasionally, patients with myxoedema present with ataxia of gait without other obvious abnormal signs. A proximal myopathy can be a feature.

NEUROLOGICAL MANIFESTATIONS OF MALIGNANCY About 20% of all malignancies are associated with some type of neurological involvement. Metastatic spread may occur to the brain, spinal cord substance, epidural space or vertebral body. Direct invasion of the brachial or lumbosacral plexus is common with breast and pelvic tumours. Occasionally, individual peripheral nerves may be directly infiltrated. A number of tumours are also capable of producing remote neurological effects without direct invasion of the nervous system - the so-called non-metastatic or paraneoplastic effects of malignancy. Neurological problems may also result directly from treatment, e.g. the peripheral neuropathy due to vincristine. Opportunistic infection of the nervous system is an important problem following immunosuppressive therapy.

Cancer Metastatic spread of cancer to the brain or spinal cord is particularly common with primaries in breast, lung, bowel, skin, kidney and testes. Direct invasion of the meninges (malignant meningitis) is relatively unusual. The two most common non-metastatic effects of cancer are a predominantly sensory polyneuropathy and a cerebellar ataxia. Cancer of the lung is by far the commonest primary associated with these non-metastatic effects. A proximal myopathy has been described, sometimes associated with an elevated CPK. There is an increased incidence of inflammatory polymyositis associated with cancer, but it still remains relatively uncommon. The incidence of underlying cancer in patients presenting with polymyositis (p. 1406) has been greatly overestimated in the past, except in the case of adult-onset dermatomyositis. A rapidly pro-

gressive encephalomyelitis has been described as a nonmetastatic complication of carcinoma, but is very rare. Characteristic antibodies are detectable in some patients with paraneoplastic ataxia, neuropathy or dementia (e.g. anti-Jo, anti-Hu), and these may be helpful in making the diagnosis. Finally, the Lambert-Eaton myasthenic syndrome is occasionally associated with small cell lung cancer. In this condition, antibodies against presynaptic ion channels within the neuromuscular junction lead to proximal weakness and fatigue (see p. 1401).

Lymphoma Lymphomas rarely metastasize to cause intracerebral mass lesions, but malignant meningitis is not uncommon. Localized masses of lymphoma tissue present occasionally in the nasopharynx, and invade either upwards to involve the lower cranial nerves or within the orbit, causing a progressive ophthalmoplegia, proptosis and, eventually, visual loss. The spinal cord may be compressed by epidural collections of lymphomatous tissue. Non-metastatic neuropathy, cerebellar ataxia and encephalitis may complicate systemic lymphoma, as does the rare demyelinating syndrome of progressive multifocal leukoencephalopathy (PML), owing to opportunist invasion by the JC virus. Other opportunist infections may also occur.

Leukaemia By far the most common form of neurological involvement in leukaemia (Ch. 23) is a malignant meningitis; this often occurs at a time of systemic remission. It is thought that small numbers of leukaemic cells which are relatively immune to the effects of systemic chemotherapy cross the blood-brain barrier during periods of systemic relapse. These cells are then able to proliferate later, causing a malignant meningitis. The frequent development of CNS relapse in leukaemia led to the early adoption of prophylactic therapy. This is standard in younger patients to avoid CNS relapse. Malignant meningitis is occasionally complicated by hydrocephalus, owing to a reduced capacity for reabsorption of CSF. As in lymphoma, opportunistic infection is very common in leukaemia; progressive multifocal leukoencephalopathy is an occasional development.

Large quantities of paraprotein occasionally lead to a hyperviscosity syndrome with the development of multiple cerebral infarcts, a situation not unlike that seen with polycythaemia rubra vera. Finally, severe hypercalcaemia is common with myeloma, and may cause neurological symptoms (p. 1433).

24

Radiation damage to the nervous system Radiotherapy can cause immediate or delayed disturbance of function in the brain, spinal cord and nerve roots. Transient headache, nausea and malaise are common during treatment of cerebral tumours, and spinal irradiation can cause an acute myelopathy which subsequently improves after treatment is completed. Localized radionecrosis is sometimes seen after stereotactic focal radiotherapy ('radiosurgery' or 'gamma knife' treatment) for small tumours and AVMs, where a single high dose of radiation is focused on a small circumscribed area. More persistent and progressive damage to neural structures typically develops after a delay of 1-5 years, probably owing to gradual obliteration of small blood vessels. The brachial and lumbosacral plexus seem particularly vulnerable after irradiation of breast or pelvic carcinomas, but other sites of delayed damage include the spinal cord, brainstem, optic nerves and cerebral hemispheres. In children with acute leukaemia treated prophylactically, the somnolence syndrome, consisting of drowsiness, lethargy, irritability and anorexia, is common. It resolves after radiotherapy is stopped. The question of whether radiotherapy produces permanent intellectual damage in children remains controversial. There is some evidence that this may occur in adults.

FURTHER READING ON NEUROLOGICAL ASPECTS OF SYSTEMIC DISEASE, INCLUDING MALIGNANCY Aminoff M J (ed) 1994 Neurology and general medicine, 2nd edn. Edinburgh: Churchill Livingstone. Henson R A, Ulrich M H 1982 Cancer and the nervous system. Oxford: Blackwell Scientific Publications.

ALCOHOL AND THE NERVOUS SYSTEM

Myeloma Spinal cord compression resulting from vertebral collapse is particularly common in myeloma. Surgical decompression is complicated by the special difficulties of spinal stabilization when several adjacent vertebral bodies are involved. A painful neuropathy may be a non-metastatic complication and, in contrast to other non-metastatic neuropathies, may show some improvement with tumour treatment. Occasionally, myeloma neuropathy is complicated by the development of amyloid, which is an independent cause of peripheral neuropathy (p. 1391).

Alcohol causes a wide range of neurological effects. These are summarized in Table 24.78 and the commoner conditions are described below.

Acute intoxication and coma Alcohol is absorbed rapidly from the gut and easily crosses the blood-brain barrier. The cerebral effect of alcohol taken acutely is due to a direct inhibitory effect on membranes, which leads to a reduction in neuron excitability. In

1435

TABLE 24.78 Neurological effects of alcohol

1436

Condition

Acute or chronic/progressive

Acute intoxication and coma

Acute

Sedation/membrane-stabi 1 izing effect

Yes

In severe cases, death from respiratory depression + vomiting with aspiration Strong association with head injuries of all types

Repetitive head injury

Chronic

Trauma

(Yes)

May lead to dementia

Delirium tremens

Acute

Alcohol withdrawal, and rebound membrane sensitivity

Yes

Acute psychosis seen in chronic alcoholics

Alcoholic fits

Acute/chronic

Alcohol withdrawal

Yes

Usually chronic alcoholics, but also seen after binge drinking. Alcohol may provoke fits in epileptics

Alcoholic 'blackouts'

Acute

Sedation

Yes

Periods of amnesia (hours) while drunk; seen in chronic alcoholics

Peripheral neuropathy

Chronic

Toxic/nutritional

Yes - slowly

Chronic alcoholics. Often painful and predominantly sensory in early stages

Cerebellar degeneration

Chronic, slowly progressive

Toxic

Partly, in early stages. Not with established severe atrophy

Usually gait/truncal ataxia is most marked feature Limb ataxia tends to develop as a later feature Dysarthria

Wernicke-Korsakoff syndrome

Acute onset; chronic deficit common

Thiamine deficiency

Alcoholic dementia

Chronic

Toxic/nutritional

No

Insidious onset, slowly progressive, irreversible once established. Cerebral atrophy

Hepatic encephalopathy

Acute/chronic

Toxic

Yes, in early stages

Usually with cirrhosis, with portosystemic shunting. Acute exacerbations provoked by bleeding from varices or continued drinking

Alcoholic amblyopia

Chronic - sometimes acute onset

Toxic/nutritional

Abstinence may prevent progression

Associated with heavy smoking -? combined toxicity

Myopathy

Acute or chronic

Toxic

Yes

Acute: severe rhabdomyolysis with renal impairment Chronic: very rare. Most 'myopathies' are probably alcoholic neuropathies

Central pontine myelinolysis

Acute/subacute

Toxic/metabolic

No

Massive pontine demyelination. Also seen in hyponatraemia with over-rapid correction. Multiple brainstem signs. Often fatal

Marchiafava-Bignami disease

Acute/subacute

Toxic

No

Long-standing alcoholics. Massive demyelination and degeneration of corpus callosum and cortex. Multifocal symptoms and signs. Almost always fatal, progression over weeks

Pathogenesis

non-alcoholics, blood ethanol concentrations of 30-70 mg/100mL will affect coordination, sensory perception and intellectual functions. Drunkenness is associated with levels of between 50 and 150mg/100mL. The effects of acute intoxication are well known. A feeling of wellbeing and relaxation is associated with loss of inhibition, loss of judgement and an inability to sustain or follow critical argument. Mood changes depend to a large extent on per-

Reversible on abstinence

Comment

Acutely: confusion, ataxia, ophthalmoplegia. Confabulatory dementia (chronic) becomes evident with recovery of acute deficit, which is usually (partly) reversible with thiamine

sonality and pre-existing mood. There may be excitement, depression or paranoia. Memory for events during the period of intoxication is usually impaired, and with very high levels of alcohol there may be amnesic periods of several hours or longer. These are sometimes known as alcoholic blackouts, though there is no loss of consciousness. The effects of acute intoxication are associated with dysarthria, ataxia and increased sympathetic activity,

CASE STUDY 24.12 AGITATION, RESTLESSNESS AND UNSTEADINESS IN A 47-YEAR-OLD MAN WHO IS A HEAVY DRINKER A man of 47 was brought to A&E by a friend who had visited him at home after he had not been seen in his usual public house for several days. He was able to tell his friend that he had a cold with a bad cough. He had lost his appetite, both for food and for his usual 6-8 pints of beer a day. His friend noticed that he seemed withdrawn. He was slow to respond and was incapable of answering anything but simple questions. In addition he seemed frightened, and was agitated and restless. His friend persuaded him to accompany him to the A&E department of the local hospital. On the way his friend noticed that he was very unsteady on his feet, as if drunk. By the time he was seen by a doctor about an hour later, he was complaining of seeing double and had become more inattentive. His friend, who had known him well for several years, was able to tell the doctor that he had been a heavy drinker during this time, often not eating at all during binges of drinking, and he recalled an episode about 2 years earlier when he had witnessed what appeared to be an epileptic fit on the day after particularly heavy drinking. On examination his temperature was 37.8°C. He was dehydrated. There was no neck stiffness. On mental state testing he was inattentive, easily distracted, restless and agitated. He was unable to retain and instantly recall simple information. His speech was sparse but not dysphasic, and further detailed testing of cognitive function was not possible. In the cranial nerves, visual acuity was not tested. Visual fields appeared full. There was a mild right ptosis with bilateral weakness of abduction, associated with diplopia and weakness of elevation and convergence. The pupils were equal and reactive. There was a mild slurring dysarthria. In the motor system there was a tremor of

the outstretched hands which worsened on action. Tone and power in the limbs were normal, the tendon reflexes were symmetrically brisk and both plantar responses were flexor. Detailed sensory examination was not possible but no gross abnormality was detected. He was able to stand only with help and was very unsteady on his feet by this time, unable to walk. By the end of the examination he was becoming increasingly drowsy.

Questions 1, What is the likely diagnosis? 2. What immediate treatment is needed? Discussion This man's presentation is characteristic of Wernicke's encephalopathy (see p. 1439). The triad of a confusional state, ataxia and ophthalmoplegia should always suggest this diagnosis. It is usually seen in chronic alcoholics, in whom it may be precipitated by intercurrent illness (a chest infection in this case), including trauma. Other causes include severe malnutrition and hyperemesis. The symptoms and signs are due to the development of multiple petechial haemorrhages in the brain, particularly around the third and fourth ventricles, and result from thiamine deficiency. Thiamine should be given as a matter of urgency. Rapid progression to coma and death is inevitable without treatment. The condition in the early stages may be manifest by a confusional state alone, and it is good practice to administer thiamine to all known or suspected alcoholics admitted to hospital, with or without confusion. Unrelated intercurrent illness probably precipitates Wernicke's encephalopathy by increasing metabolic demands for thiamine.

24

The diagnosis was immediately suspected by the casualty officer and the patient was given intravenous thiamine 100 mg stat and then 100 mg three times a day. An intravenous saline infusion was set up and he was rehydrated. In patients with thiamine deficiency it is dangerous to give intravenous glucose prior to thiamine, because glucose increases the metabolic demand for thiamine and this may exacerbate the neurological condition. Over the next 12 hours he was jn a stuporose state, waking and responding with single words only to shouted commands or gentle shaking. His conscious level then progressively improved, and within 36 hours of admission he was fully conscious and alert. On physical examination at that time he was afebrile. The right ptosis and the ophthalmoplegia had resolved, although on right lateral gaze there was small-amplitude sustained horizontal nystagmus. The dysarthria had improved. He was able to stand and walk with one assistant, the ataxia being considerably better than at the time of admission. However, his mental state was very abnormal. He seemed cheerful and talkative but very inattentive. He was disinhibited in both speech and behaviour, making inappropriate remarks about the staff and other patients, and attempting to kiss the nurses. He was disorientated in time and place. He was completely unable to retain and recall new information. He could read from a newspaper but could not sensibly discuss the content. He was never stuck for answers to questions, with clear evidence of confabulation. Over the next 10 days the nystagmus and dysarthria resolved and the gait ataxia improved to the extent that he was only unsteady on attempted heel-toe walking. Unfortunately, there was no improvement in his mental state.

1437

CASE STUDY 24.12 CONTINUED Questions 3. What additional condition is now present? 4. What is the prognosis?

Discussion The patient has developed a Korsakoff s psychosis (confabulatory dementia). This is so often seen in

association with, or on recovery from, Wernicke's encephalopathy that it is now usually known as the Wernicke-Korsakoff syndrome. Early recognition and treatment of Wernicke's encephalopathy with thiamine may prevent the development of Korsakoff s psychosis in some patients. Unfortunately, once established, Korsakoff's psychosis is usually permanent, although in some

producing flushing, pupillary dilatation and tachycardia; the respiratory rate is often increased. With increasing levels of alcohol disorientation is followed by stupor and then coma, with a reduced respiratory rate. Death may occur because of the direct toxic effects of very large amounts of alcohol; more commonly, vomiting leading to aspiration pneumonia is the cause of death. In certain susceptible people hypoglycaemia occurs, particularly when alcohol has been taken without food. In chronic alcoholism tolerance to ethanol develops, so that at levels well in excess of l00mg/l00mL there may be no apparent impairment of intellectual or motor function. Alcoholic coma is rare; disorientation and stupor are more common. Patients should be allowed to rest, and many will sleep. On the day following acute alcohol excess there is dehydration, sometimes tremulousness, headache, malaise and nausea. Many patients in coma also abuse other drugs: the combination of alcohol and barbiturate is particularly dangerous. The association of alcoholism and cranial trauma leads to an excess of subdural haematomas in this group.

Delirium tremens Delirium tremens is an acute psychosis seen in chronic alcoholics during alcohol withdrawal. The effects are probably due to withdrawal of sedation and the release of autonomic activity and neuronal irritability. There is a change in personality, the patient becoming withdrawn, restless, irritable, anorexic and sleepless; there are often frightening hallucinations, which tend to be visual more than auditory. Disorientation, dysarthria and progressive clouding of consciousness also occur. Fits occur 12-48 hours after alcohol withdrawal and, when

1

1438

MCQ 24.39

patients there is partial improvement. Living an independent life without the ability to retain and recall information, and thus without any short-term memory, is more or less impossible and such patients require very close supervision, often ending up in institutional care.

present, always precede the period of delirium. Death occasionally occurs from ventricular tachycardia secondary to hypokalaemia. The mainstay of treatment is sedation, and the drug of choice is clomethiazole (chlormethiazole), given either orally or as a continuous intravenous infusion. In severe refractory cases it may be necessary to use paraldehyde. It is necessary to correct fluid and electrolyte imbalance, to ensure adequate nutrition at an early stage, and to give thiamine to prevent the development of a Wernicke-Korsakoff syndrome (see below).

Alcoholic fits Alcoholic fits, sometimes known as 'rum fits', are a common complication of alcoholism; they may also be seen in non-alcoholics after a single acute excess of alcohol. Fits occur 12-48 hours after alcohol withdrawal, and nearly always take the form of generalized convulsions. Fits rarely occur during a period of drinking; if they do, it is usually related to a rapidly falling blood alcohol level. The majority of patients with alcohol withdrawal fits have not had previous fits, and the subsequent EEG is normal.

Alcoholic dementia and cerebral degeneration Chronic alcoholism may cause a slowly progressive dementia associated with generalized cerebral atrophy. There is often associated depression. Dementia in alcoholics may also be due to repeated head injuries, undetected subdural haematoma, insidious hepatic encephalopathy and chronic fits. In the early stages some degree of dementia may be reversible if the patient abstains completely from alcohol. Depressed patients should respond to antidepressant drugs. Many patients, however, continue to drink. In some alcoholics, without any clinical evidence of dementia or other brain damage but with cerebral atrophy on CT or MRI, the scan appearances improve with abstinence from alcohol. This improvement occurs slowly over

a period of 6 months to 3 years. Similar, partly reversible cerebral atrophy has also been observed in anorexia nervosa, kwashiorkor, and in patients treated with corticosteroids.

Wernicke-Korsakoff syndrome In 1881, Karl Wernicke described three patients with confusion, ataxia and ophthalmoplegia with nystagmus. All were dead within 2 weeks of the onset of the illness. Independently, Sergei Sergeyevich Korsakoff described 20 chronic alcoholics with severe impairment of short-term memory associated with disinhibition, leading to a confabulatory dementia. Most patients also had a peripheral neuropathy, and this led Korsakoff to describe the syndrome as psychosis polyneuritica. It was not until some years later that the close association of the two conditions was recognized, and it is now clinically useful to consider them together as the Wernicke-Korsakoff syndrome.

Aetiology The syndrome does not only occur in alcoholics. It is due to thiamine deficiency and may therefore be seen in severe starvation, malnutrition, intravenous feeding without vitamin supplementation, occasionally in hyperemasis gravidarum, and in vomiting due to high gastrointestinal obstruction. Clinical features The clinical features of the syndrome initially include a triad of ophthalmoplegia, ataxia and confusion. The ophthalmoplegia and ataxia may precede the mental symptoms by several days. In the early stages, the mental changes are dominated by confusion and restlessness, followed by drowsiness, disorientation and then coma. The Korsakoff confabulatory dementia often only becomes evident after treatment. The eye signs consist of nystagmus, sixth- and third-nerve palsies, gaze palsies, and occasionally ptosis. Hypothermia due to hypothalamic involvement may occur, and sudden death is a feature of the syndrome. The confabulatory dementia is selective, in that the ability for retention and recall and short-term memory are severely impaired, whereas other intellectual functions are relatively well preserved. A peripheral neuropathy is present in up to 80% of patients. The pathology of the syndrome includes punctate haemorrhages and non-haemorrhagic areas of necrosis in periventricular sites around the third and fourth ventricles. 1 Diagnosis and treatment The diagnosis of Wernicke-Korsakoff syndrome is essentially clinical. A high index of suspicion is needed. There may be associated alcohol withdrawal and acute delirium tremens in the early stages, and making a definite diagnosis of the Wernicke-Korsakoff syndrome can be difficult. Thiamine should be given to all alcoholics who present acutely with problems associated with alcohol withdrawal.

Biochemical abnormalities in Wernicke-Korsakoff syndrome include a raised blood pyruvate level and a reduced red cell transketolase, and these may be of retrospective diagnostic value. The response to thiamine of the ocular signs in Wernicke-Korsakoff syndrome is often dramatic, occurring within 24-48 hours. The ataxia shows some recovery, and the confusion and restlessness also improve fairly rapidly. In contrast, the Korsakoff confabulatory dementia shows a limited response to treatment. Despite early recognition and prompt treatment, about 20% of patients die during the first few days.

24

Hepatic encephalopathy From a neurological point of view, three types of hepatic encephalopathy (Ch. 16) are recognized: • Acute coma associated with fulminating hepatic failure; • Reversible hepatic encephalopathy in cirrhotics with a recognizable precipitating cause; • Hepatocerebral degeneration syndrome, which is a consequence of the portosystemic shunting of long-standing liver disease. This is a slowly progressive condition and responds poorly to treatment. The neurohistopathological abnormalities are minimal in acute fulminant hepatic failure. However, in chronic hepatic encephalopathy there is neuronal loss, diffuse gliosis, and many astrocytes containing enlarged irregular nuclei, with astrocytic proliferation. Clinical features Acute fulminant hepatic failure is accompanied by confusion, delirium, stupor and then coma. Eye movements become disconjugate and tone is increased in the limbs, with brisk reflexes; eventually, with deepening coma, decerebrate posturing, loss of tendon reflexes, fits and then death occur. In reversible chronic hepatic encephalopathy a hallmark of the condition is a fluctuating level of consciousness with confusion. Euphoria may be present and, characteristically, there is marked intellectual impairment in a patient who is alert and may have no other abnormal neurological signs. Constructional apraxia, which can be measured serially from day to day, is a useful index of improvement or deterioration. With worsening encephalopathy, drowsiness, dysarthria, asterixis, myoclonic jerks, fits, choreoathetosis and extrapyramidal rigidity, together with pyramidal signs, appear. Recovery from a deeply comatose state is unusual, as this reflects severe hepatic dysfunction. In the hepatocerebral degeneration syndrome there is a progressive dementia, extrapyramidal rigidity, asterixis, and pyramidal signs in the limbs. The neurological deficit may remain stable for many months before deteriorating. Investigation and treatment The most helpful neurological investigation in hepatic

1439

TABLE 24.79 Disorders caused by drugs and toxins

TABLE 24.79 Continued

Dementia Alcohol Mercury Lead

Optic neuropathy Ethambutol Chloroquine Methyl alcohol

Manganese Aluminium Solvent abuse

Acute or subacute encephalopathy Lead (esp. children) Thallium Mercury Solvent abuse Manganese (many others)

Lens opacities Steroids Chloroquine Amiodarone

Drug-induced confusional state or psychosis Antiparkinsonian drugs Lithium Steroids Amfetamines Isoniazid Cannabis Tricyclics LSD Alcohol withdrawal (many others)

Myelopathy Nitrous oxide abuse Lathyrism (plant toxins)

Lowered threshold for seizures Alcohol Amphetamines Neuroleptics

Tricyclics Other antidepressants

Parkinsonism Neuroleptics Flupenthixol Antiemetics Reserpine

Amiodarone Manganese MPTP

Chorea and/or dystonia L-dopa Dopamine agonists Antiemetics Neuroleptics (often 'tardive')

Phenytoin Benzhexol Manganese

Tremor B2-agonists (salbutamol etc.) Lithium Sodium valproate Amiodarone Amphetamines

Alcohol (esp. withdrawal) Levothyroxine Mercury Manganese

Cerebellar syndrome Alcohol Phenytoin Ototoxicity Aminoglycoside antibiotics Quinine Ethacrynic acid

1

1440

MCQ 24.40

Solvent abuse Mercury

Furosemide (frusemide) Aspirin (in overdose)

Peripheral neuropathy Gold Lead Arsenic Thallium Mercury

Clioquinol Chloramphenicol ?Pipe tobacco

Industrial solvents Solvent abuse Numerous drugs (Table 24.65, p. 1396)

Neuromuscular blockade Botulinum toxin Organophosphorus compounds 'Nerve gases'

Penicillamine Aminoglycosides (and other antibiotics) may exacerbate myasthenia

Myopathy Steroids Chloroquine Clofibrate

Amiodarone Zidovudine (AZT) Alcohol

encephalopathy is the EEG. This shows progressive slowing of activity, loss of the normal a rhythm, paroxysmal slow waves and, in many patients, triphasic waves. The value of the EEG is that the sequence of changes in a particular patient is a reliable index of the severity of the encephalopathy, and that the EEG changes may precede any obvious change in the clinical state. The treatment of hepatic encephalopathy is that of hepatic failure (Ch. 16). There are suggestions that large doses of L-dopa or bromocriptine may partially reverse the encephalopathy, together with an improvement in the EEG.

Cerebellar degeneration Cerebellar degeneration is a fairly common consequence of chronic alcoholism and is probably due to a combination of nutritional deficiency and alcohol toxicity. There is marked atrophy of the upper part of the vermis, but the cerebellar hemispheres are relatively spared. This leads to ataxia, which is most marked for the trunk, leading to gait ataxia, and dysarthria is common. Nystagmus is relatively

Central pontine myelinolysis

FIG. 24.71 Central pontine myelinolysis (CPM) MRI showing abnormal signal throughout the central pons in a chronic alcoholic with CPM.

uncommon, particularly in the earlier stages. A fairly acute form of cerebellar syndrome may respond well to abstinence, but recovery from chronic cerebellar degeneration is limited.

Central pontine myelinolysis (CPM) is a rare condition. It is usually seen in chronic alcoholics, but there is also an association with hyponatraemia, particularly in children, liver disease being the major cause. The development of CPM often coincides with over-rapid correction of the hyponatraemia. The pathology is a massive, progressive demyelination affecting the basis pontis and involving pontocerebellar fibres, long tracts and myelinated fibres in the pontine nuclei. The clinical features are confusion and cranial nerve palsies, particularly affecting the fourth, fifth and sixth nerves, with gaze palsies and bulbar signs; there are pyramidal signs in the limbs, occasionally cerebellar signs and, often, disturbances of vasomotor control with hypotension. The differential diagnosis includes vascular lesions affecting the pons, multiple sclerosis and brainstem encephalitis. Findings on MRI are characteristic (Fig. 24.71). In 75% of cases death occurs within 1 month, but occasionally it runs a chronic course over several months, sometimes with a partial recovery. There is no specific treatment. O

24

Peripheral neuropathy Signs of a peripheral neuropathy may be present in up to 10% of all chronic alcoholics; in most cases it is mild and asymptomatic. The neuropathy is usually, but not exclusively, seen in malnourished patients. In well-nourished alcoholics the neuropathy tends to be less painful than in malnourished patients. In the early stages the neuropathy is predominantly sensory and, characteristically, there is severe burning pain with paraesthesiae and hyperaesthesia of the feet and lower legs. The hands are usually affected later, and distal wasting and weakness develop. Some patients may be unable to walk because of pain and hyperaesthesia. Treatment is abstinence from alcohol and an adequate diet. Pain responds poorly to analgesics, and symptoms improve slowly over several months. Patients find they can relieve their severe symptoms with alcohol, and many therefore return to excessive drinking.

Alcoholic amblyopia Impairment of vision in one or both eyes due to an optic neuropathy may occasionally occur in chronic alcoholics. Fundoscopy shows optic atrophy. The pathology of the condition is a loss of ganglion cells in the retina, and necrosis of central parts of the optic nerve and chiasm.

Alcoholic myopathy Rarely an acute destructive alcoholic myopathy occurs, and the consequent myoglobinuria can cause acute renal failure. A chronic, predominantly proximal, alcoholic myopathy has also been described.

FURTHER READING ON ALCOHOL AND THE NERVOUS SYSTEM Charness M E, Simon R P, Greenberg D A 1989 Ethanol and the nervous system. N Engl J Med 321: 442-454 Lishman W A 1981 Cerebral disorder in alcoholism: syndromes of impairment. Brain 104:1-20

TOXIC AND DRUG-INDUCED DISORDERS Table 24.79 includes the more commonly encountered drugs and other toxic agents responsible for the various neurological syndromes listed, but it is not totally comprehensive. For example, a 'toxic confusional state' may sometimes result from almost any drug, particularly in the elderly.

FURTHER READING ON TOXIC AND DRUG INDUCED DISORDERS Adams R D, Victor M (eds) 1985 Principles of neurology, Chapter 41: Disorders of the nervous system due to drugs and other chemical agents. New York: McGraw-Hill Dyck P J, Thomas P K, Griffin J W, Low P A, Poduslo J F (eds) 1993 Peripheral neuropathy. Part H: Neuropathy associated with industrial agents: Metals and drugs. Philadelphia: WB Saunders, pp. 1533-1581 Feldman R G, Ricks N L, Baker E L 1980 Neuropsychological effects of industrial toxins. Am J Indust Med 1: 211

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Index

Note: Suffixes for page numbers: cs = case study f = figures ra = recent advances t = tables/summary boxes This index is in letter-by-letter order whereby spaces and hyphens between entry words are excluded from the alphabetization e.g. cataplexy precedes cat-scratch disease vs denotes differential diagnoses, or comparisons. Abbreviations ADH = antidiuretic hormone MI = Myocardial infarction MND = motor neuron disease SLE = systemic lupus erythematosus SVT = supraventricular tachycardia VT = ventricular tachycardia

A abdomen, computed tomography 832f abdominal muscles 718 abdominal pain acute pancreatitis 828 functional bowel disorders 821 pituitary hypofunction 897 polyarteritis nodosa 1182 recurrent, Cl-inhibitor deficiency 91, l00cs rheumatic fever 1165 abdominal reflexes 1303,1376 abdominal sepsis 274 abdominal tuberculosis 816 abdominal X-rays intestinal disease 830 pancreatitis 830 abducens nerve (sixth cranial) see cranial nerve, sixth abetalipoproteinaemia 792-793 c-abl genes 1237f, 1238 ABO blood group 1228 antibodies 1228,1228t antigen system 1228f grouping 1228t incidence 1228t abortion, recurrent, SLE 1176 abreaction 238

abscess amoebic liver see amoebic liver abscess (ALA) cerebral see cerebral abscess epidural 1382,1414 intracranial see intracranial abscess liver 880-881, 880t lung see lung, abscesses lymphatic filariasis 367 pancreatic 829 pyogenic 880-881, 880t, 1376 recurrent chronic granulomatous disease 93-94 cyclical neutropenia 94 subdural see subdural empyema (abscess) subphrenic, pleural effusion 712 absorption tests, coeliac disease 789 abstraction, testing 1287 ABVD chemotherapy 1252 acanthamoeba infection 342-343 acanthocytosis, hereditary 1221 acanthosis nigricans 420, 420f acarbose 998t,999 accelerated-phase hypertension 592 accessory nerve (eleventh cranial nerve) 1301 ACE inhibitors see angiotensinconverting enzyme (ACE) inhibitors acetaldehyde dehydrogenase 861 liver damage 861 acetaminophen see paracetamol acetazolamide, mountain sickness treatment 50 acetone 982 acetylcholine Alzheimer's disease 1347 anticholinergic drugs 1363,1401 botulinum toxin 1402 cholinergic drugs 1348 Lambert-Eaton myaesthenic syndrome 1401-1402 receptors, myasthenia gravis 1400, 1401 acetylcholinergic drugs, Alzheimer's disease 1348 acetylcholinesterase inhibitors 1401 acetylcysteine chronic bronchitis 664 paracetamol poisoning 29, 29t acetylsalicylic acid see aspirin achalasia 769-771 clinical features and investigation 770 management 770-771 Achilles tendon central core degeneration 1198 management of lesions 1200 tendinitis 1198 aciclovir herpes viruses 268, 287 intravenous 286 varicella (chickenpox) 285 viral encephalitis 1423 viral meningitis 1422 acid(s), management of ingestion 36-37, 37t acid-base disorders 1114-1118, 1115cs changes in Pco2 and HCO3 1114t metabolic, management 1117-1118 see also acidosis; alkalosis acid-base homeostasis 1113-1114 acid generation and elimination 1113

kidneys role 1036-1037 potassium 1111f status investigations 1114 a1-acid glycoprotein (AAG) 3 acidophil tumours 902 acidosis 1110 clinical consequences 1117, 1117f see also metabolic acidosis; respiratory acidosis acidotic (Kussmaul) breathing 587, 1114 diabetic ketoacidosis 1004 type 1 diabetes 988 acinus, liver (concept) 836 acneform eruption drug-induced 419 poisoning 18 acne vulgaris 431, 431f, 891 acoustic neuroma 1353,1353f vertigo 1317,1320 acrodermatitis enteropathica 127 acromegaly 902-906 aetiology 902-903 cardiovascular features 904 clinical features 903-904, 903f, 904t, 905cs cardiovascular 890,905cs skeletal 891 diagnosis case study 905cs investigations 904-905, 904f management 905-906,906t ACTH 893-894 actions 906 deficiency adrenal atrophy due to 928 features 897,906 disorders 906-907 ectopic secretion 933 investigation 929, 930f see also ectopic ACTH syndrome ectopic syndrome 933 excess secretion 889, 906-907 Addison's disease 931 adenomas causing 906 adrenal hypertrophy 928 physiological 906 MSH activity and pigmentation increase 893-894 physiology 906 pituitary tumours secreting 897, 906 role 893-894 secretion, rhythms 893, 906 synthesis 893 factors stimulating/inhibiting 893, 893t synthetic (synacthen) 929 ACTH-cortisol axis, dynamic function tests 892 ACTH-related peptides 893 actinic (solar) keratosis 423, 423f Actinomyces israelii 330 actinomycoses 330-331, 331t arthritis 1160 diagnosis and management 331 action potentials, heart muscle 464-465,465f activated partial thromboplastin time (APTT), haemostasis disorders 1267,1268 active transport, drugs 1 activities of daily living (ADL) 201 acute coronary syndromes (ACS) 544,552-554 management 552 non-Q-wave myocardial infarction 552

platelet IIB/IIIA receptor inhibitors 552 rest angina 552 risk stratification 552-554, 554f unstable angina 552 see also angina pectoris; myocardial infarction (MI) acute demyelinating encephalomyelitis (ADEM) 1412 acute pancreatitis see pancreatitis acute-phase proteins 1125-1126 musculoskeletal diseases 1125-1126 synthesis 1126 see also C-reactive protein (CRP) acute renal failure see renal failure, acute acute respiratory distress syndrome (ARDS) 19,697-700 causes 697, 698t clinical features 697, 698, 698t, 699f, 700f diabetic ketoacidosis (DKA) 1006 in ICU 737 management 698-700 drug therapy 700 fluid balance 698,699f inhaled nitric oxide 700 oxygenation 698-700 positive end-expiratory pressure (PEEP) 699 warning signs 698 oxygen toxicity 697 pathogenic mechanisms 697, 698f prognosis 700 acute tubular necrosis (ATN) acute renal failure 1049 diabetic ketoacidosis 1004 malaria 347 renal hypofusion 1049 adder envenomation 41-42, 41f Addisonian crisis 931, 931t Addison's disease 889, 930-932 clinical features 930-931, 931t hypercalcaemia 972 hyperpigmentation 891 hypoglycaemia 1018 investigations 928, 931 basal measurements 891 management 931 drugs affecting 932 myopathy and 1407 adenocarcinomas 701, 702t bronchial 701,702t gastric see gastric cancer renal 1091 small intestine 796 see also specific tumours adenoma adrenal 937 bronchial 708 colorectal 800 parathyroid gland 970, 971 pituitary 1353f see pituitary tumours thyroid gland 918, 919 adenomatous polyposis, familial 800 adenosine deaminase deficiency 94t adenoviral arthritis 1161 adenoviruses 290 adenylate cyclase system adrenaline action via 885 hormonal actions via 884—885, 884f adhesive capsulitis 1194 adipose tissue 108 adolescents, growth hormone excess 903

1443

1444

adrenal androgens assays 928 see also androgens (androgenic steroids) adrenal cortex adenomas 937 anatomy and physiology 925-926, 926f atrophy 928 carcinoma 888,937 palliation 936 congenital hyperplasia 933f, 951 diseases 929-937 Addison's disease see Addison's disease aldosterone secretion disorders 937 enzyme defects 932 excess glucocorticoids see Cushing's syndrome see also adrenocortical insufficiency hyperfunction, psychiatric features 890 hyperplasia, hypertension 600 hypertrophy 928 idiopathic zona glomerulosa hyperplasia 937 inborn errors of function 889 insufficiency see adrenocortical insufficiency investigations 928-929 metastases 937 physiological control 926-927 surgery 936 tumours 932 clinically silent 937 see also adrenal cortex, carcinoma adrenal crisis 898 adrenal disorders congenital hyperplasia 1018 investigation 928-929 CT scanning 929, 930f steroid assays 928 stimulation tests 929 suppression tests 928, 929f myopathy and 1407 see also adrenal cortex; adrenal medulla adrenalectomy 936 adrenal failure Addison's disease 931 see also Addison's disease management 931-932 primary vs secondary 929, 931 adrenal glands 925-929 anatomy and physiology 925-928, 926f atrophy 928 response to ACTH changes 928 see also adrenal cortex; adrenal medulla adrenaline (epinephrine) 938 action mediated by adenylate cyclase 885 a and B effects 885 biosynthesis 927, 927f discovery 883 glucocorticoids interactions 887, 887f increased sensitivity 918 increased sensitivity, in thyroid hormone excess 887, 918 inotropic therapy 731, 732t nut allergy 99 adrenal medulla 927-928 catecholamine synthesis see catecholamines

diseases 938-939 excess 938-939 see also phaeochromocytoma hyperfunction, psychiatric features 890 insufficiency 938 investigations 929 tumours 938-939 CNS features 890 adrenal steroids 925-926 androgens 927 biosynthesis pathways 926, 927f, 933f enzyme defects 932 structures 926f see also glucocorticoids; mineralocorticoids adrenergic agonists/blockers see entries beginning Adrenoreceptor adrenocortical insufficiency 929-930 acute (Addisonian crisis) 931, 931t aetiology 929-930, 930t autoimmune 930 chronic, with pigmentation see Addison's disease primary 929-930, 930t secondary 930 short synacthen test 929 adrenocorticotrophic hormone see ACTH B2-adrenoreceptor agonists, chronic bronchitis/emphysema 664 a-adrenoreceptor blocker, phaeochromocytoma treatment 938 B-adrenoreceptor blockers see beta-blockers adriamycin 876 adult respiratory distress syndrome see acute respiratory distress syndrome (ARDS) advanced life support 519-520 adverse drug reactions 5-7, 5t antituberculous drugs 643cs diagnosis 6 dose-dependent (type A) 5 dose-independent (type B) 5-6 elderly 199-200, 200f management 6 monitoring 14-15 patients at risk 5 prescription errors 6-7 prevention 6-7 pyrexia of unknown origin 275 yellow card system 6 adverse effects antituberculous drugs 645t, 646 iatrogenic lung disease 696-697 pulmonary eosinophilia 660 Aedes aegypti 296 affect frontal lobe lesion 1288 mental state examination 1287 affinity maturation 82 aflatoxins carcinogens 148 hepatocellular carcinoma 876 African tick typhus 306 African trypanosomiasis (sleeping sickness) 352-354 clinical features 353 diagnosis 353 distribution and incidence 352-353 management 353-354 parasitic myositis 1406 pathology and pathogenesis 353 prevention and control 354

transmission and epidemiology 353 after-depolarizations 505-506 afterload, heart pump performance 466,466f age arthritis relationship 1130t bone mass relationship 954f cancer incidence rates 145,146 low back pain aetiology by 1187t maternal, Down's syndrome and 66 musculoskeletal diseases 1121 osteoarthritis association 1154, 1154f ovarian changes with 946 rheumatoid arthritis relationship 1131,1131f serum uric acid levels 1166,1166f ageing 171-204 changes in the elderly population 171,171f epidemiology 172t glomerular filtration rate 1040, 1041f life expectancy 171,172f sociological aspects 173-174 theories of ageing 172-173 thirst threshold 1100 see also elderly agnosia 1287 colours 1289 visual 1287 agoraphobia 214 AIDS see HIV infection and AIDS aids and appliances, rheumatoid arthritis treatment 1139 airflow obstruction 607-608 airport malaria 345 airway calibre 608 control 654, 654f damage, asthma 652 obstruction 607-608 respiratory muscles 722 remodelling, asthma 655 akinesia 1302,1361,1362 levodopa effect 1363 akinetic-rigid syndromes see parkinsonism; Parkinson's disease alanine aminotransferase, liver function tests 841 albendazole ascariasis 360 cysticercosis 377 hookworm 361 strongyloidiasis 362-363 trichinosis 369 Albers-Schoenberg disease 978 albinism 70f albumin drug distribution 2 excretion rate (AER), diabetic nephropathy 1011 freeze-dried salt-poor blood product 1230 half-life 840 levels gastrointestinal disease 753,754t intestinal disease 341 liver function and 840 small intestine disease 786 replacement fluid 731t synovial fluid 1120 thyroxine binding 913 urine excretion 1038 alcohol 113 abuse

dietary deficiency 114cs pancreatitis 828 see also alcoholism consumption 248f, 248t Cushing's syndrome associated 933,934 dependence 248t diabetes and 994 in ethylene glycol poisoning 36 facial flushing, sulphonylurea side effect 998 hypoglycaemia 991,1019 intoxication 35, 35f nervous system involvement 1435_1438 overdose management 35 metabolism 863f nervous system involvement 1435-1441,1436t acute intoxication and coma 1435-1438 amblyopia 1436t, 1441 blackouts 1436,1436t case study 1437-1438cs cerebellar degeneration 1436t, 1440-1441 delirium tremens 1436t, 1438 dementia 1436t, 1438-1439 fits 14361,1438 Korsakoff s psychosis 1438cs Marchiafava-Bignami disease 1436t memory impairment 1436 mood changes 1436 myopathy and 1407 neuropathy 1393,1436t, 1441 Wernicke-Korsakoff syndrome see Wernicke-Korsakoff syndrome pancreatitis 830 -related pain, Hodgkin's disease 1250 tolerance 248,1438 weight management 130 withdrawal symptoms 1438 alcohol dehydrogenase 861 alcoholic blackouts 1436,1436t alcoholic liver disease acute hepatitis 855-856 chronic 861-863, 862cs diagnosis 862-863 management 863 mortality 861f pathogenesis 861-862 pathology 861-863 liver transplantation 881 Alcoholics Anonymous (AA) 251 alcohol-induced depression 220 alcoholism 247-252, 250cs aetiology 249 beriberi 584 definitions 248 management 251,251t shop-front/dry house programmes 251 physical complaints 249, 251 presentation 248-249, 249t prevention 251 psychiatric complaints 251 risk factors 249t see also alcohol, abuse aldosterone 926 assays 928 discovery 883 hyperaldosteronism 593 potassium homeostasis 1036 secretion disorders 937 see also hyperaldosteronism; hypoaldosteronism

sodium depletion 1109-1110 synthesis and secretion 926 sodium homeostasis 1100 see also renin-angiotensin-aldoster one system aldosterone antagonist ascites 872 nephrotic syndrome 1063 alendronate, osteoporosis treatment 961 alertness, mental state examination 1286 alimentary system, endocrine disorders affecting 891 aliphatic hydrocarbons, poisoning 35 alkali(s), management of ingestion 37 alkaline phosphatase 958 colorectal carcinoma 802 increased levels 958 isoenzymes 958 liver function test 841 Paget's disease 977f alkalosis 1110 clinical consequences 1117 see also metabolic alkalosis; respiratory alkalosis alkaptonuria 69,70-71 alkylating agents 147,161 alleles 63-64, 64f inheritance 64f allergens 96 food 98 see also food, allergy allergic angiitis, pulmonary eosinophilia 661 allergic bronchopulmonary aspergillosis bronchiectasis 648 pulmonary eosinophilia 660,660f allergic granulomatosis see Churg-Strauss syndrome allergic granulomatosis (ChurgStrauss syndrome) 691 allergic rhinitis 658-659 management 659 pathology 659 allergic syndromes 97-99 rhinitis 97-98 allergy 96,97 food see food, allergy insulin treatment 992 peanut (nut) 98-99, l00cs allodynia, diabetic neuropathy 1013 allograft nephropathy, chronic 1061 allopurinol chronic myeloid leukaemia 1239 drug interactions 10 gout 1171 polycythaemia rubra vera 1242 allotypes 82 all trans retinoic acid (ATRA) 1246 alopecia 433-434 chemotherapy causing 162 diffuse, in SLE 1174 drug-induced 419 inflammatory 434 traumatic 434 see also hair loss alopecia areata 434,434t a-fetoprotein (AFP) 151 hepatocellular carcinoma diagnosis 876 maternal, prenatal diagnosis 76t alphachloralose, poisoning 39 Alport's disease 1064 Alport's syndrome (hereditary nephritis) 1075

altitude sickness 49-50 acclimatization 49 aluminium hydroxide, renal failure 1057 alveolar-arterial (A-a) gradient 670-671 alveolar carcinoma 707-708, 707f alveolar spaces 605 Alzheimer's disease 176-177, 1346-1348 aetiology 1347 ApoE association 73t clinical features 1347-1348 hydrocephalus 1360 differential diagnosis 1429 investigation 1348 management 1348 pathophysiology 1347,1348f Amanita phalloides 853 amantadine influenza virus infection 291 Parkinson's disease 1363 amaurotic attacks 1291 carotid artery occlusion 1331 amblyopia 1299 alcoholic 1436t, 1441 amenorrhoea 946-949 anorexia nervosa 241 liver cirrhosis 860 macroprolactinoma 909 management 948 microprolactinoma 908 ovarian causes 947-948, 947t pituitary/hypothalamic causes 946-947 American Diabetic Association, diagnostic criteria 984 American trypanosomiases (Chagas' disease) 354-355,799 amikacin 266 aminoacidopathies 69-71 amino acids essential 110 metabolism 837-838, 838f defects 69-71 pathways 70f aminoaciduria 1065 aminogangliosides, ototoxins 1318 aminoglutethimide, Cushing's syndrome 936 aminoglycosides 266 brucellosis 319 8-Amino-laevulinic acid (8-ALA) 1026,1407 8-Amino-laevulinic acid (ALA) synthase 1026,1407 aminophylline, asthma 657 amitriptyline 222 postherpetic neuralgia treatment 1314 AML-1 gene 1244 ammonia 837 buffering in kidney 1036-1037 poisoning 34 removal, encephalopathy treatment 875 amnesia, post-traumatic 1373 amniocentesis 76t haemolytic disease of the newborn 1233,1233f amniotic fluid, monitoring Rhnegative women 1233f amoebiasis 338-341, 339t aetiology 338 clinical features 339 diarrhoea 280 complications 339 diagnosis 339-340 differential diagnosis 341

distribution and incidence 338 investigations 339-340 liver involvement 879 management 341,341t pathology and pathogenesis 338-339 prevention and control 341 transmission and epidemiology 338 amoebic colitis 879 amoebic dysentery 339 amoebic liver abscess (ALA) 338, 339 investigations 341 signs and symptoms 339 sites of spread 340f amoeboma 339 amoxicillin 265 actinomycoses 331 resistant Haemophilus 317 urinary tract infections 1085 amphetamines abuses 247 malignant hyperpyrexia 46 overdose 30 amphotericin B 267 cutaneous leishmaniasis 357 Histoplasma capsulatum infection 333,334 hypoplastic anaemia 1212 Naegleria fowleri infection 342 visceral leishmaniasis 358 ampicillin 265,458 septicaemia 274 amputations, diabetes 1015,1018 amylase, levels, pancreatitis 830 amylin deposits, type 2 diabetes 995 amyloid cardiac 573 plaques 1347 renal 1077 amyloid neuropathy 1397 amyloidosis 1262-1264 aetiology 1262t cardiac amyloid 573 classification 1263,1263t clinical features 1263,1263t diagnosis 1263 liver involvement 878 management and prognosis 1263-1264 rheumatoid arthritis causing 1138 amyloid precursor protein (APP) 1347 amyotrophic lateral sclerosis (ALS) see motor neuron disease (MND) amyotrophy diabetic neuropathy 966cs, 1013, 1396 neuralgic 1399-1400 syphilitic 1430 anabolic metabolism 979-980 catabolic vs 981 see also insulin; specific pathways anaemia 772 aetiology 1206f aplastic see hypoplastic anaemia autoimmune haemolytic see autoimmune haemolytic anaemia (AIHA) cancer 153 of chronic disease 1125t, 1226-1227 chronic myeloid leukaemia 1238 classification and causes 1205-1206,1206t Crohn's disease 809 Fanconi's see Fanconi's anaemia

giant cell arteritis 1184 haemoglobin counts 1206 haemolytic see haemolytic anaemia haemolytic disease of the newborn 1233 see also haemolytic disease of the newborn hypochromic 1124 hypochromic microcytic 1124, 1125 hypoplastic see hypoplastic anaemia iron deficient see iron deficiency anaemia macrocytic, hypothyroidism with 917 malaria 347 megaloblastic see megaloblastic anaemia musculoskeletal diseases 1124 pernicious, spinal degeneration 1383-1384 polymyalgia rheumatica 1184 pyruvate kinase deficiency 1222 renal failure 1057 rheumatoid arthritis 1125t, 1135 secondary heart disease 584 sickle cell see sickle cell disease sideroblastic 1208-1209 aetiology 1208,12081 haematological features 1208-1209 management 1209 transfusion haemosiderosis 573 ulcerative colitis 813 uraemia 1053 anaerobic bacteria 325 anaesthesia diabetic patients 1001 hypoxia-related injury 1432 inhalation pneumonia 637 refractory status epilepticus 1328 anagrelide, essential thrombocythaemia treatment 1243 anal disease, Crohn's disease 812 analgesics cancer management 166t headache treatment medication misuse 1311 migraine 1310,1310t osteoarthritis 1157 overdose 27-30 rheumatoid arthritis 1140 anaphase 63, 63f anaphylactoid purpura see Henoch-Schonlein (anaphylactoid) purpura anaphylaxis adverse drug reactions 6 snake bite 42 wasp/bee sting 42 anaplastic large cell lymphomas 1257 anatomical snuffbox 1195 Ancylostoma braziliensis 361 Ancylostoma duodenale 360 androgenic alopecia (common baldness) 433-434 androgen receptor, defects 949 androgens (androgenic steroids) adrenal 927 assays 928 Cl-inhibitor deficiency 91 deficiency 942-945, 944f assessment 943 behaviour and 952 causes 943t

1445

1446

management 943 effect on bone metabolism 956 prostatic hyperplasia due to 950 suppression agents 951 hirsutism treatment 951 aneuploidy 62 aneurysms aortic see aortic aneurysm berry 1312,1338,1343 carotid 895 Charcot-Bouchard microaneurysms 1338 management 1345 polyarteritis nodosa 1182 polycystic kidney disease association 1343 ventricular 566 angiitis allergic, pulmonary eosinophilia 661 microscopic polyangiitis 1181-1182 angina pectoris 467-468 aortic regurgitation 529 aortic stenosis 527 atheroma of coronary arteries 543-544 characteristics 467-468 crescendo 544, 552 diabetes mellitus 1016 differential diagnosis of angina 544-545 drug combinations 549 drug treatment 547-549, 550f aspirin 547 B-blocking drugs 548 calcium antagonists 548 drug combinations 549 glycerol trinitrate/nitrates 467, 468,547-548 see also glycerol trinitrate (GTN) nicorandil 548-549 platelet IIB/IIIA receptor inhibitors 551ra potassium channel openers 548-549 practical prescribing 549 schema 550f indications for coronary artery bypass 550t ischaemic preconditioning 548ra management 546-552 drug treatment see above flow diagram 546f general measures 546-547 New York Heart Association scale 468t rest angina 544, 552 unstable 544,552 vasospastic 544 angioedema see angio-oedema angiography cerebral tumours 1354 coronary see coronary angiography fluorescein, diabetic retinopathy 1009,1009f, 1010 hypopituitarism 898-899 MRA see magnetic resonance angiography (MRA) polyarteritis nodosa 1182 renal, hypertension 596 stroke investigation 1342 subarachnoid haemorrhage 1344 angio-oedema 98, 406 allergic 100-101 cs allergic vs hereditary 91

causes 98t, 406t differential diagnosis l00cs facial l00cs food intolerance 141 hereditary 91, 406t skin features 406 treatment l0lcs urticaria absent 98 angioplasty, coronary see coronary angioplasty angiotensin-converting enzyme (ACE) 926 serum (SACE) 686, 688 see also renin-angiotensin-aldoster one system angiotensin-converting enzyme (ACE) inhibitors acute MI 559 B-adrenergic blocker combination 564ra chronic renal failure 1059 contraindications 568 cough 598,612 diabetes mellitus 1016 first-dose hypertension 496 heart failure 490, 496 hypertension 496, 593, 598 post MI management 568 potassium-sparing diuretic combination 495 severe congestive cardiac failure 494 angiotensin II 926 aniline dye, bladder cancer 1093 animals, poisonous 41-43 anion gap 1114 hyperosmolar (non-ketogenic) coma 1006 ankylosing hyperostosis 1191 ankylosing spondylitis 722, 1148-1150 bowel inflammation 1148 clinical features 1149-1150 articular 1149 extra-articular 1149t, 1150 Crohn's disease 809 endocarditis 581 epidemiology 1148 genetic markers 73t, 1147,1150 HLA-B27 731,1147,1150 investigations 1150 joints involved 1149 management and prognosis 1150 pathogenesis 1148 pathology 1148-1149 prevalence and costs 1119,1148, 1149f radiology 1150 anorexia, cancer 152 anorexia nervosa 239, 240cs, 241-242 aetiology and pathogenesis 239, 239f, 239t, 241 clinical features 241, 2411 differential diagnosis 241 management 241-242 prognosis 242 anosmia 942,1290 anserine bursitis 1197 Antabuse (disulfiram) 251 antacids excess ingestion 964 reflux oesophagitis 766 antegrade kidney 1041,1042f antegrade urinary tract 1041,1042f antenatal diagnosis see prenatal diagnosis anterior cerebral artery occlusion 1336

anterior horn cells see motor neuron(s) anterior pituitary gland see pituitary gland (anterior) anterior tibial syndrome 1198 anthracycline 1245 acute lymphoblastic leukaemia 1247 induced cardiac abnormalities 1248 anthranilic acids, overdose management 28 anthrax 311-312 cutaneous 311, 312 diagnosis 312 endospores 311 gastrointestinal 312 management 312 respiratory 312 anti-androgens hirsutism management 951,951t prostatic cancer 951 antiarrhythmic drugs 498, 508t, 517t, 518t therapeutic monitoring 12-13 antibiotics 264-267 acute bacterial meningitis 1417 antituberculous 1421 in common use 265-267 control policies 271 defined 262 gastroenteritis 281 iatrogenic lung disease 697 importance of finishing prescribed course 264 infective arthritis 1159 infective endocarditis 578 mechanism of action 264 overdose management 33 prolonged carriage of organisms 281 prophylaxis, splenectomy 96 resistance 264-265, 264t, 307 sensitivity, infective endocarditis 578 septicaemia 274 therapeutic monitoring 13 urinary tract infections 1084-1085 X-linked agammaglobulinaemia 87 see also antimicrobial drugs; individual antibiotics antibodies 81-82 affinity maturation 82 antigenic specificity 82 anti-idiotypic 84-85 binding specificity and number 82 genes 82 idiotypic 82 isotypic 82 structure 81,81f,82t see also immunoglobulin(s); individual antibodies antibody deficiency diseases 86-89 common variable (CVID) 87-88, 90-91cs IgA deficiency 88 IgG subclass deficiency 88 management 87 secondary 95-96 specific antibody deficiencies 88-89 transient hypogammaglobulinaemia of infancy 89 X-linked agammaglobulinaemia 86-87 anti-c antibodies 1233 anti-CD25 antibodies 103

anticentromere antibodies 1179 anticholinergic drugs 1401 asthma 657 incontinence 1096 multiple sclerosis 1412 Parkinson's disease 1363 anticholinergic effects drugs effecting, overdose management 32 poisonous plants 40 tricyclic antidepressant overdose 25 anticholinesterases 1401 anticipation, mutations 60 anticoagulants 1275-1279 cortical venous thrombophlebitis 1419 heparin 1275-1276,1334 see also heparin oral 1276-1277 drugs that inhibit degradation 1277 indications 1277t overdose 33 paroxysmal nocturnal haemoglobinuria 1226 post MI management 568-569 pregnancy 583,1277-1278 stroke management 1342-1343 TIA management 1333-1334 indications 1333 venous sinus thrombosis 1419 warfarin see warfarin anticonvulsant drugs 1327-1328, 1328t cerebral tumour management 1357 meningitis 1417 osteomalacia due to 965 overdose management 31 pregnancy and 1328 therapeutic monitoring 12 see also epilepsy; individual drugs anti-D antibodies 1234 antidepressant drugs 221 chronic fatigue syndrome 283 depression 221 overdose management 24-27 SSRIs see selective serotonin reuptake inhibitors (SSRIs) tricyclic see tricyclic antidepressants antidiabetic drugs 997-999, 998t overdose management 32-33 antidiarrhoeals, functional bowel disorders 823 antidiuretic hormone (ADH; arginine vasopressin) cancer 154 deficiency 910-911,1101-1102 see also diabetes insipidus fluid overload in critical ill patient 730 inappropriate secretion (SIADH) 911-912,1104,1104t receptors 910 renal resistance 911 sodium depletion 1108 synthesis and secretion 910. 910f control mechanisms 910, 910f water homeostasis 1034—1035, 1099 anti-DNA antibodies 1175 SLE 1172-1173 antidotes 20-21 paracetamol poisoning 28, 29, 29f antiemetic drugs in chemotherapy 162,163t migraine treatment 1310,1310t

antifibrinolytics C1-inhibitor deficiency 91 haemophilia A 1273 antifungal agents 267-268 prophylactic, hypoplastic anaemia 1212 antigen-presenting cells (APC) 83-84 antigens cross-reactivity 99 presentation and processing 83-84, 83f T cell activation 83-84, 84f T-independent and T-dependent 81 antihistamines allergic rhinitis 97 polycythaemia rubra vera 1242 urticaria 98 antihistone antibodies 1175 antihypertensive drugs 597-599, 597t overdose management 31 anti-idiotypic antibodies 84-85 anti-inflammatory drugs ankylosing spondylitis 1150 rheumatoid arthritis 1138,1140 side-effects 1140 see also non-steroidal antiinflammatory drugs (NSAIDs) anti-La antibodies, SLE 1173 anti-LFA-1 monoclonal antibodies 103 antilymphocyte globulin bone marrow transplant 1213 hypoplastic anaemia 1213 antimalarial drugs overdose 33 rheumatoid arthritis 1142 SLE 1176 antimicrobial drugs 262-269 bacteria sensitivity 263, 263t choice of appropriate drug 263 duration of treatment 263-264 route of administration 263 suitability 262 see also antibiotics; antifungal agents; antiviral drugs antimonials, cutaneous leishmaniasis 357 anti-Mlillerian hormone 939 antineutrophil antibodies (ANCA) 1181 cytoplasmic staining (cANCA) 1181 perinuclear staining (pANCA) 1181 antinuclear antibody (ANA) 101, 1172 connective tissue disease 1126, 1126t detection methods 1172 SLE 1172 systemic sclerosis 1179 anti-obesity drugs 999ra antioxidants 139 antiphospholipid antibodies 1175, 1176 SLE 1173 antiphospholipid antibody syndrome 1125,1175,1275,1281 antiplatelet drugs 1278.1278t administration and complications 1278 aspirin 1333 dipyridamole 1333 indications 1278,1278t mechanism of action 1278 TIA management 1333

antipseudomonal penicillins 265 antipsychotic drugs 230 side effects 23It see also neuroleptic drugs; psychotropic drugs antiretroviral drugs 268-269, 450-452 combinations 451, 45 It HIV/AIDS infection acute infection 450 chronic infection 450-451 resistance 452 treatment guidelines 451, 451t antirheumatic drugs 1140 disease-modifying (DMARDs) see disease-modifying antirheumatic drugs (DMARDs) rheumatoid arthritis 1140-1146 slow-acting (SAARDs) 1141, 11411 anti-RNA antibodies 1173 anti-Ro antibodies, SLE 1173 anti-Scl-70 antibodies 1179 antisocial personality disorder 210 legal aspects 253 antispasmodics, functional bowel disorders 822-823 antistreptococcal antibiotics, glomerulonephritis 1069-1070 antistreptolysin O titre 581 antithrombin III 1266 deficiency 1280-1281 acquired 1281 congenital 1280-1281 antithrombotic drugs 1275-1279 antithyroid drugs 921 block-replace regimen 921,922 Graves' disease 920-921 pregnancy 922 radio-iodine treatment with 922 titration regimen 921 anti-TNF antibodies 103 antitoxins, botulinum 1402 a 1 -Antitrypsin deficiency cirrhosis 870 emphysema 662 antituberculous drugs 645-646, 6451, 1421 adverse effects 643cs, 645t, 646 cost 646 directly observed therapy (DOT) 646 multiple-drug-resistant TB 646 patient non-compliance 646 resistance 643cs, 646 antivenom, snake bite 42 antiviral drugs 268-269 see also aciclovir; antiretroviral drugs antrypol see suramin anuria 1045-1046 anxiety 212-217, 212t aetiology 213t, 214-215 arousal and 212-214 defence mechanisms 216-217 interpersonal component 214 management 215-216, 215t psychological component 213214 psychophysiological component 212-213 syndromes, classification 214t anxiety neurosis 209 aorta, coarctation see coarctation of aorta aortic aneurysm 600 Marfan's syndrome 72cs

syphilitic endocarditis 579 aortic arch syndrome, giant cell arteritis 1184 aortic dissection, acute 600-601, 600f aortic regurgitation 601 chest pain 468 complications 601 diagnosis/investigation 601 drug treatment 599-600 management 601 types 600, 600f aortic regurgitation acute aortic dissection 601 aetiology 528 angina 529 Austin Flint murmur 529 chest X-rays 529 clinical features 528-529, 529f, 530t combined mitral/aortic valve disease 530-531 echocardiography 529 investigation 529 management 530 mixed aortic valve disease 530 pathophysiology 528-529 symptoms/signs 528-529 syphilitic endocarditis 579 aortic stenosis 527-528 causes 527 chest X-rays 528 clinical features 526f, 527 combined mitral/aortic valve disease 530-531 investigation 527-528 management 528 mixed aortic valve disease 530 pathophysiology 527 apex beat 472, 621 aphasia 1286 aphthous ulcers 760 Crohn's disease 761 see also mouth, ulcers apocrine sweat glands 381 apomorphine 1364 apophyseal joints 1185-1186 apophysitis, retrocalcaneal 1198 apoproteins 1021,1022 Apo B, abetalipoproteinaemia 792 apoptosis 84 T cell regulation 84 APP (amyloid precursor protein) 1347 appendicitis, pyogenic abscess 880 appetite disturbances, pituitary tumours 896 appetite suppressant drugs 131 apraxia see dyspraxia (apraxia) apraxic gait 1290 arachidonic acid metabolism 1265f arboviruses, arthritis associated 1161 arcuate arteries 1032 arcus senilis 470 arenaviridae 298, 299t arginine vasopressin (AVP) see antidiuretic hormone (ADH) Argyll Robertson pupil 1295,1429 Arnold-Chiari malformations 1385 cerebellar ataxia 1376 infantile hydrocephalus 1360 syringomyelia 1383 type I 1385 type II 1385 aromatic amines 147 aromatic hydrocarbons, poisoning 35

arrhythmia 500-517 24-hour ECG (Holter monitor) 500, 501f acute myocardial infarction 560-563 acute onset of breathlessness/arrhythmia 499-500cs antiarrhythmic drugs 498, 508t, 517t, 518t athlete's heart 585, 586 atrial flutter 513 ectopic (extrasystolic) beats 501-502. 502f exercise ECG 501 heart block see heart block heart failure 490 intracardiac electrophysiological testing 501 investigative techniques 500501 long QT syndrome 517 Lown-Ganong-Levine syndrome 517 myocarditis 570 normal sinus rhythm vs 501 palpitations 468 poisoning 19 sick sinus syndrome 506cs, 516 sinus arrest 502 sinus arrhythmia 501 sinus node block 502 wandering atrial pacemaker 513 Wolff-Parkinson-White syndrome see Wolff-Parkinson-White syndrome see also bradycardia; supraventricular tachycardias (SVT); tachycardias arsenic, poisoning 39 Artemesia annua, malaria treatment 351 arterial disease, cerebrovascular 1330-1331 arterial occlusion cerebral see cerebral infarction optic fundi 1291-1292,1293f arterial oxygen tension, ventilation assessment 736 arterial pulses 470-471 apex-radial deficit 470 collapsing pulse 471 Corrigan's sign 471 diabetic macrovascular disease 1015 irregularly irregular pulse 470 jerky pulse 471 plateau pulse 471 pulse amplitude 470-471 pulse character 471 pulsus alternans 471 pulsus paradoxus see pulsus paradoxus radiofemoral delay 470 rate/rhythm 470 sinus arrhythmia 470 slow rising, anacrotic 471 arteries ulceration 430 uraemia 1053 arteriography, renal 1043,1043f see also angiography arteriopathy. cerebral infarction 1338 arteriosclerosis 602 arteriovenous fistulas 584 arteriovenous malformations 1345, 1345f, 1346f, 1383

1447

1448

arteritis 601 giant cell see giant cell arteritis (GCA) polyarteritis nodosa 1406,1431 syphilitic 1429 Takayasu's arteritis 601-602 see also Takayasu's arteritis see also vascular disease; vasculitis arthralgia Joint pain) cryoglobulinaemia 1183 leukaemia 1244 on movement 1124 osteoarthritis 1155 rheumatic fever 1164 rheumatoid arthritis 1134 systemic sclerosis 1178 arthritis additive pattern, migratory pattern 1130 age and sex relationship 1130t in alkaptonuria 71 cervical headache 1310 cervical spinal degeneration 1379 childhood see children Crohn's disease 809 degenerative 1127-1128 see also osteoarthritis (OA) episodic, before rheumatoid arthritis 1134 flexion deformity 1120 gonococcal 1159 haemochromatosis 869 infective see infective arthritis inflammatory, synovial biopsy 1127,1128f Lyme 1160 meningococcal 1159 non-septic see reactive arthritis palindromic (intermittent) pattern 1130 persistent inflammatory symmetrical (PISA) 1133 polyarthritis see polyarthritis post-infective aseptic 315 progression, patterns 1130 pseudogout 1171 rheumatic fever 580 rheumatoid see rheumatoid arthritis SLE 1174 syphilitic 1160 systemic sclerosis 1178 temporal patterns 1130 tuberculous 1160 arthritis mutilans 1151,1151f arthrogram, musculoskeletal diseases 1128 arthropathies Charcot see charcot arthropathy crystal, differential diagnosis 1169cs enteropathic 1153 Jaccoud-type 1174 psoriatic 397 pyrophosphate 1171 arthropod-borne diseases, skin 394-395 arthropod envenomation 42 arthroscopy 1129 articular cartilage 1119,1120 structure/composition 1120 artificial hearts 564ra artificial implantable pacemakers see pacemakers artificial kidney 1059 artificial plasma expanders 1230 artificial tears, thyroid disease 919 arylalkanoic acid, overdose management 28

asbestosis 693-694, 693f, 693t asbestos-related disease 693-694, 693f, 717-718, 717f ascariasis 359-360 Ascaris lumbricoides 359 ascites clinical features 872 colorectal carcinoma 801 management 872, 872t pathophysiology, 871, 871f, 872 pleural effusion 712 ascorbic acid deficiency 114,125-126 scurvy 125-126 food sources 124t reference nutrient intake 125t role/functions 124t B thalassaemia 1216 toxicity 127,127t aseptic necrosis see avascular necrosis L-asparaginase, acute lymphoblastic leukaemia 1247 aspartate aminotransferase, liver function tests 841 Asperger's syndrome 252-253 aspergilloma, persistent severe haemoptysis 614-615cs aspergillosis, allergic see allergic bronchopulmonary aspergillosis aspergillus 333 Aspergillus flavus, hepatocellular carcinoma 876 Aspergillus fumigatus pneumonia 639 pulmonary eosinophilia 660 aspergillus pneumonia 639-640 aspirin 1140,1278 acute MI 559 alternatives to 568 angina pectoris 547 antiplatelet therapy 1333 effects on uric acid excretion 1166,1167 nephrotoxicity 1086 peptic ulcers 777 polycythaemia rubra vera 1242 post MI management 568, 569 rheumatoid arthritis 1140 side-effects 1140 vs. warfarin 568-569 assisted ventilation see ventilation astereognosis 1287 asterixis liver cirrhosis 860 myoclonus 1368-1369 asthma 651-658 'acute severe' 655 corticosteroids 658 indications 658t treatment 658 airway calibre control 654, 654f airway damage 652 airway remodelling 655 atopy 652 bronchial hyperreactivity 653, 653t bronchial provocation challenge testing 653 bronchiolar casts (plugs) 654 cellular/molecular mechanisms 652-654,653f clinical features 654-655 definition 651-652 diagnosis 655-656 drug treatment 656-658, 656f, 656t B2-agonists 655-656, 656-657 aminophylline 657

anticholinergics 657 corticosteroids 657, 658 cysteinyl leukotriene receptor antagonists 657 disodium cromoglycate 657 leukotriene antagonists 657 methyl xanthine derivatives 657 sympathomimetics 656-657 theophylline 657 epidemiology 652 exercise-induced asthma 657 hyperinflation 655 immunological mechanisms 653, 653f inhaled allergens 652 inhaler therapy 657 investigation 655 late-onset 658 lung function tests 655 management 656-658, 656f, 656t mast cell degranulation 653, 654f mechanical ventilation 658 metered-dose inhalers 657 mortality 652 nebulizer therapy 657-658 non-specific trigger factors 651t pathogenesis 652-654 pathology/pathophysiology 654, 655f peak expiratory flow rate (PEFR) 608, 611, 654,655f prognosis 658 sensitizing chemicals 652t Th2-type cytokines 652 transfer factor 655 treatment 656f, 656t water loss 1103 X-ray findings 655 astrocytomas 1352t, 1355,1355f prognosis 1355,1357,1358f radiotherapy 1357 asymmetrical septal hypertrophy (ASH) 571 ataxia Friedreich's 61, 61t, 1375 tabes dorsalis 1429 Wernicke-Korsakoff syndrome 1439 see also cerebellar ataxia(s) ataxia telangiectasia 93,1375 ataxic gait 1290 atheroma acute coronary syndromes 552 atheromatous lesion progression 544f causative factors 73 cerebrovascular disease 1330-1331 coronary arteries 543-546 clinical features 543-544 signs 544 symptoms 543-544 diabetes mellitus 1015 dietary factors 136-138 lipoprotein roles 1022 atherogenic lipid profile 1023 see also atherosclerosis; thrombosis atherosclerosis acute aortic dissection 600 aortic aneurysm 600 cerebrovascular disease 1330 diabetes and 1014 early-onset 73 epidemiology 1023 pathogenesis 1022-1023 see also lipoproteins ulceration due to 430

see also atheroma; coronary artery disease athletes, amenorrhoea 947 athlete's heart 584-586 arrhythmia 585, 586 diagnosis/management 585-586 heart block 585 heart remodelling 584-585 endurance athletes 585 power athletes 584-585 atlantoaxial articulation dislocation 1135 rheumatoid arthritis 1135 atopy 97 asthma and 652 ATP7B gene 870 atrial defibrillators 511ra atrial fibrillation (AF) 510-513 acute myocardial infarction 561 acute onset of breathlessness/arrhythmia 499-500cs atrial defibrillator 5llra causes 510-511,Silt clinical features 511 ECG trace 510f lone 511 management 511-513 acute AF 511-512 cardioversion 511,512 chronic sustained AF 512-513 digoxin 511,512,5121 heparin 512 paroxysmal AF 512-513,513t mitral stenosis 522 thyrotoxicosis 583 elderly 922 atrial flutter 513 acute myocardial infarction 561 atrial natriuretic peptide (ANP) 937 sodium homeostasis 1100 atrial septal defect 538-540 clinical features 539, 539f Eisenmenger syndrome 540 investigation/management 539-540 pathogenesis 538 primum 540 secundum 539-540 sinus venosus defect 540 sites 539f atrial tachycardias 508, 510 chaotic 513 ECG trace 510f atrioventricular (AV) node AV nodal tachycardia 513-514 atropine 1401 attachment theory 214-215 attention, mental state examination 1286 'atypical antipsychotics' 230 atypical facial pain 1315 audiometry 1298 auditory hallucinations 207 Auer rods 1236,1244 aura, migraine 1308 auranofin, rheumatoid arthritis 1142 auscultation 622-623 cardiac 472-475 bell/diaphragm stethoscopes 473 heart murmurs 475 heart sounds 473-474, 473f clicks 623 crackles 622, 622t pleural rub 622 respiratory disease 622-623, 622t wheezes 622, 623t Austin Flint heart murmur 529

autism 252-253 autoantibodies 99, 99t endocrine disease 889-890 'false positive' 99 myasthenia gravis 1400,1401 primary and secondary types 99 red blood cells 1224 SLE 1172-1173,11731 type 1 diabetes 987 type 2 diabetes 996 autoimmune disorders/disease 95 adrenocortical insufficiency 930 autoantibodies 99, 99t classification and diagnosis 99,101 coagulation disorders 1275 diabetes insipidus 1102 endocrine 889-890 haemolytic anaemias see autoimmune haemolytic anaemia (AIHA) hepatitis 863-864 hypoglycaemia and 1019 hypothyroidism 889 immunosuppressive therapy 102 monoclonal antibody therapy 103 organ-specific 96-97, 889-890 panhypopituitarism due to 895-896 thyroid 913-914 see also Graves' disease type 1 diabetes 986-987 type 2 diabetes 996 autoimmune haemolytic anaemia (AIHA) 1223-1224 aetiology 1223,1224t clinical features 1223-1224 cold type 1223,1224 drug-induced 1223 laboratory features 1224 malignancy association 1223 management 1224 musculoskeletal diseases 1125 in SLE 1175 warm type 1223,1224 autoimmune polyglandular syndromes (APS) 917t autoimmunity, development 99 automated peritoneal dialysis (APD) 1060 autonomic dysfunction, in elderly 178-179 autonomic failure, progressive see Shy-Drager syndrome autonomic nervous system diabetic neuropathy 1012,1013f, 1014,1397 hypoglycaemia features 1019 Lambert-Eaton myaesthenic syndrome 1402 neuropathy and 1392-1393 autophagnosia 1287 autoradiography 58 autosomal dominant inheritance 64, 64f, 65 autosomal genetic diseases dominant 1405 see also myotonic dystrophy recessive 1405 autosomal recessive inheritance 64, 64f autosomal trisomies see trisomy avascular necrosis femoral head 1135 SLE 1174 AV node see atrioventricular (AV) node axonal degeneration diabetic neuropathy 1012 multiple sclerosis 1408

peripheral neuropathy 1012 axonal injury, diffuse 1370 azapropazone 1141ra gout 1170 azathioprine autoimmune diseases 102 autoimmune hepatitis 864 Crohn's disease 812 leukocytoclastic vasculitis 1183 renal transplantation 1061 rheumatoid arthritis 1143 side-effects 102 azithromycin 265-266 Chlamydia trachomatls 304 azlocillin 265 azodisalicylate, Crohn's disease 812 azo dyes 147 azoospermia 942 aztreonam 265

B B7 molecules 84 Babesia divergens 352 Babesia microti 352 babesiosis 352 bacillary angiomatosis 322 Bacille Calmette-Guerin (BCG) 272,646-647 Bacillus anthracis 311-312 see also anthrax Bacillus cereus infection 312 back pain 1386 acute, vertebral fractures in osteoporosis 961cs ankylosing spondylitis 1149 lower back see low back pain lumbar spondylosis 1386 paroxysmal nocturnal haemoglobinuria 1226 bacteria anaerobic 325 antibiotic resistance 264—265, 264t, 307 classification 307t sensitivity to antimicrobial drugs 263, 263t bacterial infections 307-335 infective arthritis 1158-1160 myositis 1406 nervous system 1413-1422,1430 see also meningitis pleural effusion 712 pyrexia of unknown origin 275 skin 384-389 in SLE 1175 see also individual infections bacterial overgrowth 791 diagnostic findings 791f bacterial paracentesis, ascites 872 bacterial permeability-increasing protein (BPI) 1181 bacteriology intracranial abscess 1418 meningitis 1413,1414t bacteriuria asymptomatic 1084 investigation, in elderly 196 Bacteroides fragilis 325 bagassosis 694t Baker's cysts 1157cs, 1197 rheumatoid arthritis 1134 balance in elderly 180-185 changes 180-181

examination 193 maintenance 1317f Balantidium coli infection 342 ballismus 1366,1367 balloon valvuloplasty 533 'bamboo spine' 1148-1149,1149f, 1150 band keratopathy 968 barbiturates abuse 247 head injury 745 overdose management 23-24, 24t barium enema, in elderly 195-196 barium studies achalasia 770f diverticular disease 803, 803f functional bowel disorders 822 gastric adeno-carcinoma 784, 785f gastrointestinal examination ' 754-755 giardiasis 336 intestinal disease 341 oesophageal pathology 763 oesophagus tumours 769, 769f peptic ulcers 779f, 779t schistosomiasis 373 small intestine 755 ulcerative colitis 815f barium swallow, oesophageal candidiasis 447f Barlow's syndrome see mitral valve prolapse barometric pressure disorders 49-51, 49f barotrauma, ventilation complications 740 Barrett's oesophagus 797 Bartonella bacilliformis 321-322 Bartonella henselae 322 Bartonella quintana 322 bartonellosis 321-322 Bartter's syndrome 937,1067,1112 basal cell carcinoma (BCC) 423-424, 424f basal ganglia, lesion 1302,1302f basal metabolic rate (BMR) 108-109,108t obesity 128 variations 108 basement membrane, glomerular see glomerular basement membrane (GBM) basilar artery infarction 1336 basilar migraine 1309 basiliximab (anti-CD25 antibodies) 103 basophilia 1234 basophils 1205 Bazin's disease 388 B cell lymphomas 1256 B cells 80,1205 development and differentiation 81,82 function 81 malignancy 1235-1236,1250f numbers in blood 80 origin 80 regulation by T cells, defective 87 BCG (bacille Calmette-Guerin) 272,646-647 beau's lines 435 Becker muscular dystrophy 1405 bed see ventilation bedbugs 395 bed rest see rest bed sores 428-429,429t bee sting 42 behavioural assessment, psychiatric illness 253

behavioural symptoms, food intolerance 141 Behcet's syndrome 1153 arthritis 1153 neurological features 1431-1432 Beighton score, modified 1124,1124t Bell's palsy 1369 Bence-Jones proteinuria, multiple myeloma 1260 Benedikt's syndrome 1336 benign intracranial hypertension (BHI; pseudotumour cerebri) 1358 benign positional vertigo 1319-1320 benzathine penicillin 265 benzene leukaemia aetiology 1236 poisoning 35 benznidazole, Chagas' disease 355 benzodiazepines 188-189, 749t abuse 246-247 anxiety 216 overdose management 23, 23t side-effects 216t tetanus 313 withdrawal 247t benzoyl peroxide 431 benzyl penicillin 265 anthrax 312 gonococcal arthritis 1159 Neisseria meningitidis 311 bephenium hydroxynaphthoate, hookworm 361 bereavement see grief and bereavement Berger's disease (IgA nephropathy) 1074 beriberi, secondary heart disease 584 berry aneurysm, rupture 1312,1338, 1343 berylliosis 693t, 694 beta-blockers ACE inhibitor coadministration 564ra angina pectoris 548 bradycardia 502 heart failure treatment 496-497 hypertension 598 myocardial infarction 558, 564ra post MI management 568 thyrotoxicosis 921 beta cells see islets of Langerhans bicarbonate kidney 1036 proximal reclamation 1036 renal tubular acidosis diagnosis 1066 biceps, tendinitis 1194 bicipital syndrome 1194 bile acids enterohepatic circulation 837, 837f malabsorption 794 metabolism and secretion 836-837 bile ducts 835 benign stricture 858 cancer 858-859 bile salts accumulation, cholestasis 837 transport 836-837, 837f biliary atresia 881 biliary canaliculi 836 biliary isoenzyme 841 biliary peritonitis, liver biopsy complication 844 biliary system cancer 858-859 disease 835-882 structure and function 835-839

1449

1450

bilirubin formation and metabolism 839, 840f levels amoebic liver abscess 341 liver function and 839-840, 854 in pigmented stones 856 unconjugated 840 uptake/conjugation defects 846 binge eating, bulimia nervosa 242 Binswanger's disease 1337,1351 biochemical investigations musculoskeletal diseases 1127 nutritional assessment 117,117t biological response modifiers, rheumatoid arthritis 1143ra, 1145-1146 biopsy bone 959 bone marrow 277-278 brain 1346 gastrointestinal examination 754 liver see liver biopsy lung open biopsy 630 transbronchial 629, 629f transthoracic needle 629-630 muscle 369,1403f nerve 1393 pleural 713 pyrexia of unknown origin, investigation 276 rectal 813 renal see renal biopsy skin 382 small intestine 754, 790 synovial 1127,1128f temporal artery 1184 villus 76t bipolar manic-depressive psychosis 226 bipyridilium herbicides, poisoning 38 bird fancier's lung 694t birth, trauma, brachial plexus lesions 1399 bishydroxycoumarin see warfarin bisphosphonates hypercalcaemia treatment 970 multiple myeloma 1261 osteoporosis 961, 961cs Paget's disease of bone 977, 977f Bjerrum screen 1291 black hairy tongue 762 blackouts see unconsciousness black sickness, visceral leishmaniasis 358 blackwater fever, malaria 347 bladder anatomical disorders, urinary tract infection 1083 distension, poisoning 17,17t emptying failure, urinary tract infection 1083 examination, in elderly 192 bladder carcinoma radiotherapy 160f schistosomiasis 371 transitional cell 1093,1093f transitional cell carcinoma 1093f bladder dysfunction cervical spinal cord lesion 1377 motor neurone disease 1389 multiple sclerosis 1410 neuropathic 1095 diabetic neuropathy 1014 Guillain-Barre syndrome 1397 retraining 186,186t stones, schistosomiasis 371

tumours, urinary tract infections 1084 blastic phase, chronic myeloid leukaemia (CML) 1240 Blastocystis hominis infection 341 Blastomyces dermatitidis 334 blastomycoses 334 arthritis 1160 bleach, poisoning 37 bleeding disorders see coagulation disorders; specific disorders liver biopsy 844 uraemia 1053 viruses see viral haemorrhagic fevers (VHP) vitamin K deficiency 1274 bleomycin toxicity, iatrogenic lung disease 696 blindness diabetic retinopathy 1009,1010 elderly 193f giant cell arteritis 1184 onchocerciasis 364 see also onchocerciasis trachoma 304 vitamin A deficiency 123 blind spot 1290 blink response 1297 blistering diseases 410-415, 412ra levels of skin effected 410f blisters, poisoning 17t, 18f block-replace regimen, antithyroid drugs 921, 922 blood investigations, poisoning 18 protozoal infections 343-352 in urine 1039 viscosity 1241f musculoskeletal diseases 1125 blood cultures meningitis 1416 pyrexia of unknown origin 277 blood donors 1227 criteria 1227t blood film African trypanosomiases 353 haemostasis disorders 1267 hereditary spherocytosis 1220 malaria 348 pyrexia of unknown origin 277 sickle cell disease 1218 thrombocytopenic purpura 1269 blood gas analysis 1114 see also acidosis; alkalosis; carbon dioxide; oxygen blood glucose see glucose, blood blood grouping, cross-matching and 1228-1229 blood groups 1227-1228 ABO system see ABO blood group rhesus system see Rh blood group blood pressure 589-600 age changes 590f ambulatory BP monitoring 595 control 589-590 renal failure 1057,1059 distribution in western population 591f endothelin 590 hypertension see hypertension measurement 600 neurosympathetic control 589-590 nitric oxide (NO) 590 renin-angiotensin-aldosterone system 589-590 see also hypertension; hypotension blood-testis barrier 940

blood tests liver function, and 839 see also haematology; serology blood transfusion 1227-1232 blood products 230t, 1229-1230 fresh frozen plasma 1148t whole blood 1229,1229t chronic myeloid leukaemia 1239 complications 1230-1232,12311 febrile reactions 1231 infections 1231 ion toxicity 1231 of massive transfusion 1231-1232 serological reactions 1230-1231 siderosis 1231 cross-matching 1228-1229 cytomegalovirus transmission 1231 G6PD deficiency 1222 guidelines 1232 haemolytic disease of the newborn 1233-1234 HIV transmission 1231 human T cell leukaemia virus 1 (HTLV-1) 1231 hypoplastic anaemia 1213 loiasis 368 malaria treatment 351 paroxysmal nocturnal haemoglobinuria 1226 prion contamination 1229 sickle cell disease 1218,1219 P thalassaemia 1216 variceal haemorrhage 873 blood vessels, intracerebral, headache 1312 Bloom's syndrome, leukaemia 1236 'blue bloaters' 662, 664 B lymphocytes see B cells body composition 115-116 in health 132f starvation 132f body image, development of 234-235 body lice (Pediculus humanus) 395 body mass index (BMI) 116 body schema, lesion effects 1305 Bohr shift 1204 boils 387 bone aching, osteoarthritis 1156cs ankylosis 1148 biopsy 959 cells 953-954 collagen 953,958 composition 953-954 hormonal control of metabolism 954-956 deformity, Paget's disease 975, 976, 976f 1,25-dihydroxyvitamin D effect 955 erosions gout 1127 rheumatoid arthritis 1127 formation 953 causes 960t fluoride effect 962 Paget's disease 975 growth 954 mass 959 age relationship 954f increased in osteopetrosis 978 loss see osteoporosis measurement 958-959 pathological changes 959 postmenopausal loss 959, 960 metabolism 954-956

metastases 1191 mineralization 953, 954 defective 962 Pagetic 975,976 pain leukaemia 1244 Paget's disease 976 spinal 1191 remineralization, Paget's disease treatment 977 remodelling 953, 954 resorption 954, 954f causes 960t cytokines effect 956 1,25-dihydroxyvitamin D effect 955 inhibition 962 Paget's disease 975 primary hyperparathyroidism 970-971 sarcoma, risk in Paget's disease 976 scans see bone scans subchondral, osteoarthritis 1154-1155 tumours, skull 1352t bone disease, metabolic 953-978 in chronic renal failure 973 hypophosphatasia 978 investigations 957-959 biochemistry 957-958, 957t histology 959 measurement of bone mass 958-959 radiography 958, 958f management 1191 osteoporosis see osteoporosis Paget's disease see Paget's disease of bone primary hyperparathyroidism 971 bone marrow acute leukaemia 1246,1248 biopsy, pyrexia of unknown origin 277-278 depression, chemotherapy induced 162-163 examination, multiple myeloma 1260 failure leukaemia 1244 myelodysplasia 1249 haemopoiesis 1201 irradiation 48 suppression, methotrexate associated 1142-1143 bone marrow transplantation after irradiation 49 cancer treatment 167 chronic granulomatous disease 1235 chronic myeloid leukaemia 1239 complications 1213-1214 donors 1239 hypoplastic anaemia 1213-1214 immune deficiency with hyper-IgM 89 severe combined immune deficiency 93 sickle cell disease 1219 bone scans 958 musculoskeletal diseases 1128-1129 Paget's disease 976,977f borborygmi, functional bowel disorders 821 borderline personality disorder 210 Bordetella pertussis 317 Bornholm disease 1406 Borrelia burgdorferi 352,1160, 1430

Borrelia recurrentis 329-330 botulinum toxin 314 acetylcholine release 1402 botulism 314,1402 boutonniere deformity 1134,1134f bovine spongiform encephalopathy (BSE) 1351 bowel see entries beginning gastrointestinal; intestine bowel disease/disorders see intestinal disease bowel examination, elderly 192 bowel sounds, absence in poisoning 17,17t Bowen's disease 423, 423f Bowman's space 1033 boxing encephalopathies 1372-1373 see also head injury brachial plexus lesions 1399-1400 brachycephaly, Down syndrome 66 brachytherapy 159t bradycardia 502 acute MI complication 561-562 P-blockers 502 digitalis glycosides overdose 32 poisoning 17,17t sick sinus syndrome 506cs tachycardia-bradycardia syndrome see sick sinus syndrome bradykinesia, basal ganglia lesion 1302 brain atrophy see cerebral atrophy biopsy 1346 lobes 1288f see also specific regions trauma see head injury tumours see cerebral tumours see also entries beginning Cerebral brain death see brainstem, death brainstem alcoholic central pontine myelinolysis 1436t, 1441, 1441f cranial nerve nuclei 1292,1294f see also cranial nerve(s) death 746-747 diagnosis 747t physiological complications 748t

haemorrhage 1338 lesions 1284-1285 coma 1285,1285t multiple sclerosis plaques 1408, 1410 nystagmus 13001 symptoms 1306t syringobulbia 1383 vertigo 1317 reflexes 1284-1285,1296 see also eye movements vertebrobasilar infarction 1336 bramycin 266 BRCA1 149 BRCA2 149 breakbone fever 296 see also dengue fever breakpoint cluster regions (bcr) 1237 breast development 946 males see gynaecomastia testicular feminization 949 hormone action 895t, 907 breast cancer age-specific incidence 146f familial, screening 75t hormone therapy 164-165 hypercalaemia 971 osteoporosis 960

breastfeeding drugs contraindicated 7t prolactin secretion 907 protection against type 1 diabetes 987 reflex arcs associated 907 breast milk formula feeds vs 119 protein content 110 secretion in hyperprolactinaemia 908 breath-hold diving 50-51 breath-holding attacks 1322 breathing, patterns 1285 Cheyne-Stokes breathing 1285 hypoxia 1432 Kussmaul's see acidotic (Kussmaul) breathing purse-lipped, emphysema 663 breathlessness (dyspnoea) 615, 618 bronchial carcinoma 702 cardiovascular system examination 470 chronic, on exertion 616-617cs chronic bronchitis/emphysema drug therapy 665 development time course 618t heart disease 468 history taking 615 New York Heart Association scale 468t psychogenic 615 pulmonary blood vessels abnormalities 610 sudden, pulmonary embolism 676cs, 677cs, 678 breath test C-triolein 759 C-glycocholate 791 hydrogen 757,759 Brill-Zinsser disease 305, 306 brittle bone disease see osteogenesis imperfecta 'brittle' diabetes 992-993 broad-complex tachycardias 514-516 Broca's area 1288f lesion 1286,1288 bromocriptine 1363 acromegaly treatment 905 effect on growth hormone secretion 903, 904 hyperprolactinaemia treatment 908 macroprolactinoma treatment 909 microprolactinoma treatment 908-909 pregnancy and 909 bronchial adenoma 708 bronchial calibre, determinants 607-608 bronchial carcinoma 700-707,700t adenocarcinomas 701, 702t aetiology 701,701f chest infections 702 chest X-ray 703, 703f, 704f, 705f cigarette smoking 700, 701, 701f clinical features 701-703 breathlessness 702 clubbing 703 local disease symptoms 701-702 neurological manifestations 703 common radiological abnormalities 703-704, 704t confirmation 704-705 Cushing's syndrome 703 diagnosis 703-705 extrathoracic metastasis 702 haemoptysis 701 hypercalcaemia 702, 968cs

hypernatraemia 702 intrathoracic infiltration 702, 702f large cell (undifferentiated) 701, 702t mortality 700-701, 701t non-metastatic manifestations 702-703 pathology 701,702t small cell see small-cell lung cancer squamous cell 701, 702t TNM staging system 705 see also lung cancer bronchial hyperreactivity, asthma 653, 653t bronchial obstruction 648 bronchial provocation challenge testing, asthma 653 bronchiectasis 648-649, 649f aetiology 648 allergic bronchopulmonary aspergillosis 648 clinical features 648 congenital factors 648 idiopathic 648 inflammatory factors 648 investigation 648-649 lung function tests 649 management 649 bronchiolar casts (plugs), asthma 654 bronchiolitis 696 obliterative, rheumatoid arthritis 1137 bronchiolitis obliterans, organising pneumonia (BOOP) 696 bronchitis acute 631 chronic see chronic bronchitis bronchoalveolar lavage (BAL) 629 sarcoidosis 688 bronchodilators chronic bronchitis 664 emphysema 664 bronchogenic carcinoma 628, 628f bronchoscopy fibreoptic 627-629, 628f, 629f bronchoalveolar lavage (BAL) 629 bronchogenic carcinoma 628, 628f haemoptysis 628 indications 629t interstitial lung disease 628-629 transbronchial biopsy 629, 629f rigid 629 bronchospasm, poisoning 17t bronzed diabetes 868 Brown-Sequard syndrome 1377, 1377f, 1381 brown tumours 971 Brucella abortus 318 Brucella melitensis 318 Brucella suis 318 brucellosis (undulant fever) 318-319 clinical features 319 diagnosis 319 management 319, 319t Brudzinski's sign 1414 Brugia malayi 366 Brugia timori 366 bruising, disseminated intravascular coagulation (DIC) 1270 bruits, arterial stenosis 1331 Brunner's gland 776 brush border enzyme deficiencies 793 Brushfield spots, Down's syndrome 66

Bruton's agammaglobulinaemia 86-87 Bruton's tyrosine kinase (Btk) 87 BSE (bovine spongiform encephalopathy) 1351 buboes, plague 320 Budd-Chiari syndrome 835,871 Buerger's disease 603 buffers 1113 Henderson-Hasselbach equation 1113-1114 bulimia nervosa 242 treatment 242t bullae, porphyria cutanea tarda 1028 bullectomy, emphysema 668ra bullous diseases, oral involvement 761 bullous drug eruptions 419 bullous impetigo 384 bullous pemphigoid 411-412, 725f bundle branch block acute MI 562 ECG changes 557 electrocardiogram 478, 480f SVT or VT differentiation 514t bunion 1199 bunyaviridae 298, 299t buprenorphine, pancreatitis 830 Burkholderi (Pseudomonas) pseudomallei 321 Burkitt's lymphoma 69,1257 chromosomal abnormalities 1237 Epstein-Barr virus (EBV) 149 tumour growth 150 burning feet syndrome 1398 burns electric shock 53 poisoning 16t bursae, rheumatoid arthritis 1134, 1136 bursitis anserine 1197 infrapatellar 1197 knee joint 1197 olecranon 1136,1195 prepatellar 1136,1197 rheumatoid arthritis 1136 subachilles (retrocalcaneal) 1198 subacromial see subacromial bursitis subcutaneous (postcalcaneal) 1198 trochanteric 1136 Buruli ulcer 328 busulphan, chronic myeloid leukaemia (CML) 1239 butterfly rash, in SLE 1172f, 1174

c Cl-inhibitor concentrate 91 Cl-inhibitor deficiency (Cl-INH) 91,100cs C peptide see C-peptide CA repeats 59 cabergoline macroprolactinoma treatment 909 microprolactinoma treatment 908 pituitary tumours 905 c-abl genes 1237f, 1238 cachexia 122 cancer 152 cardiac see cardiac cachexia cafe au lait macules 421 CAGE questions 249, 249t

1451

1452

CAG sequence repeats 60 Calabar swellings, loiasis 368 calcification, chest X-rays 483 calcification, ectopic 968 calcimimetic drugs 971 calcinosis, dermatomyositis 1180 calcipotriol 399 calcitonin 176,954 actions 956 hypercalcaemia treatment 970 osteoporosis treatment 961 Paget's disease 977-978 salmon 978 calcitriol see 1,25-dihydroxyvitamin D (1,25(OH)2D) calcium absorption 955 reduced in hypoparathyroidism 972 blood levels 957 deficiency osteomalacia 962 secondary hyperparathyroidism due to 973t dietary, osteoporosis treatment 961 dietary intake 176 distribution 953, 954t excretion, decreased in hypercalcaemia 966 free intracellular 953 homeostasis 955,1037 ionized concentration hypocalcaemia 972 normal 953 malabsorption 962 renal damage 1054,1055t measurement and calculation 957 metabolism regulation 955f, 1037 renal and hormonal control 1054f parathyroid hormone synthesis control 955 protein-bound 953 reference nutrient intake 125t supplements, osteoporosis treatment 961,961cs urinary tract stones 1087-1088 diagnosis and treatment 1089 dietary restriction 1090 urine levels 957 see also hypercalcaemia; hypocalcaemia calcium antagonists (calcium channel blockers) acute myocardial infarction 559 angina pectoris 548 functional bowel disorders 823 hypertension 598 incontinence 1096 overdose management 31 calcium carbonate, renal failure 1057 calcium channel blockers see calcium antagonists calcium gluconate, hypocalcaemia management 974 calcium hydroxyapatite crystals, supraspinatus tendinitis 1194 calcium pyrophosphate crystals deposition differential diagnosis 1169cs sites in chondrocalcinosis 1129f in osteoarthritis 1156-1157cs synovial fluid 1127 calcium pyrophosphate dihydrate deposition disease 1171

calculation, mental state examination 1287 calculi, urinary see urinary tract stones calmodulin 886 caloric testing, eye movements 1284, 1296,1300,1318 calyces 1032 CAMPATH-1 antibody 103 Campylobacter 324 Campylobacter infection 324-325 clinical features 324-325 diagnosis and management 325 diarrhoea 279,280 pathogenesis 324 Campylobacter jejuni 324 canal paresis 1318 cancer 145-169 aetiology 146-149 chromosomal abnormalities and 69 clinical features 151-155,153cs due to local disease 152 systemic symptoms 152-154 dietary factors 138-139 genetic influences 148f, 149,150t genetic diagnosis 150ra inherited abnormalities and malignancy 150t genodermatoses 437t incidence and epidemiology 145, 146f various countries 145,147t neurological manifestations 1434_1435 pathology 151 staging and investigation 155-157 scanning 157f tumour growth and development 149-151 tumour lysis syndrome 166-167 see also malignancy/malignant disease; metastases; tumour(s); specific cancers cancer management 157-165 alternative therapy 168-169 new approaches 167 nutritional support 166 pain relief 166 palliative care 168 psychological support 165-166 support and care 165-167 treatment trials 167-168 see also chemotherapy; radiotherapy Candida albicans 391, 446 AIDS-related cerebral abscess 1428 pneumonia in immunocompromised hosts 640 Candida infections 332, 332t HIV infected individuals 332 infective endocarditis 575 candidiasis 391-392, 391f chronic mucocutaneous 92, 891 clinical patterns 392t factors facilitating 391t oesophageal 771 HIV/AIDS infection 446,447f oral 761 HIV infection 444, 444f treatment 392 see also Candida infections cannabis 247 gynaecomastia due to 950 capillaries, fenestrated, in synovium 1119 Caplan's syndrome 693

carbamate insecticides, poisoning 38 carbamazepine 228 epilepsy treatment 1327,1328t overdose management 31 trigeminal neuralgia treatment 1314 carbimazole, thyrotoxicosis 921 carbohydrate(s) 111-112 dietary reference values 112 energy source 112t uraemia 1056 carbohydrate metabolism 981-982 fed/fasting state 839f inherited disorders 1028-1029 galactosaemia 1029 glycogen storage diseases 1028-1029 insulin effects 980,982 liver 838 principle pathways 982f gluconeogenesis see gluconeogenesis glycogenesis see glycogenesis glycogenolysis see glycogenolysis glycolysis see glycolysis see also glucose carbolic acid see phenol carbon dioxide arterial tension (PaCO2) 610 hyper-/hypo-ventilation 610 kidney excretion 1036 Pco2, acid-base disorders 1114, 1114f in red cells 1204 retention, respiratory disease 619 transport 607 ventilation assessment 736-737 carbon disulphide, poisoning 34 carbon monoxide, poisoning 33-34, 54,1432 carboxyhaemoglobin levels, smoke inhalation 54 carbuncle 387 carcinoembryonic antigen (CEA), colorectal carcinoma 802 carcinogens aflatoxins 148 chemical 147-148,148t chemotherapy agents 163 carcinoid syndrome 796-797 carcinoid tumours cardiac see cardiac carcinoid small intestine 796 carcinomas 150 see also adenocarcinomas; individual carcinomas cardiac action potentials 464-465 cardiac amyloid 573 cardiac arrhythmias see arrhythmia cardiac bypass valvular heart disease 533 see also coronary artery bypass graft surgery cardiac cachexia cardiovascular system examination 470 heart failure 491 cardiac carcinoid hypertrophic cardiomyopathy 573 see also cardiac tumours cardiac catheterization 486-487, 727 complications 487, 487t contraindications 488t coronary arteries 546 cardiac cirrhosis 870-871 cardiac compression 518-519 cardiac disease see heart disease

cardiac enzymes acute MI diagnosis 555 see also individual enzymes cardiac failure see heart failure filling pressure and 729f cardiac investigation 476-488 angiography 487 catheterization see cardiac catheterization chest X-rays see chest X-rays colour flow Doppler imaging 484 computed tomography (CT scans) 486 Doppler tissue imaging 484-485 Doppler ultrasound 483-485,485f electrocardiogram (ECG) 476-481 magnetic resonance imaging (MRI) 486 myocardial perfusion imaging 486 nuclear imaging 485-486 nuclear ventriculography 485-486, 487f transoesophageal echocardiography 484, 485f ultrasound techniques 483-485 see also ultrasound cardiac ischaemic pain 467-468 cardiac-mediated cerebrovascular disease 1330,1332t cardiac muscle 543 action potentials 464-465, 465f contraction 463-464 diseases 570-574 see also cardiomyopathies filling pressures 726-728 circumstances for nonagreement 728t pacemaker cells 464 physiology, normal/disordered 463-467 sarcomeres 463, 464f, 465f cardiac output ascites 871 assessment on ICU 728-729 dye dilution technique 728-729 in elderly 175f filling pressures and 729f hypofusion management 730 increased in Paget's disease 976 low, acute renal failure 1047 in sepsis 733 cardiac pacemakers see pacemakers cardiac pacing 520 cardiac prostheses, trauma red blood cells 1225 cardiac tamponade see pericardial tamponade cardiac transplantation see heart transplantation cardiac tumours 581-582, 582t carcinoid 573 myxomas 581-582 see also myxomas cardiogenic shock 493-494, 493t acute MI 563, 564t causes 493 management 493-494 see also pericardial tamponade cardiogenic syncope 1321 cardiolipin 1173 cardiomyopathies 570-574 acute onset of breathlessness/arrhythmia 499-500cs chemotherapy 163 congested see dilated cardiomyopathy diabetic 1015

dilated see dilated cardiomyopathy hypertrophic 571-572, 571ra see also hypertrophic cardiomyopathy myocarditis 570 peripartum 583 restrictive 572-574 see also restrictive cardiomyopathies cardiophrenic angle, X-ray 623 cardiopulmonary resuscitation 517-520 advanced life support 519-520 basic cardiac arrest procedures 518t cardiac pacing 520 closed cardiac compression 518-519 DC defibrillation 519 see also cardioversion drug therapies 519-520 endotracheal intubation 519 head injury 1371 intra-aortic balloon counterpulsation 520 intracardiac injection 520 mouth-to-mouth 518 near drowning 51-53 when to stop 520 cardiorespiratory examination, poisoning 16-17 cardiorespiratory function, comatose patients 1283 cardiothoracic ratio, chest X-ray 481 cardiovascular disease 463-604 acromegaly 904, 905cs, 960 diabetes association 996,1014 diabetic nephropathy and 1012 impaired glucose tolerance 999 risk reduction 997 morbidity/mortality 463, 464f see also heart disease cardiovascular disturbances, poisonous plants 40 cardiovascular drugs overdose management 31-32 see also antiarrhythmic drugs; digoxin cardiovascular reflexes, diabetic neuropathy 1014 cardiovascular system assessment on ICU 725-726 endocrine disorders affecting 890 intensive care unit 725-732 peripheral vascular resistance 725-726 inSLE 1174 uraemia 1053-1054 cardiovascular system examination 469-475 apex beat 472 arterial pulses 470-471 atheromatous peripheral vascular disease 475 auscultation 472-475 see also auscultation, cardiac blood pressure 470 cardiac cachexia 470 chronic lung disease 475 clubbing 469 dyspnoea 470 elderly 192 general examination 469-470 jugular venous pulse see jugular venous pulse Marfan's syndrome 469 parasternal heave 472 in poisoning 16-17

precordium 472 skin features 469-470 thrills 472 thyrotoxicosis 475 tricuspid regurgitation 475 see also cardiac investigation cardioversion atrial fibrillation 511,512 atrial flutter 513 chemically-induced 512 ventricular fibrillation 516, 519 carditis rheumatic fever 1164,1165 steroid therapy and 1165 CA repeats 59 Carey Coombs murmur 581 Caroli's disease 881 Caroli's syndrome 871 caroticocavernous fistula, cavernous sinus thrombosis vs 1420 carotid aneurysms 895 carotid artery external 1330,1331f internal 1330,1331f occlusion (stroke) 1335-1336, 1335f stenosis 1331 magnetic resonance angiogram 1334f TIAs 1331-1332 carotid sinus sensitivity, syncope 1322 carpal tunnel syndrome 1196,1200, 1393-1394 before rheumatoid arthritis 1134 cartilage articular (hyaline) 1119,1120 thinning in osteoarthritis 1154 reimplantation, osteoarthritis treatment 1157ra catabolic metabolism anabolic vs 981 diabetes mellitus 988 diabetic ketoacidosis 1004, 1004f insulin inhibition 980 stress effects 983-984 see also specific pathways cataplexy, narcolepsy 1329 cataracts, diabetic eye disease 1011 CATCH 22 syndrome 92 catecholamines action on myocardium 729 biosynthesis pathway 927, 927f insulin regulation 980 see also adrenaline (epinephrine); dopamine; noradrenaline (norepinephrine) catheterization cardiac see cardiac catheterization head injury 746 poisoning 19 catheters 186 Cat-scratch disease (CSD) 322 cauda equina claudication 1387 compression 1188 ankylosing spondylitis 1150 lesions 1306t, 1385,1387-1388 tumour 1188 causalgia 1392 cavernous sinus 892,1330,1331f thrombosis 1420 C cells see parafollicular cells (C cells) CDS antigen 82 CD4 antigen 83 CD4 cells see T cells, helper (Th) CDS antigen 82

CDS cells (cytotoxic T cells) 82-83 CD18, defective expression 95 CD28 84 CD40 ligand (gp39) see gp39 cefaclor 265 cefotaxime 265 Neisseria meningitidis 311 septicaemia 274 ceftazidime 265 ceftriaxone, Neisseria meningitidis 311 cefuroxime, acute bacterial meningitis 1417 cell division 63,63f cells, oxidase system 1235f cellular immunodeficiency 91-92 cellulitis 386,386f central nervous system (CNS) endocrine disorders effects 890 in ICU 742-747 leukaemia 1244,1248 rheumatoid arthritis 1137 SLE 1175 uraemia 1055 central pontine myelinolysis (CPM) 1436t, 1441,144lf central sleep apnoea 669 mechanism 669f sleep study 669f central venous pressure (CVP), ICU fluid challenge 727, 728f measurements 727, 727t centromeres 61 position 61 cephalgia see headache cephalosporins 265 cerebellar arteries, infarction 1336 cerebellar ataxia(s) 1290,13751376 acquired 1376 malignancy related 1435 adult onset 1376,1376t aetiology 1375,1375t, 1376t Arnold-Chiari malformation 1376 atrophy 1375,1376f cerebral palsy 1374 early-onset hereditary ataxia telangiectasia 1375 Friedreich's ataxia 61t, 1375 late-onset hereditary 1375-1376 multiple sclerosis and 1376,1410 tumours 1352 cerebellar gliomas 1355 cerebellar syndrome, drug-induced 14401 cerebellopontine angle (CPA), tumours 1353,1353f see also acoustic neuroma cerebellum 1302 alcohol-induced degeneration 1436t, 1440-1441 arteries 1336 atrophy 1375,1376f cerebral palsy 1374 function 1375 lesion 1306t motor symptoms 1302,1302f, 1352-1353,1375 multiple sclerosis plaques 1408, 1410 nystagmus 1300t, 1375 see also cerebellar ataxia(s) stroke CT scan 1341 haemorrhage 1338,1360f infarction 1336 structure 1375 tumours 1352-1353,1355 metastases 1356-1357

cerebral abscess aetiology 1418 AIDS-related 1418,1428 meningitis complication 1414, 1417 clinical features 1418 investigation 1418-1419 CT 1418,1418f management 1419 oedema 1418 prognosis 1419 viral encephalitis vs 1423 see also subdural empyema (abscess) cerebral anoxia, parkinsonism 1366 cerebral arteries 1330 anterior cerebral 1336 carotid see carotid artery disease 1330 embolism 1331,1332t, 1342-1343 see also cerebral emboli magnetic resonance imaging 1335f occlusion 1335-1337,1335f reconstructive surgery 1334-1335 stenosis 1331,1334f thrombosis 1312,1331 middle cerebral 1335-1336 posterior cerebral 1336-1337 territories 1331f vertebrobasilar see vertebrobasilar arteries cerebral atrophy alcoholic dementia 1438 Alzheimer's disease 1347,1348f hydrocephalus 1360 cerebral blood flow (CBF) 1330 head injury 732f, 742 cerebral blood vessels arteries see cerebral arteries headache 1312 venous thrombophlebitis 1419, 1419t cerebral circulation 1330,1331f see also cerebral arteries cerebral cortex functional localization 1288f see also specific areas lesion 1287-1289 coma 1285t eye movement 1296 frontal 1287-1288 motor symptoms 1301 occipital 1289,1289f parietal 1288 sensory symptoms 1305-1306 temporal 1288-1289 tumours see cerebral tumours see also cerebral infarction metabolic disturbance 1289 cerebral cysticercosis 376, 377f cerebral dysgenesis 1359 cerebral emboli 1331,1332t, 1342-1343 causes 1331 headache 1312 cerebral haematomas 1370,1370f cerebral haemorrhage 1338 causes 1341t following infarction 1335,1340cs infarct vs 1341 management 1343 see also subarachnoid haemorrhage cerebral hyperaemia, intracranial pressure 743

1453

1454

cerebral infarction 1335-1338,1335f, 1341f acute 1335f management 1342-1343 carotid territory occlusions 1335-1336,1335f, 1339cs see also carotid artery clinical features 1335 differential diagnosis, MND 1389 diffuse small vessel disease 1337, 1337f, 1338f, 1351 haemorrhage after 1335,1340cs haemorrhage vs 1341 hypertensive encephalopathy 1312,1338 hypotensive 1338 inflammatory/autoimmune 1338 lacunar infarcts 1337,1337f, 1337t, 1351 migrainous 1337 multi-infarct dementia 1336, 1350-1351 oedema 1335 SLE and 1430 vertebrobasilar territory occlusions 1336-1337 see also vertebrobasilar arteries watershed 1338 see also cerebral arteries; cerebral cortex cerebral ischaemia 742,1432,1432t stroke see stroke TIA see transient ischaemic attacks (TIAs) see also cerebral infarction cerebral lupus 1430-1431 cerebral malaria 346, 347 viral encephalitis vs 1423 cerebral metabolism, in head injury 742 cerebral oedema diabetic ketoacidosis 1005-1006 following head injury 1370,1371 following infarct 1335 intracranial abscesses 1418 liver failure 854 mountain sickness 50 poisoning complication 20 rapid fluid replacement 1104 tumours and 1355 see also haematoma; intracranial pressure cerebral oxygenation, head injury 746 cerebral palsy 1373-1375 aetiology 1374,1374t classification 1374,1374t definition 1373-1374 incidence 1374 management 1374-1375 cerebral perfusion control, in ICU 745 cerebral toxoplasmosis HIV/AIDS infection 448, 448f treatment 453 cerebral tumours 1351-1358 adult 1355,1356 AIDS-related 1428 cerebellopontine angle (CPA) 1353 childhood 1355,1356 classification 1352t, 1355-1357 see also specific types clinical features 1312,1351-1353, 1354cs differential diagnosis 1357 pseudotumour cerebri 1358 viral encephalitis 1423 grading 1355

hemispheric (cortical) 1352, 1354cs investigation 1353-1354,13571 management 1357-1358 chemotherapy 1358 radiotherapy 1357-1358 surgical 1357 metastatic 1352t, 1356-1357 pituitary 1312,13521,1353.1353f, 1356 posterior fossa 1352-1353 presentation 1357t prognosis 1355,1357 astrocytomas 1357,1358f relative frequencies 1352f ventricular 1355 cerebral ventricles CSF circulation 1358-1359,1359f see also cerebrospinal fluid; hydrocephalus dilation 1359f obstruction 1359,1360f tumours 1355 cerebritis 1418 SLE and 1430 see also cerebral abscess cerebrospinal fluid (CSF) absorption 1359 African trypanosomiases 353 circulation 1358-1359,1359f excess see hydrocephalus infection 1413 see also meningitis investigation Guillain-Barre syndrome 1397 meningitis 1416-1417,1416t, 1420-1421,1422 multiple sclerosis 1411 myelitis 1382 neurosyphilis 1429 poliomyelitis 1426 stroke 1341-1342 subarachnoid haemorrhage 1344 viral encephalitis 1423 see also lumbar puncture leakage (rhinorrhoea; otorrhoea) 1371 meningitis and 1414 malaria 346 Naegleria fowleri 342 obstruction 1359,1360f production 1359 cerebrovascular accident see stroke cerebrovascular disease 1330-1345, 1344ra aetiology 1330-1331,1332t anatomy and physiology autoregulation 1330,1331f cerebral circulation 1330,1331f arterial disease and 1312, 1330-1331 see also atheroma; cerebral arteries; thrombosis arteriovenous malformations 1345,1345f, 1346f cardiac disease and 1330,1332t definitions 1330 epidemiology 1330 haematological disease and 1330, 13321 haemorrhage cerebral see cerebral haemorrhage subarachnoid see subarachnoid haemorrhage infarction see cerebral infarction risk factors 1331,13321 stroke see stroke

TIA see transient ischaemic attacks (TIAs) cervical cancer, genital warts link 456-457 cervical dystonia (spasmodic torticollis) 1367-1368 cervical headache 1310 cervical mucus, normal menstrual cycle 946 cervical myelopathy 1380,1431 cervical rib 1399 cervical spinal cord degenerative disease 1379-1380, 1431 lesion 1377,1379f Guillain-Barre syndrome vs 1397 motor neurone disease vs 1389 multiple sclerosis 1409-1410, 1410f cervical spine, rheumatoid arthritis 1135 cervical spondylosis 1377,1386 cervical subluxation, rheumatoid arthritis 1137 cervicofacial actinomycosis 330 cestodes 375-378 human intestinal infection 375-376 larval infection 376-378 CF gene 650 C-glycocholate breath test 791 Chagas' disease (American trypanosomiases) 354-355, 799 champagne bottle legs 1399 Chandra-Khetarpal syndrome 648 charcoal, activated 20, 22 drugs not adsorbed 20t paracetamol poisoning 28,29 tricyclic antidepressant overdose 25 charcot arthropathy diabetic foot 1017,1018 osteomyelitis vs 1017 Charcot-Bouchard microaneurysms 1338 Charcot-Marie-Tooth disease (HMSN;peroneal muscular atrophy) 1399 Charcot's intermittent biliary fever 858 Charcot's joint 1160 CHD see coronary artery disease Chediak-Higashi syndrome 1235 chemical warfare 54-55 chemonucleolysis 1190 chemotherapy 160-163,161t ABVD 1252 acute myeloid 1245-1246 risk groups 1246 adjuvant 165 carcinogenesis 163 cerebral tumours 1358 CHOP 1256 chronic myeloid leukaemia 1239 colorectal carcinoma 802 combination 161,162t complications 161-163,162t CVP 1256 cyclical combinations 1247-1248 Hodgkin's disease 1252-1253 immunosuppressive action of cytotoxic drugs 102-103 mechanism of action 160-161 MOPP 1252 non-Hodgkin's lymphoma 1256 renal tumours 1091 resistance 1256

sensitive tumours 162 testing a new drug 161 chenodeoxycholic acid 836 chest examination, respiratory disease 620, 621 f chest pain 467-468, 618 angina pectoris 467-468 see also angina pectoris cardiac ischaemic pain 467-468 dissection of ascending aorta 468 see also aortic dissection, acute massive pulmonary embolism 468 myocardial infarction 555 myocarditis 570 oesophageal spasm 468 pericardial pain 468 respiratory disease 618 sharp, stabbing precordial pain 468 chest physiotherapy, emphysema 665 chest wall, movements 621 chest X-rays 623-626 air bronchogram 625, 625f anatomy 481-482, 481f, 623-626 blood vessels 482-483,624-625 cardiac silhouette 624, 626 normal 481f cardiophrenic angle 623 cardiothoracic ratio 481 clavicle/lung apex 625 costophrenic angle 623 diaphragm 623, 626 in elderly 193-194 greater oblique fissure (lung) 626 heart size 481 hilar shadows 624 horizontal (minor) fissure (lung) 624, 626 lateral 626,626f, 626t lung fields 482-483, 625 lymphatics 625 new pulmonary infiltrates 270 normal 481f, 624f oesophageal pathology 763 pleura 625 retrocardiac area 626 retrosternal area 626 ribcage 626 silhouette sign 625, 625f soft tissues 626 specific diseases/conditions amoebic liver abscess 341 aortic regurgitation 529 aortic stenosis 528 bronchial carcinoma 703, 703f, 704f, 705f calcification 483 cancer 155 cardiac disease 481-483 chamber enlargement 481-482 emphysema 663f gastric adeno-carcinoma 784 left heart failure 482f lymphatic filariasis 367 massive pulmonary embolism 682f mitral stenosis 523, 523f Pneumocystis carinii pneumonia 445, 446f pulmonary embolism and infarction 678-679, 680f pulmonary hypertension 675f schistosomiasis 372 subdiaphragmatic angle 623-624 trachea 623,626 vertebral bodies 626 viewing 623-626, 623t behind heart 624

chewing reflex 1304 Cheyne-Stokes breathing 1285 chickenpox see varicella (chickenpox) childhood dystrophy (congenital) 1405 childhood experiences body image 234 depression 221 childhood metabolic diseases, cirrhosis 871 children arthritis 1162-1166 anaphylactoid purpura 1165 differential diagnosis 1162t idiopathic see juvenile idiopathic arthritis rheumatic fever causing 1164-1165 Chagas' disease 354 chronic myeloid leukaemia 1240 dengue haemorrhagic fever 296 diet 119 energy requirements 109 enuresis 1096-1097 growth hormone excess 903 influenza virus infection 290 nematode infection 363 nephrotic syndrome 1063, 1072 nutrient supplements 114 passive smoking, effect 54 pituitary hypofunction effect 897, 898f poisoning 15f threadworms 363 thrombocytopenic purpura 1269 thyroid hormones 913, 913f toxocariasis 369 typhoid 316 whooping cough 318 Wilson's disease 869 Child's classification, cirrhosis 873t chiropody, diabetic foot 1017 Chlamydia 303-305 chlamydial infections 304t Chlamvdia pneumoniae, pneumonia 634 Chlamydia psitlaci 303-304 pneumonia 634 Chlamydia trachomalis 303, 304-305, 457 congenital infection 457 chloral hydrate, overdose management 24 chlorambucil 1255 chloramphenicol 266 actinomycoses 331 acute bacterial meningitis 1417 anthrax 312 melioidosis 321 plague 320 chlorate, poisoning 38 chloride, reference nutrient intake 125t chlorinated aliphatic hydrocarbons, poisoning 35 chlormethiazole 189 overdose management 24 2-Chlorodeoxyadenosine 1258 chloroquine 33 malaria treatment 349. 351 myopathy due to 1136 chlorpromazine 230, 853 chlorpropamine, diabetes insipidus 911 choking 520 cholangiocarcinoma 858 cholangiography, percutaneous transhepatic 842

cholangitis acute 857-858 ascending 858 HIV/AIDS infection 448. 448f liver biopsy complication 844 primary sclerosing 858 cholecalciferol (vitamin D3) 955 cholecystectomy, typhoid 317 cholecystitis acute 857 chronic 858 cholecystography, oral 842 choledochal cyst 881 cholera 322-324 aetiology 322 clinical features 323-324, 324t diagnosis 324 differential diagnosis 324 distribution and incidence 322-323. 323f management 324 pathogenesis 323 prevention and control 324 transmission and epidemiology 323 vaccine 272 cholera toxin 323f cholestasis drug-induced 853 HIV/AIDS infection 447-448 pregnancy 855 tests 841 cholestatic jaundice 856-859, 856t cholesteatoma 1352t, 1356 cholesterol 1021 CHD risk factor 137 in diet 112 gallstones, mixed cholesterol 856 hypercholesterolaemia see hypercholesterolaemia lipoprotein complexes 1015,1022 measurement 1023 see also lipoproteins lowering 141-142 in stroke 200-201 see also statins (HMG-CoA reductase inhibitors) synthesis 1021 transport in bile 837 see also triglycerides cholestipol 1025t cholestyramine see colestyramine cholic acid 836 cholinergic (muscarinic) activity, poisonous plants 40 chondrocalcinosis 1128,1129f, 1157cs clinical features and diagnosis 1171 definition 1171 management 1191 pyrophosphate deposition sites 1129f sites involved 1171 chondroitin, osteoarthritis management 1157 'chondromodulation' concept 1155, 1157ra CHOP chemotherapy 1256 chordomas 1352t, 1356,1381 chorea 1350, 1361,1367,1433 causes 1367t drug-/toxin-induced 1440t choreoathetosis, cerebral palsy 1374 chorionic villus, biopsy 76t choroid, optic fundi abnormalities 1292 Christmas disease 1276t chromatids 61

chromium-51 (51Cr), gastrointestinal examination 755 chromosomal abnormalities balanced rearrangements 66, 67cs cancer and 69 congenital heart disease 535 leukaemia and 1237 nomenclature 62 of number 62 secondary heart disease 584, 584t of structure 62 types 62,63f unbalanced rearrangements 66 see also chromosomal disorders; chromosomal translocations chromosomal analysis, acute myeloid (AML) leukaemia 1244, 1246ra chromosomal disorders 65-69 deletions and duplications 69 frequency 65-66 sex chromosomes 66, 68-69 single genes 69-72 chromosomal translocations 62 acute myeloid leukaemia 1244 chronic myeloid leukaemia 69 Down's syndrome 66, 66t, 67cs leukaemia and 1237 Robertsonian 62 chromosome 22, deletion (22qll) in DiGeorge's syndrome 92 chromosomes 57,61-62 analysis methods 61-62 banding 61 breakage, syndromes 69 crossing-over 63 crossover 63, 65 deletions 62, 69 detection by FISH 62 diploid number 62 duplications 69 gene size relative to 58f insertions 62 inversions 62 nomenclature 61.61f painting 62 recombinant 63 ring 62, 63f staining techniques 61 chronic ambulatory peritoneal dialysis see continuous ambulatory peritoneal dialysis (CAPD) chronic bronchitis 661-668 aetiology 662 'blue bloaters' 662, 664 cigarette smoke 662 clinical features 662-664 coexistence with emphysema 662 cor pulmonale 662-663 diagnosis 661 expiratory airflow limitation 662 forced expiratory volume in 1 second (FEV,) 663, 666f infection 664 management 664-667 acetyl cysteine 664 B2-adrenergic agonists 664 assisted ventilation 665 bronchodilators 664 chest physiotherapy 665 corticosteroids 664 drug therapy for breathlessness 665 non-invasive positive-pressure ventilation 667ra non-invasive ventilation 740 oxygen therapy 664-665

nocturnal hypoxaemia 664-665, 665f peripheral oedema 620 'pink puffers' 662. 664, 665 prevalence 662 pulmonary rehabilitation 665, 666f, 666ra secondary polycythaemia 665 smoking cessation 665-667 social/economic burden 662 chronic daily headache 1311 chronic fatigue syndrome 233, 236ra, 282cs. 283. 1408 antidepressant drugs 283 enterovirus 283 chronic granulomatous disease (CGD) 93-94 chronic hepatitis see hepatitis chronic lung disease, cardiovascular system examination 475 chronic lymphocytic leukaemia (CLL) see leukaemia chronic mucocutaneous candidiasis (CMC) 92.891 chronic myeloid leukaemia (CML) see leukaemia chronic obstructive pulmonary disease (COPD) see chronic bronchitis; emphysema chronic renal failure see renal failure, chronic chronotropic drive, heart pump performance 465 Chrysops flies 368 Churg-Strauss syndrome (allergic granulomatosis) 661,691, 1431 vasculitis 1182 Chvostek's sign 974 chylomicrons 838,1022 chymopapain 1190 ciclosporin/ciclosporin A autoimmune disorders 103 Behcet's syndrome 1153 nephrotoxicity 1143 primary biliary cirrhosis 868 psoriasis treatment 399 rheumatoid arthritis 1143,1145 side-effects 103 therapeutic monitoring 13 cigarette smoking see smoking cilastatin 265 cimetidine, drug interactions 10 ciprafloxacillin 458 ciprofloxacin 266 anthrax 312 Campylobacter jejuni 325 gastroenteritis 281 hypoplastic anaemia 1212 typhoid 317 Circle of Willis 1330, 1331f circulation, fetal 534f circulatory disorders, assessment on ICU 729 circulatory function maintenance, in unconscious/poisoned patient 19 cirrhosis 859-860 alcoholic 861 pancreatitis 830 a-antitrypsin deficiency 870 childhood metabolic diseases 871 classification 860. 860t complications 871-875 ascites 871-872 encephalopathy 874-875, 875t extrahepatic portal vein obstruction 873-874

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factors precipitating 875t variceal haemorrhage 873 see also individual complications congenital hepatic fibrosis 871 cystic fibrosis and 870 definition 859-860 hepatic venous congestion 870-871 presentation and clinical features 860 primary biliary see primary biliary cirrhosis (PBC) secondary biliary cirrhosis 870 citralopine 222 citrate, blood storage 1231 citrate infusion, hypocalcaemia due to 972 CJD (Creutzfeldt-Jakob disease) 1351 CK/CK-MB see creatine kinase clarithromycin 265-266 clasp-knife phenomenon 1303 claudication diabetic foot 1017 see also intermittent claudication claustrophobia 214 claw-hand posture 1395 claw toes 1199 'click-murmur' syndrome 526 clindamycin 266 babesiosis 352 Clinical Trials Certificate (CTC) 14 Clinical Trials Exemption (CTX) 14 clinodactyly, Down's syndrome 66 clobazam 1328t clodronate hypercalcaemia treatment 970 Paget's disease of bone 977 clofazimine, leprosy 328 clomiphene citrate, polycystic ovary syndrome 949 clomipramine 222 clonazepam 1328t clonidine suppression test 929 clonorchiasis 373-374 Clonorchis, lifecycle 374f Clonorchis sinensis 373, 879 clonus 1303 clostridia 313-315 skin infections 314 Clostridium botulinum 314,1402 Clostridium difficile 314-315 Clostridium perfringens 314 Clostridium tetani 313 see also tetanus Clostridium welchii 1406 clotrimazole 267 Cloward procedure 1380 clozapine 230 clubbing (finger/toe) 435, 619, 619f, 619t bronchial carcinoma 703 cardiovascular system examination 469 gastrointestinal disease 751 respiratory disease 619, 619f, 619t cluster headache see migrainous neuralgia (cluster headache) CMV see cytomegalovirus (CMV) c-myc oncogene 1237,1257 coagulation cascade 1265-1266, 1265f inhibitors 1266 acquired 1275 screening studies 1268t coagulation disorders acquired 1274-1275,1275f diabetes complications 1008

factor deficiencies 1276t hereditary 1272-1274 see also individual disorders hypercoagulation states 1279-1281,1281t liver failure 854 see also haemophilia A coagulation studies, liver function tests 840-841 coalminers' pneumoconioses 692-693,693t co-amoxiclav 265 coarctation of aorta 540-541,1343 clinical features 541, 541f definition 540 investigation 541 management 541 prognosis 541 secondary hypertension 594 cobalamin (vitamin B12) 124t coeliac disease 789 deficiency 125 aetiology 1209-1210,1210f anaemia 1209-1210 diagnosis 1210 gastrointestinal disease 751-752 management 1210 neuropathy 1398 pancreatic failure 1210 spinal degeneration 1383-1384 food sources 124t reference nutrient intake 125t role in the body 124t terminal ileal function assessment 759 cocaine abuse 247 overdose 30-31 Coccidioides immitis 334 coccidioidomycosis 334 cochlear nerve 1298 cochlear nucleus, deafness 1298 codeine, pancreatitis 830 codeine phosphate, Campylobacter jejuni 325 'codfish' vertebra 959, 960f codons 57 coeliac disease 787-790, 788ra aetiology 788 clinical features 788-789,789t food intolerance 140 gastrointestinal peptides 757 genetic markers 73t investigations 789-790 malignancy risk 790 management 790 small bowel histology 790f coeliac sprue see coeliac disease cognitive-behavioural psychotherapy (CBT) 215-216 depression 221-222 cognitive function following head injury 1373 frontal lobe lesion 1288 mental state examination 211-212,1286-1287 cogwheeling 1303 basal ganglia lesion 1302 coital cephalgia 1312 colchicine Behcet's syndrome 1153 gout 1167,1170 mechanism of action 1167 cold autoimmune haemolytic anaemia 1223,1224 cold haemagglutinin disease (CHAD) 1223 colds, common 281, 631 cold sore (herpes labialis) 287, 761

colestyramine 1025t hyperlipidaemia management 1024-1025,1025t primary biliary cirrhosis (PBC) 868 colitis amoebic 879 collagenous 816-817 Crohn's disease 812 infective 815-816 ischaemic 817 microscopic 816-817 pseudomembranous 815-816 radiation 817 ulcerative see ulcerative colitis collagen bone 953, 958 deposition in skin, in scleroderma 1177 synthesis, defects 71-72, 71t type I 953 defect in osteogenesis imperfecta 978 type II, osteoarthritis aetiology 1155ra types and functions 71t collagenase, rheumatoid arthritis pathogenesis 1133 collagenous (microscopic) colitis 816-817 collagen vascular disease, acquired, renal involvement 1077 collapsing pulse 471 colloids, sepsis 733 colon cancer age-specific incidence 146f see also colorectal carcinoma cysts of gas 804 motility, disorders 758t neuropathic 799 see also colorectal disease; intestinal disease colonoscopy 753 colorectal carcinoma 802 in elderly 195 schistosomiasis 373 colorectal carcinoma 800-803, 802ra aetiology 801 clinical features 801-802 Crohn's disease 810 investigation 802 management 802-803 colorectal disease 797-804 benign tumours 799-800 familial adenomatous polyposis (polyposis coli) 800 polyps 799-800, 801f, 801t Chagas' disease 798 constipation 797-798 Hirschsprung's disease 798 idiopathic megarectum and colon 798 malignant tumours 803 see also specific diseases colour vision 1290 coma alcoholic 1435-1438 brainstem lesions 1285,1285t endocrine disorders causing 890 examination 1283-1286 Glasgow Coma Scale 1283,1285t, 1371 hypothyroidism 890, 918, 918t metabolic causes 1285-1286,1432 diabetic see diabetes mellitus, coma myxoedema 918, 918t

neurological causes 1283, 1285-1286,1285t pituitary hypofunction 897, 899 pupillary responses 1284 comedones 431 Committee on Safety of Medicines 6,13 common bile duct stones 857 common cold 281, 631 common variable immune deficiency (CVID) 87-88, 90-91cs community-acquired pneumonia 632-634, 632t Community Care Act of 1990 202-203 compensation neurosis, low back pain 1191 complement system 80 activation by IgG and IgM 81 pathways 80, 80f by rheumatoid factors 1132 type II hypersensitivity 96 uncontrolled in hereditary angioedema 91 C2 deficiency 89,1173 lupus 1127 C3 deficiency 89 measurement in Cl-inhibitor deficiency 91, l0lcs reduced levels in lupus nephritis 1127 C4 lOlcs measurement in Cl-inhibitor deficiency 91 reduced levels in lupus nephritis 1127 deficiencies 89-91 lupus 1127 specific components 89-90 serum levels musculoskeletal diseases 1126-1127 SLE 1126-1127,1173 complete remission (CR), Hodgkin's disease (HD) 1253 complex partial seizures 1323t, 1326 computed tomography (CT) abdomen 832f adrenal disorders 929, 930f benign intracranial hypertension and 1358 bone mass measurement 959 cancer 155-156 cardiac investigation 486 cerebral abscess 1418,1418f cerebral tumours 1353-1354, 1355f cerebrovascular disease stroke investigation 1337,1337f, 1341 subarachnoid haemorrhage 1344 TIA investigation 1333 Cushing's syndrome 930f dementia investigation 1346, 1348f dysthyroid eye disease 1434f head injury 744t, 1371 hydrocephalus 1359,1359f intracranial abscesses 1418,1418f liver disease 842 low back pain 1187-1188 musculoskeletal diseases 1128 pyrexia of unknown origin 276 renal 1042,1042f renal cysts 1081 respiratory disease 627

spiral, pulmonary embolism and infarction 679 tuberculous meningitis 1420,1421 viral encephalitis 1423 conception, diabetic patients 1002 condoms 455 conduction block, mononeuropathy 1393 condylomata acuminata 457 confusional states acute delirium 1289 lesions causing 1289 dementia see dementia differential diagnosis from dementia in elderly 190, 190t drug-induced 1440t congenital abnormalities diabetic pregnancy risk 1002 multifactorial origin 72-73 recurrence risk 73t prevalence 57 spine 1191 congenital adrenal hyperplasia (CAH) enzyme defects 933f late-onset 951 congenital colonic aganglionosis 799 congenital dystrophy (childhood) 1405 congenital heart disease 463, 533-542 acquired complications 535-536 acyanotic 538-542 aortic stenosis 527 atrial septal defect 538-542 see also atrial septal defect causes 534-535, 534t chromosomal abnormalities 535 coarctation of aorta 540-541 congenitally corrected transposition 537-538 cor triatriatum 542 cyanotic 536-538 dextrocardia 542 DiGeorge's syndrome 92 Down's syndrome 535 Ebstein's anomaly of tricuspid valve 538 Pallet's tetralogy 536-537 fetal circulation 534f genetic counselling 535 incidence/aetiology 533-535 maternal illness/drug effects 535 maternal viral illnesses 535 persistent ductus arteriosus 541-542 relative frequency 534t secundum atrial septal defect 539-540 transposition of the great arteries 537 tricuspid atresia 538 Turner's syndrome (XO) 535 venous return abnormalities 538 ventricular septal defect 540 congenital hepatic fibrosis 871 congenital porphyrias 1028 congenital rubella, type 1 diabetes association 987 congenital syphilis 1430 congestive heart failure 494-495 coning 1284,1292,1353 conjunctivitis haemorrhagic, enterovirus 303 Reiter's syndrome 1152 see also keratoconjunctivitis

connective tissue disorders 71-72, 71t, 1119-1200 antinuclear antibody 1126,1126t autoimmune glomerulonephritis 1071 pyrexia of unknown origin 275 Churg-Strauss syndrome 1431 clinical assessment 1121-1130 drug history 1121,1122t history of presenting complaint 1122 history-taking 1121-1122 physical examination 1122-1124 investigations 1124—1129 see also under musculoskeletal diseases neurological involvement 1430-1431 polyarteritis nodosa 1406,1431 rheumatoid arthritis see rheumatoid arthritis rheumatoid factors 1126 secondary heart disease 584, 584t SLE see systemic lupus erythematosus (SLE) systemic sclerosis (scleroderma) 1431 Wegener's granulomatosis 1406, 1431 see also musculoskeletal diseases Conn's syndrome 600, 937 diabetes and 1000 sodium excess 1108 consciousness 1283 Glasgow Coma Scale 1283,1285t, 1371 loss 1320-1321 coma see coma differential diagnoses 1321 epilepsy see epilepsy head injury 1371 syncope see syncope see also unconsciousness consent, mental health legislation 255 constipation 797-798, 798t aetiology and diagnosis 798 functional bowel disorders 821 management 798, 800f constrictive pericarditis 588-589 aetiology 588 clinical features 589 investigation 589 management 589 pathogenesis 588-589 pericardial knock 589 pleural effusion 711 constructional dyspraxia (apraxia) 1287,1439 contact eczema 101 contigs 65t continuous ambulatory peritoneal dialysis (CAPD) 1059-1060 diabetic patients 1012 continuous positive airway pressure (CPAP) 740,741 sleep apnoea syndromes 670 continuous subcutaneous insulin infusion (CSII) 990, 993 contraceptive pills (oral) cholestasis 855 hirsutism management 951 ovarian failure treatment 948 protection against rheumatoid arthritis 1131 SLE management 1176 contraction, heart muscle 463-464 contractures, Dupuytren's 860,1196

contrast radiology, liver disease investigations 842 controlled mandatory ventilation (CMV) 739-740 conus medullaris 1377 convergence (near vision) reflex 1294-1295 conversion (dissociation) 216 disorders 233 convulsant activity, poisonous plants 40 convulsions 1321 drug-induced 1440t alcohol-induced 1436t, 1438 epileptic 1323,1323t see also epilepsy febrile 1326-1327 hypoxic 1321 meningitis and 1417,1420 poisoning 17, 20 pseudoseizures 1327 rodenticide poisoning 39 SLE and 1430 whooping cough 318 Cooksey-Cawthorne exercises 184 coordination 1303 Copaxone (glatirames acetate) 1412 copper metabolism, Wilson's disease 869f reference nutrient intake 125t coproporphyria, hereditary 1027 cordocentesis 76t cornea, onchocerciasis 364 coronary angiography cardiac investigation 487, 568 coronary artery disease 546 coronary angioplasty 551-552, 552f acute MI 559 indications 551f laser transmyocardial revascularization 554ra newer techniques 551-552 percutaneous transarterial 551-552 restenosis 551-552, 552f coronary arteries 543, 543f blood flow 542-543, 542f coronary artery bypass graft (CABG) surgery 549-552 graft deterioration 549 indications 550t internal mammary arteries (IMA) 549 laser transmyocardial revascularization 554ra surgical technique changes 551 survival advantage 549-551 valvular heart disease 533 coronary artery disease 463, 542-554 acute coronary syndromes 544, 552-554 see also acute coronary syndromes (ACS) angina, differential diagnosis 544-545 see also angina pectoris arterial pressure 542, 543f atheroma 543-546 see also atheroma coronary anatomy 543, 543f coronary angioplasty 551-552 see also coronary angioplasty coronary artery bypass graft surgery 549-552 see also coronary artery bypass graft surgery coronary artery flow 542-543, 542f coronary circulation 542-543 crescendo angina 544

diabetes association 1015 dietary factors 136-138 factors leading to 137f investigation 545-546 lipoproteins and 1023 see also lipoproteins risk tables 1027f unstable angina 544 vasospastic angina 544 see also acute coronary syndromes (ACS); atherosclerosis; myocardial infarction (MI) coronary circulation 542-543 cor pulmonale chronic bronchitis 662-663 peripheral oedema 620 corpus luteum 945f, 946 Corrigan's sign 471 corrosive agents, poisoning management 36-37 cortical venous thrombophlebitis 1419 corticospinal tracts 1376 lesion 1301 corticosteroid(s) immunosuppressant action 102 indications allergic rhinitis 659 asthma 657,658 carditis in rheumatic fever 1165 chronic bronchitis/emphysema 664 dermatomyositis/polymyositis 1180 emphysema 664 giant cell arteritis 1184,1185 juvenile idiopathic arthritis 1164 multiple sclerosis 1411-1412 polymyalgia rheumatica 1184, 1185 rheumatoid arthritis 1143 systemic vasculitis 1181ra thrombocytopenic purpura 1269 tuberculosis 646 tuberculous meningitis 1421 viral encephalitis 1423 intra-articular contraindications 1143 osteoarthritis 1156cs rheumatoid arthritis 1143 osteoporosis due to 962, 963f, 1143 side-effects 102 steroid myopathy 1407 topical 383, 383t adverse effects 383t see also steroids corticosteroid-binding globulin (CBG) 886 corticotrophin-releasing hormone (CRH) 929 petrosal sinus sampling with 929, 936cs cortisol assays 928, 934, 935cs insulin regulation 981 precursors, assays 928 secretion ACTH role 906 circadian variation 894f pulsed 893 synthesis 926 control 926-927 inhibition by oestrogens 926 see also hydrocortisone cortisone acetate, anterior hypopituitarism 900

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cor triatriatum, congenital heart disease 542 Corynebacterium diphtheriae 312-313 pathogenesis 312 see also diphtheria Corynebacterium minutissimum 387 coryza (common cold) 281, 631 cosmetic treatment, hirsutism 951 costophrenic angle 623 co-trimoxazole madura foot 331 melioidosis 321 nocardioses 332 Pneumocystis carinii pneumonia 445 cotton-wool spots, diabetic retinopathy 1009 cough 612t.613f ACE inhibitors 598, 612 dry 612 initiation 612 investigation algorithm 612f cough fractures 618 cough reflex, poisoning 19 cough syncope 1321-1322 Councilman bodies 297 counselling multiple sclerosis 1412 see also genetic counselling countertransference 217 Courvoisier's sign 832 cow's milk consumption 119 protein intolerance 141 COX-1 and COX-2 enzymes 1140, 1157 Coxiella burnetti 307 pneumonia 634 Coxsackie A virus 302 Coxsackie B virus 302 Coxsackie viruses nervous system infection 1422 type 1 diabetes association 987 viral myositis 1406 C-peptide 979, 980f diabetic patients 985, 985t, 990. 1006 hypoglycaemia investigation 1020 crack, abuse 247 crackles, lung 622, 622t cramps, muscle disease 1403 cranial arteritis see giant cell arteritis (GCA) cranial dystonia 1368 cranial irradiation, acute lymphoblastic leukaemia 1247 cranial nerve(s) 1290-1301 eighth (cochlear/vestibular) 1298-1300 anatomy 1298,1299f cochlear division 1298 lesion 1317 see also vertigo vestibular division 1298-1300 see also hearing eleventh (accessory nerve) 1301 Guillain-Barre syndrome 1397 neuropathy 1431 ninth (glossopharyngeal) 1300 oculomotor/trochlear (3rd; 4th) 1292-1297 anatomy 1292-1293,1294f compression/lesion 1284,1297 MS 1410 pupillary reflexes 1293-1295, 1295f, 1296f see also eye movements

olfactory 1290 optic see optic nerve palsies see under palsies seventh (facial) 1297f, 1298 see also facial nerve sixth (abducens nerve) anatomy 1292-1293 palsy 1283-1293 tenth (vagus/laryngeal) 13001301 examination 1301 trigeminal anatomy 1297f, 1313t see trigeminal nerve twelfth (hypoglossal nerve) 1301 see also brainstem craniopharyngioma 942, 947,1352t, 1353,1356 C-reactive protein (CRP) 80 measurement significance 1126 musculoskeletal diseases 1125-1126,1126 creatine kinase 552, 553cs acute MI diagnosis 555, 557, 558t connective tissue disease 1431 elevated, musculoskeletal diseases 1127 muscle disease 1404 creatine phosphokinase (CPK), dermatomyositis/polymyosit is 1180 creatine shuttle 982 creatinine elevation, malaria 349 plasma calculation of GFR 1039-1040 relationship with GRF 1040f crepitus joints 1124 osteoarthritis 1155 tenosynovitis 1195 crescendo-decrescendo heart murmurs 537 cresols (methylphenols), poisoning 37 CREST syndrome 1177,1179, 1179ra cretinism endemic 916 iodine deficiency 127 Creutzfeldt-Jakob disease (CJD) 1351 Crigler-Najjar syndrome 846 Crithidla luciliae 1173 critical care medicine 725-750 critically ill patients calorie requirements 748,748f general care 749 Crohn's disease 804, 806-808cs, 808-813 aetiology 808 arthropathy associated 1153 clinical features 808t, 809 complications 810-811 differential diagnosis 810 investigation 809t, 810 management 811-813 medical 811-812,8121 surgical 812 oral lesions 761 pathology 808-809 physical examination 809 tumour necrosis factor-a 812ra cromoglycate (disodium), asthma 657 croup 631 CRST syndrome 1177,1179,1179ra crusted scabies (Norwegian) 394 cryoglobulinaemia 1262

mixed 1161,1183 cryoglobulinaemic vasculitis 1183 cryoglobulins, leukocytoclastic vasculitis 1183 cryoprecipitate, blood products 1230 cryotherapy 383,393 cryptococcosis (torulosis) 333 Cryptococcus neoformans 333 HIV/AIDS infection 448 HIV-related meningitis 1428 pneumonia, HIV/AIDS infection 446 cryptogenic brachial plexus neuropathy (neuralgic amyotrophy) 1399-1400 cryptogenic fibrosing alveolitis 695, 695f cryptogenic organizing pneumonitis (COP) 696 cryptogenic pulmonary eosinophilia 661, 661f cryptosporidiosis 336, 337-338 AIDS patient 338, 446 clinical features 337-338 diagnosis and management 338 transmission and epidemiology 337 Cryptosporidiutn 337, 446 crystal arthropathy, differential diagnosis 1169cs crystalloid, replacement fluid 731t crystal synovitis 1166-1172 gout see gout CTLA4 84,103 C-triolein breath test 759 cultured specimens, infectious disease 262 cultures blood see blood cultures synovial fluid 1159 urine 1039 Curling's ulcer 777 Cushing's disease see Cushing's syndrome, pituitarydependent Cushing's syndrome 932-937 ACTH-dependent 932, 933t non-pituitary 933 pituitary-dependent see below ACTH-independent 932, 933t aetiology 932-933,9331 alcohol-induced 933, 934 bronchial carcinoma 703 case study 935cs clinical features 933-934, 934f, 9341, 935cs diabetes and 1000 differential diagnosis 933, 935cs incidence 932 investigations 928, 934, 934t CTscan 930f dexamethasone suppression test 928, 929f management 936 mental changes 1434 myopathy and 1407 pituitary-dependent (Cushing's disease) 906,933 case study 935-936cs investigations 928, 929, 935cs psychiatric features 890 secondary hypertension 593 Cushing's ulcer 777 cutaneous larva migrans 361 cutaneous vasculitis 408-409, 409f clinical features 409 multisystem vasculitides 409t cutis laxa 71t, 72 cyanide, poisoning 34, 34t

cyanobacteria 41 cyanosis 469 causes 619-620 cyanotic congenital heart disease 536-538 cyclic acetic acids, overdose management 28 cyclic AMP (cAMP) 885 hormonal actions via 884-885, 884f cyclokapron l0lcs cyclo-oxygenase (COX) enzymes 1140,1157 cyclophilins 103 cyclophosphamide 161,162 autoimmune diseases 102 leukocytoclastic vasculitis 1183 pulse therapy, vasculitis 1182-1183 rheumatoid arthritis 1143 side-effects 102,1143 systemic sclerosis 1179 systemic vasculitis 1181ra Cyclospora cayetanensis 337 cyclosporiasis 337 cyclosporine see ciclosporin/ciclosporin A cyclothorax 713 cyproheptadine, carcinoid syndrome 797 cyproterone acetate hirsutism management 951 prostatic cancer 951 cyst(s) amoebiasis 339 Baker's see Baker's cysts choledochal 881 Entamoeba histolytica 340 epithelioid 422 giardiasis 335 hydatid 377-378, 378f, 879 pilar 422 renal 1081 sebaceous 422 thyroglossal 912 cysteinyl leukotriene receptor antagonists 657 asthma 657 cystic duct 835 cysticercosis 376-377 parasitic myositis 1406 cystic fibrosis 649-651, 827 bronchiectasis 648 CF gene 650 chest physiotherapy 651 clinical consequences 650t clinical features 650 diagnosis 650 gene therapy 651 incidence 649-650 lung transplantation 651 management 650-651 prenatal diagnosis 650 recombinant human DNase 651 screening 75t sweat sodium test 650 cystine, urinary stone formation 1088-1089 treatment 1090 cystinosis 70 cystitis 1084 tuberculosis 1085 cystography, urinary tract 1041-1042 cystourethroscopy 1084 cytochrome b, defects 94 cytochrome P450 enzymes 4 cytokines acute-phase proteins synthesis 1126 effect on bone metabolism 956

multiple sclerosis aetiology 1409 release, sepsis 734 rheumatoid arthritis pathogenesis 1132 sources and functions 85t Thl and Th2 T cell patterns 85 Th2-type in asthma 652 see also individual cytokines cytomegalovirus (CMV) 283, 288-289 acute infection 288 AIDS-related retinitis 1428 blood transfusion transmission 1231 bone marrow transplant 1213-1214 HIV/AIDS infection 446, 447 immunocompromised patient 269 immunosuppressed patients 288-289 liver function 851-852 pneumonia 640 retinitis HIV/A IDS infection 448, 449f treatment 453 transmission 288,1231 cytopathies (mitochondrial myopathies) 1407-1408 cytoreductive therapy, polycythaemia rubra vera (PRV) 1242 cytosine arabinoside 1245 acute lymphoblastic leukaemia 1247 cytotoxic chemotherapy see chemotherapy cytotoxic drugs, immunosuppressive action 102-103 cytotoxic T cells (Tctx) 82-83

D D antigen, rhesus blood group 1228 Da Costa's syndrome 545 dalfoprastin 267 Dandy-Walker syndrome 1360, 1385 dapsone 453 dermatitis herpetiformis 413 leprosy 328 madura foot 331 Darier's disease 436 daunorubicin 1245 dawn phenomenon 992 DC shock see cardioversion DDAVP (desmopressin) 186 antidiuretic hormone deficiency 911 diabetes insipidus 911,1103 D-dimers, pulmonary embolism 679-680 DDT analogue see mitotane deafness conductive 1298 congenital rubella 295 cranial nerve lesion 1298 CPA tumours 1353 see also acoustic neuroma hypothyroidism 917 Meniere's disease 1320 meningitis complication 1414 peripheral lesions 1317 sensorineural 1320 l-deamino-8-D-argine vasopressin see DDAVP (desmopressin) death and dying 257-258, 258

dying patients, communication 258 palliative care in cancer 168 reactions in patient/family 258 decompression sickness 51, 51t decubitus ulcer (pressure sore) 428-429, 429t, 749 deep vein thrombosis (DVT) 604 pulmonary embolism 676cs, 678, 678cs venography 680 DEET (diethyltoluamide) 273 defence mechanisms (psychological) 216-217 defibrillation 519 see also cardioversion deformities, joints see joint(s) degenerative disease, cervical spine 1379-1380,1431 Degos' disease (malignant atrophic papulosis) 409 dehydration assessment 280t cholera 324t elderly 177 gastroenteritis 280 management 280-281 sickle cell disease 1218 dehydroepiandrosterone (DHEA) Addison's disease therapy 932 synthesis 926 delayed-type hypersensitivity 97 delirium acute confusional states 1289 alcoholic 1436t, 1438 dementia vs 1346 delirium tremens 1436t, 1438 delta virus 850-851 chronic 865 coinfection with HBV 851 epidemiology 850 structure 851f see also hepatitis D delusions definition 1287 grandiose 226 of infestation 436 psychosis/neurosis 207 schizophrenia 229 dementia 1345-1351,1349-1350cs, 1350t acute confusional states 1289 aetiology 1346,1347t AIDS-related 448-449,1428 alcoholic 1436t, 1438-1439 Alzheimer's disease see Alzheimer's disease classification 1346 Creutzfeldt-Jakob disease (CJD) 1351 definition 1345 delirium vs 1346 diagnosis 1345-1346 drug-induced 1440t elderly 176-177 investigations 194 general paralysis of the insane 1429 HIV/AIDS infection 448-449, 1428 Huntington's chorea 1350 investigation 1346,1347t, 1348 Lewy body 1348 management 1348 multi-infarct 1336,1350-1351 myxoedema madness 1434 normal pressure hydrocephalus 1350,1360 Pick's disease 1348

prion diseases 1351 demethylchlortetracycline 1102 water excess 1107 demyelinating disease 1392, 1408-1413 Guillain-Barre syndrome see Guillain-Barre syndrome infection and 1422 postviral/postvaccinial encephalomyelitis 1412 MS see multiple sclerosis remyelination and 1392 sphingolipid metabolism disorders 1413,1413t spinal cord deficits 1377 see also polyneuropathy dengue fever 295-297 arthritis and joint symptoms 1161 clinical features 296-297 control 297 distribution and incidence 296 management 297 pathology and pathogenesis 296 transmission and epidemiology 296 dengue haemorrhagic fever (DHF) 296 dengue shock syndrome 296 denial 216 dental caries, dietary factors 139-140 dental malocclusion, acromegaly 904 dental plaque 760 dentato-rubro-pallido luysian atrophy 611 deoxycholic acid 837 deoxycoformycin 1258 deoxyhaemoglobin 1204 deoxypyridinoline, urinary 958, 976 depersonalization 213 depression 218-222, 218t brucellosis 319 causes 220-221,220t chronic fatigue syndrome, and 283 clinical features 219-220 constipation 798 Cushing's syndrome 935cs differential diagnosis 220 endogenous 220 head injury and 1373 management 221-222, 221t multiple sclerosis 1411 neurotic 209,220,2201 psychotic 220 reactive 220 steroid adverse reactions 1430 De Quervain's tenosynovitis 1195-1196 de Quervain's thyroiditis 924 derealisation 213 dermatitis 399-405 allergic contact 400, 401-402cs exfoliative see erythroderma irritant contact 400. 403t perioral 433 photoallergic contact 427 phytophotodermatitis 426-427 poisonous plants 40 see also eczema dermatitis artefacta 239, 436 dermatitis herpetiformis 412-413, 413f in coeliac disease 788 small intestine involvement 790-791 dermatofibromas (histiocytomas) 422 dermatological diseases see skin disease/disorders

dermatological non-disease 436 dermatomes 1305f dermatomyositis 1180,1406 dermis 380-381 blood flow 381 desamino-D-arginine vasopressin see DDAVP (desmopressin) descartian split 235 desensitization, allergic rhinitis 98 desferrioxamine, (3 thalassaemia 1216 desmopressin see DDAVP (desmopressin) detrusor instability 185-186,1096 developmental delay, juvenile hypothyroidism 916 dexamethasone avoidance, anterior hypopituitarism treatment 900 intracranial abscess management 1419 stroke management 1342.1343 tumour management 1357 typhoid 317 water excess 1107 dexamethasone suppression test 220, 928-929, 929f low-dose and high-dose 928, 935cs overnight 928, 935cs dextrocardia 542 DHEA see dehydroepiandrosterone (DHEA) diabetes, bronzed 868 see also haemochromatosis Diabetes Control and Complications Trial (DCCT) chronic complications 1007-1008 microvascular 1008,1008f nephropathy 1012 glycosylated HbA levels 1001 hypoglycaemia fear 990 insulin regimen 990 diabetes insipidus 897, 1067-1068, 1101-1103 causes 911,1101-1102,11021 clinical features 911 CNS features 890 investigation and treatment 911 management 1103 nephrogenic 966 neurogenic 1101-1102 familial 1102 see also antidiuretic hormone diabetes mellitus 984-1021 autoimmunity type 1 diabetes 986-987 type 2 diabetes 996 see also autoantibodies; autoimmune disorders/disease 'brittle' 992-993 care delivery/organization 1001. l00lt, 1003 classification 984-985, 985t coma 1003t diabetic ketoacidosis 1006 hyperosmolar. non-ketogenic 1006-1007 lactic acidosis 1007 complications alcohol and 994, 997 amputation 1015, 1018 amyotrophy 1013.1396 chronic 1007-1018 foot disease see diabetic foot macrovascular see macrovascular disease microvascular 1008,1008f

1459

1460

necrobiosis lipoidica diabeticorum 1018 nephropathy see diabetic nephropathy neurological 1433,14331 neuropathy see diabetic neuropathy ocular 1008-1011,1009f, l0l0t see also retinopathy pathogenesis 1008 renal 1011-1012 smoking and 994, 997,1015 definition 984 diagnosis 984 criteria 984, 984f gestational diabetes 1003 type 1 diabetes 988 type 2 diabetes 995 documentation 992 driving 994 employment 994 environmental factors 987 epidemiology 984 complications 1008,1011 geographical variation 985, 994 gestational diabetes 1003 incidence with age 986f, 994 racial variation 994 seasonal variation 985 type 1 diabetes 985 type 2 diabetes 994 genetic factors insulin gene 984 twin studies 984, 995 type 1 and HLA class II antigens 984 type 2 995 hypertension 1078 impaired glucose tolerance 984, 999 insulin-dependent see diabetes mellitus, type 1 (IDDM) intercurrent events 1001-1003 infections 988,1001,1016 see also diabetic foot ketoacidosis and 1004 pregnancy 1002-1003,1002t surgery 1001-1002,1002t lactic acidosis 1007 malnutrition-related (MRDM) 1000 management anti-obesity drugs 999ra dietary advice 993-994, 993t, 997 education/lifestyle 994, 997, 1015 future treatments 994ra glucose-potassium-insulin (GKI) regimen 1002,1002t glycaemic control, importance 996-999,1002 incretin hormones 999ra insulin sensitizers 999ra insulin treatment see insulin treatment oral hypoglycaemic agents 997-999, 998t surgery guidelines 1001-1002, 1002t targets 997t transplantation 994 type 1 diabetes 988-994, 994ra type 2 diabetes 996, 996f, 999ra maturity onset of the young see maturity onset diabetes of the young (MODY) metabolic emergencies 10031007

ketoacidosis see diabetic ketoacidosis monitoring 1000-1001 errors 1000 glucose blood levels 991,1000 see also hyperglycaemia; hypoglycaemia glycosylated haemoglobin (HbA1) 997,1000-1001 ketone blood levels 1004, l005t key time-points 1000 self-monitoring 1000 urinalysis (glucose/ketones) 1000 non-insulin dependent see diabetes mellitus, type 2 (NIDDM) patient groups 994 prospective studies 987 DCCT trial see Diabetes Control and Complications Trial (DCCT) UKPDS study see United Kingdom Prospective Diabetes Study (UKPDS) renal involvement 1078 renal replacement therapy 1078 secondary 1000 gestational 1003 skin changes 415-416, 416t social/economic burden 984 syndrome X 995,1015,1015f type 1 (IDDM) 985-994 aetiology/pathogenesis 986-987 biochemistry 988 clinical features 988 dawn phenomenon 992 disease associations 986 distinguishing features 985, 985t genetic markers 73t honeymoon period 987, 987f, 990, 992 investigation 988 ketogenesis see diabetic ketoacidosis management see management (above) natural history 987, 987f pathology 985 postpartum thyroiditis risk 925ra prediabetic phase 987 prediction/prevention 987ra presentation 988, 988t prodromal phase 987 WHO classification 984, 985t type 2 (NIDDM) 994-999 aetiology/pathogenesis 994-996, 995f amylin deposits 995 biochemistry 995 clinical features 995-996 decreased insulin secretion 995 dietary factors 138 distinguishing features 985, 985t insulin-resistance 995, 995f management see management (above) MODY see maturity onset diabetes of the young (MODY) obesity and 995 pathology 985 presentation 995-996 progressive nature 996 WHO classification 984, 985t urinary tract infections 1078,1084 water loss 1103

see also insulin diabetic amyotrophy 966cs, 1013, 1396 diabetic cardiomyopathy 1015 diabetic dermopathy 415 diabetic femoral radiculopathy (amyotrophy) 966cs, 1013, 1396 diabetic foot 1016-1018,1016f aetiopathogenesis infection 1016,1017,1018 investigation 1017 ischaemia 1016 neuropathy 1013,1016 see also diabetic neuropathy amputation 1018 clinical features 1016-1017 Charcot arthropathy 1017,1018 claudication 1017 ischaemic ulceration 1016-1017, 1017t neuropathic ulceration 1013, 1016,10171 management 1017-1018 prevention 1018 diabetic glomerulopathy 1078 diabetic ketoacidosis (DKA) 983, 1003-1006,1114,1118 adult respiratory distress syndrome 1006 case study 1007cs cerebral oedema 1005-1006 clinical features 1004 coma 10031,1006 gastric dilation (acute) 1006 investigations/diagnosis 1004, 1005t management 1005-1006,1006t fluid replacement 1005,1006t insulin replacement 1005,1006t post-emergency 1006 potassium requirements 1005, 1006t problems 1005-1006 mortality 1003,1005,1006 pathophysiology 1004,1004f lipolysis 1003,1004 osmotic diuresis 1004 severe acidosis 1005 shock 1005 see also ketogenesis diabetic nephropathy 1011-1012, 1012t falling incidence 1008,1011 investigations/diagnosis 1011 management 1011-1012 end-stage renal failure 1012 hypertension control 1011,1012 macroalbuminuric stage 1011-1012 microalbuminuric stage 1011-1012 pathophysiology 1011 albumin excretion rate 1011 albuminuria 1011,1011f glomerular filtration rate 1011, 1012f retinopathy association 1011 diabetic neuropathy 1012-1014, 1013f, 1016,1396-1397 aetiological factors 1012-1013 amyotrophy 1013,1396 autonomic 1012,1013f, 1014,1397 symptoms/signs 1014,1392 diagnosis/management 1014,1397 entrapment neuropathies in 1396 see also mononeuropathy pathophysiology 1012 polyneuropathy in 1396-1397

see also polyneuropathy somatosensory 1012,1013-1014, 1013f, 1392 diffuse/symmetrical 1013 focal/multifocal 1013 see also diabetic foot diabetic retinopathy see retinopathy diabetogenic drugs 1000 diacerhein, osteoarthritis management 1157 diacylglycerol (DG), hormonal action mediated by 885-886,885f dialysis acute renal failure 1051 indications 1051 chronic renal failure 1059-1060 hyperkalaemia 1112 initiation 1060,1060t limitations 1060 malaria treatment 351 poisoning 22 see also haemodialysis; peritoneal dialysis dialysis dementia 1055 Diamond-Blackfan syndrome 1211 diaphragm chest X-rays 623, 626 respiratory system 718 weakness/paralysis 718-719, 720-721cs, 721 diaphragma sellae 892 defective 895-896 diarrhoea 279cs cholera 323 Crohn's disease 809 drug-induced 795t functional bowel disorders 821 HIV/AIDS infection 446-447, 454cs osmotic 787, 793 brush border enzyme deficiency 793 purgative abuse 793 rapid transit 794 rotavirus 303 secretory 787, 794, 794t small intestine 787t sodium depletion 1108 ulcerative colitis 813 see also gastroenteritis diascopy 381 diastolic blood pressure age changes 590f distribution in western population 591f measurement 600 diastolic heart murmurs 475 diazepam 188 amphetamine overdose 30 organophosphates poisoning 38 plasma drug concentration 3f status epilepticus 1328 DIC see disseminated intravascular coagulation (DIC) DIDMOAD syndrome 911,1000 diet diabetes management 993-994, 993t, 997 composition 993-994 timing 994 total calorie requirement 993 see also obesity high-fibre 798 hyperlipidaemia management 1024,1025 low-fat 1025 modification, obesity 130 requirements 106-107

factors effecting 107t weight-reducing 997 see also food; nutrition dietary fibre 112,798 dietary intake assessment 117-119 groups and populations 118-119 individuals 118 dietary reference values 106-107, 107f, 107t diethylcarbamazine (DEC) lymphatic filariasis 367 onchocerciasis 365 diethyltoluamide see DEET (diethyltoluamide) diffuse alopecia 434 diffuse interstitial lung disease 692-697 pulmonary hypertension 675 DiGeorge's syndrome 92, 92f digitalis glycosides, overdose management 31-32, 32t digitoxin, gynaecomastia due to 950 digoxin atrial fibrillation 511, 512, 512t inotropy 465 therapeutic monitoring 13 digoxin-quinidine interaction 11 dihydrotesterone (DHT) 940 reduced in 5a-reductase deficiency 950 synthesis 886 1,25-dihydroxyvitamin D (1,25(OH)2D) 955 control of parathyroid hormone synthesis 955 deficiency, renal disease 1054, 1055t parathyroid hormone interactions 955 supplements in hypocalcaemia 973, 974 synthesis 955 dilated cardiomyopathy 570-571 causes 570,571t clinical features 570-571 investigation 571 management and prognosis 571 dinitro compounds, poisoning 38 2,3-diphosphoglycerate 1204-1205 glycolytic pathway 1221 production 1205f diphtheria 312-313 clinical features 312-313 diagnosis 313 management and outcome 313 neuropathy 1398 vaccine 312 diphyllobothrium latum 376 Diplococcus pneumoniae, joint infections 1158 diplopia 1295,1410,1434 thyroid disease 919, 920, 920f dipyridamole 1278 antiplatelet therapy 1333 diquat, poisoning 38 directly observed therapy (DOT), tuberculosis 646 discitis 1189cs, 1191 discoid lupus erythematosus 1175 discoid psoriasis 396 disc prolapse, thoracic spinal cord 1380 discs see intervertebral discs Disease Activity Score (DAS), rheumatoid arthritis assessment 1139-1140 disease-modifying antirheumatic drugs (DMARDs) 1141, 1143ra, 1144-1145cs

combinations 1145 disequilibrium syndrome 1432 disinfectants, poisoning 37 dislocation, hip, cerebral palsy 1375 disodium cromoglycate, asthma 657 disseminated intravascular coagulation (DIC) 1270-1271 causes 1271t clinical features 1270-1271 malaria 347 management 1230,1271 pathogenesis 1270f dissociation (conversion) 216 disorders 233 distal interphalangeal joints, psoriatic arthritis 1151,1151f distal tubule (renal) acidosis (type I RTA) 1066 causes and classification 1067t acidosis with hyperkalaemia (type IV RTA) 1067 hydrogen ions 1036-1037 potassium homeostasis 1035-1036 resistance to mineralocorticoid action 1067 sodium reabsorption 1035 disulfiram (Antabuse) 251 diuresis, forced 21-22 diuretics 495-496 ascites 872 benign intracranial hypertension treatment 1358 combination 496 critical care medicine 730 heart failure 495-496 hypertension 598 hyperuricaemia due to 1166 loop see loop diuretics nephrotic syndrome 1063 potassium-sparing see potassiumsparing diuretics thiazide see thiazide diuretics diverticular disease 803, 803f diverticulosis 803, 803f diving, decompression sickness 51, 51t dizziness 1315,1320t aetiology 1319-1320,1319t cardiac causes 1317 ear disease 1318 ototoxic drugs 1317-1318 neurological examination 1318-1319 vertiginous vs non-vertiginous 1317 see also vertigo DNA 57 analysis methods 58-59, 58f antibodies 1175 SLE 1172-1173 mutations see mutations polymorphic markers 59-60 primers, in PCR 59, 59f probes 58 repair defects 93 structure 57 transcription and translation 57, 58f DNA viruses cancer causing 148-149 classification 284t enveloped double-stranded 283-289 enveloped single-stranded 289-290 non-enveloped double-stranded 290 see also specific viruses

dobutamine inotropic therapy 732t right ventricular infarction 565 doctor-patient relationship, psychiatric illness 235t doll's eye movements 18,1284, 1296-1297 doll's head manoeuvre 1296 dominant inheritance 64—65,64f donor lymphocyte infusions (DLI) 1239 L-Dopa see levodopa dopamine Parkinson's disease 1362 right ventricular infarction 564-565 dopamine agonists hyperprolactinaemia treatment 908 microprolactinoma treatment 908 Parkinson's disease management 1363-1364 dopamine hypothesis, schizophrenia 228 dopexamine, inotropic therapy 732t Doppler ultrasound aortic stenosis 528 cardiac investigation 483-485, 485f mitral stenosis 523, 523f TIA investigation 1333 dorsal-column stimulation 1014 dosulepin (dothiepin), overdose 21cs dothiapin 222 Down's syndrome 65, 66, 66f chromosomal types 66, 66t, 67cs congenital heart disease 535 genetic counselling 67cs leukaemia 1236 mosaic 66,66t recurrence risks 68t doxazosin, phaeochromocytoma treatment 938 doxorubicin 162, 876 doxycycline 266,457 brucellosis 319 malaria treatment 350 melioidosis 321 onchocerciasis 365 Q fever 307 typhus 307 dracunculiasis 369 Dracunculus medinensis 369 Dressler's syndrome 556, 566 driving diabetes and 994 epilepsy and 1329 drowning and near drowning 51-53, 52-53cs fresh-water 51,52 mortality 52t resuscitation 51-53 sea-water 51, 52 drug(s) absorption 1-2 drug interactions 9 in elderly 198-199 factors effecting 1-2 prevention in overdoses 20,20t abuse see drug dependence/abuse administration route 2 antimicrobial drugs see antimicrobial drugs buccal administration 2 Clinical Trials Certificate (CTC) 14 Clinical Trials Exemption (CTX) 14 development/regulations 13-15,

13t new drugs 14 distribution 2-3 drug interactions 9-10, l0f in elderly 199 major binding sites 2-3 dose modification, renal disease 1097-1098 excretion 4-5 drug interactions 11 in elderly 199 renal disease 1097 formulation 2 gout association 1121,1122t interactions 7-11 avoidance 11 increased drug effect 8t metabolism and 10-11, l0t, l1t pharmaceutical 7 pharmacodynamic 7, 9 reduction drug effect 8t intramuscular injection 2 intrapulmonary route 2 leukaemia aetiology 1236 metabolism 3-4 drug interactions 10-11, l0t, l1t in elderly 199 genetic factors 4 liver 839 phase 1 3-4 phase 2 4 overdose 15-16 see also drug overdose/poisoning pharmacokinetics see pharmacokinetics prescribing in renal disease see renal disease rectal administration 2 response variability 1-5 screening 247 SLE association 1121,1122t therapeutic monitoring 11-12,12t transdermal administration 2 yellow card system 11 drug dependence/abuse 243-247, 246f intravenous, endocarditis 574 nature and causes 243 prevalence 244t drug eruptions (skin involvement) 416-420, 416t fixed 418,418f investigation and treatment 420 drug history, musculoskeletal diseases 1121,11221 drug-induced disorders acneform eruption 419 alopecia 419 autoimmune haemolytic anaemias 1223 cholestasis 853 diarrhoea 795t eczema 419, 419t erythema multiforme 417 erythema nodosum 418 erythroderma 417 folate deficiency 1211 gout 1121,1122t hallucinations 247 hepatitis 852-853,866 hypertension 594 hypertrichosis 419 jaundice 852-853 liver damage 852-853, 852t lupus 1175 malabsorption 795, 795t nephropathy 1086,1087t nephrotoxicity 1086

1461

neuroleptic malignant syndrome 230

1462

neurological 1440t, 1441 ataxia 1376 cerebellar syndrome 1440t chorea 1440t confusional states 1440t dementia 1440t dyskinesia 1369 encephalopathy 1440t epilepsy 1324 hypotension 1322 myelopathy 1430t myopathy 1407,1430t neuromuscular blockade 1430t neuropathy 1398,14401 ototoxicity 1440t parkinsonism 1362,1369,1440t tremor 1440t see also alcohol photosensitivity 418, 426 purpura 419 SLE and 1121,1122t thrombocytopenia 1269 tubulointerstitial disease 1080 urticaria 417 vasculitis 418 drug overdose/poisoning accidental 15 deliberate 15,15f diagnosis 16-18 clinical examination 16-18 laboratory investigations 18 drug absorption prevention 20, 20t drug elimination enhancement 21-22, 22t homicidal 15-16 management principles 18-23,19t specific drugs 23-33 non-accidental 15 physical signs 16-18,16t, 17t prevention of complications 19-20 support services 22-23, 23f see also specific drugs drunkenness 1436,1436t drusen 1292 dual-chamber pacemakers 504-505 dual-ventricular pacemakers 504-505 dual X-ray absorptiometry (DXA; DEXA), bone mass measurement 959 Duchenne muscular dystrophy (DMD) 1404-1405 clinical features 1404 genetics 1404-1405 ductus arteriosus 295 congenital rubella 295 patent (persistent) 541-542 Duffy blood group antigen 346 Duke's classification, colorectal carcinoma 801,802f 'dumping' 780 Duncan's disease 288 duodenal ulcers 777 duodenitis 782-783 duodenum 835 anatomy and physiology 775-776 pathology clinical features 776, 777t investigations 776-177 Dupuytren's contracture 1196 liver cirrhosis 860 DVT see deep vein thrombosis (DVT) dwarfism hypopituitary 897 Laron 901

dysarthria 1286,1301,1389,1429 dyscalculia 1287 dysdiadochokinesis 1303 dysentery amoebic 339 arthritis after 1151 bacillary (shigella) 279,315-316 dysgerminoma 949 dysgraphia 1286 dyskinesia(s) 1361,1366-1369 ballismus/hemiballismus 1366, 1367 chorea 1350,1361,1366,1367, 13671 drug-induced 1369 dystonia see dystonia facial 1369.13701 myoclonus see myoclonus tardive 1369 tics 1361,1366 tremor see tremor dyslexia 1286 dysmetria 1303 dyspepsia 751 differential diagnosis 821t non-ulcer 783, 783t functional bowel disorders 821 ulcer-like 779f dysphagia 762-763, 764-765cs, 1397 after stroke 201ra causes 762t motor neuron disease 1389, 1390cs oesophagus tumours 769 systemic sclerosis 1178 tenth cranial nerve 1301 dysphasia 1286,1372,1372cs tuberculous meningitis 1420 dysphonia 1286,1389,1390cs dysplastic naevus 424-425 dyspnoea (shortness of breath) see breathlessness (dyspnoea) dyspraxia (apraxia) 1287 Alzheimer's disease 1347-1348 constructional 1287,1439 parietal lobe lesion 1288 dysthyroid eye disease 919-920, 920f, 1433-1434,1434f dystonia 1361,1366,1367-1368 aetiology 1368t cerebral palsy 1374 cervical (spasmodic torticollis) 1367-1368 cranial 1368 management 1368 torsion (dystonia musculorum deformans) 1368 writer's cramp 1368 dystonia musculorum deformans 1368 dystrophia myotonica see myotonic dystrophy dysuria 1046,1046t

E ear in elderly 175 examination, in elderly 192 'glue' (chronic secretory otitis media) 90cs infection, intracranial abscess aetiology 1418 eating, metabolic regulation 983 eating disorders 206t, 239-242

see also anorexia nervosa; bulimia nervosa Ebola virus disease 298, 299-300 Ebstein's anomaly 538 eccrine sweat glands 381 ECG see electrocardiogram (ECG) Echinococcus granulosits 359, 377, 879 lifecycle 377f Echinococcus multilocularis 879 echocardiography 483 hypertension 596 hypertrophic cardiomyopathy 572 M-mode 483, 484f aortic regurgitation 529 aortic stenosis 527-528 mitral regurgitation 526 mitral stenosis 523 myxomas 582 stroke investigation 1342 T1A investigation 1333 transoesophageal 484, 485f Echoviruses 302 eclampsia 592 see also pre-eclampsia ecstasy abuse 247 liver failure 853 malignant hyperpyrexia 46 overdose 30 ecthyma 385 ectopic ACTH syndrome 933, 934 investigations 929, 930f, 935cs management 936 see also ACTH ectopic (extrasystolic) heart beats 501-502, 502f acute MI complications 561 eczema 399-405, 400f, 401-402cs aetiological factors 400 asteatotic 404 atopic 403-404, 403f classification 404 contact 101 discoid 404 drug-induced 419, 419t food intolerance 140 gravitational 405 herpeticum 403 light-induced 400,402 pompholyx 404 seborrhoeic 404, 404f treatment 405 Wiskott-Aldrich syndrome 92-93 see also dermatitis Edinger-Westphal nucleus 1292, 1295 edrophomium (Tensilon) test 1401 Edwards syndrome (trisomy 18) 66-67 eflornithine, African trypanosomiases 353-354 Ehlers-Danlos syndrome 71, 71t, 436-437 range of movement of joints 1124 subarachnoid haemorrhage and 1343 Ehrlich's aldehyde reagent 1027 eighth cranial nerve see cranial nerve(s) Eisenmenger syndrome 540 ejection clicks 474 elbow 1395 painful 1195,11951 elderly adverse drug reactions 199-200, 200f albumin concentration 3

altered reactions to disease 189-191 multiple pathological process 190 unreported illness 190-191 attitudes towards 173 autonomic dysfunction 178-179 bacteriuria investigations 196 balance and falls 180-185 care of 194-195ra cholesterol lowering in stroke 200-201 clinical approach 191-193 assessment 191,191t history 191 physical examination 191-192 community care 202-204, 203f resources 203f constipation 798 dementia 176-177 investigations 194 drug compliance 200 drug metabolism 4 faecal incontinence 187 gastrointestinal lesions, investigation 194-196 homeostasis impairment 177-178 hypercalcaemia 971 hypothermia 46 influenza virus infection 290, 291 investigations 193-196 management/prognosis and 193 overall state of health 193 screening 193-194 megaloblastic anaemia 1209 non-Hodgkin's lymphoma 1254 normal vs pathological decrements 177t osteoporosis 960 paranoia 233 parent support ratio 174f pharmacodynamics 199 pharmacokinetics 198-199 prescribing 197-200 pyogenic abscess 880 rehabilitation 201-202 team 202 retirement 173-174 sexual function 189 sleep and insomnia 187-189 special features of disease 174-178 surgery 197-198cs assessment of fitness 177t, 196-197 thyrotoxicosis 919 management 922 urinary incontinence 185-187, 1097 visual impairment and blindness 193f world population (65 years and over) 174f see also ageing; individual problems electric shock 53-54 electrocardiogram (ECG) 476-481 24-hour ECG (Holter monitor) 500, 501f atrial activity 476-477 bundle branch block 478, 480f coronary artery disease 545 exercise ECG 480-481, 501 hyperkalaemia 1112 hypertension 595,595f lead/electrode positions 476f left anterior hemiblock 478 left axis deviation 478 left bundle branch block 478, 480f

mean frontal plane vector (QRS axis) 478, 479f myocardial infarction see myocardial infarction (MI) normal ECG 476f PR interval 475f, 477 P wave 476-477 QRS complex 477-478 normal 477-478, 478f rate dependent bundle branch block 478 recording 476 right axis deviation 478 right bundle branch block 478, 480f ST segment 478-479 tricyclic antidepressant overdose 26, 26f T wave 479-480 U wave 478f, 480 ventricular activation 477-478 ventricular hypertrophy 478 electroconvulsive therapy (ECT) 222, 222f electroencephalogram (EEG) epilepsy 1327 hepatic encephalopathy 1440 sleep 1329 viral encephalitis 1423 electrolyte disturbances following head injury 745 heart failure 490 see also individual electrolytes electromanometers 726-727 electromyography (EMG), dermatomyositis/polymyosit is 1180 electronystagmography 1318 electrophoresis, DNA 58, 58f elimination diet, food intolerance 141 ELK classification, Wegener's granulomatosis 1182 elliptocytosis, hereditary 1221 embolism air 51 arterial, optic fundi 1291 cerebral see cerebral emboli infective endocarditis 575, 576 pulmonary see pulmonary embolism emergencies cardiopulmonary resuscitation see cardiopulmonary resuscitation detention of patients already in hospital (section 5) 255 endotracheal intubation 519 Heimlich manoeuvre for choking 520 malignant hypertension 599 metabolic, diabetes mellitus 1003-1007 see also diabetic ketoacidosis (DKA) oesophageal perforation/foreign bodies 768 pericardial aspiration 588 pulmonary oedema 492t tension pneumothorax 715 emesis see vomiting emotional response affect 1287 essential tremor 1367 emphysema 661-668 a r antitrypsin deficiency 662 aetiology 662 bullectomy 668ra chest X-ray 663f

cigarette smoke effects 662 clinical features 662-664 coexistence with chronic bronchitis 662 CT scan 663f diagnosis 661-662 expiratory airflow limitation 662 forced expiratory volume in 1 second (FEV,) 663, 666f management 664-667 B2-adrenergic agonists 664 bronchodilators 664 chest physiotherapy 665 corticosteroids 664 drug therapy for breathlessness 665 lung volume reduction surgery 667. 668ra non-invasive positive-pressure ventilation 667ra non-invasive ventilation 740 oxygen therapy 664-665 mediastinal (pneumomediastinum) 51,716 physical signs 663 prevalence 662 pulmonary rehabilitation 665, 666f purse-lipped breathing 663 secondary polycythaemia 665 smoking cessation 665-667 social/economic burden 662 empty sella syndrome 895-896, 899 empyema pleural 713-714 causes 714t chronic 714 clinical features 714, 714f management 714 subdural see subdural empyema (abscess) encephalitis postencephalitic parkinsonism 1364 viral 1423-1425 case study 1424-1425cs clinical features 1423 differential diagnosis 1423 herpes simplex viruses (HSV) 1423,1424-1425cs, 1425f HIV-related 1427-1428 HSV type 1 (HSV-1) 287 investigation 1423 management/prognosis 1423 measles 1423 mumps 292 rabies 1423 subacute sclerosing panencephalitis 1422 varicella (chickenpox) 285 viruses causing 1422,1423 encephalitis lethargica 1364 encephalopathy 853 bovine spongiform (BSE) 1351 boxing 1372-1373 see also head injury clinical features 874-875 drug-induced 1440t alcoholic 1432 see also hepatic encephalopathy factors precipitating 875t hepatic see hepatic encephalopathy hypertensive 1312,1338 hypoxic-ischaemic 1432 management 875 metabolic 1432 viral encephalitis vs 1423 myoclonic 1368 pathophysiology 874

progressive multifocal leukoencephalopathy 1422 signs 854 spongiform (prion diseases) 1351 uraemic 1432 Wernicke's see Wernicke-Korsakoff syndrome endemic syphilis (bejel) 329 endocardial fibroelastosis 573-574 endocarditis ankylosing spondylitis 581 infective see infective endocarditis Libman-Sacks 581 Loffler's 574 mitral regurgitation 524 non-infective 580-581,1174 Reiters disease 581 rheumatic fever 580-581. 580t rheumatic heart disease 580-581 rheumatoid arthritis 581, 1136 endocrine diseases 883-952 aetiology 888-890 autoimmune 889-890 hormone synthesis/action abnormalities 889 primary/secondary hyperfunction 888-889 tertiary hyperfunction 889 tumours 888 classification 888 dysfunction 888 hyper-/hypofunction 888 investigations/function tests 891-892 basal measurements 891-892, 891t dynamic function tests 892, 892f, 928 see also hormones primary vs secondary abnormalities 888 systemic effects 890-891 alimentary system 891 cardiovascular system 890 genitourinary/reproductive systems 891 integumentary system 891 neurological 890,1433-1434 skeletal system 890-891 target organ disease 888 see also hormones endocrine dysfunction 1000 cancer 153-154,1541 diabetes see diabetes mellitus following leukaemia therapy 1248 hypoglycaemia and 1018-1019 multiple endocrine neoplasia syndrome 1018 pituitary tumours 1352t, 1353, 1353f, 1356 secondary hypertension 593 see also specific diseases endocrine tumours 888 familial syndromes 888 endocrinology 883-952 historical aspects 883 endocytosis 1 endolymphatic hydrops 1320 endomyocardial fibrosis 573 B-Endorphin 893 endorphins, role in opiate addiction 243, 245 endoscopic ablation therapy, variceal haemorrhage 873 endoscopic retrograde cholangiopancreatography (ERCP) 826

liver disease investigations 842-843, 843f endoscopic snaring, urinary tract stones 1089 endoscopic ultrasound 843 endoscopy in elderly 194-195 gastrointestinal examination 753-754, 756f, 756ra gastro-oesophageal reflux 765-766 peptic ulcers 779f, 779t small intestine disease 786-787 endothelial cells, inhibitors 1266 endothelin, blood pressure 590 endotoxin, sepsis 734 endotracheal intubation cardiopulmonary resuscitation 519 mechanical ventilation 737 energy 107-110 balance 109 dietary deficiency 110 expenditure 109t occupational/nonoccupational 108t intake, average requirements 109f provision, acute renal failure 1050-1051 resting energy expenditure (REE) 108 total energy expenditure (TEE) 108 factors effecting 108t enoximone, inotropic therapy 731 entacapone 1364 Entamoeba histolytica 338 cysts 340 lung abscess 648 enteral feeding 133-134 enteral removal, drugs 22 enteric fever see typhoid enterobacteria 315-317 Enterobius vermicularis 363 enteropathic arthropathies 1153 enterovirus infection 302-303, 302t chronic fatigue syndrome 283 enthesis 1119, 1192 enthesis-related arthritis, children 1163-1164 entrapment neuropathy in feet 1199 median nerve see carpal tunnel syndrome radial nerve compression 1394f, 1395 rheumatoid arthritis 1134,1137 ulnar nerve compression 13941 1395 enuresis 1046-1047,1096-1097 environment disorders 45-55 enzyme-linked immunosorbent assay (ELISA), rheumatoid factors 1126 enzymes deficiencies, adverse drug reactions 6 gastrointestinal, effect on drug absorption 1 rheumatoid arthritis pathogenesis 1132,1133 see also individual enzymes eosinophil(s), count in strongyloidiasis 1205 eosinophil colony-stimulating factor 1202 eosinophilia 879 Loffler's endocarditis 574 musculoskeletal diseases 1125 pulmonary see pulmonary eosinophilia

1463

1464

schistosomiasis 373 eosinophilic fasciitis 1177 ependymomas 1352t, 1355 radiotherapy 1357 spinal 1381 ephedrine, overdose management 32 epicondylitis, lateral 1195 epidemic hysteria 236 epidemic myositis 1406 epidermal appendages 381 epidermis 379-380 epididymo-orchitis, Q fever 307 epidural abscess 1382 meningitis 1414 epidural injections, low back pain 1190 epigastric pain 776 differential diagnosis 783t epiglottitis 631 epilepsy 1322-1329,1325-1326cs, 1327ra aetiology 1323-1324,13231 arteriovenous malformations 1345 cerebral tumours 1352,1354cs classification 1322-1323 clinical features postictal headache 1312 seizures see seizures (below) sensory phenomena 1326 vertigo 1317 definition 1321 driving and 1329 focal 1323,1323t, 1326 genetics 1323-1324 idiopathic 1323 investigation 1327 management 1327-1328 pharmacological see anticonvulsant drugs principles 1327 during seizure 1324,1326 surgical 1328 partialis continuata 1328 pathophysiology 1323 petit mal (absences) 1323,1324 atypical 1326t photosensitivity 1324 practical advice 1329t pregnancy and 1328 prognosis 1329 pseudoseizures 1327 psychiatric factors 1329 seizures 1324,1326-1327,1326t febrile convulsions 1326-1327 generalized 1323,1323t, 1324, 1326 grand mal (tonic-clonic) 1323t, 1324 infantile spasms 1326t myoclonic attacks 1323t, 1326t partial 1323,1323t, 1326,1328 provoking factors 1324 temporal lobe 1323,1326 warning signs 1324 see also specific types serial epilepsy 1328 social factors 1329 status epilepticus 1328 structural abnormalities 1323, 1324f syncope vs 1321,1322t epilepsy partialis continuata 1328 epinephrine see adrenaline (epinephrine) epiphyseal closure, delayed, gigantism 903 epiphyses, stippling, hypothyroidism 916t

epipodophyllotoxins 161 epithelial cells, kidney 1032 epithelioid cysts 422 Epley manoeuvre 184 Epstein-Barr virus (EBV) 283, 287-288, 287f, 1237 Burkitt's lymphoma and 149,1257 immunodeficiency due to 95 liver function 851 equinovarus deformity, Duchenne muscular dystrophy 1404 equinus deformity 1199 Erb's palsy 1399 erectile dysfunction 256-257 see also impotence ergocalciferol (vitamin D2) 955 ergotamine migraine treatment 1310,1310t migrainous neuralgia (cluster headache) treatment 1315 erysipelas 385-386, 386f erysipeloid 387-388 erysipelothrix insidiosa 387 erythema, poisoning 16t erythema gyratum repens 421 erythema induratum 388 erythema infectiosum 289-290 clinical features 289-290 complications 290 diagnosis and management 290 erythema marginatum 1165,1165f erythema multiforme 407,407f Crohn's disease 809 drug-induced 417 erythema nodosum 407,408f drug-induced 418 sarcoidosis 685-686, 688cs erythema nodosum leprosum (ENL) 327, 328 erythrasma 387 erythroblastosis fetalis 1233 erythrocytes see red blood cells (erythrocytes) erythrocyte sedimentation rate (ESR) ankylosing spondylitis 1150 giant cell arteritis 1184 as indicator of inflammation 1125 musculoskeletal diseases 1125 myocardial infarction 558 polymyalgia rheumatica 1125, 1184 Reiter's syndrome 1152 rheumatoid arthritis 1125 erythrocytosis, idiopathic 1242 erythroderma 409-410 causes 410t drug-induced 417 erythrodermic psoriasis 396 erythromycin 265, 457 actinomycoses 331 Campylobacter jejuni 325 post-splenectomy 96 erythropoiesis suppression, renal failure 1226 see also haemopoiesis erythropoietic protoporphyria 1028 erythropoietin 1202 Escherichia coli 260, 315 Escherichia coli 0:157 278 ESR see erythrocyte sedimentation rate (ESR) essential myoclonus 1368 essential thrombocythaemia (ET) 1243,12431 diagnosis 1243 management 1243 essential tremor 1367

estimated average requirements (EAR) 107 etanercept, rheumatoid arthritis treatment 1146 ethanol see alcohol ethosuximide, epilepsy treatment 1327,1328t ethylene glycol, poisoning 36 European Medicines Evaluation Agency (EMEA) 13 euvolaemia 1050 evoked potential, multiple sclerosis (MS) 1411 examination see physical examination; individual diseases and anatomy excitotoxicity, motor neuron disease pathogenesis 1389 exercise anorexia nervosa 241 chronic fatigue syndrome 283 energy expenditure 109,109t hypertension 597 insulin-induced hypoglycaemia 990-991, 993 low back pain (mechanical) management 1188 osteoporosis prevention 960, 961 rheumatoid arthritis treatment 1139 thrombocytosis 1272 weight management 130 exercise electrocardiography 480-481 coronary artery disease 545 exercise-induced asthma 657 exercise testing, respiratory disease 611 exfoliative dermatitis, secondary heart disease 584 exoerythrocytic schizogony (ES) 345 exons, alternative splicing 884 exophthalmic ophthalmoplegia 1434 exophthalmos 890 exostoses, dorsal 1199 experimental allergic encephalomyelitis (EAE) 1409 expressed sequence tags (ESTs) 65t expressive (motor) dysphasia 1286, 1372,1372cs extensor plantar responses, poisoning 17,17t external Shockwave lithotripsy (ESWL), urinary tract stones 1089 extracellular fluid (ECF) 1099 ion distribution 1100f osmolality 1034 extradural abscess 1418 extradural haematomas 1370,1370f extraocular muscles 1292-1293, 1295f paralysis 1297 extrapyramidal tract disease 1359-1369 clinical features 1302,1302f, 1359 drug-induced 1369 dyskinesia see dyskinesia(s) parkinsonism see Parkinsonism Parkinson's disease see Parkinson's disease lesions 1302,1302f, 1303,1306t see also basal ganglia extrasystolic heart beats see ectopic (extrasystolic) heart beats extrinsic allergic alveolitis 694-695

eye(s) complications, giant cell arteritis 1184 doll's eye response 18,1284, 1296-1297 in elderly 175 examination, elderly 192 features in thyroid disease 919, 920f rheumatoid arthritis 1138 specific disorders Chlamydia trachomatis 304—305 dysthyroid 1433-1434,1434f keratoconjunctivitis 287 onchocerciasis 364 poisoning 18 eye movements acute fulminant hepatic failure 1439 brainstem 1296 coma 1284-1285 see also brainstem conjugate 1295-1296 cranial nerves 1292-1297,1294f palsies 1297 diplopia 1295 doll's eye 18,1284,1296-1297 examination 1295-1297 extraocular muscles 1292-1293, 1295f, 1297 lesion effects brainstem 1284-1285,1296, 1297 cortical 1296 myasthenia gravis 1400-1401 nystagmus see nystagmus physiology 1296 vestibular 1296-1297,1299 vestibuloocular reflex 1317 eye muscles, thyroid disease 919, 920f

F Fab fragment 81 facial dyskinesia(s) 1369,1370t facial flushing, alcohol-induced 998 facial masking 1362 facial myokymia 1369,1411 facial nerve 1297f, 1298 anatomy 1297f, 1298 palsies 1297,1298 facial pain 1312-1315,1313t, 13151 lesions causing 1313t local structure disease 1313t management 1314,1315 neuralgias 1313t atypical 1315 migrainous 1314-1315 postherpetic (shingles) 1314 trigeminal (tic douloureux) see trigeminal neuralgia psychological 1315 see also headache; trigeminal nerve facies acromegalic 903, 903f DiGeorge's syndrome 92 leonine 328 mitral 469 facioscapulohumeral dystrophy 1405 factitious illness 238-239 Munchausen syndrome 239, 823 pyrexia of unknown origin 275 factorV 1274

deficiency 1276t factor V Leiden 1280 factor Vll 1265 factor Vlll blood products 1230 concentrates 1230 haemophilia A 1273 see also haemophilia A procoagulant activity 1265 factor IX blood products 1230 concentrates 1230 deficiency 1276t factor X 1265 deficiency 1276t factor XI deficiency 1274 factor XII deficiency 1276t factor XIII deficiency 1276t faecal incontinence 804 in elderly 187 faecal loading 187 functional bowel disorders 821 faecal-oral route, infections 278 fainting see syncope Falcipamm malaria see malaria Pallet's tetralogy 536-537 clinical features 536, 537f crescendo-decrescendo murmur 537 investigation 536 prognosis 536-537 surgical treatment 536 falls, in elderly 180-185,182t, 184-185cs history and examination 181-183 management 183-184 prevention 183ra risk factors 181t famciclovir, herpes viruses 268 familial adenomatous polyposis 800 familial combined hyperlipidaemia 1023 familial goitre 924 familial hypercholesterolaemia 1023, 1026 familial hypertriglyceridaemia 1023-1024 familial hypothyroidism 70f, 75t familial polyposis coli, screening 75t family history genetic counselling 74-75 musculoskeletal diseases 1121 psychiatric illness 211,211f Fanconi's anaemia 1211 leukaemia 1236 Fanconi's syndrome 70, 964,1065 Fansidar, malaria treatment 350 farmer's lung 694t Farr assay 1172-1173 Fas antigen 82-83, 99 fasciculation motor neuron disease 1389 neuropathies 1392 twelfth nerve lesion 1301 fasciitis eosinophilic 1177 necrotizing see necrotizing fasciitis plantar 1198 Fasciola hepatica 879 fascioliasis 374—375 fasciolopsiasis 375 Fasciolopsis buski 375 fasting, metabolic regulation 983 fat(s) 112-113 absorption, measurement 759 energy source 113 metabolism 982,1021-1022

free fatty acids (FFA) 982 insulin effects 980,982 principle pathways 982f see also lipogenesis; lipolysis in obesity 130 saturated/monounsaturated/ polyunsaturated, sources 113f see also lipids fatiguability, muscle disease 1403 fatigue, heart disease 469 fatty acids 112 essential 113 free (FFA) 982 B-oxidation 982 fatty acyl-CoA, B-oxidation 982 see also ketogenesis fatty liver of pregnancy, acute 855 favism 1222 favus 391 Fc fragment 81 febrile convulsions 1326-1327,1417 measles 293 febrile enterocolitis, yersinia 319 febrile transfusion reactions 1231 feet see foot Felly's syndrome 1137 neutropenia 1122,1125 females infertility management 948-949 pseudohermaphroditism 950 sex differentiation disorders primary 950 secondary 951 see also women femoral cutaneous nerve entrapment 1199 femoral head, avascular necrosis 1135 femoral stretch test 1187 ferritin levels, haemochromatosis 869 serum levels, musculoskeletal diseases 1125 fertility chemotherapy 1254 diabetic patients 1002 in elderly 171 restoration, anterior hypopituitarism 901 see also infertility fertilization 946 festinant gait 1290 fetal alcohol syndrome 251 fetor hepaticus 874 fetoscopy 76t fetus circulation 534 red cells, haemolytic disease of the newborn 1233 risks to in diabetic patients 1002, 10021,1003 sex differentiation 939-940 thyroid hormones 913, 913f fever(s) cancer 152 enterovirus infections 302 imported 276t, 277t infective arthritis 1158-1159 intracranial abscesses 1418 musculoskeletal diseases 1122 myocardial infarction 556 pattern, diagnostic aid 261 systemic juvenile idiopathic arthritis 1162-1163 fever of unknown origin see pyrexia of unknown origin FFP see fresh frozen plasma (FFP) fibrates 1025,10251

fibre, dietary 112,798 fibrin degradation products (FDPs) 1271 fibrinogen 1266 freeze-dried 1230 fibrinoid necrosis 1182 fibrinolysis 1275 fibrinolytic system 1266-1267,1266f fibrinolytic therapy 1279,1343 indications 1279t oral 1279 see also thrombolytic agents fibrocalculous pancreatic diabetes 1000 fibrocartilage, calcium pyrophosphate deposition 1171 fibrolamellar carcinoma 876 fibromyalgia syndrome 1194-1195 prevalence 1194 treatment 1195 fibrosing alveolitis, rheumatoid arthritis 1137 fifth disease see erythema infectiosum filarial dance sign 367 filarial lymphangitis 367-368 filariasis 364-368 loiasis 368 lymphatic filariasis see lymphatic filariasis onchocerciasis see onchocerciasis filoviridae 298, 299t finasteride benign prostatic hyperplasia 950 hirsutism management 951 fine needle aspiration, thyroid disease 915 fingernails see nails finger-nose test 1303 fingers clubbing see clubbing (finger/toe) deformities osteoarthritis 1155,1155f rheumatoid arthritis 1134,1134f 'trigger' 1195 Finkelstein's sign 1196 first aid, cardiopulmonary resuscitation 517-520 fish envenomation 42 fish oils 1025,10251 fish-tank granuloma 388-389, 389f fissure tongue 762 fistula arteriovenous 584 caroticocavernous 1420 fits see convulsions FK506 (tacrolimus) 103,1061 flail chest 722 flat feet 1199 flaviviruses 295-298 flavonoids, antioxidant properties 114-115 fleas 395 flexion deformity 1124f arthritis 1120 rheumatoid arthritis 1134 flexor tendons, systemic juvenile idiopathic arthritis 1163 flexor tendon sheaths, rheumatoid arthritis 1134 flexural psoriasis 396 floppy mitral valve (Barlow's syndrome) see mitral valve prolapse flucloxacillin 265 septicaemia 274 fluconazole 267 Candida 332

flucytosine 267 9a-Fludrocortisone 1067 fluid(s) deprivation tests 891,911 intake acute renal failure, management 1050 increase in UTI 1084-1085 restriction, renal failure 1057 replacement 730 choice of fluid 730, 731t diabetic ketoacidosis 1005, 1006t hyperosmolar (non-ketogenic) coma 1006-1007 intravenous saline 1104 oral 1103 overload 730 sepsis 733 see also oral rehydration solution (ORS) restriction, inappropriate secretion of ADH 912 see also water flunitrazepam, overdose management 23 fluorescein angiography, diabetic retinopathy 1009,1009f, 1010 fluorescent in situ hybridization (FISH) 61-62, 62f fluoride bone formation in osteoporosis 962 deficiency 126 role in dental caries 139 fluoride salts, poisoning 39 4-Fluoroquinolones 266 fluorosis, endemic 962 fluoxetine 222 flupenthixol 230 flushing, alcohol-induced, sulphonylurea side effect 998 flutamide, prostatic cancer 951 fluvoxamine 222 foamy macrophages 326 focal epilepsy 1323,1323t, 1326 focal myoclonus 1368 focal segmental glomerulonephritis 1073 folate/folic acid deficiency 125 aetiology 1211,1211f anaemia 1210-1211 coeliac disease 789 drug-induced 1211 gastrointestinal disease 751 macrocytosis 1125 malnutrition in children 121 management 1211 food sources 124t reference nutrient intake 125t role in the body 124t follicle-stimulating hormone (FSH) 895 actions, on testis and ovary 940t changes during puberty in girls 945 elevation 943t pre-menopausal 946 puberty 940 reduced levels 943t secretion 895,940 synthesis, stimuli and inhibitors 893t tumours secreting 909 follicular infections 387 follicular lymphomas 1255

1465

1466

food 105-115 allergy 98-99,140-141 allergens 98 management 141 botulism and 1402 challenges, double-blind placebo controlled (DBPCFC) 98 choice and composition 105-106 drug absorption effect 2 glycaemic index 993-994 influences on food choice 106t intolerance 98,140-141,140t sensitivity, migraine 1309 see also diet; nutrition food poisoning 278 see also gastroenteritis foot claw 1199 diabetic see diabetic foot entrapment syndromes 1199 in examination of elderly 192 flat 1199 painful 1199,11991 rheumatoid arthritis 1135 spasmodic flat 1199 footwear, osteoarthritis 1158 forced expiratory volume in 1 second (FEV1) 608, 608f, 611,617cs airflow limitation and smoking 666f in COPD 663 foreign bodies oesophagus 768 surgical, Staphylococcus aureus 309, 310 urinary tract infections 1084 formic acid, poisoning 37 Fournier's gangrene, anaerobic bacteria 325 fourth cranial nerve see cranial nerve(s) fractures cough 618 Paget's disease 975 pathological 959 skull 1371 vertebrae 959, 960f, 961cs, 1189cs wrist, carpal tunnel syndrome 1393 fragile X syndrome 611 premutation carriers 60-61 fragilitas ossium see osteogenesis imperfecta Francisella tularensis 321 Frank-Starling curve, heart pump performance 465 free fatty acids (FFA), fat metabolism 982 Frenzel's glasses 1318 fresh frozen plasma (FFP) 731t, 1229-1230,12301 liver disease 1275 Friedreich's ataxia 61t, 1375 frontal lobe 1288f lesion 1287-1288,1290 conjugate eye movements 1296 frozen shoulder 1194 fructose, in alcohol poisoning 35 frusemide see furosemide fugue states 236 functional (idiopathic) disorders, hypoglycaemia 1019,1021 fundoscopy coma examination 1283-1284 diabetic retinopathy 1010 multiple sclerosis 1409 optic nerve examination 1291-1292

fungal infections AIDS-related 1428 allergic bronchopulmonary mycoses 660 arthritis 1160 aspergilloma formation 614-615cs infective endocarditis 575, 576 nervous system 1430 AIDS-related 1428 meningitis 1421 pyrexia of unknown origin 275 skin 389-393 systemic 332-335 fungi, poisonous, ingestion 39-41 fungicides, poisoning 38-39 furosemide (frusemide), hypercalcaemia treatment 968cs, 970 furuncles (boils) 387

G G6PD see glucose-6-phosphate dehydrogenase deficiency GABA inhibitory receptor, encephalopathy 874 gabapentin, epilepsy treatment 1327ra, 1328,13281 gag reflex 1300 alcohol poisoning 35 dysphagia 762-763 gait Alzheimer's disease 1348 apraxic 1290 ataxic 1290 cerebellar tumours 1352 examination 1124 in elderly 193 hemiplegic 1290 limping 1290 neurological diagnosis 1289-1290 parkinsonian 1290 spastic 1290 steppage 1290 tandem 1289 waddling 1290 galactorrhoea 908 acromegaly 904 macroprolactinoma 909 galactosaemia 1029 gallbladder 835 cancer 858-859, 859f inflammation see cholecystitis Gallium scanning Hodgkin's disease 1251 hydatid cysts 378 infectious diseases 262 pyrexia of unknown origin 276 gallop (triple) rhythm 474 gallstones clinical features 857 Crohn's disease 809 dietary factors 139 epidemiology 856-857, 857f formation 837 hereditary spherocytosis 1220 mixed cholesterol 856 pancreatitis 828,830 pigmented 856 y-globulin, level, multiple myeloma 1260 Gamma hydroxybutyric acid (GHB), overdose 31 gamma knife, pituitary tumours 901

ganciclovir cytomegalovirus 268, 289 mechanism of action 269f ganglia 1196 ganglioneuroma 1352t, 1356 gangliosidoses 711 gangosa 329 gangrene 603 diabetes 1001,1016,1016f, 1017 Fournier's 325 gas 314 peripheral vascular disease 603 progressive bacterial synergistic 386-387 streptococcal 386 Gardner's syndrome 800 gas diffusion, respiratory 606-607. 606f abnormalities 609 diffusion capacity 606-607 gases, overdose management 33-35 gas gangrene 314 gastric acid reduction, bacterial overgrowth 791 regurgitation 762 secretion 776 studies 758 gastric aspiration, near-drowning 51 gastric bypass, Roux-en-Y 132 gastric cancer 147f adeno-carcinoma 783-785 aetiology and pathology 783-784 clinical features 784 following gastrectomy 781 incidence and mortality 784f investigation 784 management 785 B cell lymphoma 785 gastric dilation, acute, diabetic ketoacidosis 1006 gastric emptying 757 gastric lavage barbiturates overdose 24 drug overdose/poisoning 20 lithium carbonate overdose 27 gastric leiomyomas 785 gastric polyps 785 gastric surgery, complications 780-781 gastric ulcers see peptic ulcers gastrin 755 gastrinoma 781-782 gastritis 782 gastroenteritis 278-281, 279cs aetiology 278, 278t antibiotics 281 clinical features 279-280 diagnosis 280 epidemiology 278 management 280-281 pathogenesis 278-279 mucosal damage 279 toxin secretion 278-279 see also diarrhoea gastrointestinal bleeding 772-775, 773-774cs acute 772,774 aetiology 772 clinical features 772, 774 investigation 774 management 774 anti-inflammatory drugs causing 1140 causes 775t chronic 774-775 aetiology 774, 776t clinical features 774

investigation 774-775 management 775 drug overdose/poisoning complication 20 Mallory-Weiss tear 772 management 775t mortality 772f NSAIDs associated 1137 peptic ulcer complication 778 polycythaemia rubra vera 1241 rheumatoid arthritis 1137 thrombocytopenic purpura 1269 uraemia 1055 gastrointestinal complications HIV/AIDS infection 446-447 treatment 453 poisonous plants 40 gastrointestinal disease 751-834 clinical features 751,753t haematological abnormalities 754t hypoglycaemia and 1019 investigations 751-759 see also gastrointestinal examination secretion syndromes 759t signs 753t see also intestinal disease gastrointestinal enzymes, effect on drug absorption 1 gastrointestinal examination 751-759 barium studies 754-755 biopsy 754 endoscopy 753-754 function tests gastric acid studies 758 intestinal digestion and secretion 758-759 motility 757 secretion 757-758, 758f haematological and biochemical 751-753, 754t imaging techniques 755 gastrointestinal haemorrhage see gastrointestinal bleeding gastrointestinal infection anthrax 312 Chagas' disease 354 clostridia 314 protozoal infections 335-342, 343 travel health 273 see also gastroenteritis gastrointestinal lesions, investigation, in elderly 194-196 gastrointestinal motility diabetic neuropathy 1014 disorders 758t drug absorption 2, 9 functional bowel disorders 818 tests of function 757 see also small intestine gastrointestinal regulatory peptides 755-757, 757t gastrointestinal symptoms Crohn's disease 809 food intolerance 140-141 metformin 998 migraine 1307 pain, functional bowel disorders 821 gastrointestinal system rheumatoid arthritis 1137 systemic sclerosis 1178 uraemia 1055 gastrointestinal toxicity, poisonous plants 40 gastrointestinal ulceration 777-781 rheumatoid arthritis 1137

gastro-oesophageal reflux 763, 765-766 aetiology 763, 765 clinical features 765 factors predisposing 763t investigations 765-766 non-oesophageal manifestations 763t spectrum of disease 763t treatment 766t gastroplication 132 gastrostomy, motor neuron disease management 1390 Gaucher's disease 1029 Gaviscon, reflux oesophagitis 766 gay bowel syndrome 817 G-CSF (granulocyte colonystimulating factor) 1202. 1203,1204t Gell and Coombs classification 96, 96t •gene chips' 60 generalized seizures 1323, 1323t, 1324,1326 general paralysis of the insane 1429 genes analysis methods 58-59, 58f assignment 65 candidate 65t expression 65 loci, alleles and segregation 63-64, 64f maps and linkage 65 mutations 60-61, 60t number in humans 65t size relative to chromosome 58f gene therapy 74ra cystic fibrosis 651 vectors 74ra genetic anticipation 60 genetic basis of disease 57-77 disorders see genetic disorders DNA, genes and chromosomes 57-58 DNA analysis 58-59, 58f dominant and recessive inheritance 64-65, 64f genetic markers for diseases 73t human genome 65ra linkage disequilibrium and pleiotropy 73-74 loci, alleles and segregation 63-65 mutations see mutations polymorphic markers 59-60 single gene mutations 60-61, 60t X-linked inheritance 64f, 65f see also chromosomes; genes: genetic factors; genetics genetic code 57 genetic counselling 74-76 ankylosing spondylitis 1150 congenital heart disease 535 Down's syndrome 67cs Duchenne muscular dystrophy 1404-1405 Huntington's chorea 1350 risk assessment 75 steps/procedure 74-76 genetic disorders chromosomal see chromosomal disorders cystic fibrosis 649-651 frequencies in UK 57f hypertrophic cardiomyopathy 571ra management 74—76 multifactorial 72-74 diseases and genetic markers 73-74, 73t

polygenic 72 screening 74, 75t single gene (inborn errors) 69-72 aminoacidopathies 69-71 connective tissue disorders 71-72, 71t storage disorders 71,71t transport disorders 70t, 71 treatment 76t treatment 74, 76t genetic factors ageing 173 Crohn's disease 809 depression 221 drug metabolism 4 haematological malignancy 1237, 1237f malignancy 150t osteoarthritis 1155ra psychiatric illness 210 rheumatoid arthritis 1131 see also genetic basis of disease; genetics genetic maps 65t physical 65t genetic recombination, antibody genes 82 genetics Creutzfeldt-Jakob disease (CJD) 1351 diabetes mellitus 984, 995, 996 dystrophia myotonica 1405 epilepsy 1323-1324 Huntington's chorea 1350 lipids 1023 multiple sclerosis aetiology 1409 muscle diseases 1404-1405 see also autosomal genetic diseases: genetic factors; Xlinked diseases geniculate herpes zoster (RamsayHunt syndrome) 1320, 1320t genital herpes infection 456, 456f primary infection 456 recurrence 456 genitalia ambiguous 941 21-hydroxylase deficiency 932 external, development 940 testicular feminization 949 genital ulcers Behcet's syndrome 1153 increased risk of HIV 453-454 genital warts 393. 456-457, 457f genitourinary system, endocrine disorders affecting 891 genodermatoses 436-437 gentamicin 266 acute bacterial meningitis 1417 brucellosis 319 nephrotoxicity 1086 septicaemia 274 geographic tongue 762 geriatrics see ageing; elderly German measles see rubella (German measles) germ cells ovaries 945 Sertoli cells around 940, 941 gestational diabetes 1003 GH see growth hormone GHRH see growth hormonereleasing hormone (GHRH) giant cell arteritis (GCA) 602, 1183-1185,1312 aetiology and pathology 1184 clinical features 1184

investigations and diagnosis 1184-1185 management 1182-1183,1185 prevalence 1183 prognosis 1185 Giardia 337t Giardia lamblia 335, 336f giardiasis 280, 335-337, 792 aetiology 335 clinical features 336 diagnosis 336 differential diagnosis 336 distribution and incidence 335 laboratory features 336-337 management 337, 337t pathology and pathogenesis 335-336 prevention and control 337 Gi coupling protein 884 Giemsa banding 61 acute myeloid leukaemia 1244 von Gierke (type I) glycogen storage disease 1028 gigantism 902, 903 Gilbert's syndrome 846 gingivitis acute ulcerated (Vincent's angina) 761 herpetic 286, 286f. 761 Gitelman's syndrome 937,1067, 1112 glabellar reflex 1303-1304 glandular fever see infectious mononucleosis (glandular fever) Glasgow Coma Scale (GCS) 19,19t, 1283,12851,1371 head injury assessment 744 head injury outcome predictor 746, 747f mechanical ventilation indicator 737 glatirames acetate (Copaxone) 1412 glaucoma, diabetic retinopathy 1010 glimepiride 997-998. 998t glioblastoma multiforme 1355,1355f radiotherapy 1357 gliomas 1381 cranial irradiation 1248 globin genes 1202f p-globin 58f glomerular basement membrane (GBM) immune complex deposition, SLE 1174 thin GBM disease 1064 glomerular capillary endothelial cells 1032 glomerular disease 1068-1075,1073f clinical presentation and management 1069 diabetes 1011 immunological mechanisms 1068-1069,1068t initiators and mediators 1068t see also glomerulonephritis glomerular filtrate (GF) calcium 1037 formation 1033-1034 modification by tubular action 1033-1034,1035f glomerular filtration rate (GFR) 1032 depressed/reduced age changes 5 effect on drug elimination 1097f renal disease 5 diabetic nephropathy 1011,1012f drug excretion 5

drug interactions 11 effect of ageing 5,1040,1041 impairment, tubular acidosis 1065-1067 measurement 1039-1041 calculation 1039 characteristics of compounds used 1040t measurement of renal plasma flow 1040-1041 radionuclide methods 1040 relationship with plasma creatinine concentration 1040f sodium excess 1108 urinary tract obstruction 1090 glomerular sieve 1032 glomerulonephritis acute nephritic syndrome see nephritic syndrome, acute acute postinfectious 1068-1069 diffuse proliferative, SLE 1175 focal segmental 1073 Henoch-Schonlein (anaphylactoid) purpura 1165 idiopathic rapidly progressive 1074-1075 immune complexes 1068t infections causing 1070-1072, 10701 bacterial 1070 management 1071-1072 parasitic 1071 viral 1070-1071 infective endocarditis 575, 576 mesangiocapillary 1073-1074 rapidly progressive (RGPN) 1051 systemic lupus erythematosus 1074-1075,1175 glomerulopathy, diabetic 1078 glomerulosclerosis diffuse 1078 nodular (Kimmelstiel-Wilson lesion) 1078 glomerulus 1032,1034f glomus tumour 1352t, 1356 glossopharyngeal nerve 1300 glucagon blunted response in diabetes 991 gluconeogenesis stimulation 983 hypoglycaemia treatment 991-992 insulin regulation 980 ketogenesis stimulation 980, 983 glucagonoma, diabetes and 1000 glucocorticoids 926-927 antidiuretic hormone interaction 910 deficiency 889 Addison's disease 931 effect on bone growth 956 excess secretion clinical features 933-934 proximal muscle weakness 966cs see also Cushing's syndrome hypercalcaemia treatment 970 interaction with adrenaline 887. 887f pituitary hypofunction treatment 897-898 synthesis and secretion 926-927 episodic secretion 927 see also corticosteroid(s); cortisol glucokinase, MODY gene defect 995 gluconeogenesis 982 amino acid substrates 983 catecholamine stimulation 980 cortisol stimulation 981

1467

1468

glycerol substrate 982 insulin inhibition 980 glucosamine sulfate, osteoarthritis management 1157 glucose blood levels 981-982 dawn phenomenon 992 diabetic ketoacidosis 1005 elderly 177 health, starvation and stress 983-984 impaired fasting 984 measurement 991,1000,1005 see also hyperglycaemia; hypoglycaemia growth hormone secretion control 894 metabolism 979, 981-982, 981f CNS 981 see also gluconeogenesis; glycolysis; insulin storage 982 see also glycogen tolerance impairment 984, 999 tolerance test acromegaly 904, 904f, 905cs oral (OGGT) 984 'toxicity' 995,995f transporter 981f urinalysis 1000 urine examination 1038 Wernicke-Korsakoff syndrome 1432 glucose-6-phosphatase deficiency 1028 glucose-6-phosphate dehydrogenase (G6PD) deficiency 1221-1222 clinical features 1222,1222t drug-induced haemolysis 1222t laboratory features 1222 malaria protection 346 management 1222 structural types Mediterranean-Oriental type 1222 type A 1222 type A- (African) 1222 type B 1222 a-Glucosidase deficiency 1028-1029 inhibition by acarbose 999 glue ear, chronic secretory otitis media 90cs glue-sniffing 247 glutamine, metabolism 1115f y-Glutamyl transpeptidase, liver function tests 841 gluten, in coeliac disease 788 gluten-sensitive enteropathy see coeliac disease glutethimide, overdose management 24 glycaemic index 111,993-994 glycerol trinitrate (GTN) 467, 468, 547-548 acute MI 559 syncope 547 tolerance 548 C-Glycocholate breath test 791 glycogen 982,1028 glycogenesis 982,1028 insulin effect 980 glycogenolysis 838, 982,1028 catecholamine stimulation 980 insulin inhibition 980 glycogen storage diseases 71t, 1028-1029 management 1028

myopathy 1407 type I (Von Gierke) 1028 type II (Pompe) 1028-1029 type IV (McArdle) 1029,1407 glycolysis 979,1028,1221 f lactate formation 982 glycolytic pathway, red blood cells 1221 glycosylated haemoglobin (HbAlc) diabetes monitoring 997, 998,1000-1001 reduction 999 normal levels 1001 GM-CSF (granulocyte-macrophage colony-stimulating factor) 1202,1203 GnRH see gonadotrophin-releasing hormone (GnRH) goitre 913 bruit over 914 diffuse multinodular 923-924 treatment 924ra endemic 914 familial 924 iodine deficiency 127 multinodular, malignancy potential 924f, 925f simple diffuse 922 toxic multinodular 918, 919 treatment 924ra goitrogens 914 gold salts 411 rheumatoid arthritis 1142 side-effects 1142 golfer's elbow 1195 gonadal dysgenesis amenorrhoea due to 947 pure XY 947, 949 gonadotrophin(s) ectopic secretion 909 therapy, fertility treatment in hypopituitarism 901 see also follicle-stimulating hormone (FSH); luteinising hormone (LH) gonadotrophin disorders 909 deficiency amenorrhoea 946-947 isolated 942,947 see also Kallmann's syndrome males 942-944, 944f management 948 gonadotrophin-releasing hormone (GnRH) normal menstrual cycle 945f, 946 pulsatile secretion 883, 894 gonadotrophs 895 gonococcal arthritis 1158,1159 Reiter's disease vs 1159 see also Neisseria gonorrhoeae infections gonococcal septicaemia, arthritis 1158 gonorrhoea 458 Goodpasture's syndrome 690, 690f renal involvement 1076-1077 gout 1166-1171 associated conditions 1167 case study 1169-1170cs clinical features 1168,1168f, 1169cs diagnosis and investigation 1168, 1169cs, 1170 differential diagnosis 1169cs, 1170t drugs precipitating 1121,1122t epidemiology 1166,1166f factors triggering attack 1168t management 1169-1171,1170, 1170cs

pathology 1167 prevalence and costs 1119 sex differences 1121 tophi 1127,1168,1168f see also hyperuricaemia gouty nephropathy 1079 Gower's sign, Duchenne muscular dystrophy 1404 gp39 antibodies to 103 T cell expression of 89 GPI (general paralysis of the insane) 1429 G-protein, hormonal action via 885 G-protein coupled receptors 884t adenylate cyclase-coupled 884-885 hormonal 884-885,886 phospholipase C-coupled 886 graft-vs-host disease (GVHD) 1213, 1239 severe combined immune deficiency 93 graft-vs-leukaemia (GVL) 1239 Graham Steel heart murmur 532 gram-negative bacteria bacilli 315-325 intracranial abscesses 1418 Gram-negative pneumonias 638-639 gram-negative septicaemia 307 malaria 348 gram-positive bacteria bacilli 311-315 cocci 308-310, 310-311 gram staining, infectious disease 262 grand mal epilepsy see tonic-clonic seizures granulocyte(s) chronic granulomatous disease 1235 see also individual cell types granulocyte colony-stimulating factor (G-CSF) 1202,1203 indications 1204t granulocyte-macrophage colonystimulating factor (GMCSF) 1202,1203 granuloma causes 101 common variable immune deficiency 87 fish-tank 388-389, 389f histology 101 midline 691 mycobacterial infections 101 non-caseating, sarcoidosis 683-684 causes 684t pyogenic 422 rheumatoid 1136 schistosomiasis 371, 372 granuloma annulare 414, 414f granulomatosis allergic see Churg-Strauss syndrome Wegener's see Wegener's granulomatosis granulomatous conditions liver involvement 878-879, 878t oxidase system 1235f panhypopituitarism due to 895 pyrexia of unknown origin 275 granulomatous disease, chronic 1235,1235f granulomatous hepatitis 878-879 granulomatous hypersensitivity 101-102 granulomatous inflammation, tuberculous meningitis 1420

granulosa cells 945,946 graphaesthesia 1305 grasp reflex 1304 Graves' disease 889, 918 antibodies to TSH receptor 914, 918 case study 923cs clinical features 918-919 investigations 914 management 920-922 natural history 919 pregnancy 922 progression to autoimmune hypothyroidism 914 relapse 921 skeletal features 891 Graves' ophthalmopathy 919-920, 920f gravitational eczema 405 grays (Gy) 48 grey baby syndrome 4 grief and bereavement 217-218 delayed or pathological mourning 218 depression 220-221 management 218 mourning responses 217-218, 217t griseofulvin 267-268 growth catch-up, after growth hormone replacement 902 pituitary hypofunction effect 897, 898f retardation 902 spurt 946 excessive in gigantism 903 growth hormone (GH) 894 biosynthetic 902 bone growth/mineralization 954 deficiency adults 902 clinical features 897 isolated 901-902 management 902 osteoporosis 960 partial 902 effect on bone growth 956 excess 902-906 investigations 904-905, 904f management 905-906, 906t see also acromegaly gene deletion 901 insulin regulation 981 pituitary tumours secreting 897 receptor mutation 901 replacement/therapy 902 contraindications 902 osteoporosis treatment 962 secretion 893t bromocriptine effect 903, 904 control 894f,903 inhibition by somatostatin 903 suppression test 904, 904f synthesis, stimuli and inhibitors 893t growth hormone-releasing hormone (GHRH) assay in acromegaly 905 ectopic secretion 902, 905 growth hormone suppression test 904, 904f Gs coupling protein 884, 885 Guillain-Barre syndrome 1392, 1397-1398 aetiology 1397 Campylobacter jejuni 325 clinical features 1397 differential diagnosis 1397,1426, 1433

investigation 1397 management/prognosis 1397-1398 vital capacity 1398 guilt, genetic disorders and counselling 76 Guinea worm infestation 369 gummas, syphilitic 1429 gut see entries beginning gastrointestinal, intestinal Guthrie test 69 guttate psoriasis 396 gynaecological symptoms, functional bowel disorders 821-822 gynaecomastia 950 causes 950t thyrotoxicosis 919

H H2 antagonists, urticaria and angioedema 98 haem, synthesis 1026,1027f haemaccell, replacement fluid 7311 haemagglutination inhibition (HAI) test 295 haemangioblastoma 1352t, 1356 haematemesis 772, 773-774cs cirrhosis 874 pancreatic tumours 832 haematological disorders 1202-1281 cerebrovascular disease 1330, 1332t haematological malignancy 1235-1237 aetiology 1236-1237,1236t, 1237t genetic factors 1237,1237f growth rate 1236 hypercalaemia 971 pathogenesis 1235-1236 see also leukaemia; lymphomas; myeloproliferative disease/disorders haematology musculoskeletal diseases 1124-1127 SLE 1175 haematoma intracranial extradural 1370,1370f formation 1370-1371,1370f intracerebral 1370,1370f subdural 1370-1371,1372,1373f treatment 1371,1372 see also cerebral oedema intracranial pressure 743 oesophageal, dissecting intramural 767 haematuria 1044-1045 persistent asymptomatic 1064-1065,10651 recurrent 1064 sickle cell disease 1218 testing for 1039 haemochromatosis 868-869 clinical features 868-869 diabetes and 1000 diagnosis 869 management 869 restrictive cardiomyopathies 573 haemodialysis 1059 arteriovenous fistula 1059 diabetic patients 1012 lithium carbonate overdose 27 physical principles 1060f poisoning 22

haemodynamics, disorders 1008 haemoglobin 1203-1204 adult, replacement of fetal 1201 age changes 1205t anaemia 1205-1206 chronic myeloid leukaemia 1238 configuration change with oxygenation 1204,1204f electrophoresis, B-thalassaemia 1215,1215f fetal synthesis 1201 see also haemoglobin F (fetal [HbF]) glycosylated in diabetes 997, 998, 1000-1001 hereditary spherocytosis 1220 methaemoglobinaemia 1220 musculoskeletal diseases 1124-1125 oxygen dissociation curve 1204, 1204f polycythaemia 1241,1241t polycythaemia rubra vera 1241 raised, diagnostic approach 1241 f synthesis and structure defects 1214-1217 see also sickle cell disease; thalassaemias haemoglobin (HbA a2 B2) 1201 haemoglobin A (Hb A) 1216 haemoglobin A (Hb A2) 1216 haemoglobin Barts 1216-1217 haemoglobin C (HbC) 1220 Haemoglobin Constant Spring 1217 haemoglobin D (HbD) 1220 haemoglobin E (HbE) 1220 haemoglobin F (fetal [HbF]) causes of increase 1217t hereditary persistence 1217 sickle cell disease 1218 synthesis 1201 haemoglobin H disease 1216 haemoglobinopathies 1214-1220 screening 75t single gene mutation mechanisms 60t see also specific diseases haemoglobin S (HbS) see sickle cell disease haemoglobinuria 1039 march 1226 paroxysmal cold 1224 paroxysmal nocturnal 1226 haemolysis aetiology 1214 G6PD deficiency 1222 hereditary spherocytosis 1220 hyperkalaemia 1112 haemolytic anaemia 1214 autoimmune see autoimmune haemolytic anaemia (AIHA) clinical and laboratory features 1214 G6PD deficiency 1222 investigation 1214 non-immune 1224-1226 aetiology 1225t sickle cell disease 1218 haemolytic disease of the newborn 1232-1234 aetiology 1232 approach to monitoring Rhnegative women 1223f, 1233 clinical features 1233 management antenatal 1233 postnatal 1233-1234

prevention 1234 haemolytic-uraemic syndrome (HUS) 315,1079,1270 haemoperfusion, poisoning 22 haemophilia A 1272-1273 clinical features 1272-1273 complications of therapy 1273 diagnosis 1273 management 1273,1273t severity 1273t haemophilia B 1276t Haemophilus infection 317 Haemophilus influenzae 317,1413, 1414t, 1417 diseases caused by 317t pneumonia 633 respiratory infections 631, 633 Haemophilus parainfluenzae 317 haemopoiesis 1201-1203 haemopoietic differentiation 1201-1203,1202f ontogeny 1201 regulation 1202-1203 haemopoietic cells, functions 1203-1205 haemopoietic growth factors 1202-1203,1203f with chemotherapy 167 clinical use 1203t hypoplastic anaemia 1213 myelodysplasia 1249 haemopoietic stem cells 1201-1202, 1202f haemoptysis 613, 615 bronchial carcinoma 701 bronchoscopy 628 important causes 613t lung cancer 613 persistent severe 614-615cs haemorrhage brainstem 1338 cerebral see cerebral haemorrhage diabetic retinopathy 1009 gastrointestinal see gastrointestinal bleeding intracranial 1371 optic fundi 1292 papilloedema 1292 pons 1338 splinter 435, 436f subarachnoid see subarachnoid haemorrhage variceal 873 haemorrhagic conjunctivitis, enterovirus 303 haemorrhagic cystitis adenoviruses 290 cyclophosphamide causing 1143 haemorrhagic leucoencephalopathy, acute 1412 haemorrhagic telangiectasia, hereditary 437,437f, 691 haemosiderosis 868 idiopathic pulmonary 696 haemostasis 1264-1267 coagulation cascade 1265-1266, 1265f see also coagulation cascade disorders 1268-1275 diagnosis 1267-1268,1267f, 1268t see also individual disorders examination 1267 inhibitory systems 1266-1267 mechanisms 1264f platelets 1264-1265,1264f haemothorax, pleural disease 713 Hageman factor, activation 1167 hair loss

primary hypothyroidism 916 secondary sexual 897 see also alopecia hair-on-end appearance, skull X-ray 1215 hairy cell leukaemia 1258-1259 hairy leukoplakia, in HIV infection 444, 444f Hallpike manoeuvre 183,1319, 1319f hallucinations alcoholic 251 definition 1287 drug-induced 247 epilepsy 1287 hypnagogic 1329 poisonous plants 40 in psychosis/neurosis 207 schizophrenia 229 hallux valgus (bunion) 1199 haloperidol 230 halothane, liver damage 853 hamartoma, lung tumours 708 hamstring injuries 1198 hands acromegaly 904 deformities, rheumatoid arthritis 1134,1134f examination in respiratory disease 619 osteoarthritis 1123,1123f painful 1195-1196,11951 rheumatoid arthritis 1123,1123f, 1134,1134f systemic sclerosis 1178f see also fingers Hansen's disease see leprosy (Hansen's disease) haptenization 101 'hard' exudates, diabetic retinopathy 1009 Hashimoto's thyroiditis 889,917 hayfever see allergic rhinitis HbA lc see glycosylated haemoglobin (HbA lc ) hCG see human chorionic gonadotrophin (hCG) HDL see high-density lipoprotein (HDL) HDN see haemolytic disease of the newborn headache 1306-1312,1308cs aetiopathogenesis 1307,1307t cavernous sinus thrombosis 1420 cortical venous thrombophlebitis 1419 medication misuse 1310 meningitis 1312 subarachnoid haemorrhage and 1307,1312,1344 trauma 1311-1312 tumours 1312,1353 venous sinus thrombosis 1419 see also head injury cervical 1310 chronic daily 1311 classification 1307t coital cephalgia 1312 disease symptom 1306 giant cell arteritis 1184 history-taking 1307 intracerebral blood vessels 1312 migraine see migraine migrainous neuralgia (cluster headache) 1314-1315 pituitary tumours 890, 896 postictal 1312 post-traumatic 1311-1312

1469

1470

tension-type 1309,1310-1311 diagnostic criteria 1310t transformed migraine 1310 see also facial pain head injury 1369-1373 alcohol and 1436t assessment 743-745 complications extracranial 1371 intracranial abscess 1418 late 1371-1372,1372cs epidemiology 1369-1370 immediate effects 1370 management 744-745, 744t, 1371-1373 early 1371,13731 general therapy 745 haematomas 1371, 1372 neurosurgical referral 1371 monitoring 745-746 outcomes 746 pathophysiology 742-744 peptic ulcers 777 post-traumatic headache 1311-1312 post-traumatic syndrome 1373 psychological effects 1373 secondary effects 1370-1371 cerebral oedema 1370,1371 haematoma formation see haematoma meningitis 1371 head lice (Pediculus humanus) 330, 395 Heaf test 641 Health Assessment Questionnaire (HAQ), rheumatoid arthritis assessment 1139 health promotion 141-143 hearing eighth cranial nerve 1298 examination 1298 loss see deafness heart auscultation see auscultation catheterization see cardiac catheterization Chagas' disease 354 chamber enlargement, X-ray 481-482 dermatomyositis 1180 filling pressures 726-728 muscle see cardiac muscle output see cardiac output oxygen delivery, factors effecting 732t pump failure 731-732 management 731-732 rheumatoid arthritis 1136 size, chest X-rays 481 SLE 1174 systemic sclerosis 1178 see also entries beginning cardiac heart block 502-504 acute MI complication 562 athlete's heart 585 bifascicular/trifascicular 562 clinical features 503-504 complete or third degree 503, 503f, 562 first-degree 502, 502f, 562 left anterior/posterior hemiblock 562 management 504 Mobitz type II 503, 562,1241f pacemakers see pacemakers sarcoidosis 573 second-degree 502, 503f, 562 Stokes-Adams attack 503-504

Wenckebach phenomenon (Mobitz type I) 502-503, 1241f heartburn 762 heart bypass see coronary artery bypass graft (CABG) surgery heart disease 128 chest pain 467-468 congenital see congenital heart disease coronary disease see coronary artery disease dizziness 1317 dyspnoea (shortness of breath) 468 see also breathlessness examination see cardiovascular system examination fatigue 469 history taking 467 investigations see cardiac investigation myocardial infarction see myocardial infarction oedema 469 palpitations 468 pregnancy 535, 582-583 anticoagulants 583 diagnosis 583 management 583 peripartum cardiomyopathy 583 Still's murmur 583 presyncope 468-469 secondary 583-586 anaemia 584 arteriovenous fistulas 584 athlete's heart 584-586 see also athlete's heart beriberi 584 chromosomal abnormalities 584, 584t connective tissue disorders 584, 584t exfoliative dermatitis 584 inborn errors of metabolism 584, 584t Paget's disease of bone 584 skeletal syndromes 585t sternal depression 586 straight back syndrome 586 thyrotoxicosis 583 signs/symptoms 467-476 structural 1333 syncope 468-469, 1321 valvular see valvular heart disease see also cardiovascular disease heart failure 488-500, 490 ACE inhibitors 490, 494, 496, 564t acute 492-494 diagnosis 492-494 left-heart failure 491, 492 management 492-494 right-heart failure 493, 499-500cs see also myocardial infarction (MI) acute MI 563 see also myocardial infarction (MI) acute onset of breathlessness/arrhythmia 499-500cs acute vs. chronic 490 aetiology 491 antecedent hypertension 491 arrhythmia see arrhythmia artificial hearts/ventricular assist devices 564ra

B-receptor downregulation 490 cardiac cachexia 491 cardiogenic shock 493-494, 493t chronic, in outpatients 495-498 drug therapies 495-498 investigations 495t management 495, 497f classification 490-491 congestive (severe) 494—495 decompensation 490 diuretics 495-496 combination 496 loop 496 potassium-sparing 495 thiazide 495 drug therapies 495-498 antiarrhythmic agents 498 p-blockers 496-497 diuretics see above inotropic agents 497-498 nitrates 496 potassium-sparing diuretics 490, 495 vasodilators 490, 495-496 Duchenne muscular dystrophy 1404 electrolyte imbalance 490 epidemiology 490-491 excessive vasoconstriction 490 haemolytic disease of the newborn 1233 hypoperfusion 491 intra-aortic balloon pump (IABP) 732 left- vs. right-sided 490 major effects 488 management 497f mechanical support 732 mitral regurgitation 524 see also mitral regurgitation myocardial hypertrophy 489 myocarditis 570 natural history 491 pathophysiology 488-490 peak cardiac performance 488 primary defects 488-489, 489t prognosis 491 progressive heart damage 489, 489f progressive ventricular dysfunction 491-492 clinical features 491 symptoms/signs 491 pulmonary oedema 492-493 renin-angiotensin-aldosterone system 489-490, 489f secondary defects 489-490, 489f symptoms/signs 491, 4911 systolic vs. diastolic (forward vs. backward) 490 tertiary effects 490 heart-lung transplantation 500 heart murmurs 474-475 Austin Flint 529 Carey Coombs 581 causes 474 'click-murmur' syndrome 526 crescendo-decrescendo 537 description 474 diastolic 475 dynamic auscultation 475 early diastolic 475 Graham Steel 532 innocent 474, 475 late systolic 475 mitral/tricuspid mid-diastolic 475 musical/mewing 475 pansystolic 475 of pregnancy 583

SLE 1174 Still's 583 systolic 475 heart muscle see cardiac muscle heart pump performance 465—467 afterload 466, 466f chronotropic drive 465 Frank-Starling curve 465 inotropy 465 Laplace equation 467 normal function 465-467 preload 465-466 rate 466 rhythm 466 tamponade 466 ventricular dilatation 466-467 ventricular function curve 465, 466f ventricular hypertrophy 467 heart sounds ectopic (extrasystolic) beats 501-502, 502f ejection clicks 474 first/second (S1/S2) 473, 474f gallop (triple) rhythm 474 midsystolic (non-ejection clicks) 474 opening snap 474 pericardial rubs/knock 474 third/fourth (S3/S4) 473-474 tumour plops 474 heart transplantation 498-500 artificial hearts/ventricular assist devices 564ra complications 498 heart-lung transplantation 500 immunosuppressive regimens 498 indications 498 management 498-499 prognosis 499 surgery 498 heart valves disease see valvular heart disease repair/replacement 533 see also individual valves heat, intolerance, thyrotoxicosis 919 heat cramps 45 heat excess disorders 45-46 in elderly 179 heat exhaustion 45 heatstroke 45-46, 46t heavy-chain disease (HCD) 1262 a 1262 heavy metal poisoning 43 Heberden's nodes 1154,1155 heel pain behind 1198 painful 1198-1199,1198t pain under 1198-1199 heel pad, tenderness 1199 heel-shin test 1303 Heimlich manoeuvre 520 Helicobacter pylori diagnostic tests 781t eradication 823 lymphomas 1255 peptic ulcers 777, 778ra treatment 782t HELLP syndrome, pregnancy 855 helminth infection 358-378, 359f chemotherapy 359 classification 358t pulmonary eosinophilia 660 see also individual infections hemianopia, bitemporal, pituitary tumours 896 hemianopic defects 1291,1291t tuberculous meningitis 1420 hemiballismus 1367

hemifacial spasm 1369 hemiparesis carotid artery occlusion 1331 frontal lobe lesion 1288 tuberculous meningitis 1420 hemiplegia, spastic 1374 hemiplegic gait 1290 hemiplegic migraine 1309 hemizygous allele 64 hemlock (coniine), ingestibn 39-40 Henderson-Hasselbach equation 1113-1114 Henle'sloop 1032 Henoch-Schonlein (anaphylactoid) purpura 409,1074,1183 joint involvement 1165 renal involvement 1076 heparin 1275-1276,1334 acute MI 559 administration 1276 anticoagulation therapy 1334 atrial fibrillation 512 complications 1276 cortical venous thrombophlebitis 1419 deep vein thrombosis 604 indications 1275-1276 low-dose, hyperosmolar (nonketogenic) coma 1007 mechanism of action 1275 pregnancy 1278 prophylaxis after head injury 745 pulmonary embolism 680, 681 venous sinus thrombosis 1419 heparin cofactor II 1266 hepatic artery 835 hepatic cirrhosis see cirrhosis hepatic disease see liver disease hepatic encephalopathy 1432,1436t, 1439_1440 acute fulminant hepatic failure 1439 hepatocerebral degeneration syndrome 1439 investigation/treatment 1439-1440 reversible chronic 1439 hepatic failure see liver failure hepatic nuclear factors (HNF), MODY link 995 hepatic veins 835 hepatic venous congestion 870-871 hepatitis acute 846-852, 848cs alcoholic 855-856 viral causes 847-852, 847t autoimmune 863-864 chronic 863-866 classification 863t drug-induced 866 clinical aspects 851t drug-induced 852-853, 866 granulomatous 878-879 HIV/AIDS infection 447-448 liver failure 853 viral 847-852,8471 arthritis 1161 see also specific hepatitis viruses hepatitis A immunoglobulin 272 vaccine 273 hepatitis A virus (HAV) 847, 848cs structure 847f hepatitis B chronic 864-865 autoimmune reactions 864 management 865 clinical features 850 epidemiology 849-850, 850f glomerulonephritis 1070-1071

immune response 866cs immunoglobulin 272 serological changes 849f vaccine 273 hepatitis B virus (HBV) 848-850 HBsAg levels 864 hepatoma and 149 immunopathology 850 virology 848-849, 849f hepatitis C chronic 865 cryoglobulinaemia and arthritis 1161,1183 glomerulonephritis 1070-1071 hepatocellular carcinoma (hepatoma) 149,876 immune response 866cs hepatitis C virus (HCV) 851 serological markers 865 hepatitis D hepatocellular carcinoma 149, 876 polyarteritis nodosa 878 hepatitis D virus (HDV) see delta virus hepatitis E virus 847-848 hepatoblastoma, hCG secretion 909 hepatocellular carcinoma (hepatoma) 875-877 clinical features 876 diagnosis 876 hepatitis infection and 876 hypoglycaemia 1018 incidence, epidemiology and aetiology 875-876, 875f liver cirrhosis 860 management 876-877 metastases 876 hepatocerebral degeneration syndrome 1439 hepatocytes 836 hepatolenticular degeneration see Wilson's disease (hepatolenticular degeneration) hepatoma see hepatocellular carcinoma (hepatoma) hepatomegaly, porphyria cutanea tarda 1028 hepatopulmonary syndrome 691-692 hepatorenal syndrome 1047-1048 hepatosplenomegaly Hodgkin's disease 1250 Q fever 307 schistosomiasis 372 hepatotoxicity, methotrexate 1143 herbicides, poisoning 38 hereditary acanthocytosis 1221 hereditary coproporphyria 1027 hereditary elliptocytosis 1221 hereditary haemorrhagic telangiectasia 437, 437f, 691 hereditary motor and sensory neuropathy (HMSN) 1399 hereditary nephritis (Alport's syndrome) 1075 hereditary persistence of fetal haemoglobin (HPFH) 1217 hereditary pyropoikilocytosis 1221 hereditary spastic paraplegia 1384 hereditary spherocytosis 1220-1221 membrane defects 1220 hereditary stomatocytosis 1221 herpes labialis (cold sore) 287, 761 herpes simplex virus(es) (HSV) 283 HSV-1 286 HSV-2 286 herpes simplex virus (HSV) infections 286-288, 760-761

HIV/AIDS infection 447 liver function 852 management 287 nervous system 1422 encephalitis 1423,1424-1425cs, 1425f multiple sclerosis aetiology 1409 oesophagus 771 reactivation 287 type 1 (HSV-1) 286-287 encephalitis 287 type 2 (HSV-2) 287 herpesviruses 283-284 drugs active against 268 morphology 283 reactivation 270 see also specific viruses herpes zoster (shingles) 285-286, 285f immunocompromised patient 270, 286 latency 285 nervous system infection 1314, 1422 geniculate (Ramsay-Hunt syndrome) 1320 Herpes zoster ophthalmicus 1314 herpetic encephalitis 287 herpetic gingivostomatitis 286, 286f, 761 herpetic whitlow 286 hespan, replacement fluid 731t heterozygous alleles 64 hexose monophosphate shunt 1221, 1221f HHV-6 (human herpesvirus type 6) 289 HHV-8 (human herpesvirus type 8; Kaposi's sarcoma associated) 289 hiatus hernia 766-767 hidradenitis suppurativa 432 high-density lipoprotein (HDL) 839. 1022 metabolism 1022,1022f protective effects 1022,1023 high-fibre diet 798 hilar gland 684f sarcoidosis 684 unilateral enlargement, bronchial carcinoma 703, 703f hilar shadows, chest X-rays 624 hip joint osteoarthritis 1155 rheumatoid arthritis 1135 transient synovitis 1159 Hirschsprung's disease 799 hirsutism 434-435,4351,891,951 management 951,951t polycystic ovary syndrome 948, 951 histamine, carcinoid syndrome 796 histiocytic medullary reticulosis 1257 histiocytomas (dermatofibromas) 422 histiocytosis X (Langerhans' cells histiocytosis) 95,12571258 histocompatibility antigens see HLA system histocyte disorders 1257-1258 histones 57 Histoplasma capsulatum 333 clinical features 333-334 Histoplasma capsulatum var. duboisii 334 histoplasmosis 333-334 disseminated 333

history-taking drug history 6 in elderly patient 191 haemostasis disorders 1267 headache 1307 infectious disease 261 musculoskeletal disorders 1121-1122 neurological disease 1283,12841 psychiatric illness 211-212,2111 sexual function 256 see also family history histrionic personality disorder 210, 238 conditions related to 238t HIV 439, 442, 442f CD4 count and viral load, prognosis to AIDS 445f CD4 molecule 442-443 myopathy 1428 replication 443f HIV-1 442 HIV-2 442 HIV infection and AIDS 439-456 blood transfusion 1231 Candida infections 332 CD4 T cell depletion 444f, 445f classification 441t complications 445 control strategy 453-455 cryptosporidiosis 338 cytomegalovirus (CMV) infections 1428 definition 439-440 epidemiology 440-441 size of the problem 441f, 4411 gastrointestinal complications 446-447 glomerulonephritis 1051ra, 1070 hepatic complications 446-448 hepatitis B virus 850 immunodeficiency due to 95, 444f immunological abnormalities 443t immunology 442-443 indicator diseases (AIDS) 440t kidney 1070t mycobacterial infection 645 natural history 443-444 nervous system involvement 1422, 1427-1428,14271 cerebral abscess 1418, 1428 cerebral tumour 1428 dementia 1428 encephalitis 1427-1428 meningitis 1423,1428 myelopathy 1428 peripheral neuropathy 1428 progressive multifocal leukoencephalopathy 1427 retinitis 1428 viral meningitis 1423,1428 neurological complications 448-450 opportunistic infections 444-445 Pneumocvstis carinii 344 treatment 452-453, 452t pneumonia 638-640 prevention strategies 452t pulmonary complications 445446 rheumatic features 1161 skin manifestations 426, 426t, 427f transmission 440-441 exposure category 442f tuberculosis 640 tumours 449-450. 450f visceral leishmaniasis 357 HLA-B27 ankylosing spondylitis 1147,1150

1471

1472

Klebsiella and molecular mimicry 1147-1148 B2-microglobulin interaction failure 1148 HLA-DR4, rheumatoid arthritis 1131 HLA system 83, 83t class I and class II antigens 83 synthesis 84 class II deficiency 94t diseases associated 73t, 83t class II antigens and type 1 diabetes 984 endocrine 889 genes 83 multiple sclerosis aetiology 1409 HMG-CoA reductase, cholesterol synthesis 1021 feedback inhibition 1023 HMG-CoA reductase inhibitors (statins) 1025,1025t acute MI 559 post MI management 569 Hodgkin's disease (HD) 145, 1250-1254,12511,1252ra, 1253cs age-specific incidence 146f classification 1251t clinical features 1250-1251 combination chemotherapy 161 herpes zoster (shingles) infection 286 histological classification 1251 infertility 163 management 1251t, 1252-1253 prognosis 1253-1254,1253t stage IA and IIA 1252 stage IIB 1252 stage IIIA 1252 stage IIIB 1252 stage IV 1252 staging 1251-1252 Ann Arbor system 1251t Holmes-Adie syndrome (tonic pupil) 1295,1296f Holler monitoring (24-hour ECG) 500, 501f Homan's sign 604 homocystinuria 70 Marfan's syndrome vs 72cs homogentisic acid 71 homogentisic acid oxidase, deficiency 70-71, 70f homosexuality 940-941 homozygous alleles 64 honeycomb lung 696 hookworm 360-361 anaemia 361 lifecycle 361f hormonal therapy see hormone therapy hormone-binding proteins 886-887 hormone replacement therapy (HRT) osteoporosis 176 ovarian failure treatment 948 see also oestrogen therapy hormones actions via cell surface receptors 884-886 adenylate cyclase-mediated 884-885, 884f calcium transport/release mediating 885-886, 885f phosphatidyl inositol-mediated 885-886, 885f tyrosine kinase-mediated 886 via second messenger cAMP 885

action via intracellular receptors 886 assays 891 basal measurements 891-892, 8911 pituitary hypofunction investigation 898 bioassays 883 calcaemic 955 see also 1,25-dihydroxyvitamin D (1,25(OH)2D); parathyroid hormone (PTH) carbohydrate metabolism 838 circulation and metabolism 886-887 control of calcium/phosphorus metabolism 954-956 dynamic tests 892, 892f pituitary hypofunction 898, 899f episodic secretion 886 free, concentrations 887 gene expression regulation 884 half-life 886 interactions 887, 887f measurement of circulating concentrations 883 hypopituitarism 899 mechanism of action 886f, 887f metabolism by kidney 1037 normal physiology 883-888 polypeptide signal sequences 884 synthesis 884 pulsed secretion 886 receptors 884-886 renal actions 1037,1038t steroid see steroids synthesis 884 abnormalities 889 synthesis by kidney 1037 thyroid see thyroid hormones as transcriptional regulatory factors 884 see also specific hormones hormone therapy 163-164 adjuvant 165 hirsutism 951 see also anti-androgens; hormone replacement therapy (HRT); oestrogen therapy Horner's syndrome cluster headache 1315 posterior inferior cerebellar artery (PICA) occlusion 1336 pupillary responses 1295,1296f hospital-acquired pneumonia 634-635, 634f, 634t hospitalized patients acquired infections 270 control of infection 271 methicillin-resistance Staphylococcus aureus (MRSA) 264 host defences 79-80 house dust mites 97 housemaid's knee 1197 rheumatoid arthritis 1136 Howell-Jolly bodies 752-753 coeliac disease 789 HPV see human papillomavirus (HPV) HTLV-1 infection see human T-cell lymphotrophic virus 1 (HTLV-1) human chorionic gonadotrophin (hCG) ectopic secretion 909 fertility treatment in hypopituitarism 901

secretion 946 Human Genome Project 65ra human herpesvirus type 6 (HHV-6) 289 human herpesvirus type 8 (HHV-8; Kaposi's sarcoma associated) 289 human immunoglobulin (ivlg), Guillain-Barre syndrome treatment 1398 humanized CD20 monoclonal antibody, non-Hodgkin's lymphoma 1256 human leukocyte antigen system see HLA system human papillomavirus (HPV) 393, 456 HIV/AIDS infection 450 human placental lactogen (HPL) 894 human T-cell lymphotrophic virus 1 (HTLV-1) 1237 non-Hodgkin's lymphoma 1257 tropical spastic paraparesis 1384 humeral epicondylitis 1195 Huntington's chorea 61t, 1350 HUS see haemolytic-uraemic syndrome (HUS) Hutchinson's freckle 424 hyaline bodies 1292 hyaline cartilage see articular cartilage hyaluronan, high molecular-weight, osteoarthritis treatment 1155 hyaluronic acid, synovial fluid 1120 hydatid cysts 377-378,378f, 879 hydatid disease 377-378, 378f of bone 378 hydralazine-induced lupus 1175 hydrocarbons, poisoning 34-35 hydrocephalus 1358-1361 acute 1359f causes 1359-1360,1359t brain atrophy 1360 cerebral dysgenesis 1359,1360 cerebral tumours 1352,1353 CSF abnormalities 1359,1359f. 1360f meningitis 1414,1417 communicating 1359 infantile 1360 investigation 1360 management 1360,1417 normal pressure 1360-1361,1361f dementia 1350,1360 pituitary tumour causing 890 ventricular dilation 1359f hydrochloric acid poisoning 34 secretion 776 see also gastric acid hydrocortisone Addison's disease 931 intravenous, hypopituitarism treatment 899 oral, anterior hypopituitarism 900 see also cortisol hydrocortisone acetate, soft tissue rheumatism 1200 hydrogen breath test 757, 759 hydrogen cyanide poisoning 54 hydrogen ions secretion by gastric parietal cell 1036f transport/secretion 1036 hydrogen sulphide, poisoning 34 hydrophobia, rabies 301 hydrops 1233

hydrostatic pressure 1099 hydrotherapy osteoarthritis 1157 rheumatoid arthritis 1139 hydroxyapatite 953 3-hydroxybutyrate 982 hydroxybutyrate dehydrogenase, levels 1270 y-hydroxybutyric acid (GHB), overdose 31 hydroxychloroquine (HCQ) rheumatoid arthritis 1142,1145 side-effects 1142 SLE 1176 hydroxycobalamin supplements 1210 hydroxyethyl starch 1230 1-hydroxylase 955,971 llp-hydroxylase, inhibitor see metyrapone llp-hydroxylase deficiency 932, 950 21-hydroxylase deficiency 889, 950 clinical features 932 hydroxyproline 976 3p-hydroxysteroid dehydrogenase, deficiency 950 llp-hydroxysteroid dehydrogenase deficiency 937,1112 5-hydroxytryptamine (serotonin) carcinoid syndrome 796 receptors, migraine 1309 synthesis and degradation 797t 5-hydroxytryptamine antagonists carcinoid syndrome 797 functional bowel disorders 823 hydroxyurea chronic myeloid leukaemia 1239 essential thrombocythaemia 1243 25-hydroxyvitamin D hydroxylation 955 reduced in osteomalacia/rickets 964 measurement 958 hymenolepiasis 376 hyperaldosteronism primary see Conn's syndrome secondary 937 hyperbilirubinaemia, unconjugated 846 hypercalcaemia 965-972,1067 accelerating 968cs Addison's disease 931, 972 aetiology 965, 969t bronchial carcinoma 702, 968cs cancer 154 cardiovascular features 890 causes 957 clinical features 965-969, 971 diabetes insipidus 1102 elderly 971 familial hypocalciuric 969t, 972 gastrointestinal features 891 investigations 969, 970t of malignancy 968cs, 971-972 differential diagnosis 967cs mechanism 971-972, 972f tumours associated 971 management 969-970, 969t multiple myeloma 1259 neurological involvement 1407 parathyroid hormone synthesis suppression 955 primary hyperparathyroidism causing 967cs, 970-971 psychosis and CNS effects 890 renal transplantation before 889

sarcoidosis 972 syndromes associated 972 thiazide diuretics causing 972 thyrotoxicosis 972 hypercalciuria absorptive 1087 idiopathic 1087,1089 renal 1087 resorptive 1088 urinary tract stone formation 1087-1088 hyperchloraemic metabolic acidosis 1066 hypercholesterolaemia 839 familial 1023,1026 hypothyroidism with 917 management 1025-1026 polygenic 1023,1025 hyperextension injuries 1379 whiplash 1373 hyperflexia, poisoning 17t hyperglycaemia cardiovascular disease association 1014-1015 diabetes and diabetic neuropathy 1012 fasting 992 hyperosmolar (non-ketogenic) coma 1006 neonatal 1002 rebound 992 type 1 diabetes 992 type 2 diabetes 995 see also diabetes mellitus parenteral feeding 134 hyperhidrosis 431-432 asymmetrical 432 generalized 431-432 palmoplantar/axillary 432 hyperhomocysteinaemia 1280 hyper-IgM 89 X-linked 94t hyperinflation, respiratory disease 608 hyperinsulinaemia 1015 hyperkalaemia 1112-1113 Addison's disease 931 causes 11131 hyperkalaemic periodic paralyses, myopathy 1407 hyperlipidaemia diabetes association 1015 features 1024t optic fundi changes 1291 management 1024-1026 general measures 1024 hypercholesterolaemia 1025-1026 hypertriglyceridaemia 1026 lipid-modifying drugs 1024-1025,10251 nephrotic syndrome 1064 primary 1023-1024 classification 1024t familial combined hyperlipidaemia 1023 familial hypercholesterolaemia 1023 familial hypertriglyceridaemia 1023-1024 polygenic hypercholesterolaemia 1023 secondary 1024, 1024t prevention 1026 skin involvement 416 see also lipids; lipoproteins hypermagnesaemia 957 hypermobility syndromes 1124

hypernatraemia antidiuretic hormone deficiency 911 bronchial carcinoma 702 hyperosmolar (non-ketogenic) coma 1006 neurological involvement 1432-1433 hyperosmolar (non-ketogenic) coma 1006-1007 hyperoxaluria 1090 hyperparathyroidism bone disease of 971 renal failure 1055 bone erosions 958f MEN type I 938-939 primary 888, 889f causes 969t hypercalcaemia 967cs, 970-971 nephrocalcinosis 970f skeletal features 890-891 secondary 888-889, 889f, 962 causes 973t hypocalcaemia associated 972-973, 973 tertiary 889, 889f, 973 hyperphagia, pituitary tumours 896-897 hyperpigmentation 427t Addison's disease 891, 931 Nelson's syndrome 906-907 hyperprolactinaemia 907-909 aetiology 907-908 classification (aetiological) 908t management 909t, 948 see also macroprolactinoma; microprolactinoma hypersensitivity 96-102 classification 96, 96t clinical diseases associated 97-102 type I (immediate) 96 see also allergy type II (antibody-mediated) 96-97 see also autoimmune disorders/disease type III (immune complexmediated) 97 type IV (delayed) 97 diseases associated 101-102 granulomatous 101-102 hypersplenism 1224-1225 causes 1225t (3 thalassaemia 1216 hypertension accelerated-phase 592 acromegaly 905cs adrenocortical hyperplasia 600 ambulatory blood pressure monitoring 595 antecedent, heart failure 491 benign intracranial 1358 blood tests 595 borderline 591 causes of renal disease 1083 cerebrovascular disease and 1331, 1332t, 1343 cerebral haemorrhage 1338 cerebral infarction 1312,1337, 1338 TIA risk factor 1332t, 1333 chest X-ray 595 clinical features 594—595 complications 596 Conn's syndrome 600 control 1011,1012,1015 definitions 590-591 diabetes association 1011,1012, 1015 drug treatment 597-599, 597t

ACE inhibitors 598 B-adrenoreceptor blockers 598 calcium antagonists 598 combination therapy 599 diuretics 598 drug selection 598-599 hypertensive emergencies 599-600 methyldopa 598,599 sympathetic ganglion blocking drugs 598 ECG 595, 595f eclampsia and pre-eclampsia 592 encephalopathy 1312,1338 endocrine disorders causing 890 essential 592 drug treatment 597-599, 597t investigation 595-596 isolated systolic 592, 596 labile 591 malignant 592 drug treatment 599 management 1343 optic fundi, blood vessel abnormalities 1291-1292, 1293f phaeochromocytoma 938 poisoning 17,17t in pregnancy 592 drug treatment 599 primary 591-592 isolated systolic hypertension 596 white coat hypertension 595 pulmonary see pulmonary hypertension renal see renal hypertension renal angiography 596 renal disease association 593,1045 renal failure 600 risk stratification 591 secondary 593-594, 594t causes 593t coarctation of aorta 594 Cushing's syndrome 593 drug-induced 594 endocrine disease 593 hyperaldosteronism 593 phaeochromocytomas 593-594, 600 renal disease 593 Sipple's syndrome 593-594 SLE 1174 sodium intake 136 special community groups 591 treatment methods 597-600 dietary measures 597 drug treatment see above drug withdrawal 597 exercise 597 non-pharmacological methods 597 relaxation 597 treatment suitability 596 ultrasound techniques 596 urine tests 595 white coat 591-592, 595 see also blood pressure; renal hypertension hypertensive encephalopathy 1312, 1338 hyperthermia, poisoning 17t hyperthyroidism see thyrotoxicosis hypertrichosis 435 drug-induced 419 hypertrichosis lanuginosa 420-421, 420f hypertriglyceridaemia familial 1023-1024

management 1026 hypertrophic cardiomyopathy 571-572 aetiology 571-572 asymmetrical septal hypertrophy (ASH) 571 cardiac carcinoid 573 clinical features 572 genetics 571ra investigation 572 management 572 obstructive (HOCM) 571 pathology 571-572 hypertrophic pulmonary osteoarthropathy 619 hypertrophy, muscle 1403,1404 hyperuricaemia associated conditions 1167 asymptomatic 1171 causes 1166-1167 prevalence 1166,1166f psoriatic arthritis 1151 see also gout hyperventilation 610 panic attacks 213,214 hyperviscosity 1259 hypervitaminosis A, benign intracranial hypertension and 1358 hypnagogic hallucinations, narcolepsy 1329 hypnotics 187 in elderly 188-189,189f overdose management 23-24 hypoadrenalism, neurological symptoms 1434 see also adrenocortical insufficiency hypoalbuminaemia in hookworm infection 361 hypocalcaemia due to 972 pleural effusion 711 hypoaldosteronism 937 hypocalcaemia 972-974 causes 957. 972-973,973t specific 973-974 clinical features 974, 975cs coeliac disease 789 differential diagnosis 974 hypomagnesaemia with 957, 974 malaria 347 management 974, 975cs neurological involvement 1407 in osteomalacia 974 parathyroid hormone synthesis 955, 972, 973 physiology 972-973, 973t psychosis and CNS effects 890 secondary hyperparathyroidism 889, 972, 973 hypochondriasis 214 hypocitraturia 1090 hypogammaglobulinaemia 1259 acquired (CVID) 87-88, 90-91cs transient, of infancy 89 hypoglossal nucleus 1301 hypoglycaemia 1018-1021 autoimmune 1019 case study 1021cs causes 1018-1019,1019t endocrine dysfunction 1018-1019 ethanol-induced 1019 gastrointestinal disease 1019 hepatic disease 1019 insulin-induced 990-992,1019 see also insulin treatment malaria 1019 pentaminide-induced 1019

1473

1474

starvation 1019 sulphonyurea-induced 998,1019 tumours 1018 clinical features 991,1019-1021 autonomic features 1019 neurological involvement 1432 symptoms/signs 9911 contributing factors 1018 alcohol 990-991, 1019 diet 990, 1019 exercise 990-991, 993,1019 medication 990 definition 1018 diabetic nephropathy 1012 diagnosis/investigation 991, 1020-1021,1020f hypoglycaemia provocation tests 1020 Whipple's triad 1020 functional (idiopathic) 1019 management 991-992, 991t, 1020-1021 mild episodes 991 severe episodes 991-992 neonatal 1019 nocturnal 991,992 pituitary hypofunction 897 reactive 1019 self-induced (factitious) 1019 stress effects 1020 unawareness 991 Wernicke-Korsakoff syndrome 1432 hypoglycaemic agents, oral 997-999, 998t hypogonadism after puberty 942 male 942-943, 944f hypokalaemia 1067,1111-1112 causes llllt, 1112 Conn's syndrome (primary hyperaldosteronism) 937 investigations 1111-1112 management 1112 neurological involvement 1407, 1433 periodic paralysis 1112,1407 severe congestive cardiac failure 494 hypokalaemic periodic paralyses 1112,1407 hypokinesia, basal ganglia lesion 1302 hypomagnesaemia 956-957 hypocalcaemia with 957, 974 neurological involvement 1407 hypomania 226, 228 hyponatraemia 1107cs ascites 872 central pontine myelinolysis ' (CPM) 1441 evaluation 1106f inappropriate secretion of ADH 911 neurological involvement 1432 treatment 1106ra water excess 1104,1106 hypoparathyroidism calcium absorption reduction 972 DiGeorge's syndrome 92 hypocalcaemia due to 972, 973-974 idiopathic 973-974 management 974 postsurgical 975cs hypocalcaemia due to 973 thyroid surgery and 922 hypophosphataemia familial 964

plasma measurements 965t X-linked 964 treatment 965 hypophosphatasia 978 hypopigmentation 427-428,428t hypopituitarism, anterior children 897, 898f clinical features 897 hypothermia 46 investigations 897-899 management 899-901, 901t pregnancy 895 stupor 890 surgery/radiotherapy causing 906 see also panhypopituitarism; pituitary gland (anterior); pituitary gland (anterior), hypofunction hypopituitary crisis 897 hypoplastic anaemia 1211-1214 acquired 1211-1214 aetiology 1212 clinical features 1212 laboratory features 1212 congenital/inherited 1211 management 1212-1214,1213t bone marrow transplantation 1213-1214 specific 1213 support 1212-1213 hypospadias 949 hyposplenism 752-753 hypotension Addison's disease 931 chronic idiopathic 1322 endocrine disorders causing 890 management 727f in head injury 744 orthostatic see postural hypotension poisoning 19 postural see postural hypotension sepsis 734, 736 hypotensive cerebral infarction 1338 hypotensive treatment, stroke management 1343 hypothalamic hormones 893t hypothalamus antidiuretic hormone action 1099 causes of amenorrhoea 946-947 disorders, thirst mechanism interference 1103 hypothermia 46-47. 47t ECG 47,47f in elderly 178-179,179f in hypothyroidism 917 poisoning 17t sickle cell disease 1218 hypothyroidism adult 916-918 autoimmune 889, 914 clinical features 915-917 gastrointestinal 891 neurological 890,1434 coma 890 congenital 915-916, 916t familial 70f screening 75t hypothermia 46 investigations 914-915,917 juvenile 916,917 laboratory assessment 914-915 management 917-918 guidelines 916t myopathy 1407 prevention 917, 918 . primary 915-918 see also myxoedema

secondary (pituitary), investigations 915 hypoventilation 610 hypovolaemia 911 acute renal failure and 1050 see also water, depletion hypoxanthine-guanine phosphoribosyl transferase, deficiency 1167 hypoxia cyanosis 619 main causes 610 neurological involvement 1432, 1432t ventilation-perfusion (V/Q) abnormalities 610 hypoxic-ischaemic encephalopathy 1432 hysteria 209, 233, 235-238 classification and clinical features 235-237 diagnosis 236-237 dissociation (conversion) disorders 233 epidemic 236 management 237-238, 237t meaning and aetiology 237 monosymptomatic (conversion disorder) 235-236 polysymptomatic (Briquet's syndrome, somatization disorder) 236 psychological mechanisms 236t hysterical psychosis 236

I iatrogenic disease, Creutzfeldt-Jakob disease (CJD) 1351 IBS see irritable bowel syndrome (IBS) ibuprofen 1141ra nephrotoxicity 1086 rheumatoid arthritis 1140 ichthyosis 405, 405f acquired 405, 421 sex-linked recessive 405 vulgaris 405 ICP see intracranial pressure ICU see intensive care unit (ICU) idealization 216-217 idiopathic erythrocytosis 1242 idiopathic interstitial pneumonia 695-696 idiopathic pulmonary haemosiderosis 696 id reaction 389 IHD see ischaemic heart disease ileal dysfunction/resection 794-795 ileitis 811-812 ileostomy complications 814 ulcerative colitis 814 illusion, definition 1287 imaging hypopituitarism 898-899 infectious diseases 262 kidney and urinary tract 1041-1043 pyrexia of unknown origin 277 thorax/respiratory system 623-627 see also specific imaging methods imidazoles 267 imipenem 265 imipramine 222

immobilization, soft tissue rheumatism 1200 immune complexes 97 SLE 1174 type III hypersensitivity 97 immune evasion mechanisms 79 immune response impairment 260-261 nervous system 1422 multiple sclerosis aetiology 1409 primary 80, 81f regulation 84-85 secondary 80, 81f immune system/immunity 79-85 adaptive 79, 79t, 80-85 functions 79 impairment 260-261 innate 79-80, 79t, 260 evasion by microorganisms 79 rheumatoid arthritis aetiology 1131 mucosal 81 overactivity see hypersensitivity underactive see immunodeficiency immunization 271-272 abnormal response, in common variable immunodeficiency 90cs active 271-272 contraindications 272 passive 272 travel 273, 273t UK schedule 272t see also vaccination immunocompromised patient cytomegalovirus infection 269 infectious disease 269-271 microorganisms causing 269t live vaccines 272 meningitis and 1414 pneumonia 270t progressive multifocal leukoencephalopathy 1427 reactivation of herpes virus 270 see also immunodeficiency; immunosuppression immunodeficiency 85-96 acquired 269 chemotherapy induced 163 primary diseases (PID) 80, 85-95 antibody deficiency 86-89 cellular (T cell) 91-92 combined 92-93, 94t complement deficiencies 89-91 diagnosis and investigations 86 hyper-IgM with 89 infection characteristics 86 phagocytic 93-95, 94t severe combined immune deficiency 93, 94t warning signs 86. 86t see also antibody deficiency diseases secondary 95-96 syndromes involving skin 437 immunofluorescence, anti-DNA antibodies 1173 immunoglobulin(s) class switching 82 defective 89 functions 82t hypervariable regions 81f, 82 immunoglobulin-producing cells, tumours 1259-1262 intravenous see intravenous immunoglobulin (ivIg) light chains, glomerular filtrate 1033

production in multiple myeloma 1260t secretory chain (Sc) 81-82 somatic mutations 82 structure 81,81f, 82t see also antibodies immunoglobulin A (IgA) 81-82 deficiency 88, 90cs glomerular injury 1068 nephropathy (Berger's disease) 1074 secretory 81-82 immunoglobulin D (IgD) 82 immunoglobulin E (IgE) 82 food allergy 98 immunoglobulin G (IgG) 81 actions/functions 81 glomerular injury 1068 glycosylation defect and rheumatoid factors 1126 mesangiocapillary glomerulonephritis 1074 primary antibody deficiencies 87 rheumatoid factors 1126 structure 81,81f subclass deficiency 88 immunoglobulin M (IgM) 81 glomerular injury 1068 immune deficiency with hyper IgM 89 rheumatoid factors 1126,1126t immunological disorders 79-104 in rheumatoid arthritis 1132 see also autoimmune disorders/disease; immunodeficiency immunological memory 80 immunology, investigations in musculoskeletal diseases 1124-1127 immunopathogenesis, rheumatoid arthritis 1131-1133,1132f, 1133ra immunosuppression 102-104 'biological' 103-104 bone marrow transplant 1213 hypoplastic anaemia 1213 liver transplant 882 new strategies/agents 103-104 renal transplantation 1061 strongyloidiasis 1213 toxoplasmosis reactivation 343 immunosuppressive drugs 102-104 cytotoxic 102-103 dermatomyositis/polymyositis 1180 immunodeficiency due to 95 multiple sclerosis treatment 1412 myasthenia gravis 1401 non-cytotoxic 103 rheumatoid arthritis 1143 SLE 1176 vasculitis 1183 see also corticosteroid(s) impaired fasting glucose (IFG) 984 impaired glucose tolerance (IGT) 984, 999 impetigo 384-385, 385f impotence 256-257, 943-944 acromegaly 904 causes 944, 944t in elderly 189 investigations 943-944 macroprolactinoma 909 management 944 psychogenic 943-944 inborn errors of metabolism 69-72 glycogen storage diseases 1028-1029

hypoxanthine-guanine phosphoribosyl transferase deficiency 1167 lysosomal storage diseases 1029 porphyrias 1026-1028 secondary heart disease 584, 584t see also genetic disorders, single gene inclusion body myositis 1406-1407 incontinence see faecal incontinence; urinary incontinence incretins 979 diabetes management 999ra indigestion 751 indometacin (indomethacin) ankylosing spondylitis 1150 gout 1170 rheumatoid arthritis 1140 side-effects 1140 industrial exposure to radiation 48 infantile hydrocephalus 1360 infantile spasms 1326t infants feeding practices 119 hypothyroidism 915-916, 916t protein 110 testes 940 B-thalassaemias 1215 transient hypogammaglobulinaemia 89 see also neonates infections/infectious disease control 271-273 Crohn's disease 809 diabetes mellitus 988 examination 261 history 260t in immunocompromised patient 269-271 incubation time of tropical diseases 277t leukocyte abnormalities 1234 microorganisms causing 259-261 see also microorganisms notifiable disease in UK 27It parenteral feeding 136 in primary immunodeficiency diseases 86,89,92-93 antibody deficiencies 86 characteristics 86 principles of diagnosis and management 261 in rheumatoid arthritis 1135 serious, persistent, unusual or recurrent (SPUR) 86 syndrome of infection 273-283 World Health Organization 260t see also individual diseases, microorganisms infectious mononucleosis (glandular fever) 287-288 arthritis 1161 chronic fatigue syndrome 283 clinical features 287-288 differential diagnosis 288 laboratory features 288 management 288 pathology and pathogenesis 287 see also Epstein-Barr virus (EBV) infective arthritis 1158-1162 bacterial infections 1158-1160 clinical features 1158-1159 diagnosis 1159 differential diagnosis 1159,1169cs fungal 1160 management 1159 viral infections 1160-1161,1161t infective endocarditis 574-580

acute bacterial 574 antibiotic therapy 578 blood cultures 577 Candida spp. 575 characteristics 574 classification 574 clinical features 576-577, 576t, 577t cardiac manifestations 576, 576t immunological phenomenon 576-577 Janeway lesions 577 joint manifestations 1159 Osier nodes 577 retinal lesions 577 Roth spot 577 systemic embolism 576 culture-negative 577 diagnosis 577 infecting organisms 575-576 management 577-578 pathogenesis 574-575 bacteraemia 574-575 embolism 575, 576 glomerulonephritis 575, 576 immune complex manifestations 575 pre-existing cardiac lesions 574 valve involvement 575 prophylaxis 578, 579t Staphylococcus aureus 574, 575 Staphylococcus epidermis (albus) 575 Streptococcus viridans 574, 575, 577 subacute bacterial (SEE) 574 surgery 578 syphilitic 578-579 see also syphilitic endocarditis tricuspid valve 578 valve replacement 578 see also endocarditis infertility chemotherapy 163 female, management 948-949 male androgen deficiency with 942-943, 944f causes 942t management 943 without androgen deficiency 941-942 thyrotoxicosis 919 inflammatory bowel disease 804-815, 805-808cs arthropathy associated 1153 see also Crohn's disease; ulcerative colitis inflammatory mediators 1203 rheumatoid arthritis pathogenesis 1132,1133 sepsis 734 inflammatory response erythrocyte sedimentation rate as indicator 1125 sepsis 734 infliximab, rheumatoid arthritis treatment 1146 influenza virus infection 290-292 complications 291 epidemiology 290-291 management and prevention 291-292 pandemics 291 pneumonia following 291 vaccine 291-292 infrapatellar bursitis 1197 infraspinatus lesions 1194

inhalation pneumonia 637-638 inhaled p-agonists, bronchiectasis 649 inhalers, metered-dose, asthma 657 inheritance dominant and recessive 64-65, 64f 'dominant negative,' IFNyR deficiency 95 polygenic 72 X-linked 64f, 65f see also genetics inhibin 895 innate immunity see immune system/immunity, innate inorganic mercurials, poisoning 39 inosine monosphosphate dehydrogenase (IMPDH) 102 inositol 1,3,4-trisphosphate (IP3), hormonal action mediated by 885-886, 885f inotropic agents in heart failure management 731, 732t negative 732 inotropy 465 insect bites 394 insecticides, poisoning 37-38 insect repellent 273 insight in psychosis/neurosis 208 testing 1286 insomnia, in elderly 187-189 causes 188, 188t inspiratory pressure support 741 ventilation 740 insulin 979-980 allergies 992 clearance from circulation 979 counter-regulation 980-981 catecholamines 980 cortisol 981 glucagon 980 growth hormone 981 loss 991 see also hypoglycaemia somatostatin 981 stress effects 981, 993 see also specific regulators diabetes management see insulin treatment dynamic test in pituitary hypofunction 898, 899f exercise-induced hypoglycaemia 990-991,993 hyperkalaemia 1112 mechanism of action 886. 886f metabolic actions 979-980, 980t intracellular 981f preparations see insulin treatment receptor 980, 981f signalling pathway 886 resistance 993 clinical 993 immune 992 obesity link 995 see also obesity syndrome X and 995,1015, 1015f type 2 diabetes 995. 995f secretion 979, 980f, 981f basal 979,990 defective 995 see also diabetes mellitus diurnal 979, 980f fasting 983 first-phase 979 in hypoglycaemia 1020 incretins 979

1475

1476

post-prandial 979, 983, 990 prolonged starvation effects 983 second-phase 979 secretagogues 979, 997-998, 998t see also glucose secretory granules 980f stress effects 983-984, 993 sensitizers 999ra species differences 979, 988 structure 979, 980f synthesis 979 therapeutic see insulin treatment insulin Glargine 989 insulinitis 986-987 insulin-like growth factor-1 (IGF-1) 886 assay in acromegaly 904-905, 905cs bone growth/mineralization 954 secretion control 894f insulinomas diagnosis 1020,1020f hypoglycaemia 1018,1020 treatment 1020 insulinopathies 979 insulin sensitizers 999ra insulin treatment 988-990 average daily requirement 992 delivery devices 990,1005 continuous subcutaneous infusion (CSII) 990, 993 intraperitoneal infusion 990 pen devices 990 diabetic ketoacidosis 1005,1006t dose timing 990 gestational diabetes 1003 human vs animal insulin 988 hyperosmolar (non-ketogenic) coma 1007 injection area 990, 992 preparations 988-990, 989t modified 994ra problems 990-993 allergic response 992 brittleness 992-993 delivery devices 990 hypoglycaemia 990-992 insulin resistance 992, 993 intercurrent illness 993 lipoatrophy 992 lipohypertrophy 992 poor overnight control 992 starting treatment 992 variable absorption 991 wrong dose 990 see also hypoglycaemia prolonged-action insulins 989, 989t, 992 insulin Glargine 989 insulin-zinc suspensions 989 isophane insulins 989 premixed (biphasic) 989 regimens 989-990 basal-bolus 989,992 intensified 990 meal-coordination 994 new patients 992 short-acting insulin analogues 989, 989t short-acting (soluble) insulins 988-989, 989t 'sick-day' rules 993, 993t standard concentration 988 type 2 diabetes 999 insulin-zinc suspensions 989 integumentary systems, endocrine disorders affecting 891 intellectualization 217

intensive care unit (ICU) 725-750 common causes for admission 726t history 725 malaria treatment 351 outcome 750, 750t typical bed side 726f intercostal muscles 718 interferon(s) 79, 268-269 resistance to viruses 260 sources and functions 85t interferon-a (IFN-a) 268-269 chronic HBV 865 chronic HCV 865 chronic myeloid leukaemia 1239 essential thrombocythaemia 1243 multiple myeloma 1261 non-Hodgkin's lymphoma 1256 interferon-p, multiple sclerosis treatment 1412 interferon-y (IFN-y) cutaneous leishmaniasis 357 receptor (IFNyR), deficiency 95 interleukin(s) effect on bone metabolism 956 sources and functions 85t interleukin-1 (IL-1) effect on bone metabolism 956 inhibitors, rheumatoid arthritis treatment 1146 rheumatoid arthritis pathogenesis 1132 interleukin-3 (IL-3) 1202 interleukin-5 (IL-5) 1202 monoclonal antibodies 103 interleukin-6 (IL-6), rheumatoid arthritis pathogenesis 1132 interleukin-8 (IL-8), receptor antagonists 103 interleukin-12 (IL-12), defective 95 interlobar arteries 1032 intermittent claudication 602-603 diagnosis/investigation 603 management 603 International Headache Society 1309 International Normalized Ratio (INR), oral anticoagulants 1277 International Sensitivity Index (ISI), oral anticoagulants 1277 interpersonal therapy, depression 221-222 interphase 63 interstitial fluid compartment 1099 interstitial lung disease 628-629 diffuse 692-697 pulmonary hypertension 675 interstitial pneumonia 695-696 interstitial pneumonitis, cytomegalovirus (CMV) 288-289 intervertebral discs 1185-1186 anatomy 1186 ankylosing spondylitis 1148 degenerative changes 1186 diagnosis 1188 infections 1189cs lumbar, lesions 1186 protrusions/prolapses 1186,1186f, 1187f, 1188 case study 1189-1190cs pain 1188 sites/direction 1186f, 1189cs intestinal angina 795 intestinal disease amoebiasis 341 functional 817-823, 819-820cs aetiology 818, 820

clinical features 820-822, 820t examination 822 incidence 817-818 investigation 822-823 management 822-823 prognosis 822 investigations 340-341 pyrexia of unknown origin 275 self-induced 823 trichinosis 369 see also colorectal disease; gastrointestinal disease; irritable bowel syndrome (IBS) intestine digestion and absorption 758-759, 759f examination, elderly 192 large secretion syndromes 759t see also colon; entries beginning colorectal small see small intestine intra-aortic balloon counterpulsation, cardiopulmonary resuscitation 520 intra-aortic balloon pump (IABP) 732 intracellular fluid (ICF) 1099 ion distribution 1100f intracerebral haematomas 1370, 1370f intracranial abscess 1417-1419 aetiology 1418 bacteriology 1418 cerebral see cerebral abscess cerebral oedema 1418 clinical features 1418 extradural 1418 intracranial pressure 1418,1419 investigation 1418-1419,1418f management 1419 meningitis complications 1414, 1417 subdural see subdural empyema (abscess) intracranial haematomas see under haematoma intracranial haemorrhage 1371 intracranial pressure cerebral tumours 1352,1357 management 1357 control 744-745 headache 1307 head injury 743-744 intracranial abscesses 1418,1419 management 1417,1419 meningitis 1416,1417,1420 pressure-volume relationship 743f see also cerebrospinal fluid (CSF); hydrocephalus intraretinal microvascular abnormalities (IRMA), diabetic retinopathy 1009 intrasellar tumours 895 intrathecal methotrexate, acute lymphoblastic leukaemia 1247 intravascular coagulation renal involvement 1078-1079 see also disseminated intravascular coagulation (DIC) intravenous drug abuse infective endocarditis 574 see also drug dependence/abuse intravenous fluids, diabetic ketoacidosis 1005,1006t

intravenous immunoglobulin (ivIg) common variable immune deficiency 88 high-dose therapy 103 immune deficiency with hyper-IgM 89 primary antibody deficiencies 87 self-administration 87 side-effects 87 transient hypogammaglobulinaemia of infancy 89 intravenous urography (IVU) kidney 1041,1041f recurrent haematuria 1064 urinary tract 1041,1041f infections 1084 stones 1089 introns 82 intubation 519 inulin, measurement of GFR 1039 inverted supinator reflex 1377 investigation 1346 iodide, transport 912 iodination 912 iodine deficiency 127 organification 912 radioactive see radio-iodine treatment reference nutrient intake 125t water sterilization 273 iodotyrosine 912 ionizing radiation, leukaemia 1236 ipecacuanha, syrup 20 iritis, ankylosing spondylitis 1150 iron deficiency 1208cs gastrointestinal disease 751 paroxysmal nocturnal haemoglobinuria 1226 see also iron deficiency anaemia levels haemochromatosis 869 musculoskeletal diseases 1125 overload blood transfusion 1231 in (3 thalassaemia 1216 poisoning 43, 43t reference nutrient intake 125t renal failure 1057 replenishment, gastrointestinal bleeding 775 retention by reticuloendothelial cells 1124-1125 supplementation, iron deficiency anaemia 1207 total iron-binding capacity (TIBC) 1207 uptake 1207 iron deficiency anaemia 1206-1207 aetiology and investigation 1207, 1207f clinical features 1207 diagnosis 1207 hookworm infection 361 management 1207 pathophysiology 1206-1207 iron dextran 1207 iron-responsive element-binding protein (IRE-BP) 1207 iron-sorbitol-citric acid complex (Jectofer) 1207 irradiation carcinogenic effect 148 cranial, acute lymphoblastic leukaemia 1247 testicular, acute lymphoblastic leukaemia 1247

total body, chronic myeloid leukaemia 1239 irritable bowel syndrome (IBS) 783. 817 aetiology 818, 820 clinical features 820-822 differential diagnosis 821t ischaemia cerebral see cerebral ischaemia diabetic foot 1016-1017 limb 1397 myocardial 567 renal 1047 retinal see retinal ischaemia small intestine disease 795, 795t vertebrobasilar arteries 1320 ischaemic colitis 817 ischaemic heart disease 463 see also coronary artery disease ischaemic preconditioning 548ra ischaemic ulceration, diabetic foot 1016-1017 Ishihara charts 1290 islet-cell antibodies (ICA) 987 islet cells, malignancy 833 islets of Langerhans amylin deposits 995 glucagon secretion (a cells) 980 insulin secretion (P cells) 979 diabetic insulinitis 986-987 secretory granules 980f tumours 1018 type 2 diabetes 995, 996 see also diabetes mellitus; insulin somatostatin secretion (5 cells) 981 transplantation 994, 994ra isochromosome 62 isoflurane 749t isoniazid, overdose 33 isophane insulins 989 isoprenaline, inotropic therapy 732t isopropanol (isopropyl alcohol), overdose 36 Isospora belli infection 342 itraconazole 267 madura foot 331 ivermectin cutaneous larva migrans 361 onchocerciasis 365 strongyloidiasis 363

J Jaccoud-type arthropathy 1174 Janeway lesions 577 Janus (JAK) family 886 Japanese B virus 1422 jaundice 845-846, 846cs cholestatic 856-859, 856t clinical features 845, 845t cytomegalovirus 851-852 differential diagnosis 845 drug-induced 852-853 haemolytic 846 investigations 845-846 malaria 347 pancreatic tumours 832 paroxysmal nocturnal haemoglobinuria 1226 physical examination 845 pregnancy 855 without bilirubinuria 840 jaw jerk 1298

jerk nystagmus 1299 Jod-Basedow phenomenon 918 joint(s) 1119-1121 aspiration 1127 method 1169cs rheumatoid arthritis 1143 bleeds, haemophilia A 1273 clinical features, onset of symptoms 1122 crepitus 1124 deformity 1123-1124,1124f contributory factors 1124t knee 1124f rheumatoid arthritis 1134,1134f see also flexion deformity destruction in rheumatoid arthritis 1131.1132 erosions, rheumatoid arthritis 1127 examination 1122-1123,1123t instability 1124 pain see arthralgia palpation 1123 range of movement 1124 replacements, rheumatoid arthritis 1146 rheumatic diseases, patterns of involvement 1123,1123f, 1123t sensation 1120 spaces, narrowing, rheumatoid arthritis 1127 stiffness management 1140 musculoskeletal diseases 1122 osteoarthritis 1155 rheumatoid arthritis 1134, 1144cs stress pain 1124 structure and function 1119-1121, 1120f swelling causes 1123 rheumatoid arthritis 1134 tenderness 1124 joint capsule 1119 sensory innervation 1120 structure and function 1119,1120f thickening 1123 joint diseases dermatological signs 1123t ophthalmic complications 1123t polyarticular, patterns 1123t Jowell-Lang-Nielsen syndrome 517 judgement, testing 1286 jugular foramen syndrome, glomus tumour 1356 jugular venous pressure (JVP) 620 jugular venous pulse (JVP) 471-472 arterial (carotid) pulse differentiation 471t cannon waves 472 pericardial tamponade 471 water homeostasis and 1101 waveform 472, 472f junctional tachycardias 513-514 AV nodal tachycardia 513-514 AV re-entry tachycardia 513-514, 513f management 513-514 non-paroxysmal AV nodal 514 paroxysmal supraventricular tachycardia 513-514, 514t prevention 514 juvenile chronic myeloid leukaemia 1240 juvenile idiopathic arthritis (JIA) 1162-1164 diagnosis and classification 1162

enthesis-related 1163-1164 management 1163-1164 oligoarthritis 1163 poly articular-onset 1163 psoriatic arthritis 1163 systemic 1162-1163,1162f juxtaglomerular apparatus (JGA) 1032 tubular acidosis 1067

K Kallmann's syndrome 942, 944f, 947 Kaposi's sarcoma 425-426 HIV/AIDS infection 439f, 449-450 human herpesvirus type 8 289 Kartagener's syndrome 648 karyotype, nomenclature 62 katayama syndrome, schistosomiasis 372 Kawasaki's disease 601,1182 Kayser-Fleischer rings 870,1366 keloid 422-123 Kennedy's syndrome 61t keratin 379 keratinocytes 379 keratoacanthomas 422 keratoconjunctivitis 287 adenoviruses 290 keratoderma blennorrhagica 1152 keratosis, actinic (solar) 423, 423f kerion 391 Kernig's sign 1414 ketamine 749t ketoacidosis, diabetic see diabetic ketoacidosis (DKA) ketoconazole 267 Cushing's syndrome treatment 936 Histoplasma capsulatum 333 madura foot 331 ketogenesis 982-983, 983f creatine shuttle 982 fatty acyl-CoA substrate 982 glucagon stimulation 980, 982 insulin inhibition 983 ketone bodies 982 CNS metabolism in starvation 838 formation see ketogenesis prolonged starvation 983 urinalysis 1000 uses 983 kidney anatomy 1031-1032,1033f artificial 1059 biopsy see renal biopsy blood flow 1032 calculi see urinary tract stones carcinoma see renal tumours cystic disease 1080-1081,10801 damage, malaria 347 disease see renal disease drugs elimination 1097,1097f prescribing 1097-1098,1097t function see renal function glutamine metabolism 1115f hypertension see renal hypertension imaging 1041-1043 microanatomy and physiology 1032-1077,1032t, 1033f nerve supply 1032 rheumatoid arthritis 1137-1138

specific homeostatic functions 1034-1037 body water regulation 1034-1035 calcium/phosphate metabolism regulation 1037 endocrine function 1037,10381 potassium content regulation 1035-1036 sodium content regulation 1035 transitional cell carcinoma 1091-1092 transplant see renal transplantation tumours see renal tumours urinary tract obstruction effect 1090 water excretion rate 1035 see also entries beginning nephro-; entries beginning renal kidney disease see renal disease Kimmelstiel-Wilson nodular lesions 1011 kinin system, activation, angioedema 98 Klebsiella 315,1418 antigens and HLA-B27 mimicry 1147_1148 lung abscess 648 pneumonia 639 Klinefelter's syndrome 68, 944f androgen deficiency 942 Klippel-Feil deformity 1385 Klumpke's paralysis 1399 knee joint effusion 1157cs housemaid's 1136,1197 ligament injuries 1197 MRIscan 1120f osteoarthritis 1156cs painful 1196-1198,11971 rheumatoid arthritis 1134-1135 tendon lesions 1197 Koebner phenomenon 414 koilonychia (spoon-shaped nails) 435, 435f gastrointestinal bleeding 772 gastrointestinal disease 751 Koplik's spots 293 Korsakoff s psychosis 124,1438cs Korsakoff s syndrome, pituitary tumours features similarity 896 Kugelberg-Welander syndrome 1391 Kupffer cells 836 Kuru 1351 Kussmaul breathing see acidotic (Kussmaul) breathing Kussmaul's sign 587 Kveim test 686 kwashiorkor 121 kyphosis 1380

D labour, diabetic patients 1003 laburnum (cytisine), ingestion 39-40 B-Lactalbumin 907 p-Lactamase, antibiotic resistance 264 p-Lactamase-resistant penicillins 265 p-Lactams 265 ring structure 264f lactase deficiency 793

1477

1478

lactate concentration, peripheral hypoperfusion and 730 lactate dehydrogenase, myocardial infarction 557, 558t lactation nutritional requirements 120 see also breastfeeding lactic acid metabolism 1113 lactic acidosis diabetes 1007 metformin causing 998 see also metabolic acidosis lactose maldigestion, giardiasis 336 lactotrophs 907 lactulose 875 lacunar infarcts 1337,133711337t, 1351 Lambert-Eaton myaesthenic syndrome 1401-1402,1435 lamivudine, chronic HBV 865 lamotrigine, epilepsy treatment 1327ra, 1328,1328t Langerhans, islets see islets of Langerhans Langerhans' cell(s) 380 Langerhans' cell histiocytosis (histiocytosis X) 95, 1257-1258 laparoscopy cholangiography 843 ovarian cancer 156 laparotomy, colorectal carcinoma 802 Laplace equation 467 large cell (undifferentiated) bronchial carcinoma 701, 702t Laron dwarfism 901 laryngeal oedema, Cl-inhibitor deficiency 91, l0lcs larynx, examination 1301 laser transmyocardial revascularization 554ra lassa fever 298-299 clinical features 299 diagnosis 299 management 299 transmission 299 lateral femoral cutaneous nerve entrapment 1199 lateral geniculate body 1290 lateral medullary infarction (Wallenberg syndrome) 1336 lateral popliteal nerve, lesions 1199 latex agglutination, rheumatoid factors 1126,1126f latrines, ascariasis prevention 360 law see legal issues laxatives 798 abuse 793, 823 functional bowel disorders 823 LDL see low-density lipoprotein (LDL) lead poisoning 43 learned helplessness 221 learning difficulties 252-253 following leukaemia therapy 1248 LE cells 1174-1175 lecithin, transport in bile 837 leflunomide rheumatoid arthritis 1143ra, 1145 side-effects 1145 left heart failure acute 491,492 aortic stenosis 527 left atrial myxomas 582 left- vs. right-sided 490

mitral stenosis 521, 522 pleural effusion 711 radiological features 482f left ventricular dysfunction 567, 568, 731-732 management 731-732 legal issues mental health legislation 253-255 see also mental health legislation opiate abuse 245 psychiatry 253 legionella pneumonia 633 leg length, differences 1191 leg pain, osteoarthritis 1156cs leg ulceration 429-430, 429t arterial 430 Felly's syndrome 1122 venous 429-430, 430f Leishmania, life cycle 355f Leishmania chagasi 357 Leishmania donovani 357 Leishmania infantum 357 leishmaniasis 355-358, 356t cutaneous 355-357, 356f aetiology, distribution and incidence 356, 356f clinical features 356-357 diagnosis/differential diagnosis 357 management 357 pathology and pathogenesis 356 prevention and control 357 transmission and epidemiology 356 visceral 357-358 Leishmania tropica 356 LEMS (Lambert-Eaton myaesthenic syndrome) 1401-1402,1435 lens dislocation, Marfan's syndrome vs homocystinuria 72cs lente insulins 989 lentigo maligna (Hutchinson's freckle) 424 leonine facies 328 leopard skin, onchocerciasis 365 lepromin skin 326 Lepromin test 101 leprosy (Hansen's disease) 325-328 aetiology 325-326 borderline (BB) 327 borderline lepromatous (BL) 327-328 borderline tuberculoid (BT) 327 clinical features 327-328, 327t diagnosis 328 distribution and incidence 326, 326f indeterminate 327 lepromatous (LL) 101, 328 management 328,328t neuropathy 1398 pathogenesis and pathology 326-327, 327f prevention and control 328 reactional states 328 reversal reactions 327, 328 transmission and epidemiology 326 tuberculoid 101,327 leptin 128 Lesch-Nyhan syndrome 1167 leucoencephalopathy, acute haemorrhagic 1412 leukaemia acute 1243-1249 blast cells 1236 children 1243 clinical features 1244

acute lymphoblastic (ALL) 1246-1249 chromosomal analysis 1247 classification 1247 diagnosis 1246 management 1247-1248 prognosis 1248,1248t subcategories 1247t acute myeloblastic 167 trials of treatment 167 acute myeloid (AML) 1236, 1244-1246 chromosome analysis 1244-1245 classification 1244 diagnosis 1244 management 1245-1246 prognosis 1246 subdivisions 1245t CD4+ 1259 CD8+ 1259 chronic lymphocytic (CLL) 1258 clinical features 1258 management 1258 prognosis 1258 chronic myeloid (CML) 1236, 1239ra acute transformation 1240 blastic crisis 1240 in childhood 1240 chromosomal translocations 69 clinical features 1238,1240 differential diagnosis 1238-1239 haematological features 1238 management 1239-1240 Philadelphia (pH') chromosome 1237,1238 growth rate 1236 hairy cell 1258-1259 hereditary/congenital factors 1236 ionizing radiation and drugs 1236 late effects 1248,1248t mortality 1244f neurological manifestations 1435 prolymphocytic 1258 pyrexia of unknown origin 275 second malignancies 1248 skin involvement 425 T-cell chronic 1259 treatment 1247f tumour lysis syndrome in 166 leukaemoid reaction 1238 leukocyte adhesion deficiency (type 1) 95 leukocytes 1205 causes of low count 1234t non-malignant abnormalities 1234-1235 oxidase system 1235f polymorphonuclear see neutrophils see also white cell count; specific cell types leukocytoclastic vasculitis 408,1183 leukodystrophies 1413,1413t leukonychia (white nails), gastrointestinal disease 751 leukopenia, SLE 1125 leukoplakia 762 leukotriene antagonists 657 levator palpebrae superioris, thyrotoxicosis 919 levetiracetam, epilepsy treatment 13281 levodopa adverse reactions 1363 autoimmune haemolytic anaemias 1223 MAO inhibitor effects 1364

Parkinson treatment 1363 Lewy body dementia 1348 Leydig cells 939, 940, 941f Libman-Sacks endocarditis 581 SLE 1174 lice 395 head (Pediculus humanus) 330, 395 lichenoid drug eruption 418 lichen planus 413-414,414f oral involvement 761 lichen sclerosus 415 Liddle's syndrome 937 lidocaine (lignocaine), plasma drug concentration 3f life expectancy 171,172f life support advanced 519-520 basic procedures 518t see also emergencies Li-Fraumeni syndrome 149 ligaments knee, injuries 1197 structure and function 1119 light reflex 1293-1294 limb-girdle dystrophy 1405 limbs, neurological examination 1285 limping gait 1290 linezolid 267 lingual lipase 760 linkage disequilibrium 73 lipaemia retinalis 1024 lipid-lowering agents post MI management 569 see also HMG-CoA reductase inhibitors (statins) lipid-modifying drugs 1024—1025, 1025t lipids cholesterol see cholesterol ethnic variations 1023 genetics 1023 hyperlipidaemia see hyperlipidaemia lipid-modifying drugs 1024-1025, 1025t metabolism 1021-1022 liver 838-839 see also fat(s), metabolism plasma measurement 1023 solubility, drug distribution 2 triglycerides 1021 uraemia 1056 see also fat(s) lipid storage diseases 1413,1413t lipoatrophy, injection sites 992 lipodystrophy, antiretroviral related 452 lipogenesis 982 insulin effect 980 lipohypertrophy, injection sites 992 lipolysis 982 cortisol stimulation 981 diabetic ketoacidosis 1003,1004 insulin inhibition 980 lipomas 422 spinal 1381 lipoproteins 838,1022f apoproteins 1021,1022 CHD risk factor 136-137 cholesterol-association 1021,1022 see also cholesterol in diet 113 disease-associations 1022 atherogenic lipid profile 1023 diabetic heart disease 1015 hyperlipidaemia see hyperlipidaemia

see also atheroma; atherosclerosis HDL see high-density lipoprotein (HDL) IDL (intermediate density) 1022. 1023 LDL see low-density lipoprotein (LDL) normal metabolism 1021-1022, 1022f endogenous pathway 1021-1022 exogenous pathway 1021,1022 VLDL see very low-density lipoprotein (VLDL) B-Lipotrophin (LPH) 893 liquid ecstasy, overdose 31 liquorice 926 Listeria infections 1430 HIV-related meningitis 1428 Listeria monocytogenes 313 HIV-related meningitis 1428 lithium carbonate 228 diabetes insipidus, drug-induced 1102 overdose 27 therapeutic monitoring 13 lithocholic acid 837 livedo reticularis 1174 liver abscess amoebic see amoebic liver abscess (ALA) pyogenic 880-881, 880t biopsy see liver biopsy blood flow 835 clotting factors 840t congenital disorders 881 disease see liver disease drug-induced damage 852-853, 852t glutamine metabolism 1115f hydatid cysts 378f lymphomas 877 metastatic disease 877 non-viral infections 879-881 poisonous plants 40 shunts, variceal haemorrhage 873 structure and function 835-839, 836f, 838f anatomy/microanatomy 835-836,837f bile acid metabolism and secretion 837-838 carbohydrate metabolism 838 drug metabolism 3-4, 839 lipid metabolism 838-839 protein metabolism 837-838, 838f in systemic disease 877-879 transplantation see liver transplantation see also entries beginning hepatoliver biopsy 843-844 complications 844, 844t extrahepatic portal vein obstruction 874 giant cell arteritis 1184 guidelines 844t hepatocellular carcinoma 876 indications and contraindications 843-844, 844t pyrexia of unknown origin 277-278 liver disease 835-882 anaemia 1227 cirrhosis see cirrhosis coagulation disorders 1274-1275 dietary factors 139 drug metabolism, effect 4

geographical variation 835 hypoglycaemia and 1019 inflammatory see hepatitis investigations 839-845 computed tomography 842 contrast radiology 842 endoscopic retrograde cholangiopancreatography 842-843, 843f magnetic resonance imaging 842, 842f oral cholecystography 842 percutaneous transhepatic cholangiography 842 positron emission tomography 842 scintiscanning 841-842 ultrasound 841,841f vascular studies 843 neurological manifestations 1432 see also hepatic encephalopathy non-hepatotropic viruses 851-852 polycystic disease 881 see also alcoholic liver disease; individual diseases liver failure acute 853-855 clinical features 853-854 coma 854t complications and management 854, 854t epidemiology 853 pathophysiology 853 assist devices 854, 855cs fulminant 1439 paracetamol poisoning 28, 29 liver flukes 879 liver function abnormalities in musculoskeletal diseases 1127 polymyalgia rheumatica and giant cell arteritis 1184 liver function tests 839-841, 840t impaired, non-hepatic causes 839t prothrombin time 840-841 serum alanine aminotransferase 841 serum albumin 840 serum alkaline phosphatase 841 serum aspartate aminotransferase 841 serum bilirubin 839-840 serum y-glutamyl transpeptidase 841 'liver palms' 860 liver transplantation 835, 854, 881-882,882f chronic HBV 865 chronic HCV 865 donors 882 indications 881 paracetamol poisoning 28, 29 primary biliary cirrhosis 868 results 882 Loa loa worm 368 loci, gene 63-64, 64f 'locked-in' syndrome 1336 lofepramine 222 Loffler's endocarditis 574 loiasis 368 long QT syndrome 517 loop diuretics 496 ascites 872 renal failure 1056 loopofHenle 1032 Looser's zones 965 lorazepam overdose management 23 status epilepticus 1328

lordosis, lumbar 1187 lormetazepam 189 louse-borne relapsing fever 330 louse-borne typhus 305-306 low back pain 1185-1192 acute, vertebral fractures in osteoporosis 961cs aetiology 1186,1186t, 1189cs, 1190-1191 age-related 1187t anatomy and biomechanics 1185-1186 case study 1189-1190cs chronic, management 1190 clinical features 1186-1187,1187t, 1189cs degenerative disease 1190-1191 examination 1187 inflammatory 1186-1187,1188t, 1191 investigations 1187-1188,11881, 1189cs management 1188,1190-1191. 1190cs mechanical 1186-1187,11881 management 1188 neoplastic 1187,11881,1191 low-density lipoprotein (LDL) 839, 1022 disease associations 1022,1023 diabetes mellitus 1015 hyperlipidaemia see hyperlipidaemia LDL-receptor, mutations 1023 metabolism 1022,1022f reduction 1025 Lowenstein-Jensen medium 328 lower limb entrapment syndromes 1199 see also entries beginning leg lower motor neurons lesions 1298, 1301,1302,1302f lower reference nutrient intake (LRNI) 107 Lown-Ganong-Levine syndrome 517 LSD abuse 247 overdose 31 Ludwig's angina 282 lumbar canal stenosis 1387 lumbar lordosis, flattening 1187 lumbar puncture benign intracranial hypertension treatment 1358 cortical venous thrombophlebitis 1419 meningitis 1416,1416t, 1420-1421 Naegleria fowleri 342 stroke investigation 1341-1342 subarachnoid haemorrhage 1344 venous sinus thrombosis 1419 see also cerebrospinal fluid (CSF) lumbar spondylosis 1386-1387,1387t lumbar supports, low back pain 1190 lumbrosacral plexus lesions 1400 lung abscesses 647-648, 647f causes 647t definition 647 Entamoeba histolytica 648 pneumonias 648 presentation 647-648 subphrenic, pleural effusion 712 assessment of oxygen uptake 737t biopsy open 630 transbronchial 629, 629f

transthoracic needle biopsy 629-630 cancer see lung cancer complications, HIV/AIDS infection 445-446, 446t dermatomyositis 1180 elastic recoil 605, 606 fields, chest X-rays 482-483, 625 function, Guillain-Barre syndrome 1398 function tests see lung function testing greater oblique fissure, X-ray 626 honeycomb 696 horizontal (minor) fissure. X-ray 624, 626 hyperinflation 608 infections see respiratory infections rheumatoid arthritis 1136-1137, 1136t rupture 51 systemic sclerosis 1178-1179 transplantation see lung transplantation ventilation-perfusion scans 679, 681,681f volume reduction surgery 667, 668ra volumes, static 606, 606f see also entries beginning pulmonary, respiratory, respiratory system lung cancer 147f, 700-710 alveolar carcinoma 707-708, 707f bronchial adenoma 708 diagnosis, bronchoscopy 628 haemoptysis 613 see also haemoptysis hamartoma 708 Hodgkin's disease and 1254 malignant pericarditis 587 management 705-707 advanced bronchogenic carcinoma 707 chemotherapy 706 continuous hyperfractionated accelerated radiotherapy (CHART) 707 endobronchial therapy 707 pain control 707 radiotherapy 706-707 surgery 705-706, 706f mediastinal tumours 709-710, 709f see also mediastinal tumours neurological manifestations 1434-1435 Lambert-Eaton syndrome 1401-1402,1402.1435 Pancoast tumour (apical) 152, 702t, 705f pleural see pleural tumours relative frequency 700t small-cell see small-cell lung cancer solitary pulmonary nodules 708-709,709f see also bronchial carcinoma lung disease chronic, cardiovascular system examination 475 diffuse interstitial 692-697, 696 pulmonary hypertension 675 iatrogenic 696-697 antibiotics 697 bleomycin toxicity 696 cytotoxic agents 696, 696t-697 methotrexate 697,1142

1479

1480

oxygen toxicity 697 radiation injury 697 occupational 692-694 see also pneumoconioses restrictive 608-609 veno-occlusive 675 see also respiratory disease lung function testing 611, 611t bronchiectasis 649 indications 611t patterns of abnormality 612t lung transplantation 674 candidate suitability 674t cystic fibrosis 651 heart-lung transplantation 500 indications 674, 674t lupoid hepatitis 877 lupus anticoagulant 1275 lupus erythematosus discoid 1175 drug-induced 418,1175 systemic see systemic lupus erythematosus (SLE) lupus nephritis, complement component levels 1127 lupus vulgaris 388, 388f luteinising hormone (LH) 895 actions, on testis and ovary 940t elevation 943t polycystic ovary syndrome 948 pulsatile secretion at puberty 940 reduced levels 943t secretion 895,940 surge, menstrual cycle 945f, 946 synthesis, stimuli and inhibitors 893t luteinization 945f, 946 luteinizing hormone-releasing hormone (LHRH) 164 Lutzomyia verrucarum 321 Lyme disease 330,1430 arthritis 1160 lymphadenopathy persistent generalized 443-444 sarcoidosis 686 see also lymph node enlargement lymphangiectasia 792 lymphangiography, Hodgkin's disease (HD) 1251 lymphatic filariasis 366-368 aetiology and transmission 366 clinical features 367 diagnosis/differential diagnosis 367 distribution and incidence 366 lifecycle 366f management 367 pathology and pathogenesis 366-367 prevention and control 367-368 lymphatic system chest X-rays 625 meningitis and 1414 lymph node(s) Hodgkin's disease 1250 structure 80 lymph node enlargement rheumatoid arthritis 1135 systemic juvenile idiopathic arthritis 1163 see also lymphadenopathy lymphoblasts, differentiation from myeloblasts 12451 lymphocytes 80-85,1205 infusion, bone marrow transplant 1240 origin 80 proliferation 1249-1250

recirculation 81 trafficking 80-81 see also B cells; T cells lymphocytopenia, SLE 1175 lymphogranuloma venereum 457-458 lymphography 156 lymphoid follicles, rheumatoid arthritis pathogenesis 1132 lymphoid organs primary 80 secondary 80 lymphomas 149 Burkitt's see Burkitt's lymphoma gastric B cell 785 high-grade see non-Hodgkin's lymphoma Hodgkin's see Hodgkin's disease (HD) liver 877 low-grade see non-Hodgkin's lymphoma neurological manifestations 1435 brachial plexus invasion 1400 cerebral 13521,1355,1428 progressive multifocal leukoencephalopathy 1427 pyrexia of unknown origin 275 skin involvement 425 small intestine 797 thyroid 924 lymphopenia Hodgkin's disease 1250 severe combined immune deficiency 93 lymphoproliferative disorders, secondary antibody deficiency 95-96 lymphoproliferative malignancy 1249-1262 B cells 1250f chronic lymphocytic leukaemia 1258-1259 histiocyte disorders 1257-1258 Hodgkin's lymphoma 1250-1254 non-Hodgkin's lymphoma 1254-1257 T cells 1250f tumours of immunglobulinproducing cells 1259-1262 see also individual malignancies lysergic acid diethylamide see LSD lysosomal storage diseases 1029 mucopolysaccharidoses 1029 sphingolipidoses 1029

M Machado-Joseph disease 61t MacLeod's syndrome 648 macroalbuminuria, diabetic nephropathy 1011, l0llf macroamylasaemia 827 macrocytosis 1125 folate deficiency 1125 a2-Macroglobulin 1266 macroglossia, acromegaly 904 macrolides 265 macrophage 79 foamy 326 macrophage inflammatory protein la(MIP-lcc) 1203 macroprolactinoma 908, 909 macrosomia, diabetic pregnancy risk 1002,1003

macrovascular disease contributing factors 1014-1015 diabetic complications 1008, 1014-1016 case study 1017cs examination/investigation 1015 management 1015-1016 manifestations 1015 syndrome X 1015,1015f macula densa 1032 maculopathy, diabetic retinopathy 1010 madura foot 331 Madurella mycetomatis 331 magic mushrooms 247 magnesium homeostasis 956-957 reference nutrient intake 125t supplementation 957 magnesium carbonate, renal failure 1057 magnetic resonance angiography (MRA) arteriovenous malformations 1345f carotid artery stenosis 1334f cortical venous thrombophlebitis 1419 dementia investigation 1346 stroke investigation 1342 venous sinus thrombosis 1419 magnetic resonance imaging (MRI) 486 cancer 156 cardiac investigation 486 central pontine myelinolysis 1441, 1441f chronic coronary artery disease 486 epilepsy 1327 intracranial abscesses 1418 knee joint 1120f liver disease investigations 842, 842f low back pain 1187-1188 multiple sclerosis 1411,1411f musculoskeletal diseases 1128 pituitary tumours 900f renal 1043,1044 respiratory disease 627 spinal cord lesions 1378,1379f myelitis 1382 Pott's disease 1381f rheumatoid arthritis 1380f syringomyelia 1383f spine 1128 stroke cerebral infarction 1335f, 1339cs small vessel disease 1338f tumours, cerebral 1353,1353f, 1354cs viral encephalitis 1423,1425f 'main d'accouncheur' 974 major histocompatibility antigens see HLA system malabsorption bile acids 794 calcium see calcium drug-induced 795,795t HIV/AIDS infection 446-447 postinfection tropical 792 small intestine 787 gastric surgery complication 780 malade-a-petite-papier 217 maladie de Roger 540 malaria 346, 350cs anaemia 347 chemoprophylaxis 351, 352t clinical features 347,348t

complications 347-348 late 348 diagnosis 348 differential diagnosis 348t distribution and incidence 344f, 345, 345f hypoglycaemia 1019 laboratory features 349 life cycle 345-346, 345f management 349-351 maternal immunity 346 pathogenesis and pathology 346-347 prevention and control 351 renal involvement 1071 sickle cell gene 1217 transmission and epidemiology 345-346 vectors 346 malarone, malaria treatment 351 Malassezia furfur 392 males infertility see infertility pseudohermaphroditism 949-950 causes 941,942t sex differentiation disorders primary 949-950 secondary 950-951 malignancy/malignant disease anaemia 1227,1227f genetic abnormalities 150t haematological 1235-1237 hypercalcaemia see hypercalcaemia lymphoproliferative disorders 1249-1262 neurological manifestations 1434-1435 pyrexia of unknown origin 275, 276 renal involvement 1077,1077t secondary following leukaemia 1248 Hodgkin's disease 1254 skin 420-426,4201 skin manifestations 420-426, 420t factors predisposing 424t urinary tract obstruction 1091 see also cancer; tumour(s); individual diseases malignant atrophic papulosis (Degos' disease) 409 malignant hyperpyrexia 46 malignant melanoma see melanoma, malignant malignant meningitis 1434,1435 malingering 237 Mallory's hyaline, alcoholic liver disease 861 Mallory-Weiss tear 772 malnutrition 122 alcohol abuse 863 in children 120-122,120t growth 121f management 121-122,122t organ changes 121 in elderly 180t gastrointestinal disease 751 protein-energy (PEM) 120 trichuriasis 363 malnutrition/infection syndrome 120 malnutrition-related diabetes mellitus (MRDM) 1000 Malta fever 318 malt worker's lung 694t mania 226, 228 manic-depressive psychosis 208, 232 manipulation, low back pain (mechanical) 1188,1190

mannan-binding lectin (MBL) 80 mannitol cerebral abscess management 1419 cerebral tumour management 1357 common bile duct stones 857 head injury 745 manometry, oesophageal pathology 763 mantle cell lymphomas 1256 Mantoux test 101, 641 pyrexia of unknown origin 277 maple bark stripper's lung 694t marasmus 121 marble bone disease 978 Marburg virus disease 298,299-300 march haemoglobinuria 1226 Marchiafava-Bignami disease 1436t Marfan's syndrome 71t, 72 acute aortic dissection 600, 601 aortic aneurysm 72cs cardiovascular system examination 469 homocystinuria vs 72cs lens dislocation 72cs range of movement of joints 1124 massive pulmonary embolism see pulmonary embolism mast cells degranulation 96 asthma 653, 654f epidermal activation in urticaria 98 matrix metalloproteinases inhibitors, osteoarthritis management 1157 rheumatoid arthritis pathogenesis 1132,1133 maturity onset diabetes of the young (MODY) 994,996 genetic factors 995, 996 McArdle (type IV) glycogen storage disease 1028,1407 McCune-Albright syndrome 941t MDR1 (multidrug resistance) gene 10 mean cell haemoglobin (MCH) 1206 iron deficiency anaemia 1207 mean cell haemoglobin concentration (MCHC) 1206 measles 293-294 clinical features 293, 293t complications 293-294 diagnosis 294 encephalitis 1423 epidemiology 293 immunization 294 immunodeficiency due to 95 management 294,294t mortality 294f neuropathy 1398 pathogenesis 293 subacute sclerosing panencephalitis 1422, 1426-1427 measles/mumps/rubella (MMR) vaccine 272,293,294, 295 mebendazole ascariasis 360 hookworm 361 hydatid cysts 879 trichinosis 369 mechanical support, myocardial function 732 Meckel's diverticula 772 meconium ileus 827 meconium ileus equivalent 827

median nerve, compression 1196, 1200,1393-1395,1394f see also carpal tunnel syndrome mediastinal emphysema (pneumomediastinum) 51, 716 mediastinal pain 618 mediastinal tumours 709-710,709f metastatic 709 neurogenic tumours 710 teratomas 710 thymomas 710 mediastinoscopy 630 mediastinotomy 630 medical exposure to radiation 48 Medical Research Council (MRC), muscle power grade 1303 medication misuse headache (MMH) 1310 medicine and emotions 255-256 Medicines Control Agency (MCA) 13,14 Medicines For Human Use Regulations (1994) 13-14 medulla infarction 1336 tumours 1381 medulloblastoma 1352t, 1355 radiotherapy 1357 Mee's lines, poisoning 17,18f mefanamic acid, autoimmune haemolytic anaemias 1223 megaloblastic anaemia 180t, 1209-1211 aetiology and investigation 1209 clinical features 1209 haematological features 1209 see also cobalamin (vitamin B12); folate/folic acid Meig's syndrome 711-712 meiosis 63,63f meiosis I (reduction division) 63, 63f meiosis II 63,63f melaena 772,773-774cs pancreatic tumours 832 melanin 427 melanocytes 379 cc-melanocyte-stimulating hormone (MSH) 893 melanoma, malignant 424-425,424f prevalence 424t melarsoprol, African trypanosomiases 353 melioidosis 321 melphalan amyloidosis 1264 multiple myeloma 1261 membrane receptors classes 884t hormones see hormones memory impairment alcohol intoxication 1436 dementia 1347,1349-1350cs loss pituitary tumours 896 post-traumatic 1373 mental state examination 1286 temporal lobe lesions 1289 a Menetrier's disease 782 Menghini needle, liver biopsy 844 Meniere's disease 1317,1320 meninges gummas 1429 infection see meningitis irritation 1312 meningiomas 1352t, 1355-1356, 1355f skull X-ray 1353

spinal 1381,1382f vertigo 1317 meningism cerebral haemorrhage 1338 intracranial abscesses 1418 syphilis 1429 meningitis acute bacterial 1413-1417, 1415-1416cs differential diagnosis 1414,1416 infection mechanisms 1414 organisms causing 1413,1414t prevention 1417 prognosis 1416,1417 amoebic 1416 bacterial 310-311 clinical features 1414,1420,1422, 1428 fits 1417,1420 headache 1312,1414 neck stiffness 1414 rash 1414 complications 1414 differential diagnosis 1414,1416 following head injury 1371 fungal 1421 investigation 1416-1417, 1420-1421,1422 lumbar puncture 1416,1416t malignant 1434,1435 management acute bacterial 1417 tuberculous 1421 viral 1422-1423 meningococcal 310-311,1416 pneumococcal, antibiotic choice 263t tuberculous 1420-1422,1421f, 1421t differential diagnosis 1421 pathology 1420 prognosis 1421 see also tuberculosis vaccines 1417 viral 1414,1422-1423 differential diagnosis 1421 enterovirus 302 HIV/AIDS 1423,1428 prognosis 1423 meningocele 1384 meningococcal arthritis 1159 meningococcal meningitis 310-311 fatality 1416 see also Neisseria meningitidis (meningococcus) infection meningococcal septicaemia 310311 adrenocortical insufficiency due to 929-930 meningococcal vaccine 273, 311 meningomyelocele 1384 meningovascular syphilis, epilepsy 1327 menopause 946 osteoporosis after 959,960, 960f premature 947 chemotherapy 163 symptoms 946 menstrual cycles anovulatory 945 erratic, microprolactinoma 908 normal 945-946,945f menstruation 945 migraine 1309 MEN syndrome see multiple endocrine neoplasia (MEN) mental handicap 252 management 253t Mental Health Act (1983) 222, 254

mental health legislation 253-255, 254cs admission for assessment (section 2) 254-255 admission for treatment (section 3) 255 consent to treatment (section 57, 58) 255 emergency detention of patients already in hospital (section 5) 255 place of safety order (sections 136) 255 powers of the courts (sections 36, 37,38) 255 mental illness 252 mental state examination 211-212, 1286-1287 mini-mental state 1286,1287, 1288t see also cognitive function meprobamate, overdose management 24 meralgia paraesthetica 1199 6-Mercaptopurine, acute lymphoblastic leukaemia 1247 mercury, poisoning 39 Merkel cells 380 mesangial cells, kidney 1032 mesangiocapillary glomerulonephritis 1073-1074 mesenchymal tumours diagnosis 1021 hypoglycaemia 1018 mesenteric artery occlusion, diabetes 1015 Mesna (uromitexan), rheumatoid arthritis 1143 mesothelioma, diffuse 717-718,717f messenger RNA (m-RNA) 57 metabolic acidosis 1114-1115 blood gas analysis 1114 causes 1115t cholera 323 chronic 964 consequences 1115f hyperchloraemic 1066 management 1117-1118,1118ra non-circulatory causes 730t parenteral feeding 134 peripheral perfusion and 730 renal failure 1055 see also lactic acidosis metabolic alkalosis 1115 blood gas analysis 1114 causes 1117t management 1117-1118,1118ra metabolic bone disease see bone disease, metabolic metabolic disturbance neurological involvement 1432-1433,1432t acute confusional state 1289 coma 1285-1286 diabetic coma 1003t, 1006-1007 headache 1307 sphingolipid metabolism disorders 1413,1413t see also specific metabolic diseases metabolic myopathy 1407-1408 metabolic neuropathy see neuropathy metabolic regulation 979-984 anabolism vs catabolism 981 carbohydrate metabolism 981-982, 982f fasting 983

1481

1482

fat metabolism 982, 982f insulin role see insulin ketogenesis 982-983, 983f post-prandial 983 prolonged starvation 983 protein metabolism 983, 983f severe stress 983-984 see also specific hormones/processes metabolic syndrome 138 metabolic tests, urinary tract stones 1089 metacarpophalangeal joints 1395 metachromic leukodystrophy 1413 metallic mercury, poisoning 39 metals, poisoning 43 metaphase 63, 63f metastases 150-151 adrenal cortex 937 bone 1191 bronchial carcinoma 702 cerebral 1352t, 1356-1357,1356f cerebral tumours 1356-1357 hepatocellular carcinoma (hepatoma) 876 in liver 877 mediastinal tumours 709 neurological manifestations 1434-1435 oesophagus tumours 769 pleural 718 radiotherapy 1357 spinal 1381 unknown primary site 154 metatarsalgia 1199 Morton's 1199 metatarsal head, subluxation, rheumatoid arthritis 1135 metformin 998-999, 998t adverse effects 998 clinical use 999 mechanism of action 998 methadone, treatment of opiate abuse 246, 246t methaemoglobinaemia 1220 methanol, overdose management 35-36 methicillin 265 methicillin-resistance Staphylococcus aureus (MRSA) 264, 270, 310 methimazole, thyrotoxicosis 921 methionine, in paracetamol poisoning 29, 29t methotrexate 161 acute lymphoblastic leukaemia 1247 complications/adverse effects, macrocytosis 1125 drug interactions 1142 iatrogenic lung disease 697 inflammatory diseases 103 juvenile idiopathic arthritis 1163-1164 mechanism of action 103,1142 nodules associated 1136 psoriasis treatment 399 psoriatic arthritis 1151 rheumatoid arthritis 1142-1143, 1144-1145cs, 1145 with biological agents 1146 side-effects 103,1142-1143 methyldopa 598,599 autoimmune haemolytic anaemias 1223 methylene chloride, poisoning 3334 methylphenols (cresols). poisoning 37

methylprednisolone in ARDS 737 bone marrow transplant 1213 depot injections, rheumatoid arthritis 1143 hypoplastic anaemia 1213 intra-articular, rheumatoid arthritis 1143 pulse therapy, vasculitis 1182-1183 thrombocytopenic purpura 1269 methylprednisone, intramuscular, polymyalgia rheumatica 1185 methyl xanthine derivatives, asthma 657 methysergide, carcinoid syndrome 797 metronidazole 266 giardiasis 337 septicaemia 274 tetanus 313 trichomoniasis 462 metyrapone adrenal disorder diagnosis 929 Cushing's syndrome treatment 936 MI, acute see myocardial infarction (MI) mianserin 222 micelles 837 miconazole 267 microaerophilic streptococci 325 microalbuminuria diabetic heart disease association 1015 diabetic nephropathy 1011 microaneurysms, diabetic retinopathy 1009 microangiopathic haemolytic anaemia 1079,1225 microangiopathic thrombocytopenia 1270 microdeletion syndromes 69 microglioma 1352t, 1355 B2-Microglobulin 83 HLA-B27 interaction failure 1148 micronutrients 113-115 dietary reference values 114 parenteral feeding requirements 134 safe intakes 115t microorganisms choice of antimicrobial 262 immunity 259 investigations 262, 262f pathogenicity 260 relationship with humans 259261 susceptibility to infection 260-261 see also bacteria; fungal infections; protozoal infections; viruses microprolactinoma 908-909 surgical treatment 909 microscopic polyangiitis (MPA) 1181-1182 microscopy infectious disease identification 262 malaria diagnosis 348 microvascular disease, diabetes complications 1008,1008f micturition frequency 1046,10461 neurological control 1095f normal 1095,1095f urgency 1046 see also urinary incontinence micturition syncope 1321-1322 midbrain, infarction 1336

middle cerebral artery occlusion (MCAO) 1335-1336,1335f, 1339cs midline granuloma 691 midstream urine (MSU) test, in elderly 196 mid upper arm circumference (MUAC) 116 migraine 1307-1310,1308cs basilar 1309 classic 1307 clinical features 1307-1309 aura 1308 gastrointestinal 1307,1309 headache 1309 mood changes 1308 neurological symptoms 1308-1309 prodrome 1308 common 1307 definitions 1307 diagnostic criteria 1307t epidemiology 1307 food intolerance 141 hemiplegic 1309 management 1309-1310 acute 1309,1310t prophylactic 1310,1310t stratification 1310t ophthalmoplegic 1309 pathogenesis mechanism 1309 provoking factors 1309 tension headache association 1309 transformed migraine 1310 see also migrainous neuralgia (cluster headache) migrainous infarction 1337 migrainous neuralgia (cluster headache) 1314-1315 clinical features 1314-1315 management 1315 miliary tuberculosis 640, 641f, 644f military exposure to radiation 48 milk alkali syndrome 969t, 972 milkers' nodules 394 Miller Fisher syndrome 1398 milrinone, inotropic therapy 731 mineral metabolism, uraemia 1054-1055 mineralocorticoids 926 assays 928 deficiency 889 Addison's disease 931 physiological control 926 sodium excess 1108,1108t sodium homeostasis 1035 therapy, Addison's disease 931-932 tubular acidosis 1067 see also aldosterone minerals distribution in skeleton 953 reference nutrient intakes 115f, 125t miner's elbow 1195 minimal change nephropathy clinical features and diagnosis 1072-1073 management 1073 pathogenesis and pathology 1072 mini-mental state examination (MMSE) 1286,1287,1288t minocycline osteoarthritis 1157 rheumatoid arthritis 1145 miosis, Horner's syndrome 1295 mirtazapine, overdose 26 misoprostil, NSAIDs side-effect reduction 1140

mites 395 mithramycin, Paget's disease 977 mitochondria, metabolism glycolysis see glycolysis ketogenesis see ketogenesis mitochondrial myopathies (cytopathies) 1407-1408 mitosis 63, 63f mitotane, Cushing's syndrome 936 mitral facies 469 mitral regurgitation 524-526 aetiology 524 'click-murmur' syndrome 526 clinical features 524 combined mitral/aortic valve disease 530-531 congenital 524 endocarditis 524 floppy mitral valve (Barlow's syndrome) see mitral valve prolapse investigation 526 Libman-Sacks endocarditis 581 management 526 mitral valve prolapse 525-526 with stenosis 526-527 symptoms/signs 524, 525f valve ring calcification 524 mitral stenosis 521-524 aetiology 521-522 anticoagulation 523, 524t chest X-rays 523, 523f clinical features 521-522, 523f opening snap 474, 522 symptoms 522, 522t closed/balloon mitral valvotomy 524 combined mitral/aortic valve disease 530-531 Doppler ultrasound 523, 523f echocardiography 523 investigation 522-523 open valvotomy 524 prognosis 524 silent 522 surgical interventions 524 mitral valve, calcification 524 mitral valve prolapse 524, 525526 'click-murmur' syndrome 526 differential diagnosis of angina 545 mitral valvotomy 524 mixed aortic valve disease 530 mixed connective tissue disease 689-690,1175 M-mode echocardiography see echocardiography MMR vaccine 272, 293, 294, 295 MODY see maturity onset diabetes of the young (MODY) molecular mimicry 99 Klebsiella and HLA-B27 1147-1148 molluscum contagiosum 393,394f, 456 monoamine oxidase inhibitors (MAOIs) 222 overdose management 26 Parkinson's disease management 1364 monoarthritis, differential diagnosis 1169cs monoclonal antibodies 151 autoimmune disease treatment 103 cancer therapy 167 rheumatoid arthritis treatment 1133ra, 1146

monocyte(s) 1205 progenitor cells 1201-1202 monocyte colony-stimulating factor (M-CSF) 1202,1203 mononeuritis multiplex 1182 rheumatoid arthritis 1137 see also multifocal neuropathy mononeuropathy 1394t definition 1392 in diabetes 1396 see also diabetic neuropathy median nerve compression 1393-1395, 1394f carpal tunnel syndrome see carpal tunnel syndrome proximal lesions 1394-1395 radial nerve compression 1394f, 1395 symptoms 1394,1394f, 1395 ulnar nerve compression 1394f, 1395 see also nerve compression mononucleosis see infectious mononucleosis (glandular fever) mono-oxygenase 3 drug interactions 10 monosodium urate 1166,1169cs, 1170 monosomy 62 Monospot tests 288 monounsaturated fats, sources 113f mood changes alcoholic 1436,1436t frontal lobe lesion 1288 mental state examination 1287 migraine 1308 see also depression MOPP chemotherapy 1252 morbidity/mortality, cardiovascular disease 463,4641' morbilliform eruptions 417, 417f morphoea 1177 mortality, cardiovascular disease 463, 464f Morton's metatarsalgia 1199 mosaicism Down's syndrome 66, 66t XO/XY 947 mosquito lymphatic filariasis 366 malaria 346 protection 273 motor cortex 1288f lesion 1301 motor (expressive) dysphasia 1286 motor dyspraxia (apraxia) 1287 motor fits 1323,1326 motor neuron(s) 1301,1306t degeneration see motor neuron diseases lower lesions 1298, 1301, 1302, 1302f syringomyelia 1383 upper lesions 1298,1301,1302f motor neuron disease (MND) 1388-1391 aetiopathogenesis 1388-1389 excitotoxicity 1389 SOD mutations 1389 case study 1390cs clinical features 1389 diagnosis 1389t differential diagnosis 1389 familial 1389 investigation 1389,1391cs management/prognosis 13891391 pathology 1388

respiratory muscle weakness 720-721cs motor neuron diseases 1384, 1388-1391,1388t MND (ALS) see motor neuron disease (MND) spinal muscular atrophy (SMA) 1391 motor neuropathy cranial nerves 1297,1298 diabetic 1013 multiple with conduction block (MMN), MND vs 1389 motor seizures, focal 1369 motor symptoms 1302f, 1388t cerebellar 1302,1302f, 1352-1353 cortical 1301 corticospinal 1301,1302f disc prolapse 1387t extrapyramidal 1302,1302f, 1361 see also extrapyramidal tract Huntington's chorea 1350 lower motor neuron 1298,1301, 1302,13021 1388t mononeuropathies 1394-1395, 1394f muscular 1302 neuropathy 1392 upper motor neuron 1298, 1301, 1302f, 1388t motor system 1301-1304 anatomy 1301-1302,1302f basal ganglia 1302 cerebellum see cerebellum cortex 1288f, 1301 corticospinal tracts 1301,1302f motor unit 1301 see also motor neuron(s); muscle(s) see also spinal cord; specific regions disorders 1359-1369 lesions 1301-1302,1302f symptoms see motor symptoms see also specific disorders examination 1298,1302-1304. 1304t muscle 1302-1303 reflexes 1303-1304, 1304t motor unit 1301 see also motor neuron(s); muscle(s) mountain sickness 50 acute 50 chronic 50 mourning, guided 218 mouth 760-762 carcinoma 762 dermatological conditions involving 760t diseases 760-762, 760t plaque lesions 761-762 ulceration 760-761 involvement in systemic disease 761t latrogenic disorders 761t normal and abnormal function 760 poisoning 16 ulcers Behcet's syndrome 1153 musculoskeletal diseases 1122 see also aphthous ulcers mouth-to-mouth resuscitation 518 MPTP parkinsonism 1362 mucocutaneous lymph node syndrome (Kawasaki's disease) 601,1182

mucopolysaccharidoses 71t, 1029 mucormycosis 335 mucosa, damage and gastroenteritis 278 mucosa-associated lymphoid tissue (MALToma) 1255 gastric lymphoma 785 mucosal immune system 81 mucosal ulceration, chemotherapy causing 162 Mullerian ducts 939 multidisciplinary team, schizophrenia 231 multifocal neuropathy 1392,1392t, 1395,1396 see also mononeuritis multiplex multi-infarct dementia 1336, 1350-1351 multiple-drug-resistant tuberculosis 646 multiple endocrine adenomatosis, screening 75t multiple endocrine neoplasia (MEN) 938-939, 939t, 970 hypoglycaemia and 1018 tumours associated 939 type 1 833, 938-939 type 2 (2a and 2b) 939 multiple mononeuropathy see multifocal neuropathy multiple motor neuropathy with conduction block (MMN), MND vs 1389 multiple myeloma 1259-1261, 1261ra, 1435 clinical and laboratory features 1259,1259f diagnostic criteria 1260 differential diagnosis 1260t immunoglobulin production 1260t investigations 1260 management 1260-1261 osteoporosis 960,1259 prognosis 1261,1261t renal dysfunction 1077,1077t, 1259-1260 multiple personality disorder 238 multiple sclerosis (MS) 1408-1412, 1411f, 1412t, 1413ra aetiology 1409 clinical features 1409-1411 brainstem 1408,1410 cerebellar ataxia 1376,1410 cervical spinal cord 1409-1410, 1410f depression 1411 facial myokymia 1369,1411 optic neuritis 1409 paroxysmal symptoms 1410 sensory symptoms 1410 temperature-dependent conduction block 1411 vertigo 1320 counselling 1412 course/prognosis 1411 diagnosis 1411 differential diagnosis, Behcet's disease 1432 epidemiology 1408 management 1411-1412 pathology 1408 plaques 1408 multiple system atrophy (MSA) 1364-1366,1365-1366cs olivopontocerebellar degeneration 1364,1366 progressive autonomic failure (Shy-Drager syndrome) 1322,1364

striatonigral degeneration 1366 mumps 292-293, 293t arthritis 1161 clinical features 292 diagnosis 292 management 292 prevention 293 vaccine 272, 293 mumps virus encephalitis 1423 neuropathy 1398 type 1 diabetes association 987 Munchausen's syndrome 239, 823 Murine typhus 305 muscle(s) anatomy 1402-1403,1403f biopsy 1403f trichinosis 369 cramps 1403 disease see muscle disease examination biopsy 1403f bulk 1302-1303 power 1303, 1392 tone 1303 innervation 1303t see also neuromuscular junction (NMJ) pain see myalgia power, assessment 1124 proximal, stiffness in polymyalgia rheumatica 1184 respiratory see respiratory muscles spasm, hypocalcaemia 974 wasting see muscle wasting weakness see muscle weakness muscle disease 1302.1402-1408 chronic fatigue syndrome (ME) 1408 classification 1403t endocrine myopathies 1407 enzyme levels 1404 hereditary dystrophia myotonica 1405 muscular dystrophies 1404-1405,14041 myotonia congenita (Thompsen's disease) 1405 see also individual dvstrophies HIV/AIDS 1428 inflammatory 1405-1407,1406t idiopathic 1406 inclusion body myositis 1406-1407 infective 1406 malignancy-related 1434 prognosis 1406 investigation 1404 metabolic 1407-1408 post-polio syndrome 1426 proximal. SLE 1174 rheumatoid arthritis and 1431 symptoms/signs 1306t, 1403 cramps/fatiguability 1403 hypertrophy 1403,1404 see also muscle wasting; muscle weakness; myalgia toxic 1407 alcoholic 1407.1436t muscle wasting 1403 neuropathy 1392.1393f rheumatoid arthritis 1134.1134f. 1136 syringomyelia 1383 twelfth nerve lesion 1301 muscle weakness 1403 examination 1303 myasthenia gravis 1400-1401 neuropathy 1392

1483

1484

carpal tunnel syndrome 1394 Guillain-Barre syndrome 1397 hereditary motor and sensory neuropathy 1399 polymyositis 1180 proximal see proximal muscle weakness musculoskeletal diseases 1119-1200 age and sex relationship 1121 clinical assessment 1121-1130 drug history 1121,1122t history of presenting complaint 1122 history-taking 1121-1122 physical examination 1122-1124 costs and prevalence 1119 investigations 1124-1129 biochemical 1127 miscellaneous 1128-1129 radiological 1127-1128,1128f synovial biopsy 1127,1128f synovial fluid 1127 polyarthritis, differential diagnosis 1129-1130,11291 see also arthritis; connective tissue disorders; joint diseases; individual diseases musculoskeletal system, examination 1122-1124 mushroom poisoning, liver failure 853 mushroom worker's lung 694t mustard gas (sulphur mustard) poisoning 54 mutations new 65 single gene 60-61, 60t trinucleotide repeat 60 triplet repeat 61t types 60t see also chromosomal abnormalities myalgia 1403 viral myositis 1406 see also polymyalgia rheumatica myalgic encephalomyelitis see chronic fatigue syndrome myasthenia gravis 1400-1401,1401t clinical features 1400-1401 diagnosis 1401 epidemiology 1400 Guillain-Barre syndrome vs 1397 management/prognosis 1401 neonatal 1400 ocular 1400 pathophysiology 1400 thymus involvement 1400,1401 mycobacteria 325-329 rheumatoid arthritis aetiology 1126 mycobacterial infections atypical 388-389 granulomas 101 skin 388-389 Mycobacterium avium-intracellulare (MAI) 645 HIV/AIDS infection 447 Mycobacterium bovis 325, 640 Mycobacterium kansasii 325 Mycobacterium leprae 325-326 Lepromin test 101 see also leprosy (Hansen's disease) Mycobacterium marinum 388-389 Mycobacterium tuberculosis 325, 640,1160,1420 HIV/AIDS infection 446 chemoprophylaxis 453 Mantoux test 101,641 see also tuberculosis

Mycobacterium ulcerans 328-329 mycophenolate mofetil, autoimmune diseases 102-103 mycophenolic acid (MPA) 102 mycoplasma 305 mycoplasma infections arthritis, in X-linked agammaglobulinaemia 86 pneumonia 634 Mycoplasma pneumoniae 305 mycoses infective endocarditis 576 see fungal infections mycosis fungoides 425, 425f, 1257 myelinated nerve fibres 1391 myelinolysis, central pontine 1436t, 1441,1441f myelitis 1381-1382,1422 myeloblasts, differentiation from lymphoblasts 1245t myelodysplasia classification 1249t clinical features 1249 management 1249 myelodysplastic syndromes (MDS) 1249 myelofibrosis 1243 myelogram, spinal meningiomas 1382f myeloma see multiple myeloma myeloma kidney 1077 myelopathy AIDS-related 1428 cervical spinal 1380,1431 myeloperoxidase (MPO) 1181 myeloproliferative disease/disorders 1236,1238f myelodysplasia 1249 myocardial hypertrophy 489 myocardial infarction (MI) 554-569 accelerated idioventricular rhythm 561 acute anterior 555 acute inferior 555 arrhythmia 567 cardiogenic shock 564t clinical features 555-556 complications 560-566 arrhythmia 560-563,567 atrial fibrillation 561 atrial flutter 561 bradycardia 561-562 cardiac failure 563 cardiac rupture 566 cardiogenic shock 563, 564t Dressler's syndrome 556, 566 heart block 562 papillary muscle rupture 566 paroxysmal atrial tachycardia 561 postmyocardial infarction syndrome 566 right ventricular infarction 563-566 sinus bradycardia 562 sinus tachycardia 561 supraventricular tachycardia 561 tachycardias 561 ventricular aneurysm 566 ventricular ectopic beats 561 ventricular fibrillation 516, 561 ventricular septal rupture 566 ventricular tachycardia 561 diabetes association 996,1015 diagnosis 555 differential diagnosis 558 Dressler's syndrome 566 ECG 556-557, 557f

anterior infarction 557f changes in acute infarction 556f inferior infarction 557f localization of infarction 557, 557f non-Q-wave infarction 557 posterior infarction 557f Q-wave formation 556 ST segment elevation 556, 556f, 557f T-wave inversion 556, 556f examination 555-556 history 555 imaging techniques 558 intra-aortic balloon pump (IABP) 732 investigation 556-558 laboratory tests 557-558,558t creatine kinase 558t lactate dehydrogenase 558t myoglobin 558t troponins 558t left ventricular dysfunction 567, 568,731 management, post infarction 567-569 ACE inhibitors 568 anticoagulants 568-569 antithrombotics 568 aspirin 568, 569 B-blockers 568 cardiac rehabilitation 569 drug therapy 568-569 investigations 567-568 lipid-lowering agents 569 statins 569 warfarin 568-569 management of acute infarction 558-560, 560t ACE inhibitors 559 acute B-adrenoreceptor blockade 558 analgesia 558 angioplasty 559 aspirin 559 bed rest 559 calcium antagonists 559 heparin 559 infarct size limitation 558-559 mobilization 559 nausea 558 nitrates 559 oxygen 558 rehabilitation 559 statins (HMG-CoA reductase inhibitors) 559 thrombolysis 558-559, 560t thrombolysis, contraindications 560t mechanical support 732 mitral regurgitation 524 mortality 554-555,555f, 555t myocardial ischaemia 567 non-Q-wave 552,557 pacemakers, temporary transvenous 562-563, 563t prognosis 566-567 arrhythmia 567 left ventricular dysfunction 567 myocardial ischaemia 567 right ventricular 563-566 combination therapy 565-566 dobutamine 565 dopamine 564-565 management 564-566 mechanical support 566 stroke association 1331 see also acute coronary syndromes (ACS)

myocardial perfusion imaging 486 cardiac investigation 486 myocarditis 570 causes 570t rheumatic fever 580 rheumatoid arthritis 1136 myocardium 543 see also cardiac muscle myoclonic encephalopathies 1368 myoclonic epilepsy 1323t, 1326t myoclonus 1368-1369 asterixis 1368-1369 encephalopathy 1368 epilepsy 1323t, 1326t essential 1368 facial 1369 focal 1368 myoglobin, acute MI 558, 558t myokymia, facial 1369 myopathy see muscle disease myopericarditis, enterovirus 303 myositis 1406,1422 rheumatoid arthritis 1136 myotonia 1403 myotonia congenita (Thompsen's disease) 1405 myotonic dystrophy 61t, 1405 genetic anticipation 60 myxoedema 914 clinical features 917t 'madness' 917,1434 neuropathy 1397 pretibial 920, 921f primary 917 see also hypothyroidism myxoedema coma 918 features 918t myxoedema madness 917,1434 myxomas 581-582 investigation/management 582 left or right atrial 582

N Naegleria fowleri infection 342 naevi 421 dysplastic 424-425 epithelial 421 multisystem disease and 421 pigmented (melanocytic) 421 vascular 421 nails 435-436 clubbing see clubbing (finger/toe) fungal infection 391, 391f onycholysis 391 onychomycosis 391 psoriasis 397, 397f psoriatic arthritis 1150,1151f respiratory disease 619 splinter haemorrhages 435, 436f, 469 spoon-shaped see koilonychia tinea 391,391f vasculitis 1181f white (leukonychia) 751 yellow nail syndrome 435 nalidixic acid 266 naloxone, in opiate overdose 30 narcolepsy 1329 narcotics 749t nasogastric tube, motor neuron disease management 1390 nasopharyngeal tumour 152f National Food Survey 118-119

National Institute For Clinical Excellence (NICE) 14 natural killer (NK) cells 79, 80 deficiency 92 nausea, chemotherapy causing 162 near-drowning see drowning and near drowning near-infrared spectroscopy (NIRS), head injury 746 near vision (convergence) reflex 1294-1295 nebulizer therapy, asthma 657-658 Necator americanus 360 neck injuries 1371 cervical headache 1310 psychological effects 1373 neck pain cervical spine disease 1379 migraine 1309 neck stiffness coma examination 1283 meningitis 1414 necrobiosis lipoidica 414,415f necrobiosis lipoidica diabeticorum 1018 necrotizing fasciitis 309, 386 anaerobic bacteria 325 necrotizing vasculitis 601 needle exchange programmes 455 needles Menghini 844 TruCut 844 needle-stick injuries 441, 455 needle tracks, poisoning sign 17, 17t nefazodone, overdose 26 neisseria 310-311 Neisseria gonorrhoeae infections 458 joint infections 1158,1159 see also entries beginning gonococcal Neisseria meningitidis (meningococcus) infection 310-311,1413,14141 clinical features 311 management and prevention 311 see also entries beginning meningococcal Nelson's syndrome 906-907, 936 nematodes 359-370 animal intestinal infection 368-370 human intestinal infection 359-363 neonatal myasthenia gravis 1400 neonates a1-acid glycoprotein (AAG) concentration 3f albumin concentration 3 drug metabolism 4 haemolysis 1222 risks following diabetic pregnancy 1002-1003,1002t SLE 1176 thrombocytopenic purpura 1269 thyroid hormones 913, 913f thyrotoxicosis 922 varicella (chickenpox) 285 vitamin K deficiency 1274 neoplasia see cancer; malignancy/malignant disease; tumour(s) nephritic syndrome, acute 1051 causes 1051t nephritis crescentic 1051 hereditary (Alport's syndrome) 1075

immune complex 1068,1069t lupus 1127 radiation 1086 see also glomerulonephritis nephroblastoma (Wilms' tumour) 1091 nephrocalcinosis, primary hyperparathyroidism 970f, 971 nephron 1032 nephropathy allograft, chronic 1061 chemical toxins 1086 diabetic see diabetic nephropathy drug-induced 1086,1087t gouty 1079 immunoglobulin A (IgA) 1074 membranous 1072 causes 1072t minimal change 1072-1073 see also minimal change nephropathy physical and chemical agents 1086 salt-losing 1067-1068 thin membranous 1075 tubulointerstitial see tubulointerstitial nephropathy uric acid 1079 nephrotic syndrome 1062-1064 aetiology 1062-1063,1063t complications and management 1063-1064,1063t, 1064t investigations 1063 pathophysiology 1063,1063f nephrotoxic drugs 1086,1087t glomerulonephritis 1070 nephrotoxicity aspirin 1086 ciclosporin A 1143 drug-induced 1086 gentamicin 1086 paracetamol 1086 phenacetin 1086 nerve biopsy, neuropathy investigation 1393 nerve compression 1393 cranial nerve(s) 1284,1297 spinal cord 1377,1378,1379t, 1386,1435 see also carpal tunnel syndrome; mononeuropathy nerve conduction, temperaturedependent block (MS) 1411 nerve conduction tests 1404 nerve fascicles 1391 nerve fibres, myelinated 1391 nerve gas poisoning 55 nerve roots 1186f, 1187 irritation 1187,1189cs lesions 1306t, 1377,1380 pain 1187,1191 see also spinal root diseases/lesions nervous system see central nervous system (CNS); peripheral nervous system nesidioblastomas, hypoglycaemia 1018 netilmicin, brucellosis 319 neuralgia(s) facial 1313t atypical 1315 migrainous (cluster headache) 1314-1315 occipital 1380 postherpetic (shingles) 1314 trigeminal see trigeminal neuralgia

neuralgic amyotrophy (cryptogenic brachial plexus neuropathy) 1399-1400 neural transplantation, Parkinson's disease 1364 neurapraxia 1393 neurodegenerative disorders, extrapyramidal tract 1359-1369 neurofibrillary tangles 1347 neurofibromas 1381,1382f neurofibromatosis (Von Recklinghausen's disease) 421, 422f neurofibromatosis-1 gene (NF-1), chronic myeloid leukaemia (CML) 1240 neurogenic tumours 710 neuroleptic drugs Huntington's chorea management 1350 side effects, tardive dyskinesia 1369 see also antipsychotic drugs neuroleptic malignant syndrome 46 drug-induced 230 neurological disease 1283-1441 African trypanosomiases 353 alcoholic 1435-1441 see also alcohol cerebrovascular see cerebrovascular disease common patterns of deficit 1306t cortical lesions 1286-1289,1288f, 1289f, 1306t eye movements 1296 motor symptoms 1301 sensory system 1305-1306 see also cerebral cortex; head injury; specific areas cranial nerves 1290-1301 see also cranial nerve(s) demyelinating see demyelinating disease diagnosis 1283-1306 diffuse 1285-1286,1306t examination see neurological examination infections bacterial 1413-1422 enterovirus 302 fungal 1421,1428,1430 mycoplasma 1430 spirochete (Lyme disease) 1430 viral 1422-1427,1423t see also HIV infection and AIDS; meningitis; neurosyphilis motor system 1301-1304 extrapyramidal 1359-1369 see also extrapyramidal tract; motor system neuromuscular junction 1306t, 1400-1402 peripheral nervous system 1391-1400 see also neuropathy; peripheral nerves sensory system 1305-1306 see also sensory system spinal see spinal cord disease/lesion systemic diseases and 1430-1435 toxin/drug-induced 1440t, 1441 see also drug-induced disorders tumours/cancers 1398,14341435 brachial plexus 1400 cerebral see cerebral tumours

spinal 1381,1382f see also specific conditions neurological examination 1283-1287,12841 acute confusional state 1289 brainstem reflexes 1284-1285 see also brainstem; eye movements comatose patients 1283-1286, 1285t see also coma coordination 1303 cranial nerve function 1290-1301 see also cranial nerve(s) in elderly 192-193 gait and station 1289-1290 head injury 1371 history-taking 1283,1284t headache 1307 involuntary movement 1302 level of consciousness 1283 Glasgow Coma Scale 1283, 1285t, 1371 head injury 1371 limbs 1285,1302-1303 mental state 1286-1287,1288t motor system 1302-1304 bulbar signs 1389 extrapyramidal signs 1302, 1302f pyramidal signs 1285,1301, 1302f see also motor symptoms muscle bulk/power/tone 1302-1303 posture 1302 pupillary responses see pupillary responses sensory system 1297-1298, 1304-1305 see also sensory symptoms symptom review 1284t transient ischaemic attacks (TIAs) 1332-1333 vertigo/dizziness 1318-1319 see also specific tests/signs neurological symptoms, food intolerance 141 neuroma, acoustic see acoustic neuroma neuromuscular disease, respiratory muscles 721 neuromuscular disorders, respiratory muscles 718-722 clinical assessment 718-722 diaphragm weakness/paralysis 718-719, 719, 719f, 721 lung function 719 respiratory pressures 719 neuromuscular excitability, increased in hypocalcaemia 974 neuromuscular junction (NMJ), disease/lesion 1306t, 1400-1402 botulism 1402 Lambert-Eaton myaesthenic syndrome 1401-1402 myasthenia gravis 1397, 1400-1401,1401t see also muscle(s) neuropathic bladder see bladder dysfunction, neuropathic neuropathic foot, diabetic neuropathy 1013,1016, 1017t neuropathy 1391-1399,1395t amyloid 1397 classification 1392 clinical features 1392-1393

1485

1486

autonomic involvement 1392-1393,1397 motor involvement 1392,1393f pain 1013,1392 sensory involvement 1392 'stocking and glove' pattern 1013,1013f see also motor symptoms; sensory symptoms cobalamin (vitamin B 12 ) deficiency 1398 cranial, systemic sclerosis 1431 diabetic see diabetic neuropathy diagnosis/investigation 1393 entrapment see entrapment neuropathy hereditary 1399 see also porphyria HIV-related 1428 infective 1398 inflammatory 1392,1397-1398 metabolic/endocrine 1014, 1396-1397 amyloid 1397 diabetic see diabetic neuropathy myxoedema 1397 mixed sensory and motor, rheumatoid arthritis 1137 mononeuropathies see mononeuropathy multifocal neuropathy (mononeuritis multiplex) 1392,13921,1395,1396 multiple motor with conduction block (MMN) 1389 neoplastic 1398 nutritional 1398 paraproteinaemic 1398,1435 pathophysiology 1392 polyneuropathies see polyneuropathy toxic/drug-induced 1398,1440t. 1441 alcoholic 1393,1436t see also demyelinating disease neurophysin 910 neuropsychiatric features, SLE 1175 neuroradiology, interventional 1345 neurosis 207-208,209 psychosis vs 207t relationship to normality 208 relationship to reality 207-208 neurosurgical referral, head injury 1371 neurosyphilis 1428-1430 Argyll Robertson pupil 1295,1429 congenital 1430 diagnostic tests 1429 management 1429,1430 meningovascular 1327,1429 parenchymatous 1429-1430 general paralysis of the insane 1429 syphilitic amyotrophy 1430 tabes dorsalis 1429-1430 syphilitic gummas 1429 neurotransmitters, in depression 221 neutropenia cyclical 94-95 Felly's syndrome 1122 fever 270, 270t SLE 1175 neutrophil alkaline phosphate (NAP), in chronic myeloid leukaemia (CML) 1239 neutrophilia 1234 Hodgkin's disease 1250 musculoskeletal diseases 1125 neutrophils 1201,1205

acute myeloid leukaemia 1244 causes of low count 1234t count, myocardial infarction 558 polycythaemia rubra vera 1241 respiratory burst, failure 94 urate crystal uptake 1167 NFkB, receptor activator (RANK) Paget's disease 975 rheumatoid arthritis pathogenesis 1132 niacin deficiency 124-125 pellagra 124-125 food sources 124t reference nutrient intake 125t role in the body 124t nickel hypersensitivity 101 nicorandil, angina pectoris 548-549 nicotine replacement therapy 667 nicotinic acid, triglyceride-lowering drug 1025,10251 nifedipine. systemic sclerosis 1179 nifurtimox, Chagas' disease 355 Nikolsky sign 381-382,411 nitrazepam 187,188 nitric oxide (NO) blood pressure 590 inhaled, acute respiratory distress syndrome 700 sepsis 734, 736 nitric oxide synthetase (NOS) inhibitors 736 sepsis 734,736 nitroblue tetrazolium test (NET) 94, 1235 nitrosamines 147 Nocardia asteroides 331 Nocardia brasiliensis 331 Nocardia caviae 331 Nocardia pneumonia 640 nocardioses 331-332 aetiology, pathogenesis and epidemiology 331 clinical features 331-332 diagnosis 332 management 332 nocturia 185-186,1046, 1046t nocturnal hypoglycaemia 991 nocturnal hypoxaemia, chronic bronchitis 664-665 nodular lymphoid hyperplasia (NLH) 87 non-Hodgkin's lymphoma 1254-1257 B cells 1254 classification 1255t clinical features 1254 coeliac disease 790 combination chemotherapy 161 high grade 1255f, 1256-1257 histological classification 1254 HIV/AIDS infection 450 International Prognostic Index 1256,1256t low grade 1255-1256,1255f staging 1254-1255 non-invasive positive-pressure ventilation (NIPPV) 667ra chronic bronchitis 667ra non-nucleoside reverse transcriptase inhibitors (NNRTIs) 451 non-steroidal anti-inflammatory drugs (NSAIDs) 1140 COX-2-specific 1140,1157 gastrointestinal haemorrhage 1137 gout 1170 juvenile idiopathic arthritis 1163-1164,1164 nephrotoxicity 1086

peptic ulcers 777 prescribing guidelines 1140 rheumatoid arthritis 1140 safety issues 1141ra side-effects 1140,1141ra, 1141t soft tissue rheumatism 1200 stomach and duodenum 780ra non-tuberculous mycobacterial (NTM) infections 95 non-volatile acid, kidney excretion 1036 noradrenaline (norepinephrine) 938 excess secretion, phaeochromocytoma 938 inotropic therapy 731,732t norfloxacin, urinary tract infections 1085 Norwegian scabies (crusted) 394 nosocomial infection 270-271 notifiable diseases, in UK 2711 NSAIDs see non-steroidal antiinflammatory drugs (NSAIDs) nuclear factor kappa-B see NFicB nuclear imaging, cardiac investigation 485-486 nuclear ventriculography, cardiac investigation 485-486, 487f nucleoside reverse transcriptase inhibitors (NRTIs) 451 nucleotide bases 57 nucleus pulposus 1186,1186f chemonucleolysis 1190 nut allergy 98-99, l00cs 'nutcracker' oesophagus 771 nutrients 106 factors effecting requirements 107t nutrition 105-144,143ra ageing and 179-180 balance 106 chronic renal failure management 1056-1057,10561 cofactor in disease and therapy 136-140 colorectal carcinoma 801 Crohn's disease 809 current diet and proposal for change 141-143 feeding practices for growth 119-120 food and its uses 105-115 functional bowel disorders 818 future targets 143 intensive care unit 748-749 recommended daily amount (RDAs) 106-107 risk of deficiency 107f targets 142t thyroid disease associated 914 uraemia 1055-1056 see also diet; food nutritional composition, of food 105 nutritional deficiencies Crohn's disease 809 in elderly 179-180 neurological involvement alcohol and 1440 see also Wernicke-Korsakoff syndrome cerebellar degeneration 1440-1441 neuropathy 1398 see also individual deficiency diseases nutritional neuropathy 1398 nutritional status assessment 115-117 anthropometry 116-117

biochemical 117 body composition 115-116 intensive care unit 749 infectious disease and 259 nutritional support 132-136 body composition 132f cancer management 166 conditions where necessary 133t enteral feeding 133-134 food and sip feed supplements 133 head injury 745 liver failure 854 monitoring support 135-136,135t parenteral feeding 134-136 postoperative malnutrition 135cs nystagmus 1295,1297,1300t cerebellum lesion 1300t, 1375, 1410 directional preponderance 1318 jerk 1299 optokinetic 1318 poisoning 16t sawtooth 1299 types 1299 vestibuloocular testing 1318-1319, 1319f nystatin 267 hypoplastic anaemia 1212

o oat-cell carcinoma see small-cell lung cancer obesity 128-132,242 anti-obesity drugs 999ra benign intracranial hypertension and 1358 causes 128 consequences 128-129,128t, 129t diabetes association diet/lifestyle changes 997 insulin resistance and 995 see also diabetes in elderly 179f reflux oesophagitis 766 treatment criteria 129-132 drugs 131-132 surgery 132 waist watchers 130t ob gene 128 object recognition, mental state examination 1287 obliterative bronchiolitis 1137 obsessional defences 217 obsessional personality disorder 210 obsessive-compulsive neurosis 209 obstructive sleep apnoea see sleep apnoea syndromes occipital lobe 1288f, 1290 occupational disorders, carpal tunnel syndrome 1393-1394 occupational lung disease 692-694 see also pneumoconioses occupational therapist, in elderly 202 occupational therapy, rheumatoid arthritis 1139 occupations, musculoskeletal diseases 1121 ochronosis 71 management 1191 octreotide 903,904 acromegaly treatment 906 variceal haemorrhage 873

ocular myasthenia 1400 oculomotor nerve see cranial nerve(s) oculomotor system cranial nerves 1292-1297,1294f extraocular muscles 1292-1293, 1295f oedema cardiovascular system examination 470 cerebral see cerebral oedema differential diagnosis 1108 heart disease 469 laryngeal, Cl-inhibitor deficiency 91,101cs peripheral chronic bronchitis 620 gastrointestinal disease 751 respiratory disease 620 pitting, rheumatoid arthritis 1123 pulmonary see pulmonary oedema renal disease association 1045 rheumatoid arthritis 1123,1136 oesophageal Doppler ultrasound probe 727-728 oesophagitis reflux 766.766t systemic sclerosis 1178,1179 oesophagus 762-772 achalasia 769-771 anatomical abnormalities 771 Barrett's 797 cancer 145 corrosive and foreign body ingestion 768 dissecting intramural haematoma 767 diverticula 771 dysmotility syndromes 771 gastro-oesophageal reflux 763, 765-766 hiatus hernia 766-767 infections 771 investigations 763 irritable, functional bowel disorders 820 motility 757 disorders 758t pathology, clinical features 762-763, 763t, 764-765cs peptic stricture 767 spasm, chest pain 468 systemic sclerosis 771,1178, 1179f tumours 768-769,7691 classification 768t see also squamous cell carcinomas ulceration 767 webs and rings 771 oestradiol functions/actions 946 normal menstrual cycle 945, 945f production from testosterone 941 pubertal growth spurt 946 surge (preovulatory) 945f, 946 oestrogen(s) cortisol synthesis inhibition 926 deficiency, osteoporosis 959 effect on bone metabolism 956, 959 osteoporosis 175 progesterogens interactions 887 prolactin secretion control 894 protein-binding tests in thyroid disease 915 oestrogen therapy anterior hypopituitarism 901 osteoporosis prevention 960

osteoporosis treatment 961 patches, ovarian failure treatment 948 olanzapine 230 olecranon bursitis 1195 rheumatoid arthritis 1136 olfactory hallucinations 207 olfactory nerve 1290 oligoarthritis extended, juvenile idiopathic arthritis 1163 juvenile idiopathic arthritis subtype 1163 persistent, juvenile idiopathic arthritis 1163 psoriatic arthritis 1151 oligodendrocytes, viral infection 1427 oligodendrogliomas 13521,1355 oligomenorrhoea 946-949 see also amenorrhoea oligonucleotide microarrays 60 oliguria 1037,1045-1046 potassium 1050 olivopontocerebellar degeneration 1364,1366 omega-3 oils 1025,1025t omeprazole NSAIDs side-effect reduction 1140 systemic sclerosis 1179 Onchocerca volvulus 359, 364 immunohistology 365f, 366f life cycle 364f see also onchocerciasis onchocerciasis 364-366 aetiology and transmission 364 clinical features 365 diagnosis/differential diagnosis 365 distribution 364, 364f epidemiology 364 lymphatic filariasis see lymphatic filariasis pathology and pathogenesis 364-365 prevention and control 365-366 treatment 365 Onchocerciasis Control Programme 365-366 oncogenes 1237, 1257 oncogenous rickets 1065 onion peel 1082 onycholysis 391 onychomycosis 391 opening snap 474 ophthalmic artery 1330,1331f ophthalmic complications, joint diseases 1123t ophthalmopathy congestive 919,920 Graves' 919-920, 920f thyroid-associated 919-920, 920f, 922 ophthalmoplegia exophthalmic 1434 migraine 1309 Wernicke-Korsakoff syndrome 1439 ophthalmoplegic migraine 1309 opiate addiction 243, 245-246 biochemical factors 243,245 causes 243 examination and history 245t management 245-246, 246t presentation 245 psychiatric/psychological factors 245 rehabilitation 246

opioids. overdose management 29-30, 30t opisthorchiasis 374 Opisthorchis felineus 374 Opisthorchis sinensis 374 Opisthorchis viverrini 374 opportunistic infections 261 HIV/AIDS infection 444-445 treatment guidelines 452-453. 452t opsonization 81 optic atrophy 1292,1293f causes 1294t multiple sclerosis 1409 optic chiasm 1290,1353,1420 optic cup 1292 optic disc optic atrophy 1292,1293f papilloedema 1292, 1293f swelling 1291 optic foramen 1290 optic fundi assessment 1291-1292,1293f see also fundoscopy blood vessel abnormalities 1291-1292, 1293f arterial occlusion 1291-1292, 1293f haemorrhage 1292 hypertensive/sclerotic 1291, 1293f venous occlusion 1291 choroid abnormalities 1292 retinal abnormalities 1292 see also retinopathy optic nerve assessment 1290-1292 optic discs 1292, 1293f optic fundi 1291-1292, 1293f see also fundoscopy; optic fundi visual acuity 1290 visual fields 1290-1291, 1291t multiple sclerosis plaques 1408 pituitary tumour effects 890 optic neuritis giant cell arteritis 1184 multiple sclerosis 1409 optic radiation 1290 optokinetic nystagmus 1318 oral carcinoma 762 oral contraceptive pill see contraceptive pills (oral) oral diseases see mouth, diseases oral glucose tolerance test (OGGT) 984 see also under Glucose oral hairy leukoplakia, in HIV infection 444, 444f oral hypoglycaemic agents 997-999. 998t see. also specific agents oral rehydration solution (ORS) 280-281,2801 cholera 324 oral ulcers see mouth, ulcers orbital decompression, thyroid disease 920 orchidometer 941 orchitis 292,1182 orf 394 orf virus 289 organ donation, brainstem dead patients 747-749, 747f organic mercurials, poisoning 3839 organic psychosis 232 organophosphates, poisoning 37-38 Orientalis tsutsugamushi 305, 307

orientation, mental state examination 1286 orlistat 131-132 ornithosis, pneumonia 634 orthomyxoviruses 290-292 orthoses, rheumatoid arthritis treatment 1139 orthostatic hypotension see postural hypotension orthostatic proteinuria 1038 Osgood-Schlatter disease 1197 Osler-Rendu-Weber syndrome (hereditary haemorrhagic telangiectasia) 437, 437f, 691 Osier's nodes 469, 577 osmolality 1099 calculation 1106 serum, low, inappropriate secretion of ADH 911 osmoregulation, elderly 177-178 osmotic diuresis, diabetic ketoacidosis 1004. 1004f osmotic pressure 1099 osteitis deformans see Paget's disease of bone osteitis fibrosa cystica 891, 971 osteoarthritis (OA) 1154-1158 aetiology 1154,1155ra secondary causes 1154t age and sex distribution 1154, 1154f clinical features 1155. 1155f, 1156cs crystal arthropathy with 1156-1157cs definition 1154 differential diagnosis 1156cs epidemiology 1154 genetic factors 1155ra hands 1123, 1123f inflammatory 1155 investigations 1155 joints involved 1155 knee deformity 1124f management 1155, 1156cs, 1157 non-drug therapies 1156cs physical therapies 1157-1158 recent advances 1157ra surgical 1158,1158t pathology 1154-1155 prevalence 1119,1154 osteoblasts 953 osteocalcin 953, 958 osteochondritis, Scheuermann's 1191 osteoclasts 954 bone resorption 954, 954f hormonal control 954 Paget's disease 974-975 parathyroid hormone effect 955 osteocytes 953 osteogenesis imperfecta 71, 71t, 978 osteoid 953,962 osteomalacia 962, 964-965 aetiology 962, 964, 964t anticonvulsants causing 965 clinical features 964 in elderly 180 hypocalcaemia 974 investigations 964-965, 965t management 965 oncogenic 964 radiology 1188t renal failure 1055 osteomyelitis charcot arthropathy vs 1017 infective arthritis vs 1159 osteopenia 971

1487

1488

osteopetrosis (marble bone disease) 978 osteoporosis 175-176,175t, 954, 959-962 causes 960, 960t clinical features 959 coeliac disease 790 corticosteroid-induced 962, 963f, 1143 definitions 959 following leukaemia therapy 1248 idiopathic 959 investigations 959-960 juvenile-onset 959 juxta-articular, rheumatoid arthritis 1127 management 960-962 multiple myeloma 1259 oestrogen deficiency role 956 postmenopausal (type 1) 175,959, 960, 960f prevention 176, 960, 962t radiology 1188t in rheumatoid arthritis 1135 risk factors 962t senile (type 2) 175 vertebral fracture 959, 960f, 961cs, 1189cs osteoporosis circumscripta 976 osteosclerosis, renal failure 1055 Othello syndrome 232 otitis media 281 chronic secretory ('glue ear') 90cs otorrhoea 1371,1414 ototoxic drugs, vertigo/dizziness 1317-1318,1320,14401 ovale malaria see malaria ovarian follicles 945 ovaries 945-949 anatomy and physiology 945-946 changes during puberty 945 menopause and age-related changes 946 menstrual cycle (normal) 945_946, 945f cancer, age-specific incidence 146f dysfunction 946-949 failure 947,948 LH and FSH actions 940t polycystic disease see polycystic ovary syndrome ovulation 945 normal 945-946, 945f oxalate, urinary stone formation 1088 oxicams, overdose management 28 oxidase system 1235f oxidative metabolism, ageing 173 oximeters 737 oxybutyrin 186 oxygen administration, face masks 740 arterial tension (PaO2) 610 cyanosis 619 assessment uptake by lungs 737t carbon monoxide poisoning 34 delivery to myocardium, factors effecting 732t saturation, measurement 728 tissue content 736t toxicity, acute respiratory distress syndrome 697 transport 607 oxygen dissociation curve 607, 607f Bohr shift 1204 effect of pH, CO2 and 2,3-DPG 1204,1204f polycythaemia rubra vera diagnosis 1242

oxygen therapy administration by face masks 740 chronic bronchitis 664—665 emphysema 664-665 oxymethalone, hypoplastic anaemia 1213 oxytocin secretion, suckling-induced 907 synthesis and secretion 910

p p53gene 149,1237 pacemaker cells, heart muscle 464 pacemakers artificial implantable 504-505, 505t complications 505 dual-chamber pacemakers 504-505 dual-ventricular pacemakers 504-505 implantation 505 indications 504 sick sinus syndrome 506cs temporary transvenous 562-563 atrial/dual-chamber pacing 562-563 indications 563t pachydermoperiostosis 421 Paget's disease of the nipple 425 spinal cord lesion 1380 Paget's disease of bone 974-978 aetiology and pathophysiology 974-975 bone deformity 975,976, 976f clinical features 976, 976f differential diagnosis 1156cs investigations 976, 977f management 976-978,1191 prevalence 974 radiology 1188t secondary heart disease 584 pain abdominal see abdominal pain absence, elderly 190 back see back pain carpal tunnel syndrome 1394 causalgia 1392 cavernous sinus thrombosis 1420 chest see chest pain facial see facial pain headache see headache joints see arthralgia (joint pain) low back see low back pain mediastinal 618 muscle disease 1403 see also myalgia musculoskeletal diseases 1122 neck 1309,1379 neuralgia see neuralgia(s) neuropathic 1392 diabetic neuropathy 1013,1392 perception, loss in diabetic neuropathy 1013 pleural 618 referred 1307 renal 1045,10451 rib 618 shoulder 1192-1195 tabes dorsalis 1429 thalamic 1337 treatment analgesics see analgesics

cancer 166 diabetic neuropathy 1014 lung cancer 707 urinary tract obstruction 1090 painful arc syndrome 1194 palate, examination 1301 palindromic rheumatism 1130,1134 palliative care, cancer 168 pallor 469 palmoplantar keratoderma 436 palpation, joints 1123 palpitations, heart disease 468 palsies Bell's 1369 cerebral palsy see cerebral palsy cranial nerve diabetic neuropathy 1013 facial 1297,1298 meningitis 1414 oculomotor 1297,1410 cryptococcosis 333 diabetic neuropathy 1013 Erb's 1399 progressive supranuclear (SteeleRichardson-Olszewski syndrome) 1366 Saturday night 1395 pamidronate hypercalcaemia treatment 970 Paget's disease of bone 977, 977f PAN (polyarteritis nodosa) see polyarteritis nodosa (PAN) pancarditis, rheumatic fever 580 Pancoast tumour (apical tumours) 152, 702t, 705f pancreas 824-834 abscesses, pancreatitis 829 glucose-sensing 979 insufficiency 827 islet cells see islets of Langerhans normal insulin levels 989 secretion syndromes 759t structural abnormalities accessory pancreatic tissue 826 annular pancreas 826 pancreas divisum 826 transplantation 994 pancreatic disease 825cs carcinoma, diabetes and 1000 clinical features 824 congenital anatomical abnormalities 826 congenital functional abnormalities 827 diabetes and 1000 see also diabetes mellitus dietary factors 139 endocrine tumours 833-834, 833t investigation 833 management 833-834 exocrine tumours 831-833 aetiology and pathology 831-832, 832f clinical features 832 investigations 832-833 management 833 investigations 824-826, 826t imaging techniques 826 tube function tests 824-825 tubeless function tests 825-826, 826f pancreatic ducts 835 pancreatic enzyme, supplementation 831 pancreatic panniculitis 421 pancreatitis acute 827-829 aetiology 828, 828t clinical features 828

complications 828t, 829 hypercalcaemia 968 investigation 828, 829t management 829f pleural effusion 712 aetiology 829, 830t chronic 829-830, 831f gastrointestinal peptides 757 prognosis 831 clinical features 829 diabetes and 1000 investigation 829,830t management 829-830 mumps 292 panhypopituitarism 895 aetiology 895-896, 896t investigations 898-899 differential diagnosis 917 pituitary tumour treatment causing 906 see also hypopituitarism panic attacks (hyperventilation syndrome) 213,214,610 panniculitis, pancreatic 421 pannus, rheumatoid 1132 panretinal photocoagulation (PRP), diabetic retinopathy treatment 1010 papillary ducts of Bellini 1032 papillary muscle, rupture 566 papillitis, multiple sclerosis (MS) 1409 papilloedema 1292,1293f, 1294t benign intracranial hypertension and 1358 cavernous sinus thrombosis 1420 cerebral tumours 1352 hypertensive encephalopathy 1338 subdural haematoma 1372 papovaviruses 290 paracetamol liver damage 852, 853f nephrotoxicity 1086 overdose 25cs, 28-29, 853f antidote 28, 29, 29f paracoccidioidomycoses 334 paracrine action of hormones 884 paracrine regulatory peptides 756 parafollicular cells (C cells) 912 cancers derived from 924 paragonimiasis 375 Paragonimus westermani 375 parainfluenza virus infection 292 paralysis diaphragm 718-719, 720-721cs, 721 extraocular muscles 1297 general, of the insane 1429 hypokalaemic periodic 1112,1407 Klumpke's 1399 poliomyelitis 1426 sleep 1329 paramyxoviruses 292-294 paraneoplastic syndromes 152,154, 154t paranoid personality disorder 210, 232-233 paranoid psychosis 232 paranoid states 231-233 conditions causing 23It paraparesis acute/subacute 1378t aetiology 1378t chronic 1378t spastic hereditary 1375 spinal cord lesion 1377 tropical 1384 paraphrenia 229

paraplegia, spastic 1374 hereditary 1384 see also paralysis paraproteinaemic neuropathy 1398, 1435 paraquat, poisoning 38 parasitic infections leukocyte abnormalities 1234 see also helminth infection; protozoal infections parasitic myositis 1406 parasternal heave 472 parasuicide 223-226, 227cs clinical profile 223-224, 223t see also self-harm; suicide parathyroid gland adenoma 970 treatment 971 autoantibodies, hypocalcaemia due to 973 1,25-dihydroxyvitamin D effect 955 disease, myopathy and 1407 overactivity 970 primary hyperplasia 888, 938 surgery 971 parathyroid hormone (PTH) 955 actions/functions 955 bone metabolism regulation 954 1,25-dihydroxyvitamin D interactions 955 increased secretion 888, 889, 958 hypercalcaemia 970-971 see also hyperparathyroidism low levels, hypocalcaemia associated 973-974, 973t measurement 958 PTH-rp, secretion, hypercalcaemia of malignancy 967cs, 968cs, 971-972 receptor defect 974 synthesis and precursors 955 control by calcium/phosphate 955 parenchymatous syphilis 1429 parenteral feeding 134-136 parietal lobe 1288f lesion 1288 sensory symptoms 1305 tumour 1354cs parkinsonian gait 1290 parkinsonism 1362t, 1364-1366 basal ganglia lesion 1302,1302f cerebral anoxia 1366 drug-induced 1440t MPTP parkinsonism 1362 neuroleptic drugs 1369 gait 1290 Lewy body dementia 1348 MSA see multiple system atrophy (MSA) postencephalitic (encephalitis lethargica) 1364 Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy) 1366 Wilson's disease (hepatolenticular degeneration) 1366 Parkinson's disease 201-202, 1361-1364,1363ra aetiology 1362 clinical features 1362-1363,1362t akinesia 1302,1362 gait 1290 postural abnormality 1362 speech 1362 tremor 1302,1362 see also specific symptoms glabellar reflex 1304

management 1363-1364,1364t anticholinergic drugs 1363 dopamine agonists 1363-1364 levodopa 1363 MOA inhibitors 1364 neural transplantation 1364 surgery 1364 pathophysiology 1362,1363 see also parkinsonism paronychia 436 parotitis 760 paroxysmal atrial tachycardia, acute MI complication 561 paroxysmal cold haemoglobinuria (PCH) 1224 paroxysmal nocturnal dyspnoea, heart disease 468 paroxysmal nocturnal haemoglobinuria (PNH) 1226 clinical features 1226 diagnosis and management 1226 paroxysmal supraventricular tachycardia (SVT) 513-514, 514t partial seizures 1323,1323t, 1326, 1328 parvobacteria 317-321 parvoviruses 289-290 arthritis and joint symptoms 1161 passive diffusion, drugs 1 passive smoking 54 Patau syndrome (trisomy 13) 68 patch testing 382,400,402 patellar tendinitis 1197 patent ductus arteriosus 541-542 pathergy 1153 patient isolation, infectious disease control 271 Paul-Bunnell tests 288 peak expiratory flow rate (PEFR), asthma 608,611, 654,655f peanut allergy 98-99, l00cs Pediculus humanus 330, 395 PEFR see peak expiratory flow rate (PEFR) pellagra, niacin deficiency 124-125 pelvic floor exercises 1096 laxity 1096 pemphigus vulgaris 410-4ll, 411f 'pencil in cup' deformity 1151,1151f Pendred's syndrome 917, 924 penetrance, alleles 65 incomplete 65 D-Penicillamine myopathy and 1407 rheumatoid arthritis 1142 side-effects 1142 Wilson's disease 869, 870 penicillin(s) 265 actinomycoses 331 anthrax 312 haemolysis 1223 pharyngitis 281 rheumatic fever 1165 septicaemia 274 toxicity 265 penicillin G 265 penicillin V, post-splenectomy 96 Penicillium griseofulvum 267-268 penile erection diabetic neuropathy 1014 dysfunction see impotence multiple sclerosis 1410 pen injection devices 990 pentamidine, African trypanosomiases 353 peptic oesophageal stricture 767

peptic ulcers 777-781 aetiology 777, 777t clinical features 778 complications 778,780 genetic marker 73t incidence 777f investigations 778 management 779f, 780-781, 781t perforation 778 polycythaemia rubra vera 1241 risk associated with NSAIDs 1140 surgery indications 782t uraemia 1055 peptide hormones, uraemia 1052 peptostreptococci 325 perception, mental state examination 1287 perchlorate discharge test 917 percutaneous transarterial coronary angioplasty (PTCA) 551-552,553 percutaneous transhepatic cholangiography 842 pergolide 1363 pericardial aspiration 588 pericardial disease 586-589 acute see pericarditis aetiology 586-587 angina, differential diagnosis 544 causes 586-587,5861 clinical features 587 constrictive pericarditis 588-589 see also constrictive pericarditis investigation 587-588 pericardial aspiration 588 see also pericarditis pericardial effusions, clinical features 1136 pericardial knock 474,589 pericardial pain 468,587 management 588 pericardial rubs 474,556,587 pericardial tamponade 471,587 aetiology 587 clinical features 587 Kussmaul's sign 587 pulsus paradoxus 587 pericarditis acute pyogenic 586 acute viral 586 constrictive see constrictive pericarditis malignant 587 rheumatoid arthritis 1136 SLE 1174 systemic juvenile idiopathic arthritis 1163 tuberculous 586 uraemia 1053-1054 pericardium 586, 587 perichondritis 618 periodic paralyses, myopathy 1112, 1407 periostitis 329 Reiter's syndrome 1152 peripartum cardiomyopathy 583 peripheral arterial disease 602 peripheral blood stem cell (PBSC) transplant 167,1252ra peripheral nerves 1305f, 1391-1392, 1394t diseases/lesions 1306t, 1391-1400 brachial plexus lesions 1399_1400 lumbrosacral plexus lesions 1400 neuropathies see neuropathy palsies see palsies polyarteritis nodosa and 1431

rheumatoid arthritis and 1431 peripheral nervous system rheumatoid arthritis 1137 uraemia 1055 peripheral neuropathies see neuropathy peripheral oedema see oedema peripheral perfusion 729-730 failure 726, 727f peripheral vascular disease 602-604 arterial disease 602-603 arteriosclerosis 602 Buerger's disease 603 deep vein thrombosis 604 diabetes association 1015 gangrene 603 intermittent claudication see intermittent claudication peripheral arterial disease 602 Raynaud's syndrome/phenomenon 603 smoking 603 varicose veins 603-604 venous disease 603-604 venous thrombosis 604 peristalsis, loss, in systemic sclerosis 1178,1179f peritendinitis 1198 peritoneal dialysis 1059-1060 chronic ambulatory see continuous ambulatory peritoneal dialysis (CAPD) poisoning 22 peritoneal disease 823-824 peritoneal malignancy 824 peritonitis 823-824 acute bacterial 823 biliary, liver biopsy complication 844 primary (spontaneous) 823 tuberculous 824 Perl's iron stain 1208 permethrin 351 pernicious anaemia, spinal degeneration 1383-1384 peroxisome proliferator-activated receptor (PPAR)-y, thiazolidenedione action 999 persistent ductus arteriosus 541542 persistent generalized lymphadenopathy (PGL), HIV infection 443-444 persistent inflammatory symmetrical arthritis (PISA) 1133, 1144cs personality disorders 209-210, 210t classification 210t paranoid 210 schizoid 209 pertussis see whooping cough (pertussis) pethidine, pancreatitis 830 petit mal (absence) epilepsy 1323, 1324 petrosal sinus sampling 929, 936cs Peutz-Jeghers' syndrome 799 P-glycoprotein, distribution and bioavailability of drugs 10, 11, llf pH arterial 610, 611f effect on drug absorption 1-2 urine 1038,10381 phaeochromocytoma 938 diabetes and 1000 investigations 594, 600, 929, 938 management 594, 600, 938

1489

1490

secondary hypertension 593-594, 890 phagocytes 79 see also macrophage; neutrophils phagocytic disorders 93-95, 94t phagocytosis 79 abnormalities 1235,1235t opsonization 81 urate crystals 1167 phagosome 1167 phalanges, telescoping 1151,1151f pharmacodynamics drug interactions 7, 9 elderly 199 variability 1 pharmacokinetics 4t absorption 1-2, 9 distribution 2-3, 9-10, l0f in elderly 198-199 excretion 4-5,11 interactions 9-11 metabolism 3-4,10-11, l0t, l1t see also drug(s) pharyngeal pouches, abnormal development 92 pharyngitis 281 streptococcal 281 phenacetin, nephrotoxicity 1086 phenindione administration 1276-1277 complication 1276-1277 indications 1276 phenobarbitone epilepsy treatment 1327,1328t status epilepticus 1328 meningitis 1417 phenol (carbolic acid) incontinence 1096 poisoning 37 phenoxyacetic acids 38 phenoxybenzamine, phaeochromocytoma treatment 938 phenoxymethyl penicillin 265 phenylalanine, metabolic pathway 70f phenylalanine hydroxylase, defect 69-70, 70 phenylbutazone, ankylosing spondylitis 1150 phenylketonuria 69-70 metabolic pathway 70f screening 69, 75t phenytoin bacterial meningitis 1417 epilepsy treatment 1327,1328t status epilepticus 1328 overdose management 31 teratogenicity 1328 trigeminal neuralgia treatment 1314 Philadelphia (pH') chromosome acute lymphoblastic leukaemia 1247 chronic myeloid leukaemia 1237, 1238 phobias 209, 214 phorbol esters 886 phosphate binders, renal failure 1057 buffering in kidney 1036-1037 depletion causes 964t osteomalacia/rickets due to 964 treatment 965 distribution 953 inorganic, plasma levels and measurement 957-958 intracellular 953

metabolism, regulation 1037 parathyroid hormone synthesis control 955 renal tubular reabsorption 957-958 retention hypocalcaemia associated 973 renal failure 1054-1055,1055t serum, elevated 958 transport defects 1065 phosphatidyl inositol biphosphate, hormonal action mediated by 885-886, 885f phosphodiesterase inhibitors, inotropic therapy 731, 732t phospholipids, in diet 112 phosphoribosyl pyrophosphate synthetase, overactivity 1167 phosphorus inorganic, calcium relationship 954-955 reference nutrient intake 125t photoallergic contact dermatitis 427 photochemotherapy (PUVA) 399 photocoagulation (PRP), panretmal, diabetic retinopathy treatment 1010 photosensitivity drug-induced 418,426 epilepsy 1324 porphyrias 1026,1028 SLE 1174 Phthirius pubis 395 physical activity see exercise physical and environmental disorders 45-55 physical examination in elderly patient 191-192 musculoskeletal diseases 1122 see also individual anatomical structures physical signs, infectious disease, diagnostic aid 261 physiological changes in depression 219 in grief 218 physiological tremor 1303 physiotherapy cerebral palsy 1374 chest, emphysema 665 multiple sclerosis treatment 1412 osteoarthritis 1157 rheumatoid arthritis 1139 physostigmine, tricyclic antidepressant overdose 26 phytophotodermatitis 426-427 Pick's disease 1348 picornaviruses 302-303 pigmentation 427-428 blue/grey in ochronosis 71 drug-induced changes 418, 419t increased, Addison's disease 891, 931 reduced 427-428, 428t see also hyperpigmentation pig renal transplant 1061-1062 pilar cysts 422 'pill-rolling' 1362 pilosebaceous follicles 381 pinealoma 1352t, 1356 'pink puffers,' chronic bronchitis 662, 664, 665 pinta 329 piperacillin 265 septicaemia 274 piperazine citrate ascariasis 360 threadworms 363

piroxicam juvenile idiopathic arthritis 1164 rheumatoid arthritis 1140 pituitary apoplexy 895 pituitary gland 892-912 anatomy and relations 892-893, 892f anterior see pituitary gland (anterior) development 892 disease, myopathy and 1407 historical research 883 lesions 1306t posterior see pituitary gland (posterior) tumours see pituitary tumours pituitary gland (anterior) 893-910 anatomy 892-893, 892f causes of amenorrhoea 946-947 dynamic function tests 892 hormones 893t synthesis and secretion 893-895, 893t see also ACTH; growth hormone; prolactin hypofunction 895-901 management 899-901, 901t see also ACTH; growth hormone; hypopituitarism; panhypopituitarism; prolactin tumours see pituitary tumours pituitary gland (posterior) 892, 910-912 anatomy 910 hormone deficiency treatment 900,911 see also diabetes insipidus hormone synthesis/secretion 910, 910f pituitary snuff taker's lung 694t pituitary stalk 892 damage, prolactin deficiency 907 pituitary tumours 888, 896-897, 1312,1352t, 1353,1353f, 1356 ablative treatment 901 acidophil 902 adenomas 902,1352t, 1353,1353f ACTH secretion 897, 906 Cushing's syndrome due to 932 gonadotrophin secretion 909 growth hormone secretion 902-906 see also acromegaly hormone-producing, features 896t, 897 hyperprolactinaemia 907-908, 909 imaging 899f, 900f local expansion, CNS effects 890 local pressure effects 896-897 management guidelines 897t microadenoma 905cs Cushing's disease 936cs panhypopituitarism due to 895 see also hypopituitarism, anterior; panhypopituitarism prolactin secretion 907-908, 909 radiotherapy 906,936 suprasellar see suprasellar tumours surgery 901,905,936 complications 906 pityriasis rosea 413 pityriasis versicolor 392-393, 392f Pityrosporum orbiculare 392 plague 320-321 transmission 320, 320f vaccine 321

plant alkaloids 161 plantar calcaneonavicular ligament, strains 1199 plantar digital neuritis 1199 plantar fasciitis 1198 plantar spur, Reiter's disease 1152f plants, poisonous see poisonous plants plaque psoriasis 396 plaques, multiple sclerosis (MS) 1408 plasma artificial expanders 1230 drug concentration diazepam 3f lidocaine (lignocaine) 3f theophylline 3f therapeutic monitoring 11-12 fresh frozen (FFP) 731t, 1229-1230,12301,1275 viscosity, musculoskeletal diseases 1125 plasma cells, abnormal, multiple myeloma 1259 plasmacytomas 1261-1262 plasma exchange 103 leukocytoclastic vasculitis 1183 myasthenia gravis 1401 plasma proteins 1230 abnormalities, multiple myeloma 1260 drug distribution 2-3 electrophoresis, multiple myeloma 1260f glomerular filtrate 1033 synovial fluid 1120 plasminogen 1266,1267 Plasmodium falciparum 345 malaria, sickle cell gene 1217 Plasmodium ovale 345 Plasmodium vivax 345 platelet IIB/IIIA receptor inhibitors 551ra, 552,553 platelets 1264-1265,1264f activation and aggregation 1265 aggregation studies 1268 arachidonic acid metabolism 1265f blood products 1229 chronic myeloid leukaemia 1240 concentrates 1229 count malaria 349 thrombocytosis 1272 destruction, microangiopathic 1270 disorders 1268-1272 congenital 12711 qualitative abnormalities 1271-1272 thrombocytopenia 1268-1272 thrombocytosis 1272 uraemia 1053 see also thrombocytopenia; thrombocytosis; individual disorders functions, drugs interfering 1278t musculoskeletal diseases 1125 pleiotropy 73-74 pleura biopsy 713 chest X-rays 625 parietal 710 pleural disease 710-718 cyclothorax 713 dry pleurisy 714-715, 715t empyema 713-714 clinical features 714f see also empyema

haemothorax 713 parietal pleura 710 pleural effusion see pleural effusion pleuritic chest pain without effusion 714-715 pneumothorax see pneumothorax tumours see pleural tumours pleural effusion 710-713 acute pancreatitis 712 ascites 712,872 bacterial infections 712 biopsy 713 bloodstained 712 constrictive pericarditis 711 cytology 712 differential diagnosis 710-712 exudates 712 heart failure 711 hypoalbuminaemia 711 investigation 712-713 malignancies 712 management 713 Meig's syndrome 711-712 peritoneal dialysis 712 postmyocardial infarction syndrome 712 protein concentration 712 radiology 710,711 rheumatoid arthritis 1136-1137 SLE 689,712 subphrenic abscess 712 transudates 710-712 viral infections 712 pleural membranes 710 pleural pain 618 pleural rub 622 pleural thickening 616cs, 617cs chest X-rays 625, 626 pleural tumours 717-718 diffuse mesothelioma 717-718. 717f fibroma 717 metastases 718 pleural metastases 718 pleurisy SLE 1174 see also pleural disease pleurodynia (Bornholm disease) 303 Plummer-Vinson syndrome 768-769 PML see progressive multifocal leuko-encephalopathy (PML) pneumatosis coli 804 pneumaturia, Crohn's disease 809 pneumococcal meningitis, antibiotic choice 263t pneumococcal pneumonia 632, 632t pneumoconioses 692-694, 693t asbestosis 693-694, 693f berylliosis 694 Caplan's syndrome 693 coalminers' 692-693 complicated 693 management 694 silicosis 693 simple 692 Pneumocystis carinii 344 bone marrow transplant 1213 HIV infection and AIDS 344 treatment 344 pneumonia 639, 639f HIV/AIDS infection 445, 446f immune deficiency with hyperIgM 89 prophylaxis in vasculitis 1183 treatment 452,453 pneumomediastinum (mediastinal emphysema) 51, 716

pneumonia 631-640 aetiology 631 aspiration pneumonia 635, 635t bronchiolitis obliterans, organising (BOOP) 696 chlamydial 634 Chlamydia pneumoniae 634 Chlamydia psittaci 634 classification 632t community-acquired 632-634, 632t Coxiella burnetti 634 cryptogenic pulmonary eosinophilia 661,661f differential diagnosis 632t Haemophilus influenzae 633 hospital-acquired 634-635, 634f, 634t idiopathic interstitial 695-696 in immunocompromised hosts see pneumonia in immunocompromised hosts inhalational 637-638 Legionella 633 lung abscess 648 mycoplasmal 634 ornithosis 634 pleuritic chest pain/night sweats 636-637cs pneumococcal 632, 632t polio complications 1426 psittacosis 634 pulmonary oedema in heart failure 492-493 recurrent 635,635t, 637 rickettsial (Q fever) 307, 634 staphylococcal 633 viral/viral-like 633-634, 633t pneumonia in immunocompromised hosts 638-640 Aspergillus 639-640 Aspergillus fumigatus 639 Candida albicans 640 cytomegalovirus 640 fever/pulmonary infiltrates 638t Gram-negative 638-639 important causes 638t Klebsiella 639, 648 management 638 Nocardia 640 Pneumocystis carinii 639f see Pneumocystis carinii at risk groups 638t unusual pneumonias 640, 640t pneumonic plague 320 pneumonitis cryptogenic organizing (COP) 696 interstitial, cytomegalovirus 288-289 methotrexate 1142 ventilator 694t pneumothorax 715-716 causes 715, 715t clinical features 715-716 liver biopsy complication 844 management 716, 716f mediastinal emphysema (pneumomediastinum) 51, 716 recurrence 716 spontaneous 715, 715t tension 715 ventilation complication 740 poisoning alcohols 35-36, 35f animals 41-43 cardiovascular system examination 16-17 corrosive agents 36-37

drugs see drug overdose/poisoning fungicides 38-39 gases and volatile solvents 33-35 herbicides 38 insecticides 37-38 metals 43 plants and fungi 39-41 rodenticides 39 poisonous plants 39-41, 41t cholinergic (nicotinic) activity 39-40 polarized light microscopy, urate crystals 1170 poliomyelitis 1426 clinical features 1426 differential diagnosis 1426 Guillain-Barre syndrome vs 1397,1426 investigation/management 1426 oral vaccine 271 contraindications 86 post-polio syndrome 1426 polio virus, nervous system infection 1422 polyarteritis, renal involvement 1076 polyarteritis nodosa (PAN) 409, 1181-1182,1406,1431 associated HBV 878 clinical features 1182,1182t renal involvement 1076 white cell counts and eosinophilia 1125 polyarthritis differential diagnosis 1129-1130, 1129t clinical clues 1129t gout 1168 joint and system symptoms 1130, 11301 juvenile idiopathic 1163 psoriatic arthritis 1151 polycyclic hydrocarbons 147 polycystic kidney disease adult clinical features 1080-1081 diagnosis and management 1081 screening 75t anaemia 1053 aneurysm association 1343 juvenile 1081 medullary 1081 neoplastic 1081 polycystic ovary syndrome 947t, 948 following leukaemia therapy 1248 hirsutism 948.951 management 949 polycythaemia management 1242 pseudopolycythaemia 1240,1241f rubra vera see polycythaemia rubra vera (PRV) secondary 1240 polycythaemia rubra vera (PRV) 1236,1240-1242 clinical features 1241,1241t diagnosis 1241-1242,1242t haematological features 1241 leukaemia transformation 1242 polydipsia 1105cs investigations 1102-1103,1103f psychogenic, differential diagnosis 911 type 1 diabetes 988 type 2 diabetes 995 see also diabetes insipidus polyglandular endocrinopathy (type 2), type 1 diabetes association 986

polymerase chain reaction (PCR) 59, 59f viral encephalitis 1424cs polymorphic light eruption 426 polymorphic markers 59-60 polymorphonuclear leukocytes see neutrophils polymyalgia rheumatica 1183-1185 aetiology and pathology 1184 clinical features 1183,1184 differential diagnosis 966cs erythrocyte sedimentation rate 1125 investigations and diagnosis 1184-1185 management 1182-1183,1185 prevalence 1183 prognosis 1185 polymyositis 1180,1406 malignancy and 1434 polyneuropathy 1392,1395 aetiology 1396t in diabetic neuropathy 1396-1397 see also diabetic neuropathy inflammatory 1397-1398 Guillain-Barre syndrome see Guillain-Barre syndrome Miller Fisher syndrome 1398 see also demyelinating disease polyol pathway, overactivity and diabetes 1008 polypeptide hormones see hormones polyposis coli 800 polyps colorectal 799-800, 801f, 801t gastric 785 polyunsaturated fats, sources 113f polyuria 1037,1046,1105cs antidiuretic hormone deficiency 911 causes 1046t hypercalcaemia 966 investigations 1102-1103,1103f type 1 diabetes 988, 988t type 2 diabetes 995 see also diabetes insipidus Pompe (type II) glycogen storage disease 1028-1029 pons haemorrhage 1338 infarction 1336 lesions 1284-1285,1297 popliteal cysts see Baker's cysts popliteal nerve, lesions 1199 porphobilinogen (PEG) 1026 porphobilinogen (PEG) deaminase 1026 defects 1027 porphyria 1026-1028 acute 1026-1028,10271 hereditary coproporphyria 1027 intermittent 1027 precipitants 1026 variegate porphyria 1027 classification 1026,1027t diagnosis 1027,1028 liver involvement 878 management 1027-1028 neurological symptoms 1407 neuropathy 1399 non-acute 1027t, 1028 congenital 1028 erythropoietic protoporphyria 1028 porphyria cutanea tarda 1028 photosensitivity 1026,1028 psychiatric symptoms 1027 urine 1026 porphyria cutanea tarda 1028

1491

1492

porphyrin metabolism 1026,1027f, 1433 dysfunction see porphyria see also haem portal hypertension 879 portal vein obstruction, extrahepatic 873-874 Portuguese man of war (Physalia physalis) 42 port wine stain 421 positive end-expiratory pressure (PEEP) 740 acute respiratory distress syndrome 699 positron emission tomography (PET) Hodgkin's disease 1251 liver disease investigations 842 respiratory disease 627 postcalcaneal bursitis 1198 postencephalitic parkinsonism 1364 posterior cruciate ligament 1120f posterior inferior cerebellar artery (PICA), occlusion 1336 postherpetic neuralgia (shingles) 1314 see also herpes zoster (shingles) postictal state headache 1312 period 1321 postinfection tropical malabsorption 792 postinflammatory hyperpigmentation 414 postmenopausal osteoporosis 959, 960, 960f postmyocardial infarction syndrome 566 pleural effusion 712 post-polio syndrome 1426 post-translational processing 884 post-traumatic amnesia 1373 post-traumatic headache (PTH) 1311-1312 post-traumatic stress disorder (PTSD) 219ra post-traumatic syndrome 1373 postural hypotension (orthostatic hypotension) 1322 Addison's disease 931 diabetic neuropathy 1014 syncope 1322,1322t posture ankylosing spondylitis 1150 in bed, musculoskeletal diseases 1122 problems, in elderly 180-181, 181f postviral syndrome see chronic fatigue syndrome potassium dietary intake 1035 homeostasis 1110-1113 effect of acid-base changes lll0f kidneys role 1035-1036 intake, acute renal failure and 1050 reference nutrient intake 125t restriction, renal failure 1057 potassium channel openers (KCO) angina pectoris 548-549 nicorandil 548-549 potassium iodide, preoperative in thyrotoxicosis 922 potassium perchlorate, thyrotoxicosis 921 potassium-sparing diuretics 495, 1057

combination with ACE inhibitors 495 heart failure 490, 495 potassium supplements, salicylates overdose 28 Pott's disease of the spine 1380, 1381f pox viruses 289 Prader-Willi syndrome 128 praxis, mental state examination 1287 praziquantel clonorchiasis 374 cysticercosis 377 prednisolone acute lymphoblastic leukaemia 1247 anterior hypopituitarism 900 Crohn's disease 812 giant cell arteritis 1185 loiasis 368 paroxysmal nocturnal haemoglobinuria 1226 polymyalgia rheumatica 1185 prednisone, SLE treatment 1176 pre-eclampsia 592 drug treatment 599 see also eclampsia pregnancy acute fatty liver 855 anticoagulants 1277-1278 anticonvulsant drugs and 1328 carpal tunnel syndrome 1393 cholestasis 855 coccidioidomycosis 334 diabetic patients 1002-1003,1002t fetal risk 1002 maternal risk 1002 neonaterisk 1002-1003 drugs contraindicated 7t eclampsia and pre-eclampsia 592 energy requirements 119-120 exposure to rubella 295 folate supplementation 125,1211 gastro-oesophageal reflux 765 heart disease and 535,582-583 heart murmurs 583 HELLP syndrome 855 heparin 1278 hepatitis E virus 847 hypertension 592 methyldopa treatment 598, 599 hypopituitarism 895 jaundice 855 nutritional requirements 119-120, 120t phenylketonuria 69-70 prolactin secretion 894, 907 rubella vaccine 272 sickle cell disease 1219 in SLE 1176 B thalassaemia screening 1216 thirst threshold 1100 thromboembolism 1278 thyroid hormones 913, 913f thyrotoxicosis and 922 toxaemia 855 ulcerative colitis 814—815 urinary tract infections and 1083-1084 warfarin 1278 pre-hormones 884 preload, heart pump performance 465-466 premenstrual tension 949 premutation carriers 60-61 prenatal diagnosis 75, 76t cystic fibrosis 650 B-thalassaemia 1216

prepatellar bursitis 1197 rheumatoid arthritis 1136 preprohormones 884 preproinsulin 979 pressure sores 428-429,429t in intensive care unit 749 presyncope (dizziness) 469 pretibial myxoedema 920, 921f priapism, sickle cell disease 1218 primaquine, malaria treatment 349 primary biliary cirrhosis (PBC) 866-868 clinical features 868 course and management 868 immunopathogenesis 867-868 incidence and aetiology 866 pathology 866 scleroderma 878 primary immunodeficiency diseases (PID) see immunodeficiency primary sclerosing cholangitis (PSC) 858 Crohn's disease 809 primidone, epilepsy treatment 1328t primitive reflexes 1304 prion diseases 1351 prion protein 1351 blood transfusion contamination 1229 probenecid 1171 procaine 265 proctalgia fugax 751 proctoscope 753 prodrome, migraine 1308 progesterone breast development 946 normal menstrual cycle 945f, 946 osteoporosis prevention 960 progestogens cyclical 948 oestrogens interactions 887 ovarian failure treatment 948 progressive bacterial synergistic gangrene 386-387 progressive massive fibrosis 693 lung 693 progressive multifocal leukoencephalopathy (PML) 1422,1427 HIV/AIDS infection 448 progressive supranuclear palsy (Steele-RichardsonOlszewski syndrome) 1366 prohormones 884 projection 216 prokinetic drugs functional bowel disorders 823 reflux oesophagitis 766 prolactin 894 action on breast 907 deficiency 897,907 excess 907 amenorrhoea due to 947 management 948 'short loop feedback' 947 see also hyperprolactinaemia hypopituitarism investigation 899 physiology 907 secretion and control of 894, 907 pregnancy 894,907 synthesis, stimuli and inhibitors 893t, 907 prolactin disorders 907 prolactinoma 895, 899, 908 treatment 901 see also macroprolactinoma; microprolactinoma prolymphocytic leukaemia 1258

pro-opiomelanocortin (POMC) 893 ACTH synthesis 906 intermediates/end-products relationship 894f post-translational processing 884 properdin, deficiency 89 prophase 63, 63f Propionibacterium acnes 431 propofol 749t head injury 745 propylthiouracil, thyrotoxicosis 921 prosopagnosia 1287 parietal lesion 1288 prostacyclin, systemic sclerosis 1179 prostaglandins action mediated by adenylate cyclase 885 effect on bone metabolism 956 PGE,, intracavernosal injections 944 prostate cancer 951,1093,1095 clinical features and diagnosis 1093,1095 management 1095 osteoporosis 960 prostatectomy 1093 prostate-specific antigen (PSA), serum levels 1093 prostatic hyperplasia, benign 950-951 protease inhibitors (PIs) 451 protein(s) 110-111, 110t absorption, measurement 759 content of food 110t deficiency 111 dietary intake 1056 dietary restriction, acute renal failure 1051,1056 glycation, diabetes 1008 malnutrition, nephrotic syndrome 1063-1064 metabolism 983 insulin effects 980 liver role 837-838, 838f major pathways 983f prolonged starvation effects 983 provision, acute renal failure 1050-1051 synthesis 111,983 insulin effect 980 variation in rate 111, lilt uraemia 1055-1056 urine excretion measurement 1038-1039 diagnostic implications 1038-1039 protein-binding tests, thyroid disease 915 protein C 1266 deficiency 1281 protein-deficient pancreatic diabetes 1000 protein-energy malnutrition (PEM) 120 protein S, deficiency 1281 proteinuria 1038-1039,1039t, 1045 Bence-Jones 1260 drug-induced 1138 gold salts causing 1142 orthostatic 1038 D-penicillamine causing 1142 persistent asymptomatic 1064-1065,10651 proteoglycans degradation, rheumatoid arthritis pathogenesis 1133 turnover increased in osteoarthritis 1154 proteolysis, cortisol stimulation 981

Proteus 315 prothrombin gene, mutation 1280 prothrombin time haemostasis disorders 1267 international normalized ratio (INR) 840 liver failure 854 liver function test 840 small intestine disease 786 prothrombotic disorders, TIAs and 1332-1333,1333t proton pump inhibitors peptic ulcers 780 reflux oesophagitis 766 proto-oncogenes 1237 protoporphyrin IX 1026 protoporphyrinogen oxidase, defect 1027 protozoa classification 336t free-living, causing human disease 342-358 protozoal infections 335-358 blood 343-352 gastrointestinal 335-342, 343 tissue and blood 343-352 protrusio acetabuli 1135 proximal muscle weakness differential diagnosis and investigations 966cs vitamin D deficiency 966cs proximal myopathy, SLE 1174 proximal tubule (renal) acidosis (type II RTA) 1066 bicarbonate reabsorption 1036 calcium reabsorption 1037 potassium reabsorption 1035-1036 sodium reabsorption 1035 pruritic pseudomonas folliculitis 388 pruritus 433 drug-induced 419 Hodgkin's disease 1250 jaundice 845 onchocerciasis 365 polycythaemia rubra vera 1241 vulvae see pruritus vulvae pruritus ani 363, 433t, 804 threadworms 363 pruritus vulvae iron deficiency anaemia 1207 type 2 diabetes 995 pseudo-acromegaly 905cs pseudo-Cushing's syndrome 935cs, 936cs pseudocysts, pancreatitis 829 pseudofractures 965 pseudogoitre 922 pseudogout 1157cs, 1171 pseudohermaphroditism 941 female 950 male 949-950 causes 941,942t pseudohypoaldosteronism 937 pseudohypoparathyroidism 974 pseudologia phantastica 239 pseudomembranous colitis 314-315, 815-816 Pseudomonas 321 nosocomial infection 270 skin infections 388 Pseudomonas aeruginosa 321, 388 Pseudomonas pseudomallei 321 Pseudomonas septicaemia 388 pseudopolycythaemia 1240,1241f pseudopolyps 813 pseudopseudohypoparathyroidism 974 pseudoseizures 1327

pseudotumour cerebri (benign intracranial hypertension) 1358 pseudoxanthoma elasticum 71t, 72, 437 psittacosis 634 psoriasis 395-399,398cs, 1150 aetiology 395-396 arthritis 396f clinical features 396-397, 396f management 397,399, 399t nail involvement 397, 397f of palms and soles 396 pathology and pathogenesis 396 psoriatic arthropathy 397 pustular 397, 397f psoriatic arthritis 1150-1151 juvenile 1163 types 1150-1151 psychiatric disorders alcoholism 247-252 anxiety see anxiety causes 210 classification 205-210, 206t minds and brains 205-207 death and dying 257-258 depression see depression diagnosis difficulties 207 drug dependence 243-247 see also drug dependence/abuse eating disorders see eating disorders epidemiology 206t in general practice 235t histrionic and related conditions 238-239 hysteria see hysteria legal aspects 253-255 link to physical illness 235 loss, grief and bereavement 217-218 mania and hypomania 226,228 medicine and emotions 255 mental handicap/learning difficulties 252-253 paranoid states 231-233, 231t prevalence 206t psychosis see psychosis schizophrenia see schizophrenia sexual function 256-257 skin disease 436 somatoform disorders see somatoform disorders suicide and parasuicide 223-226, 224f, 225cs see also suicide treatment 212, 213t anxiety 215-216, 215t depression 221-222, 221t see also individual disorders psychiatric examination 211-212, 211t psychiatric factors, epilepsy 1329 psychiatric symptoms, porphyrias 1027 psychogenic rheumatism 1192 psychogenic symptoms 233 psychological development, psychiatric illness 210 psychological effects head injury 1373 whiplash 1373 psychological factors depression 221 facial pain 1315 functional bowel disorders 818, 820, 822 low back pain 1191 tension-type headache 1310

psychological medicine 205-258 psychological support, cancer treatment 165-166 psychological therapy see psychotherapy psychosis 207-208 classification 208t functional vs acute organic 208, 209t neurosis vs 207t relationship to normality 208 relationship to reality 207-208 psychosomatic illness 233 psychotherapy 213t alcoholism 251 anorexia nervosa 241 exploratory 215, 221 hysteria 237-238 impotence 944 psychodynamic 221 schizophrenia 230-23l,232ra psychotropic drugs 216 functional bowel disorders 823 see also antipsychotic drugs ptosis 1296f Horner's syndrome 1295 myasthenia 1400,1401 third-nerve palsy 1297 puberty delayed 902,942 failure 941 hormonal changes 940 ovary changes 945 precocious 941,941t secondary sexual changes in females 946 testes during 940-941 pubic lice (Phthims pubis) 395 pulmonary arteriovenous malformations and shunts 691-692 hepatopulmonary syndrome 691-692 hereditary haemorrhagic telangiectasia 691 pulmonary artery catheters 728, 728f pulmonary artery wedge pressure (PAWP) 728 cardiac index and 729f pulmonary blood vessels, abnormalities 609-610 dyspnoea 610 pulmonary embolism 610 pulmonary capillary blood flow 607 pulmonary disease see lung disease pulmonary embolism 678-680 case study 676-678cs clinical features 678 sudden breathlessness 676cs, 677cs, 678 deep vein thrombosis 676cs, 678, 678cs, 680 diagnosis 678-680, 679f investigations chest X-ray 678-679, 680f D-dimers 679-680 spiral CT scan 679 ventilation and perfusion lung scans 679,681f management 680 heparin 680,1275 warfarin 680 massive 681-682 chest pain 468 chest X-ray 682f clinical features 681 deep vein thrombosis 604 diagnosis 681-682 embolectomy 682

heparin 681 myocardial infarction, differential diagnosis 558 recurrent pulmonary embolism 682 streptokinase 682 treatment 681-682 ventilation-perfusion scan 681 pyrexia of unknown origin 275 recurrent 682 see also pulmonary infarction pulmonary eosinophilia 659-661 allergic angiitis 661 allergic bronchopulmonary mycoses 660 Churg-Strauss syndrome 661 classification 659t cryptogenic 661, 661f drugs/toxins 660 helminthic infections 660 pathogenesis 659-661 unknown causes 661 pulmonary fibrosis bronchiolitis 696 chemotherapy 163 clinical features 692, 692t cryptogenic fibrosing alveolitis 695, 695f diffuse interstitial lung disease 692-697, 696 extrinsic allergic alveolitis 694-695 honeycomb lung 696 iatrogenic lung disease 696-697 idiopathic interstitial pneumonia 695-696 idiopathic pulmonary haemosiderosis 696 occupational lung disease 692-694 pneumoconioses 692-694, 693t see also pneumoconioses progressive massive fibrosis 693 pulmonary haemosiderosis, idiopathic 696 pulmonary hydatids 377f pulmonary hypertension 674-675 causes 675t chest X-ray 675f classification 674t clinical features 674 diffuse lung disease 675 primary pulmonary hypertension 675 pulmonary veno-occlusive disease 675 tricuspid regurgitation 532 pulmonary infarction 675, 678-680 clinical features 678 sudden breathlessness 676cs, 677cs, 678 deep vein thrombosis 676cs, 678, 678cs, 680 diagnosis 678-680, 679f investigations chest X-ray 678-679,680f D-dimers 679-680 spiral CT scan 679 ventilation and perfusion lung scans 679, 681f management 680 heparin treatment 680 warfarin therapy 680 see also pulmonary embolism pulmonary infections see respiratory infections pulmonary nodules, solitary 708-709, 709f pulmonary oedema acute, treatment 492t

1493

1494

heart failure 492-493 malaria 347 mechanical ventilation 732 withdrawal 741 mountain sickness 50 poisoning 17t poor contractility of ventricle 731 salicylates overdose 28 pulmonary regurgitation 532 pulmonary rehabilitation 665. 666f pulmonary-renal syndrome 1076-1077 pulmonary sequestration 648 pulmonary stenosis 532-533 clinical features 532 congenital rubella 295 investigation/management 532-533 pulmonary thromboembolism 675-682 pulmonary veno-occlusive disease 675 pulses see arterial pulses; jugular venous pulse (JVP) pulsus alternans 471 pulsus paradoxus 471, 620 pericardial tamponade 587 pupillary responses Argyll Robertson pupil 1295 coma 1284 Horner's syndrome 1295,1296f hypoxic-ischaemic injury 1432 light reflex 1293-1294 multiple sclerosis 1409 near vision (convergence) reflex 1294-1295 oculomotor reflexes 1293-1295, 1295f pupil size 1293 signs in poisoning 16,16t tonic pupil (Holmes-Adie syndrome) 1295, 1296f unconscious patient 16 pure XY gonadal dysgenesis 947. 949 purgatives see laxatives purines dietary, hyperuricaemia due to 1166 metabolites in uraemia 1052 purpura drug-induced 419 Henoch-Schonlein see Henoch-Schonlein (anaphylactoid) purpura SLE 1174 thrombocytopenic 1269 thrombotic thrombocytopenic 1079 purse-lipped breathing, emphysema 663 pustular psoriasis 397, 397f PUVA (photochemotherapy) 399 pyelonephritis acute 1084,1086 treatment 1085 chronic aetiology and pathogenesis 1085 clinical features 1086 investigation and treatment 1086 with obstruction 1085 vesicoureteric reflux and 1085-1086 Pygmies 901 pyloric sphincter 775-776 pyloric stenosis 778 peptic ulcer complication 778

pyoderma gangrenosum 407-408. 408f pyogenic abscess 1376 liver 880-881,8801 pyogenic granulomas 422 pyramidal signs 1285 pyrazalone, overdose management 28 pyrexia see fever(s) pyrexia of unknown origin (PUO) 274-278 approach to patient in tropics 276-277 causes 274-276, 276t diagnosis 276 investigations 277-278 management 278 pyridinoline 958 pyridostigmine 1401 pyridoxine (vitamin B6) deficiency 125 food sources 124t overdose 33 reference nutrient intake 125t role in the body 124t toxicity 127,127t pyrimethamine 453 pyrophosphate arthropathy 1171 clinical features and diagnosis 1171 management 1171 see also calcium pyrophosphate crystals pyropoikilocytosis, hereditary 1221 pyruvate kinase (PK) deficiency 1222 pyrvinium pamoate, threadworms 363

Q Q fever 307, 634 qinghaosu, malaria treatment 351 quadriceps, wasting, rheumatoid arthritis 1134 quandrantanopias 1291.1291t homonymous 1288,1289 quartan nephrotic syndrome 351 malaria 348 quetiapine 230 quinacrine banding, chromosomes 61 quinidine malaria treatment 349, 350 thrombocytopenia 1269 quinine, overdose 33 quinolones 266 quinuprastin 267

R rabies 300-302 aetiology 300 clinical features 301 distribution and incidence 300 encephalitis 1423 laboratory diagnosis 301 pathology 301 pre-exposure vaccine 273, 301 prevention, control and treatment 301-302

transmission and epidemiology 300-301, 300f rabies immunoglobulin (RIG) 301 radial keratitis 343 radial nerve compression 1394f, 1395 radiation-induced disease colitis 817 enteritis 793 nephritis 1086 neurological 1435 brachial/lumbrosacral plexus lesions 1400,1435 myelopathy 1384 radionecrosis 1435 radiation injury exposure 47-49 iatrogenic lung disease 697 management 49 tissue damage 48 see also irradiation radiculopathy diabetic femoral 966cs diabetic neuropathy 1013 spinal cord degeneration 1379-1380 radioactive uptake tests, thyroid disease 915 radioallergosorbent test (RAST) 97 radiofemoral delay, arterial pulses 470 radiography bone disease 958, 958f chest X-rays see chest X-rays kidney and urinary tract 1041 osteomalacia 964-965, 965f osteoporosis 959, 960f see also X-rays radioimmunoassay, thyroid hormones 914-915 radio-iodine treatment 922 simple goitre 924, 924ra thyroid cancer 924, 925 radiolabelled isotopes fat tests, coeliac disease 789 gastrointestinal examination 755 small intestine disease 787 see also radionuclide studies radiology ankylosing spondylitis 1150 chest X-rays 623-626 see also chest X-rays gout 1168f low back pain 1187-1188,11881 musculoskeletal diseases 1127-1128,1128f psoriatic arthritis 1151 Reiter's disease 1152f rheumatoid arthritis 1127-1128, 1128f seronegative spondarthritides 1147 small intestine disease 787 see also radiography: other specific techniques radionuclide studies bone disease 958 bone scans see bone scans glomerular filtration rate 1040 liver disease 841-842 renal 1042, 1043f see also radiolabelled isotopes radiosurgery 1357 radiotherapy 158-160,160ra, 160t acromegaly 906 acute lymphoblastic leukaemia 1247 cerebral tumours 1357-1358 chronic myeloid leukaemia 1239 complications 160t

fields in Hodgkin's disease 1170f high-dose 167 Hodgkin's disease 1252,1252f macroprolactinoma treatment 909 multiple myeloma 1260-1261 non-Hodgkin's lymphoma 1256 pituitary tumours 906, 936 sensitivity of tumours 159t tissue penetrating power 159,159f see also irradiation RAG1 and RAG2 genes 82 ragged red fibres 1408 Ramsay-Hunt syndrome (geniculate herpes zoster) 1320,1320t RANK-L Paget's disease 975 rheumatoid arthritis pathogenesis 1132 rash butterfly, in SLE 1172f, 1174 dermatomyositis 1180 erythema marginatum 1165,1165f leukocytoclastic vasculitis 1183 meningitis 1414 poisoning 16t systemic juvenile idiopathic arthritis 1162-1163,1162f varicella (chickenpox) 284 rat handler's lung 694t Raynaud's phenomenon 603,1259, 1262 management 1179 rheumatoid arthritis 1134 scleroderma 1177,1178 Raynaud's syndrome 603 reactive arthritis 1151-1153 aetiology 1151-1152,1152t differential diagnosis 1169cs enteric (ERA) 1151 sexually-acquired (SARA) 1151 reading dyslexia 1286 mental state examination 1286 reasoning, mental state examination 1286-1287 receptive (sensory) dysphasia 1286. 1289 receptors, hormones see hormones recessive inheritance 64-65, 64f recombinant human DNase, cystic fibrosis 651 recombinant proteins, factor VIII 1273 recommended daily amount (RDAs) 106-107 rectal biopsy, ulcerative colitis 813 rectal cancer see colorectal carcinoma rectal examination colorectal carcinoma 801-802 poisoning 17 schistosomiasis 372 recurrent laryngeal nerve 1301 recurrent pneumonia 635, 637 causes 635t red blood cells (erythrocytes) 1203-1204 antigens and antibodies 1227-1228 concentrates 1229 congenital enzyme defects 1221-1223 congenital membrane defects 1220-1221 enzymopathies, general approach 1223 frozen 1229 G6PD levels 1222 megaloblastic anaemia 1209

normal mass 1204-1205 osmotic fragility 1221f substitutes 1229 trauma cardiac prostheses 1225 march haemoglobinuria 1226 5a-Reductase 940 deficiency 950 inhibitor see finasteride Reed-Sternberg cells, Hodgkin's disease 1251 refeeding syndrome 134.136 referred pain headache 1307 to shoulder 152,1193t reflexes 1303-1304,1304t abdominal 1303, 1376 brainstem 1284-1285. 1296 cardiovascular 1014 chewing 1304 cough 19 eye movements 1284-1285, 1296 gag see gag reflex glabellar 1303-1304 grasp 1304 inverted supinator 1377 jaw jerk 1298 plantar 1303 primitive 1304 pupillary light reflex 1293-1294 near vision (convergence) reflex 1294-1295 segmental levels 1304t snout 1304 sucking 1304 tendon 1303 diabetic neuropathy 1013,1014, 1396 muscle disease 1403 vestibular 1296-1297,1299 vestibuloocular (VOR) 1317 reflex sympathetic dystrophy syndrome, shoulder 1194 reflux oesophagitis 766, 766t Refsum's disease 1399 registration (immediate recall), testing 1286 regression 217 rehabilitation, low back pain 1190 Reiter's syndrome/disease 315,581, 1151-1153 aetiology 1151-1152 after Shigella exposure 1147 age and sex relationship 1121 clinical features 1122,1152 genetic markers 73t gonococcal arthritis vs 1159 infections associated 1148 investigations 1152 management and prognosis 1153 pathogenesis 1148 relapsing fever 329-330 Relenza, influenza virus infection 291 remote memory, testing 1286 REM sleep 1329 renal amyloid 1077 renal angiography, hypertension 596 renal artery stenosis 1082-1083 angioplasty 1083 renal biopsy 1043-1044,1045t recurrent haematuria 1064 renal blood flow 1032 renal calculi, gout 1168 renal carcinoma see renal tumours renal damage, malaria 347 renal disease 1031-1098 cvstic 1080-1081, 1080t

diabetic 1011-1012 see also diabetic nephropathy dietary factors 139 end stage, epidemiology 1031 epidemiological considerations 1031 glomerulonephritis see glomerulonephritis hypotension and 1081-1083 multiple myeloma 1077,1077t. 1259-1260 polycystic see polycystic kidney disease prescribing in 1097-1098,1097t body clearance 1097 dose modification 1097-1098 secondary hypertension 593 sodium loss, causes 1109t symptoms and signs 1044-1047, 1046t systemic lupus erythematosus 1075-1076 see also specific diseases renal failure acidosis 1115 acute 1047-1051, 1048-1049cs causes 10471 liver disease 1047 management 1050-1051 postrenal 1050 prerenal 1047-1048 prerenal vs renal 1049t renal 1049-1050 structural abnormalities 1049 acute vs chronic 1047t anaemia 1226-1227 associated with liver failure 854 chronic 1051-1062 aetiology 1051,10521 assessment 1052t bone disease 973 clinical features and investigation 1051-1056 control of blood pressure 1057, 1059 dietary management 1056-1057 hypocalcaemia associated 972-973 management 1056-1057,1059 measures to halt progression 1057,1059 plasma measurements 965t systemic sclerosis 1178 end-stage age-related incidence 1059f diabetic nephropathy 1012 hyperuricaemia 1166 intensive care unit 748 tumour lysis syndrome in 166 urinary tract obstruction 1090 renal function assessment 1037-1044 biopsy 1043-1044,10451 examination of urine 1037-1039 imaging of kidney and urinary tract 1041-1043 measurement of GFR 1039-1041 impairment and fluid overload 748 see also kidney, specific homeostatic functions renal glycosuria 1038,1065 renal haemodynamics, ascites 872 renal hypertension 1081-1083. 1082f cause of renal damage 1082 consequence of renal disease 1081-1082

management 1082-1083 with renal parenchymal disease 1082 renal vascular disease 1082 unilateral 1083 renal ischaemia 1047 renal osteodystrophy 1054f renal pain 1045,1045t renal parenchyma 1031 renal replacement therapy (RRT) 1059-1060 diabetes mellitus 1012,1078 epidemiology 1031 requirements 1059 see also dialysis renal support, diabetic nephropathy 1012.1078 renal syndromes 1047-1068,1047t see also individual syndromes renal system in SLE 1175 systemic sclerosis 1178 renal transplantation 1060-1062 anatomy 1061f cadaveric donation 1060 diabetic nephropathy 1012 donor kidney 1060 hypercalcaemia after 889 immunosuppression therapy 1061 living relation donation 1060 rejection 1061 survival 1062f tertiary hyperparathyroidism after 889 xenotransplantation 1061-1062 renal tubular acidosis (RTA) 1065-1067 classification 1066t plasma measurements 965t renal tubular syndromes 1065-1068 multiple defects 1065-1067 renal tubules 1032-1033 mechanisms of action 1036f see also distal tubule; proximal tubule reabsorption 1034 secretion 1034 transport 1034t renal tumours 1091-1095, 1091 cs, 1091f adenocarcinoma 156f, 1091 chemotherapy 1091 cysts formation 1081 nephroblastoma (Wilms' tumour) 1091 TNM classification 155 transitional cell carcinoma 1091-1092 renal veins, thrombosis 1064 renin 926 renin-angiotensin-aldosterone system 1100 blood pressure 589-590 heart failure 489-490, 489f renal disease and hypertension 1081 secondary hypertension 593 sodium homeostasis 1035 system inhibition 1082 reoviruses 303 repaglinide 997-998, 998t repetitive strain injuries, hand and wrist 1196,1196t repetitive strain syndrome 1196, 1196t reproductive systems, endocrine disorders affecting 891 resins, lipid-modification 1024-1025, 1025t

respiratory acidosis 1115-1116 blood gas analysis 1114 respiratory alkalosis 1116-1117 causes 1117t hypocalcaemia due to 972 respiratory disease 605-723 airflow obstruction 607-608 airway calibre 608 arterial carbon dioxide tension (PaCO2) 610 arterial oxygen tension (PaO2) 610,619 arterial pH 610, 611 f auscultation crackles 622t wheezes 623t breathlessness see breathlessness (dyspnoea) bronchial calibre, determinants 607-608 bronchogenic carcinoma 628f carbon dioxide retention 619 chest X-rays see chest X-rays clinical examination 619-623, 623t auscultation 622-623, 622t chest 621f finger/toe clubbing 619f, 619t percussion 621-622 clinical features chest pain 618 cough 612. 612t. 613f cough fractures 618 dyspnoea see breathlessness (dyspnoea) finger/toe clubbing 619, 619f, 619t haemoptysis 615 see haemoptysis mediastinal pain 618 pleural pain 618 rib pain 618 symptoms/signs 611-618 wheeze 618 cyanosis 610,619-620 diaphragm weakness/paralysis 718-719, 719, 719f, 721 dietary factors 139 forced expiratory volume in 1 second (FEV,) 608, 608f, 611,617cs gas diffusion abnormalities 609 hyperinflation 608 infections see respiratory infections inhaled B2 agonists 608 investigations biopsy see lung, biopsy bronchoalveolar lavage 629, 688 CT scanning 627 exercise testing 611 fibreoptic bronchoscopy 627-629. 628f, 629f imaging 623-626 magnetic resonance scans 627 mediastinoscopy 630 mediastinotomy 630 peak expiratory flow rate 608, 608f, 611,617cs positron emission tomography 627 rigid bronchoscopy 629 thoracoscopy 630, 630ra ultrasound 627 lung function testing 611, 611t indications 611t patterns of abnormality 612t mortality/morbidity, UK 605 neuromuscular disorders 718-722 pathophysiology 607-618

1495

1496

pleural effusion see pleural effusion pulmonary embolism see also pulmonary embolism and infarction right heart failure 620 sputum 612-613 surgery, thoracoscopy 630, 630ra thoracic deformity 722-723 upper airway obstruction 608 vital capacity 608, 611, 617cs respiratory weakness 719, 719f see also lung disease; individual diseases respiratory distress syndrome adult (acute) see acute respiratory distress syndrome (ARDS) neonates, following diabetic pregnancy 1002 respiratory drugs, overdose management 32 respiratory failure 670-675 acute 671 admission to ICU 736-742 alveolar-arterial (A-a) gradient 670-671 assessment of oxygen uptake 737t case study 672-673cs causes 670t chronic 671, 673 clinical features 671 definition 670-671 management 671-673 neurological involvement 1432 respiratory function, Guillain-Barre syndrome 1398 respiratory infections 631-647 acute bronchitis 631 allergic rhinitis 631 common cold 631 croup 631 enterovirus 302-303 epiglottitis 631 Haemophilus influenzae 631, 633 Histoplastna capsulatum 333 lower respiratory tract infections 631 pneumonia 631-640 see also pneumonia schistosomiasis 372 sinusitis 631 Streptococcus pneumoniae 631 upper respiratory tract infections see upper respiratory tract infections viral 631 respiratory muscles 718-722 airways obstruction 722 diaphragm weakness/paralysis 718-719, 719, 719f, 721 fatigue 722 impairment, metabolic abnormalities 741t lung function 719 mechanical pump 741t neuromuscular disease 718-719, 721 weakness 720-721 cs management 721 metabolic disorders 721-722 weight loss 722 respiratory paralysis, poliomyelitis 1426 respiratory support, poisoning and self-poisoning 19 respiratory syncytial virus (RSV) infection 292 respiratory system abdominal muscles 718

alveolar spaces 605 carbon dioxide transport 607 chest X-rays see chest X-rays clinical examination 619-623, 623t chest 621f finger/toe clubbing 619f, 619t diaphragm 718 see also diaphragm elastic recoil 605, 606 food intolerance responses 141 gas diffusion 606-607, 606f see also gas diffusion imaging 623-627 intercostal muscles 718 oxygen dissociation curve 607, 607f oxygen transport 607 pathophysiology 607-618 pulmonary capillary blood flow 607 respiratory muscles 718 SLE 1174-1175 static lung volumes 606, 606f structure/function 605-611 ventilation see ventilation see also respiratory disease respiratory tract infections see respiratory infections rest juvenile idiopathic arthritis 1164 low back pain (mechanical) 1188 rheumatoid arthritis treatment 1139 restenosis 551-552, 552f restriction enzymes 58, 58f restriction fragment length polymorphisms (RFLP) 59, 60f, 73 restriction map 59 restrictive cardiomyopathies 572-574 cardiac amyloid 573 endocardial fibroelastosis 573-574 endomyocardial fibrosis 573 haemochromatosis 573 Loffler's endocarditis 574 sarcoidosis 573 transfusion haemosiderosis 573 restrictive lung diseases 608-609 resuscitation see cardiopulmonary resuscitation reticular dysgenesis 94t reticuloendothelial cells, anaemia in musculoskeletal diseases 1124 Reticulo-endothelial (RE) system 1207 retina detachment, diabetic retinopathy 1009-1010 lesions, infective endocarditis 577 oedema, mountain sickness 50 onchocerciasis 364 retinal ischaemia central artery occlusion 1291-1292,1293f diabetic retinopathy 1009 retinitis, AIDS-related 1428 retinitis pigmentosa 1292 retinoic acid 431 retinopathy diabetic 1008-1010, l0l0t, 1291, 1293f advanced disease 1009-1010 background retinopathy 1008, 1009 early signs 1008-1009,1010 fluorescein angiogram 1009, 1009f, 1010

maculopathy 1010 management 1010 nephropathy association 1011, 1012 referral guidelines lOlOt screening/investigation 1010, lOlOt stages/lesions 1009,1009f type 2 diabetes and 996 light reflex 1293-1294 pigmentary degeneration 1292 sickle cell disease 1218 see also optic fundi retrocalcaneal apophysitis 1198 retrocalcaneal bursitis 1198 retrograde urography 1041 retroviruses, type 1 diabetes association 987 Reye's syndrome 1164 rhabdoviruses 300-302 rhachischisis 1384 Rh blood group 1228 antibody formation 1228 D antigen 1228 indirect 1228 Kleihauer test 1234 prevention of sensitization 1234 see also haemolytic disease of the newborn rheopro 1278 Rhesus disease see Rh blood group rheumatic fever 580-581, 580t, 1164-1165 antistreptolysin O litre 581 arthritis 580,1164-1165 'migratory' ('flitting') 1164 clinical features 580-581, 580t, 1164-1165 diagnosis 580-581, 580t diagnostic criteria 1165t differential diagnosis 581 erythema marginatum 1165, 1165f heart disease see rheumatic heart disease investigation 581 management 581,1165 myocarditis 580 pancarditis 580 pathology 580 prophylaxis 581 Sydenham's chorea (St. Vitus' dance) 581,1367 rheumatic heart disease 463, 580-581 aortic stenosis 527 Carey Coombs murmur 581 mitral regurgitation with stenosis 526 mitral stenosis 521 rheumatism palindromic 1130,1134 psychogenic 1192 soft tissue see soft tissue rheumatism rheumatoid arthritis 1130-1137 aetiology 1126,1131 age and sex relationship 1121, 1131,1131f amyloidosis associated 1138 anaemia 1125t, 1135 assessment of disease activity 1139t cervical spine 1135 cervical subluxation 1137 clinical features 1122,1133-1138, 1144cs articular 1134-1135,1134f extra-articular 1135,1135t

organs involved 1136-1137, 1136t periarticular 1135-1136 presenting features 1133-1134, 11341 pulmonary complications 1136-1137,1136t diagnosis 1133 diagnostic criteria 1133t, 1144cs differential diagnosis 1144cs Disease Activity Score (DAS) 1139-1140 drug therapy 1139-1146, 1144-1145CS adverse effects 1137,1138 analgesics 1140 anti-inflammatory drugs 1138 antirheumatic drugs 1140-1146 combination 1145 indometacin 1140 NSAIDs 1140 pyramidal approach 1141,1142f, 1143ra recent advances 1143ra economic impact 1119,1130 endocarditis 581 epidemiology 1131,1131f erythrocyte sedimentation rate 1125 feet 1135 hands 1134,1134f joints involved 1123,1123f radiology 1128f hip joint 1135 HLA-DR4 1131 infections 1135 joint deformities 1134,1134f knee joint 1134-1135 deformity 1124f liver 877 lymph node enlargement 1135 management principles 1138-1139,11381 mortality 1130 neurological involvement 1431 carpal tunnel syndrome 1393 spinal cord 1380,1380f oligoarticular, rheumatoid factors absent 1126 osteoporosis 1135 outcome prediction 1139 pannus 1132 pathogenesis 1131-1133,1132f, 1133ra persistent inflammatory symmetrical (PISA) 1133, 1144cs prevalence 1119,1131,1131f prognosis 1146 poor, indicators 1146 progression, prevention 1139 radiology 1127-1128,1128f, 1141 referral 1141 renal involvement 1076 septic arthritis in 1158f seronegative spondarthritides vs 11471 treatment aims 1138-1139 biological 1143ra biological response modifiers 1145-1146 drugs see rheumatoid arthritis, drug therapy early, outcome improvement 1139 monoclonal antibodies 1133ra, 1146 patient support 1144cs, 1146

physiotherapy and occupational therapy 1139 surgery 1146,1146t vasculitis complication 1138, 1181ra rheumatoid disease 409 rheumatoid factors 1126 complement activation 1132 detection methods 1126,1126f diseases with and causes 1126, 1126t rheumatoid arthritis 1126,1132 rubella arthritis and 1160 rheumatoid granulomata 1136 rheumatoid nodules 1137 pulmonary 1137 subcutaneous 1135-1136,1136f rheumatology, terminology 1121t rhinitis allergic see allergic rhinitis differential diagnosis 97t seasonal/perennial 97-98 rhinorrhoea 1371,1414 rhinoviruses, immune evasion 79 rhinovirus infection 302 ribavirin 268 chronic HCV 865 ribcage, chest X-rays 626 riboflavin (vitamin B2) deficiency 125 food sources 124t reference nutrient intake 125t role in the body 124t ribonucleic acid see RNA ribosomes 57 rib pain 618 rickets 962,964-965 vitamin D-dependent type I 964 vitamin D-dependent type II 964 vitamin D-resistant 964 see also osteomalacia rickettisial infections 305-307, 305t Rickettsia 1430 rickettsial pneumonia (Q fever) 307, 634 'rickety rosary' 964 Riedel's thyroiditis 924 rifampicin 267 brucellosis 319 overdose 33 right heart failure acute 493, 499-500cs aortic stenosis 527 left- vs. right-sided 490 mitral stenosis 521 oedema 469 pleural effusion 711 right atrial myxomas 582 severe respiratory failure 672673 right ventricular infarction 563-566 rigidity 1361 Riluzole 1389 rimantadine, influenza virus infection 291 Ringer's lactate 280 cholera 324 Rinne's test 1298 risk assessment genetic counselling 75 psychiatric illness 253 risperidone 230 risus sardonicus, tetanus 313 river blindness see onchocerciasis RNA (ribonucleic acid) 57 antibodies 1173 RNA viruses cancer caused by 148-149 classification 284t

enveloped single-stranded 290-302 non-enveloped double-stranded 303 non-enveloped single-stranded 302-303 Robertsonian translocation 62 roboxetine, overdose 26 Rochalimaea henselae 322 rocker-bottom foot 66 Rocky Mountain spotted fever 305-307 see also typhus rodenticide, poisoning 39 rodenticides, poisoning 39 rodent ulcer 423-424, 424f Romano-Ward syndrome 517 Romberg's sign 1013 Romberg's test 1289-1290,1318 ropinirole 1363-1364 rosacea 432-433, 432f Ross River virus 1161 rotator cuff rupture 1194 tendinitis 1193 rotavirus, diarrhoea 279, 303 Roth spot 577 rough endoplasmic reticulum (RER), HLA antigen synthesis 84 Roux-en-Y, gastric bypass 132 rubella (German measles) 294-295 arthritis 1160-1161 congenital 295, 295t exposure during pregnancy 295 vaccination, arthritis after 1161 vaccine 272,295 rubeosis iridis, diabetic retinopathy 1009,1010 Rye classification, Hodgkin's disease (HD) 1251

s sabre tibia 329 sacroiliac tenderness, ankylosing spondylitis 1149 sacroiliitis ankylosing spondylitis 1148 Crohn's disease 809 enteropathic arthropathies 1153 psoriatic arthritis 1151 salazopyrin, rheumatoid arthritis 1144-1145CS salbutamol, overdose management 32 salicylates Crohn's disease and ulcerative colitis 812t overdose 27-28, 28t diagnosis 27 management 27-28 see also aspirin salicylism 1140 salicylsulphonic acid test 1038 saline infusion, hypercalcaemia treatment 968cs, 969 salivary glands, secretion syndromes 759t salivation, excess, poisoning 16t Salmonella 315 diarrhoea 279 Salmonella enteritidis 278 Salmonella paratyphi (A,B,C) 317 salt depletion 45

Sarcocystis bovihominis 342 Sarcocystis suihominis 342 sarcocystosis 342 sarcoidosis 414, 415f, 682-689,1406 aetiology 683-684 case study, fever and X-ray abnormalities 687-688cs clinical features 684-686, 684t extrathoracic 685-686 stage 1 684 stage II and III 685, 685t thoracic 684-685, 685t diagnosis 686 bronchoscopy 628-629 erythema nodosum 685-686,688cs extrathoracic 685-686 bone sarcoidosis 686 erythema nodosum 685-686 eyes 686 lymphadenopathy 686 skin 685-686 hilar gland enlargement 682, 684, 684f hypercalcaemia 972 Kveim test 686 lung function tests 689 management 686-688 bronchoalveolar lavage 688 radiology 686 serum angiotensin-converting enzyme (SACE) 686, 687-688cs, 688, 688t steroid treatment 689 treatment 689 neurological complications 1431, 1431t non-caseating granulomas 683-684 pathogenesis 683-684, 683f persistent severe haemoptysis 614-615cs prevalence/distribution 682-683 prognosis 689 restrictive cardiomyopathies 573 sarcoma bone 976 Kaposi's see Kaposi's sarcoma skin involvement 426 sarcomeres, heart muscle 463,464f, 465f Sarcoptes scabiei 394 saturated fats, sources 113f Saturday night palsy 1395 sawtooth nystagmus 1299 scabies 394-395, 394f scalp psoriasis 396 scarlet fever 259, 308-309, 309f, 580 complications 309 Scheuermann's osteochondritis 1191 Schilling test 751-752,1210f Schistosoma 370 lifecycle 371f Schistosoma haematobium 370-372 Schistosoma japonicum 370-372 Schistosoma mansoni 370-372 schistosomiasis 273, 370-373, 373t aetiology 370-371 clinical features 372 diagnosis 372-373 distribution and incidence 371, 371f liver involvement 879 management 373, 373t pathology and pathogenesis 371-372 prevention and control 373 transmission and epidemiology 371

schizoid personality disorder 209 schizophrenia 208, 228-231 aetiology 228-229, 228f clinical features 229-230 differential diagnosis 230 management 229t, 230-231, 232ra chronic disability 231 prognosis 230 relapse, prevention 231 relapse rate 229t Schmidt's syndrome, type 1 diabetes association 986 Schneider's first-rank symptoms, schizophrenia 229t schwachman syndrome 827 Schwann cells 1392 diabetic neuropathy 1012 leprosy 326 schwannomas 1352t, 1356 sciatica 1188 sciatic nerve, examination 1187 scintiscanning see radionuclide studies scleroderma 1177-1180 classification 1177,1177t, 1179ra clinical features 1177-1179,1178f diffuse cutaneous 1177 limited cutaneous (CRST) 1177, 1179,1179ra localized (morphoea) 1177 management 1179,1179t see also systemic sclerosis scleroderma sine scleroderma 1177 sclerotic changes, optic fundi 1291 scoliosis 722-723,1187 causes 723f disorders causing 723t scombroid fish poisoning 42-43 scotomas 1291,1291t screening adult polycystic kidney disease 75t complement deficiencies 91 cystic fibrosis 75t diabetic retinopathy 1010, l0l0t drug 247 elderly (routine) 193-194 familial breast cancer 75t familial hypothyroidism 75t familial polyposis coli 751 genetic disorders 74, 75t haemoglobinopathies 75t haemolytic disease of the newborn 1233 haemostasis disorders 12671268 MEN type 2 939 multiple endocrine adenomatosis 75t phenylketonuria 69, 75t sickle cell disease (anaemia) 751 small intestine disease 790 Tay-Sachs disease 75t thrombophilia 1281t scrub typhus 307 scurvy 125-126 seafood, poisonous 42 sebaceous cysts 422 seborrhoeic warts 422 secondary heart disease see heart disease, secondary secondary hypertension see hypertension secretin 755 discovery 883 secundum atrial septal defect 539-540 sedation, in intensive care medicine 749-750, 749t seizures see convulsions; Epilepsy

1497

1498

selective oestrogen receptormodulating agents (SERMS), osteoporosis treatment 961 selective serotonin reuptake inhibitors (SSRIs) 222 overdose management 26-27 selegiline 1364 selenium deficiency 127 reference nutrient intake 125t selenium sulphide 393 self-antigens 96, 99 non-self vs 99 self-esteem, in depression 219 self-harm 223,224-226 assessment 226t causes 224-225 history 226 management 225-226 pyrexia of unknown origin 275 see also parasuicide sella turcica 892 empty 895-896 semen, analysis 943 semilente insulins 989 Sengstaken-Blakemore balloon, variceal haemorrhage 873 senile cataracts, diabetic eye disease 1011 senile osteoporosis 175 senile plaques 1347 sensorineural deafness 1320 sensory cortex 1288f lesion 1305-1306 sensory (receptive) dysphasia 1286. 1289 sensory fits 1326 sensory nerve supply, joints 1120 sensory neuropathies, rheumatoid arthritis 1137 sensory symptoms 1305-1306 Brown-Sequard syndrome 1377. 1377f diabetic neuropathy 1013,1014 disc prolapse 1387t malignancy associated 1434 multiple sclerosis 1410 neuropathy 1392 mononeuropathies 1394-1395, 1394f polyneuropathies 1397 syringomyelia 1383 tabes dorsalis 1429-1430 sensory system 1304-1306 anatomy cortex 1288f dermatomes 1305f peripheral nerves 1305f see also peripheral nerves; spinal cord examination 1297-1298, 1304-1305 lesions cortical 1305-1306 sensory tract 1305 primary sensations 1304-1305 see also specific senses sepsis 733-736 abdominal 274 circulation optimization 733-734 clinical presentation 733 induced vasodilation 729 inflammatory mediators 734 mediator response 735f nitric oxide 734, 736 therapy 733ra strategies 733 tissue hypofusion 733

see also septicaemia septicaemia 273-274, 315 acute bacterial meningitis 1413, 1414t aetiology 274 antibiotics 274 Candida 332 clinical features and diagnosis 274 liver biopsy complication 844 liver involvement 880 management 274 meningococcal see meningococcal septicaemia pathogenesis 274 see also sepsis septic arthritis see infective arthritis septic shock 274, 733, 734, 736 septic thrombosis, meningitis 1414 serial epilepsy 1328 serology blood crossmatching 1230-1231 Chagas' disease 355 pyrexia of unknown origin 277 rubella (German measles) 295 seronegative spondarthritides 1147-1154 concept 1147 conditions included 1148t differential diagnosis 1147,1147t pathogenesis 1147-1148 pathology 1147 radiology 1147 rheumatoid arthritis vs 1147t see also ankylosing spondylitis serotonin see 5-Hydroxytryptamine serotonin syndrome 26 Sertoli cells 939, 940 sertraline 222 serum angiotensin-converting enzyme (SACE), sarcoidosis 686, 688 serum sickness 97 severe combined immune deficiency (SCID) 93, 94t Sever's disease 1198 sex chromosome anomalies 66, 68-69 amenorrhoea associated 947 pure XY gonadal dysgenesis 947 XO/XY mosaicism 947 sex differences (epidemiological) musculoskeletal diseases 1121 arthritis types 1130t osteoarthritis association 1154, 1154f rheumatoid arthritis 1131,1131f serum uric acid levels 1166,1166f sex differentiation 939-940 disorders 949-952 primary 949-950 secondary (female) 951 secondary (male) 950-951 steroid biosynthesis disorders 950 see also pseudohermaphroditism sex-hormone-binding globulin (SHBG) 886,940 sex hormones behaviour and 951-952 deficiency, effects 897 effect on bone metabolism 956 replacement therapy hypopituitarism treatment 900 ovarian failure 948 see also hormone replacement therapy (HRT); testosterone see also specific hormones

sexual characteristics regression with GnRH deficiency 947 secondary development in females 946 development in males 940 disorders affecting see sex differentiation sexual function 256-257, 256t attachment 256 continuity 256 diabetic neuropathy 1014 in elderly 189 history taking 256 Masters and Johnson approach 257, 257t sexual identity 256 sexually-acquired reactive arthritis (SARA) 1151 sexually transmitted disease (STDs) 439, 456-462 prevalence and incidence 439, 440f see also specific infections Sezary syndrome 1257 SH2 domains 886 Sheehan's syndrome 895 sheep cell agglutination test (SCAT) 1126 shellfish poisoning 42 Shigella 315 diarrhoea 279 dysentery 279,315-316 infection, Reiter's disease after 1147 Shigella dysenteriae 315 Shigella flexneri 315 Shigella sonnei 315 shingles see herpes zoster (shingles) shock cardiogenic see cardiogenic shock diabetic ketoacidosis 1005 head injury 1371 septic 274,733,734,736 shock lung syndrome see acute respiratory distress syndrome (ARDS) short gut 794 short leg syndrome 1191 short synacthen test 929, 931 short tandem repeat polymorphisms (STRPs) 59 short-term memory, testing 1286 shoulder examination 1193 extracapsular soft tissue lesions 1192-1195 clinical features 1193t frozen (adhesive capsulitis) 1194 night pain 1192 painful 1192-1195 causes 1193t management 1200 referred pain 1193t shoulder-hand syndrome 1194 shunts, pulmonary arteriovenous malformations 691-692 Shy-Drager syndrome 1322,1364 sialadenitis 760 sibutramine 131 sick euthyroid syndrome 915, 915t sickle cell disease (anaemia) 1217-1220,1219cs, 1219ra clinical features 1218,1218t contraception 1219 laboratory features 1218 management 1218-1219 renal involvement 1078 screening 75t

sickle cell gene 1217 association with other abnormal Hb genes 1220 geographical incidence 1217f sickle cell trait 1217-1218 malaria and 346 sick sinus syndrome 516 artificial implantable pacemakers 506cs episode of collapse 506cs sideroblastic anaemia see anaemia siderosis 693t blood transfusion complication 1231 Sievert (Sv) 48 sigmoidoscopy 753 functional bowel disorders 822 schistosomiasis 372 ulcerative colitis 813 sildenafil 944 silhouette sign, chest X-rays 625, 625f silicosis 693, 693t simple partial seizures 1323t, 1326 Simulium blackfly 364 Sinding-Larsen disease 1197 single gene disorders see genetic disorders single-nucleotide polymorphisms (SNPs) 60 sinoatrial node B-adrenoreceptors 464 block 502 pacemaker cells 464, 465f sinus arrhythmia, arterial pulses 470 sinus bradycardia, acute MI complication 561-562 sinuses, cerebral cavernous 1330,1331 f, 1420 dural, venous 1419 sinusitis 281,631 sinus node block 502 sinus rhythm, normal 501 sinus tachycardia 507-508 acute MI complication 561 thyrotoxicosis 583 sinus venosus defect 540 Sipple's syndrome 593-594 Sjogren's syndrome, rheumatoid arthritis association 1137 skeletal metabolism, uraemia 1054-1055 skeletal syndromes, secondary heart disease 585t skeletal system 953 endocrine disorders affecting 890-891 mineral distribution 953 skin 379-381 atrophy 1178 barrier from disease 260 biopsy 382 changes, in elderly 192 disease see skin disease/disorders dry 433 examination 381 in cardiovascular disease 469-470 functions 379 infections, clostridia 314 involvement in systemic diseases dermatomyositis 1180 diabetes mellitus 415-416, 416t psoriatic arthritis 1151f Reiter's disease 1152 rheumatoid arthritis 1137 scleroderma 1177-1178 signs in joint disease 1123t SLE 1174

vasculitis 1181f lesions, terminology 382t protection 272-273 rashes see rash structure 379-381, 380f tags 422 tumours 421-426 basal cell carcinoma 423-424, 424f benign/cysts 422-423 squamous cell carcinomas 423, 423f see also melanoma, malignant skin disease/disorders 379-437, 380ra arthropods 394-395 bacterial 384-389 blistering diseases 410-415 diagnosis 381-382 drug eruptions 416-420 eczema and dermatitis 399-405 fungal diseases 389-393 genodermatoses 436-437 associated with cancer 437t hirtsutism/hypertrichosis 434-435 history taking 382t ichthyosis 405, 405f malignancy manifestations 420-426, 420t mouth involvement 760t pigmentation 427-428 prevalence 380t psychological causes 436 reaction patterns 405-410, 406t therapy 382-383, 384ra viral disease 393-394 skin-prick tests 97 skull fractures 1371 platybasia 976 tumours 1352t skull X-ray cortical venous thrombophlebitis 1419 hair-on-end appearance 1215 head injury 1371 hypopituitarism 898, 899f infantile hydrocephalus 1360 intracranial abscesses 1418-1419 intracranial tumours 1353 venous sinus thrombosis 1419 slapped check appearance 289 slapped check disease see erythema infectiosum SLE see systemic lupus erythematosus (SLE) sleep 1329 disorders 1329 disturbances ankylosing spondylitis 1149 see also insomnia elderly 187-189 normal 187,188f REM sleep 1329 sleep apnoea 1329 sleep apnoea syndromes 668-670 central sleep apnoea 669 mechanism 669f sleep study 669f continuous positive airway pressure 670 obstructive sleep apnoea 668669 features 668t respiratory failure 672-673cs palatopharyngoplasty 670 treatment 669-671 sleeping sickness see African trypanosomiasis

sleep paralysis, narcolepsy 1329 slow-acting antirheumatic drugs (SAARDs) 1141,1141t Sm, antibodies 1173 small-cell lung cancer 701, 702t chemotherapy 936 inappropriate secretion of ADH 911-912 Lambert-Eaton syndrome and 1402,1435 prognosis 156f trials of treatment 167 small intestine 786-797 bacterial overgrowth 791 diagnostic findings 791 barium studies 755, 756f biopsy 754,790 coeliac disease 787-790 dermatitis herpetiformis 790-791 digestion and absorption 757-759, 759f histology 789, 790f malabsorption, gastric surgery complication 780 motility 757 disorders 758t secretion syndromes 759t tumours see small intestine disease small intestine disease clinical features 786, 786t diarrhoea 793-794 investigations 786-787, 786t ischaemia 795,795t malabsorption 787 systemic sclerosis 793 tumours 795-797 adenocarcinomas 796 carcinoid 796 lymphomas 797 see also specific diseases smoke inhalation 54 smoking bronchial carcinoma 700, 701, 701f Crohn's disease 809 diabetes and 994,1015 drug interactions 10 hyperlipidaemia and 1024 pancreatic tumours 831 passive 54 peptic ulcers 777 peripheral vascular disease 603 smoking-related diseases 666, 667t smoking cessation bronchial carcinoma 700,701,701f chronic bronchitis/emphysema 665-667 nicotine replacement therapy 667 smoking-related diseases 666, 667t snake bite 41-42, 41f sneeze syncope 1321-1322 Snellen chart 1290 snout reflex 1304 snowflake cataracts, diabetic eye disease 1011 social factors ageing 173-174 depression 221 psychiatric illness 210 social history, musculoskeletal diseases 1121 social phobia 214 social services, community care, elderly 203 social workers, care for elderly 191 sodium depletion 1108-1110 clinical features 1109-1110 diabetes insipidus 1102 evaluation 1109f

hypercalcaemia of malignancy 968cs management 1110 renal consequences 1109f salt-losing nephropathy 1067-1068 dietary intake acute renal failure and 1050 hypertension 136 restriction 136,142 dietary restriction nephrotic syndrome 1063 renal failure 1056 elevated see hypernatraemia homeostasis 1100-1101 aldosterone production, and 1100 clinical assessment 1101 disorders 1107-1110 indicators of disturbance ll0lt kidneys role 1035 loss Addison's disease 931 21-hydroxylase deficiency 932 plasma concentrations interpretation 1110,11101 malaria 349 reference nutrient intake 125t renal disease and hypertension 1081 retention 1107-1108 causes 1108t see also hypernatraemia; hyponatraemia sodium aurothiomalate, rheumatoid arthritis 1142 sodium bicarbonate salicylates overdose 28 tricyclic antidepressant overdose 26 sodium chloride, inappropriate secretion of ADH treatment 912 sodium fusidate 266 sodium-hydrogen ion exchange 1099 sodium nitrite, in cyanide poisoning 34 sodium phosphate infusion, hypercalcaemia treatment 970 sodium-potassium (Na + /K + ATPase) 1099 sodium stibogluconate cutaneous leishmaniasis 357 visceral leishmaniasis 358 sodium thiosulphate, in cyanide poisoning 34 sodium valproate see valproate 'soft' exudates diabetic retinopathy 1009 papilloedema 1292 soft palate, examination 1301 soft tissue lesions classification 1192,1192t generalized 1192,11921 localized 1192,11921 rheumatoid arthritis 1127 sites 1193f soft tissue rheumatism 1192-1200 management 1200 see also individual anatomical regions solar (actinic) keratosis 423,423f solitary pulmonary nodules 708-709, 709f solvents abuse 247 overdose management 33-35

somatic mutations, immunoglobulins 82 somatization disorders 233 somatoform disorders 233-235 experimental advice 234 mind-body models 233-234 minor psychiatric illness 235 psychological approaches 234-235 development of body image 234-235 repression and unconscious 235 somatomedin C see insulin-like growth factor-1 (IGF-1) somatosensory system, diabetic neuropathy 1012, 1013-1014,1013f somatostatin analogue see octreotide carcinoid syndrome 797 growth hormone secretion inhibition 903 insulin regulation 981 somatotrophs 894 sore throat, streptococcal, viral arthritis after 1122 Southern blotting 58-59, 58f sowda 365 space blanket 47 space-occupying lesions 888 space of Disse 836 spasmodic torticollis (cervical dystonia) 1367-1368 spastic gait 1290 spastic hemiplegia, cerebral palsy 1374 spasticity, cerebral palsy 1374 spastic paraparesis hereditary 1375 spinal cord lesion 1377 tropical 1384 spastic paraplegia cerebral palsy 1374 hereditary 1384 specimen collection, infectious diseases 262 speech disorders 1286,1301 following head injury 1372, 1372cs mental state examination 1286 Parkinson's disease 1363 spermatogenesis 940 spherocytosis, hereditary 1220-1221 sphincter of Oddi 836 sphingolipid metabolism disorders 1413,14131 sphingolipidoses 711 Gaucher's disease 1029 spider naevi, liver cirrhosis 860 spinabifida 1384-1385 aetiology 1384 clinical features 1384 associated abnormalities 1384 management 1384-1385 spina bifida cystica 1384-1385 spina bifida occulta 1385 spinal arachnoidosis, tuberculous meningitis 1420 spinal cord 1376-1377 blood supply 1385 cervical see cervical spinal cord corticospinal tracts 1301,1376 disorders see spinal cord disease/lesion motor neurons see motor neuron(s) reflexes see reflexes spinal roots 1385 spinothalamic tracts 1376

1499

see also spinal root diseases/lesions spinal cord disease/lesion 1306t, 1376-1385,1379f aetiology 1378t arachnoidosis, tuberculous meningitis 1420 Brown-Sequard syndrome 1377, 1377f, 1381 canal stenosis 1387 cervical see cervical spinal cord compression 1377,1378,1379t, 1386 myeloma and 1435 conus medullaris 1377 degenerative cervical 1379-1380 motor neuron diseases see motor neuron diseases Pott's disease 1380,1381f rheumatoid arthritis 1380,1380f subacute combined degeneration 1383-1384 developmental 1384-1385 Arnold-Chiari malformations see Arnold-Chiari malformations Dandy-Walker syndrome 1360, 1385 Klippel-Feil deformity 1385 spina bifida 1384-1385 disc prolapse 1380,1387,1387f, 1387t, 1388 epidural abscess 1382 hereditary spastic paraplegia 1384 incontinence 1096 injury 1378-1379 investigation/management 1378, 1378t motor symptoms 1301,1302,1302f myelitis 1381-1382 Paget's disease 1380 patterns of deficit 1377 poliomyelitis 1426 radiation myelopathy 1384 sarcoidosis 1384 schistosomiasis 372 sensory symptoms 1305 syringomyelia 1383 thoracic 1377,1380 tropical spastic paraparesis 1384 tumours metastatic 1381 primary 1381,1382f see also specific types vascular disease 1382-1383 see also nerve roots; paraparesis spinal manipulation, low back pain (mechanical) 1188,1190 spinal muscular atrophy (SMA), hereditary 1391 spinal nerves 1186f spinal root diseases/lesions 1385-1388 aetiology 1386 cauda equina lesions 1306t, 1385, 1387-1388 cervical spondylosis 1386 clinical features 1386,1386t diagnosis 1386 lumbar canal stenosis 1387 lumbar spondylosis 1386-1387, 1387t management 1386 thoracic disc prolapse 1388 spinal stenosis 1191 spine anatomy and biomechanics 1185-1186,1186f

'bamboo' 1148-1149,1149f, 1150 cervical, rheumatoid arthritis 1135 congenital abnormalities causing pain 1191 fusion in ankylosing spondylitis 1148 infections 1191 inflammatory disease, features 1150 manipulation, low back pain (mechanical) 1188,1190 mobility limitations, ankylosing spondylitis 1149 MRI 1128 tuberculosis 1191 see also vertebrae spinobulbar muscular atrophy 611 spinocerebellar ataxia 61t spinocerebellar degeneration 1375 hereditary ataxias 1375-1376 spinothalamic tracts 1376 spirochaetes 329-330 Lyme disease 330,1160,1430 spironolactone, hirsutism management 951 splenectomy antibiotic prophylaxis 96 blood changes 1225,12251 hereditary spherocytosis 1220 immune deficiency due to 96 infections after 96 thrombocytopenic purpura 1269 splenic infarct, sickle cell disease 1218 splenomegaly causes 1225t polycythaemia rubra vera 1241 pyruvate kinase deficiency 1222 rheumatoid arthritis 1137 systemic juvenile idiopathic arthritis 1163 splinter haemorrhages 435, 436f, 469 splints osteoarthritis 1157-1158 rheumatoid arthritis 1139 splitting (defence mechanism) 216 spondarthritides, seronegative see seronegative spondarthritides spondylitis, psoriatic 1151 spondylolisthesis 1191 spondylolysis 1191 spondylosis cervical 1377,1386 lumbar 1386-1387,1387t spongiform encephalopathies (prion diseases) 1351 spontaneous haemothorax 713 spontaneous pneumothorax 715, 715t Sporothrix schenkii 335 sporotrichosis 335 spotted fever group 305-307 see also typhus 'spring' ligament 1199 sprue, coeliac see coeliac disease sprung back 1191 sputum 612-613 examination 613 squamous cell carcinomas 423, 423f anus 803 bronchial 701,702t HIV/AIDS infection 450 oesophagus 768 incidence 768f treatment 770t precursors to 423 SRY gene 939

SSPE (subacute sclerosing panencephalitis) 1422, 1426-1427 St. Virus' dance (Sydenham's chorea) 581,1367 stannosis 693t staphylococcal scalded skin syndrome 385, 385f staphylococci 309-310 Staphy loco ecus acute pyogenic pericarditis 586 bacterial myositis 1406 intracranial abscess 1418 pneumonia 633 skin infections 385t Staphy loco ecus aureus 384, 385 infective endocarditis 574 invasive disease 309t joint infections 1158 management of deep infections 309-310 surgical foreign body 309, 310 toxin mediated disease 310t Staphylococcus epidermidis 309, 310, 575 starch 112 starvation. 838 statins (HMG-CoA reductase inhibitors) acute MI 559 lipid-modification 1025,1025t post MI management 569 station definition 1289 neurological diagnosis 1289-1290 status epilepticus 1328 steatorrhoea 787 pancreatitis 830 Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy) 1366 stem cell factor (SCF) 1203 stem cells haemopoietic 1201-1202,1202f peripheral blood (PBSC) transplant 167,1252ra stenosing tenosynovitis 1195 stents (angioplasty) 551,552f steppage gait 1290 stereognosis 1305 sternal depression 586 steroid myopathy 1407 steroids acute bacterial meningitis 1417 adrenal see adrenal steroids adverse reactions depression 1430 myopathy 1407 anterior hypopituitarism 900 injections, rheumatoid arthritis 1143 mechanism of action 887f nephrotic syndrome 1063 protection from degradation 886 receptors 886 renal transplantation 1061 replacement, Addison's disease 931-932 see also corticosteroid(s); glucocorticoids; specific drugs Stevens-Johnson syndrome 407, 407f stomatitis 282 stiffness, musculoskeletal diseases see joint(s) stilboestrol 164 Still's disease adult 1164

lymph node enlargement 1135 Still's murmurs 583 'stocking and glove' neuropathy 1013,1013f Stokes-Adams attack 469, 503-504, 506cs, 516 stomach anatomy and physiology 775-776 benign tumours 785 malignant tumours 783-785 see also gastric cancer motility, disorders 758t pathology clinical features 776, 777t investigations 116-111 secretion syndromes 759t see also entries beginning gastric/gastrostomal-derived factor-1 (SDF-1) 1203 stomatitis, acute 281 stomatocytosis, hereditary 1221 storage disorders 71, 71t strabismus, poisoning 16t straight back syndrome 586 straight-leg raising test 1187,1189cs 'Strawberry tongue' 308 streak gonads 949 streptococcal infections gangrene 386 glomerulonephritis 309,1069 pharyngitis 281 skin 385t streptococcal sore throat rheumatic fever 1164 viral arthritis after 1122 streptococci 308, 308t antistreptolysin O titre 581 p-haemolytic 308,1164 group A B-haemolytic, rheumatic fever 1164 infective endocarditis 575 non-infective endocarditis 580, 581 rheumatoid arthritis aetiology 1126 Streptococcus mutans 760 Streptococcus pneumoniae 1413, 1414t respiratory infections 631 see also entries beginning pneumococcal Streptococcus pyogenes 308, 384, 385 joint infections 1158 Streptococcus viridans 1418 infective endocarditis 574, 575, 577 streptokinase 559, 682,1279 streptomycin brucellosis 319 plague 320 tularaemia 321 stress cortisol response/ 927 linked to physical disease 207 metabolic regulation 983-984 striatonigral degeneration 1366 stroke 1339-1340cs, 1342t aetiology 1330,1338 age distribution of deaths 192f carotid vs vertebrobasilar occlusion 1335 cerebral infarction see cerebral infarction clinical features 1335,1338 complications 1341,1342t definition 1330 diabetes association 1015 differential diagnosis 1340-1341

elderly cholesterol lowering 200-201 dysphagia 201ra rehabilitation 201 ra, 202, 202f epidemiology 1330 intracerebral haemorrhage see cerebral haemorrhage investigation 1333t, 1341-1342 angiography 1342 CT scan 1337,1337f, 1341 echocardiography 1342 lumbar puncture 1341-1342 MRI scans 1335f, 1338f, 1339cs, 1342 MRI vs CT 1342t see also specific techniques management 1342-1343 meningitis complication 1414 myocardial infarction association 1331 prognosis 1343 rehabilitation 1343 risk, hypertension 596 risk factors 1331 secondary prevention 1343 stroke volume, assessment on ICU 727-728 Strongyloides stercoralis 362 strongyloidiasis 362-363 structure-modifying osteoarthritis drugs (SMOADs) 1155, 1157 struvite, urinary stones 1090 strychnine, poisoning 39 stupor, hypopituitarism 890 subachilles bursitis 1198 subacromial bursitis 1194 rheumatoid arthritis 1136 subacute bacterial endocarditis (SEE) 574 see also infective endocarditis subacute sclerosing panencephalitis (SSPE) 1422,1426-1427 subarachnoid haemorrhage 1292, 1343-1345,1344f associated conditions 1343 clinical features 1344 headache 1307,1312,1344 common sites 1343 investigation 1344 management/prognosis 1344-1345 meningitis vs 1414 mortality 1345 see also cerebral haemorrhage subclavian steal syndrome 1332 subcutaneous (postcalcaneal) bursitis 1198 subcutaneous nodules rheumatic fever 1165 rheumatoid 1135-1136,1136f systemic juvenile idiopathic arthritis 1163 subdiaphragmatic angle, chest X-rays 623-624 subdural empyema (abscess) 1417-1418 aetiology 1418 clinical features 1418 investigation 1418-1419 management 1419 meningitis 1414 prognosis 1419 see also cerebral abscess subluxation, spinal cord 1380f subphrenic abscess, pleural effusion 712 subscapularis lesions 1194 substantia nigra, Parkinson's disease 1362

sucking reflex 1304 sucrase-isomaltase deficiency 793 sudden death cardiac rupture 566 diabetic neuropathy 1014 hypertrophic cardiomyopathy 572 sudden transient hypotension, liver biopsy 844 sudden unexplained death, diabetic neuropathy 1014 sugars 111-112 suicide 223-226, 224f, 225cs clinical profile 223-224, 223t death rate 223f management of failed suicide 224 reasons 224f see also parasuicide sulfasalazine (sulphasalazine) Crohn's disease 811 infertility due to 943 juvenile idiopathic arthritis 1164 rheumatoid arthritis 1141-1142, 1145 sulfinpyrazone (sulphinpyrazone) 1171,1278 sulphonamides 266 overdose 33 sulphonylureas adverse effects 998 clearance 997 clinical use 998 contraindication 998 efficacy 997 first vs second generation 997 hypoglycaemic effect 997, 998t, 1018 mechanism of action 997 overdose management 32 sumitriptan, migraine treatment 1310,13101 sun exposure disorders aggravated by 427 malignant melanoma 424 skin and 426-427, 426t skin cancer 148 superoxide dismutase (SOD) mutations 1389 supraorbital ridges, acromegaly 903, 903f suprasellar tumours 895 local pressure effects 896-897 supraspinatus tendinitis, calcific 1193-1194,1194f supraventricular tachycardias (SVT) 507-508 acute MI complication 561 atrial fibrillation 510-513 see also atrial fibrillation (AF) atrial flutter 513 atrial tachycardia 508, 510, 510f chaotic 513 see also atrial tachycardias clinical features 507 diagnosis 507 differentiation from VT or bundle branch block 514t management 510 paroxysmal 513-514, 514t sinus tachycardia 507-508 treatment 515t wandering atrial pacemaker 513 suramin African trypanosomiases 353 onchocerciasis 365 surgery cerebral arteries 1334-1335 cerebral tumours 1357 diabetic patient 1001-1002,1002t

epilepsy management 1328 low back pain 1190 neurosurgical referral 1371 osteoarthritis 1158,1158t Parkinson's disease management 1364 radiosurgery 1357 rheumatoid arthritis 1146,1146t vitreoretinal 1010 see also individual procedures swallowing difficulties see dysphagia examination 1301 Swan-Ganz catheters 733 swan-neck deformity 1134,1134f sweating abnormal, diabetic neuropathy 1014 excessive see hyperhidrosis increased, acromegaly 904 sweat sodium test, cystic fibrosis 650 sweeteners 112 Sydenham's chorea (St. Vitus' dance) 581,1367 sympathetic nervous system blood pressure control 589-590 Horner's syndrome 1295 hypoglycaemic symptoms 1019 noradrenaline release 938 sympathomimetics, asthma 656-657 synacthen test, short 929, 931 synchronized intermittent mandatory ventilation (SIMV) 740 syncope 1321-1322 aortic stenosis 527 breath-holding attacks 1322 cardiogenic 1321 carotid sinus sensitivity 1322 cough syncope 469,1321-1322 definition 1321 in elderly 182t epilepsy vs 1321,1322t glycerol trinitrate 547 heart disease 468-469 micturition 469,1321-1322 orthostatic hypotension 1322, 1322t sneeze 1321-1322 Stokes-Adams attack 469 vasovagal 469,1321 syndrome of inappropriate secretion of antidiuretic hormone (SIADH) 911-912,1104, 1104t syndrome X 545, 995,1015,1015f synovectomy, rheumatoid arthritis 1146 synovial biopsy 1127,1128f synovial cells, type A and type B 1119,1131-1132 rheumatoid arthritis 1131-1132 synovial fluid 1119 aspiration, infective arthritis 1159 composition 1120 crystals 1127,1127f culture 1159 examination 1127 functions 1120 synovial hypertrophy, rheumatoid arthritis 1131,1132,1134 synovial joints 1119 synovial membrane 1119 sensations 1120 thickening 1123 synovial tissue 1119,1120f synovitis Crohn's disease 1153 crystal see crystal synovitis inflammatory 1120

persistence prediction 1133 recurrent 1130 SLE 1174 thorn 1169cs transient, of hip 1159 viral infections 1160-1161 syphilis 458-462, 460f congenital 461,1160,1430 diagnostic tests 1429 latent period 460 management 461 neurological involvement see neurosyphilis quaternary 460-461 secondary 459-460,4601 serological tests 1173 syphilitic endocarditis 578-579 tertiary 460 syphilitic amyotrophy 1430 syphilitic arteritis 1429 syphilitic arthritis 1160 syphilitic endocarditis 578-579, 579 aortic aneurysm 579 aortic regurgitation 579 clinical features 579 diagnosis/investigation 579 pathogenesis 578 syphilitic gummas 1429 syringomyelia 1383,1383f syrinx formation 1383 syrup of ipecacuanha 20 systemic disease endocrine see endocrine diseases metabolic see metabolic disturbance neurological involvement 1430-1435 systemic inflammatory response syndrome (SIRS) 733 systemic lupus erythematosus (SLE) 689,877-878,1172-1177 aetiology 1173 age and sex relationship 1121 autoantibodies 1172-1173,11731 clinical features 1172f, 1174-1175, 1174t musculoskeletal 1174 renal 1075-1076 complement levels 1126-1127 drugs precipitating 1121,1122t epidemiology 1172 heart murmurs 1174 immunological features 1172-1173 leukopenia 1125 Libman-Sacks endocarditis 581 management 1176 drug therapy 1176,1176t neurological involvement 1430-1431 pathogenesis 1174 pathology 1172 pleural effusion 712 pregnancy 1176 prevalence 1172 prognosis 1176 relapse prevention 1176 syndromes related to 1175 thrombocytopenia 1125 systemic sclerosis 690,1177-1180 aetiology and pathology 1177 clinical features 1177-1179,1178f management 1179,1179ra neurological involvement 1431 primary biliary cirrhosis and 878 recent advances 1179ra renal involvement 1076 see also scleroderma systolic blood pressure age changes 590f

1501

measurement 600 systolic murmurs 475

T

1502

tabes dorsalis 1160,1429-1430 taboparesis 1430 TACE (transcutaneous arterial chemoembolization) 877 tachycardia-bradycardia syndrome see sick sinus syndrome tachycardias 505-516 acute MI complication 561 atrial tachycardia see atrial tachycardias AV nodal 513-514 AV re-entry 513-514,513f broad-complex 514-516 chaotic atrial 513 diagnosis decision tree 509f features/classification 507t junctional see junctional tachycardias mechanisms 505-507 abnormalities of automaticity 505 abnormal pulse conduction/reentry 506-507, 510f early after-depolarizations 505-506 pre-excitation syndromes 506-507 non-paroxysmal AV nodal 514 paroxysmal atrial, acute MI complication 561 paroxysmal supraventricular 513-514,514t poisoning 17,17t sick sinus syndrome 506cs supraventricular see supraventricular tachycardias (SVT) ventricular 514-516 see also ventricular tachycardia (VT) tacrolimus (FK506) 103,1061 tactile hallucinations 207 taenia saginata 375-376 taenia solium 376 Takayasu's arteritis 601-602,1185 clinical features 602 management/prognosis 602 talcosis 693t tamoxifen 164,164f tamponade heart pump performance 466 pericardial, jugular venous pulse 471 variceal haemorrhage 873 see also pericardial tamponade tandem gait 1289 TAP-1 and TAP-2 transporters 84 TAP-2 deficiency 94t tar, psoriasis treatment 397 tardive dyskinesia 1369 tarsal tunnel syndrome 1199 Tay-Sachs disease, screening 75t TB see tuberculosis T cell lymphomas, non-Hodgkin's lymphoma 1257 T-cell receptor 83,83f T cells 80, 82-83,1205 activation 84, 84f antigen presentation 83-84, 83f, 84f

autoreactive, rheumatoid arthritis aetiology 1131 B cell regulation defect 87 CD4 and CD8 antigens 1205 cytotoxic (Tctx) 82-83 deficiency 91-92 DiGeorge syndrome 92 depletion, bone marrow transplant 1246 differentiation 85f downregulation by CTLA4 84. 103 epitopes, autoimmunity development 99 functions 82 gp39 expression 89 helper (Th) 83 activation by antigen presentation 83-84, 84, 84f costimulatory signals 84 cytokines 85, 85t ThO 85 Thl, rheumatoid arthritis pathogenesis 1132 Thl and Th2 balance in mycobacterial infections 101 Thl and Th2 cells 85 HLA restriction 83, 83f immune deficiency with hyper IgM 89 malignancy 1235-1236,1250f numbers in blood 80 origin 80 rheumatoid arthritis pathogenesis 1132 self-reactive, apoptosis 80, 84, 99 suppressor 85 Th2-type cytokines, asthma 652 tears, artificial, thyroid disease 919 technetium-99m (99mTc) sulphur colloid 755 technetium pertechnetate, musculoskeletal diseases 1129 teicoplanin 266 telangiectases, ataxia-telangiectasia 93,1375 telangiectasia, hereditary haemorrhagic 437, 437f, 691 telophase 63, 63f temazepam 189 temperature measurement, peripheral hypofusion diagnosis 730 regulation disorders see heat excess disorders; hypothermia sensation, examination 1305 temperature-dependent conduction block, multiple sclerosis 1411 temporal arteritis see giant cell arteritis (GCA) temporal artery biopsy, giant cell arteritis 1184 temporal lobe 1288f epilepsy 1323,1326 lesion 1288-1289 tendinitis Achilles tendon 1198 biceps 1194 knee 1197-1198 patellar 1197 rotator cuff 1193 supraspinatus, calcific 1193-1194, 1194f tendon(s) lesions 1192

reflexes see under reflexes rheumatoid arthritis 1136 rupture, pain behind heel 1198 tenesmus 751 colorectal carcinoma 801 functional bowel disorders 821 tennis elbow 1195 tenosynovitis 1195 acute frictional 1196 De Quervain's 1195-1196 management 1200 stenosing 1195 Tensilon test 1401 tension-type headache (TTH) 1309-1310 diagnostic criteria 1310t migraine association 1309,1310 psychological factors 1310 teratogens anticonvulsant drugs 1328 diabetic pregnancy 1002 teratomas 710 terbinafine 268 terbutaline, overdose management 32 terlipressin, variceal haemorrhage 873 testes 939-945 anatomy and physiology 939-941 adults 941 infancy and childhood 940 puberty 940-941 in utero 939-940 assessment of function 941, 943 defective function in adults 941-945 with androgen deficiency 942-945 without androgen deficiency 941-942 defective function in utero 941 descent 940 function, regulation 940f irradiation, acute lymphoblastic leukaemia 1247 LH and FSH actions 940t size assessment 941 steroidogenesis 939 testicular cancer, tumour markers 158f testicular feminization 949 testicular tubules 941f testosterone deficiency 944 derivatives C-17 substituted, liver damage 853 replacement 943 replacement, anterior hypopituitarism 900-901 therapy, delayed puberty 942-943 test-strips, blood glucose 991 tetanus 313-314 clinical features 313 epidemiology and pathogenesis 313 management 313 prevention 313-314 vaccine 273,313-314 tetany, hypocalcaemia 974 tetrachlorethylene, hookworm 361 tetracycline labelling, bone 959, 965 tetracyclines 266 actinomycoses 331 anthrax 312 Chlamydia psittaci 304 plague 320 Reiter's syndrome 1153 tetranucleotide repeat sequences 59 tetraplegia 1374

cerebral palsy 1374 thalamic pain, stroke 1337 thalamus, infarction 1337 thalassaemias a 1214 hydrops fetalis 1216 B 1215-1216 antenatal diagnosis 1216 clinical features 1215,1215t laboratory features 1215-1216 management 1216 thalassaemia intermedia 1215 thalassaemia major 1215 thalassaemia trait 1215 causes of raised HbF 1217 8-chain production 1217 Haemoglobin Constant Spring 1217 HbLepore 1217 hereditary persistence of fetal haemoglobin (HPFH) 1217 sickle cell trait with 1220 transfusion haemosiderosis 573 thalidomide 13 Behget's syndrome 1153 thelarche, premature 9411 theophylline asthma 657 overdose management 32 plasma drug concentration 3f therapeutic monitoring 13 therapeutic drug monitoring 11-12, 12t sample collection 12 specific drugs 12-13 therapeutics 1-43 see also drug(s) thermocoagulation gangliolysis, trigeminal neuralgia treatment 1314 thermoregulation in elderly 178-179 see also heat excess disorders; hypothermia thiamin (vitamin B1) deficiency 114,124 Wernicke-Korsakoff syndrome 1432,1439 food sources 124t reference nutrient intake 125t role in the body 124t thiazide diuretics 495 hypercalcaemia due to 972 thiazolidenediones 997, 998t adverse effects 999 mechanism of action 999 6-Thioguanine 1245 thioridazine 230 thiourea compounds 921 thirst 1099-1100 antidiuretic hormone deficiency 911 hypercalcaemia 966 type 1 diabetes 988 type 2 diabetes 995 Thompsen's disease (myotonia congenita) 1405 thoracic actinomycosis 330 thoracic deformity 722-723 ankylosing spondylitis 722 scoliosis 722-723 thoracic disc prolapse 1388 thoracic spinal cord lesion 1377 disc prolapse 1380 thoracoscopy 630, 630ra respiratory disease 630, 630ra thorn synovitis 1169cs threadworms 363 lifecycle 363f

thrills, cardiovascular system examination 472 thrombin 1264,1265,1266 time, haemostasis disorders 1267 thrombocythaemia, essential see essential thrombocythaemia (ET) thrombocytopenia 1268-1272 autoimmune, SLE 1125 causes 1268t drug-induced 1269 heparin 1276 isoimmune neonatal 1269 microangiopathic 1270 musculoskeletal diseases 1125 D-penicillamine causing 1142 post-transfusion 1269 production 1268 in SLE 1175 Wiskott-Aldrich syndrome 92-93 thrombocytopenic purpura 1269 thrombotic (TTP) 1270 thrombocytosis 1272 aetiology 1272t musculoskeletal diseases 1125 thromboembolism heparin 1275 pregnancy 1278 see also thrombosis thrombolytic agents 1343 acute aortic dissection 601 contraindications 560t haemorrhagic complications 559 myocardial infarction 558-559, 560t streptokinase 559 see also fibrinolytic therapy; individual drugs thrombophilia causes 1280t coagulation abnormalities 1279-1280 investigations 1280t screening 1281t thrombophlebitis, cortical venous 1419,1419t thrombopoietin (TPO) 1202 thrombosis cerebral 1331 cavernous sinus 1420 headache 1312 venous sinus 1419.1419t see also cerebral arteries deep vein see deep vein thrombosis (DVT) management thrombolysis 1343 see also anticoagulants renal veins 1064 septic, meningitis 1414 venous see venous thrombosis venous occlusion, optic fundi 1291 see also atheroma thrombotic thrombocytopenic purpura 1079 thrombus formation 1331 prothrombotic disorders 1332-1333,1333t thymectomy, myasthenia gravis 1401 thymomas 710 thymoxamine, systemic sclerosis 1179 thyroglobulin (TG) 912 functions 912 thyroglossal cysts 912 thyroid acropachy 891, 920 thyroid arteries 912 thyroid-associated ophthalmopathy 919-920, 920f, 922

thyroid disease 913-914 autoimmune 913-914 see also Graves' disease carcinoma 939 management 924-925 types 924 CNS features 890 hypothyroidism see hypothyroidism investigation 914-915 lymphoma 924 myopathy 1407 neurological symptoms 1433-1434,1434f nutrition and 914 pathology 913-914 simple diffuse goitre 922 thyrotoxicosis see thyrotoxicosis tumours 914,924 see also goitre; hypothyroidism; thyrotoxicosis thyroidectomy subtotal 921 thyroid cancer 925 thyroid gland 912-925 anatomy and physiology 912913 embryology 912 enlargement see goitre examination 914 function, iodine deficiency 127 localized swellings 924-925 solitary nodules 924 surgery 921-922 toxic adenoma 918, 919 thyroid hormones actions 912,913,919 anterior hypopituitarism treatment 900 circulation and metabolism 913 deficiency see hypothyroidism excess see thyrotoxicosis mechanism of action 887f physiological changes 913, 913f protection from degradation 886 radioimmunoassay 914-915 replacement hypothyroidism 917,918 thyroid cancer 925 structures 913f synthesis and secretion 912, 912f in vitro uptake test 915 see also thyroxine (T4); triiodothyronine (T3) thyroiditis Hashimoto's 889,917 postpartum 923cs, 925ra Riedel's 924 subacute (de Quervain's) 924 thyroid peroxidase (TPO) 912 antibodies 923cs, 925ra thyroid-stimulating antibodies 922 thyroid-stimulating hormone (TSH) 895 abnormal levels, causes 915t actions 912 deficiency 910 pituitary hypofunction causing 897 disorders 909-910 excess 910 causes 915t hypopituitarism investigation 899 hypothyroidism 917 immunoassays 910 primary hypothyroidism 914 receptor

antibodies 914,918 Graves' disease 914 secondary hypothyroidism 915 suppressed causes 915t diffuse multinodular goitre treatment 923 synthesis, stimuli and inhibitors 893t thyrotoxic crisis ('storm') 921 thyrotoxicosis (hyperthyroidism) 918-922 cardiovascular features 890 cardiovascular system examination 475 case study 923cs causes 918 see also goitre, toxic multinodular clinical features 918-919, 919t, 923cs CNS features 890 eye signs 919, 919t, 920f gastrointestinal 891 differential diagnosis 923cs elderly 919 management 922 examination 918-919 heart disease 583 hypercalcaemia 972 increased sensitivity to adrenaline 887, 918 investigations 915 laboratory assessment 914-915 management 920-922, 922t guidelines 916t pre-/post-operative 922 myopathy 1407 natural history 919 neonatal 922 neurological complications 1433_1434 pregnancy and 922 prevalence 918 proximal muscle weakness 966cs see also Graves' disease thyrotrophin see thyroid-stimulating hormone (TSH) thyrotrophinoma 910 thyrotrophin-releasing hormone (TRH), prolactin secretion control 894 thyroxine (T4) 912 actions 913 circulation and metabolism 913 discovery 883 effect on bone growth 956 hypothyroidism 917 normal levels 913 physiological changes 913 radioimmunoassay 914-915 structure 913f therapy hypothyroidism 917 simple goitre 924ra thyroxine-binding globulin (TBG) 886, 913 thyroxine-binding prealbumin (TBPA) 913 tiabendazole, cutaneous larva migrans 361 tiagabine 1328t tiaprofenic acid 1141ra tibia, sabre 329 tibialis anterior, pain 1199 tibialis posterior, pain 1199 tic douloureux see trigeminal neuralgia tick-borne relapsing fever 330

tics 1361,1366 tinea 389-391, 389f hand 391 nails 391, 391f tinea capitis 390-391,3901 tinea corporis 390, 390f tinea cruris 390 tinea pedis 389-390, 390f Tinelsign 1394 tinidazole, giardiasis 337 tissue factor pathway inhibitor (TFPI) 1266 tissue inhibitors of metalloproteinases (TIMPs) 1132 tissue oxygenation, measurements 736t tissue plasminogen activator (t-PA) 1266, 1267,1279 thrombolysis 1343 TNM classification 155 tobramycin, nephrotoxicity 1086 toes claw 1199 clubbing see clubbing (finger/toe) gout 1168 togaviruses 294-298 tolterodine 186 tongue black hairy 762 fasciculation 1301,1389 fissure 762 geographic 762 innervation 1301 strawberry 308 tonic-clonic seizures 13231,1324, 1326 tonic pupil (Holmes-Adie syndrome) 1295, 1296f tonic seizures 1323t topagraphagnosia 1287 parietal lesion 1288 tophi, gout 1127,1168,11681 topical treatment 382-383, 384t herpes zoster (shingles) 286 psoriasis 397,399 vehicles 382-383, 383t see also corticosteroid(s) topiramate 1327ra. 1328.1328t torsade de pointes ventricular tachycardia 515-516 ECG trace 515f management 515-516 torsion dystonia (dystonia musculorum deformans) 1368 torulosis (cryptococcosis) 333 total iron-binding capacity (TIBC) 1207 touch cortical lesion effects 1305 examination 1304-1305 toxaemia, pregnancy 855 TOXBASE 22 toxic epidermal necrolysis 417 toxicology 1-43 see also drug overdose/poisoning toxins botulinum 314,1402 chemical, nephropathy 1086 cholera 323f endotoxin, sepsis 734 gastroenteritis pathogenesis 278-279 Staphylococcus aureus 310t type 1 diabetes association 987 uraemia 1052-1053 Toxocara canis 369 Toxocara cati 369

1503

1504

toxocariasis 369-370 ocular 369 Toxoplasma gondii 343 AIDS-related cerebral abscess 1428 parasitic myositis 1406 toxoplasmosis 343-344 acquired 343 congenital 343 management 344 reactivation in immunosuppressed 343 transmission 343f trace elements 127 trachea chest X-rays 623,626 examination 621 tracheostomy diphtheria 312 indications 741t trachoma 304 traction, low back pain (mechanical) 1188 tranexamic acid Cl-inhibitor deficiency 91 gastrointestinal bleeding 774 tranquillizers, overdose management 23-24 see also antipsychotic drugs transcalciferin (vitamin D transport globulin) 886 transcranial Doppler (TCD), head injury 746 transcription 57, 58f transfer RNA (t-RNA) 57 transformed migraine 1310 transforming growth factor B (TGFp) 1203 transfusion haemosiderosis, restrictive cardiomyopathies 573 transfusions see blood transfusion transgenic pigs 1062 transient ischaemic attacks (TIAs) 1331-1335 carotid 1331-1332 clinical features 1331-1332 definition 1330 examination 1332-1333 investigation 1333,1333t management/prognosis 1333-1335,13341 anticoagulants 1333-1334 antiplatelet therapy 1333 reconstructive surgery 1334-1335 risk factors 1332t, 1333 subclavian steal syndrome 1332 vertebrobasilar 1332 transitional cell carcinoma bladder 1093,1093f kidney 1091-1092 translation 57, 58f transoesophageal echocardiography 484, 485f transplantation neural 1364 organ donation, brainstem dead patients 747-749, 747f see also individual organs transport disorders 70t, 71 transposition of the great arteries 537 transsphenoidal surgery complications 906 pituitary tumours 901 transthyretin (thyroxine-binding prealbumin) 913

trauma birth 1399 brachial plexus lesions 1399 head see head injury infantile hydrocephalus 1360 post-traumatic disorders amnesia 1373 headache (PTH) 1311-1312 post-traumatic syndrome 1373 spinal cord 1378-1379 see also individual injuries travel health 272-273 immunization 273, 273t malaria protection 273 protection of gut 273 skin protection 272-273 traveller's diarrhoea 340cs see also diarrhoea; travel health trematodes 370-375 tremor action 1303 aetiology 1367t drug-induced 1440t extrapyramidal disease 1302,1361, 1366-1367 essential tremor 1367 Parkinson's disease 1362,1362t general paralysis of the insane 1429 physiological 1303 'pill-rolling' 1362 rubral, MS 1411 tongue 1301 trench fever 322 Treponemal diseases, skin 388-389 Treponema pallidum 1160 syphilitic endocarditis 578-579 Treponema pallidum (TP) 329, 459, 1428,1429 Treponema pertenue 329 triamcinolone, intra-articular, rheumatoid arthritis 1143 triazine, poisoning 38 triazoles 267 tribavirin 268 Trichinella spiralis 368 life cycle 369f trichinosis 368-369 aetiology 368 clinical features 369 diagnosis and management 369 distribution, incidence and transmission 368 parasitic myositis 1406 pathology 369 Trichomonas vaginalis 462 trichomoniasis 462 trichuriasis 363 Trichuris dysentery syndrome 359 Trichuris trichiuria 359, 363 tricuspid atresia 538 tricuspid regurgitation 475 clinical features 531, 531f investigation 532 management 532 tricuspid stenosis 532 tricuspid valve endocarditis 578 tricyclic antidepressants 222 enuresis 1096-1097 facial pain treatment 1315 incontinence 1096 overdose electrocardiogram 26,26f management 24t, 25-26 trifluoperazine 230 trigeminal nerve 1297-1298,1297f anatomy 1297,1297f, 1313f, 1313t cavernous sinus thrombosis 1420

cutaneous fields 1313f facial pain 1313t non-cutaneous innervation 1313t trigeminal neuralgia 1313-1314 clinical features 1313-1314 common sites 1314,1314f epidemiology 1313 management 1314 pathology 1313 'trigger finger' 1195 triglycerides 1021 chylomicrons 1022 hypertriglyceridaemia (familial) 1023-1024 management 1026 triglyceride-lowering drugs 1025, 1025t see also cholesterol triiodothyronine (T3) 47, 912 actions 913 circulation and metabolism 913 normal levels 913 physiological changes 913 reverse 913 structure 913f structure 913f trimethoprim 266 methotrexate interactions 1142 urinary tract infections 1085 trinucleotide repeats 60-61 triolein breath test 759 triplet repeat mutations 61t trismus (lockjaw), tetanus 313 trisomy 62 double 62 frequency 65-66 trisomy 13 (Patau's syndrome) 68 trisomy 19 (Edwards' syndrome) 66-67 trisomy 21 see Down's syndrome trochanteric bursitis, rheumatoid arthritis 1136 trophozoites 336 Trophyrema whippelli 792 tropical pulmonary eosinophilia (TPE) 367 tropical spastic paraparesis 1384 tropical splenomegaly syndrome (TSS) 351 malaria 348 tropical sprue 792 troponins acute MI diagnosis 555, 557-558, 558t increasing chest pain 553cs risk stratification 553, 554f TruCut needle, liver biopsy 844 Trypanosoma cruzi 354 lifecycle 354f Trypanosoma gambiense 352 trypanosomal chancre 353 Trypanosoma rhodesiense 352 trypanosomiases 352-355 American (Chagas' disease) 354-355, 799 parasitic myositis 1406 see also African trypanosomiasis (sleeping sickness) tuberculin testing 641 tuberculomas 1376,1421,1421f tuberculosis 640-647 abdominal 816 adrenocortical insufficiency 930 arthritis 1160 at-risk groups 640 atypical mycobacteria 645 BCG vaccination 646-647 clinical features 641 cough/weight loss 642-644cs

persistent severe haemoptysis 614-615cs complications 644-645 cutaneous 388 cystitis 1085 diagnosis 644, 644t drug adverse effects 645t, 646 epidemiology 640 extrapulmonary 641, 644t, 645 treatment 646 Heaftest 641 HIV/AIDS 645 immunology 640-641 infectivity 640-641 investigation 641 management 645-646,1421 corticosteroids 646 treatment regimens 645-646 see also antituberculous drugs Mantoux test 641 meningitis 1420-1422,1421t miliary 640, 641f, 644f multiple-drug-resistant TB 646 Mycobacterium avium intracellulare 645 Mycobacterium bovis 640 Mycobacterium tuberculosis 640 pathology 640-641 pericarditis 586 peritonitis 816, 824 postprimary infection 640-641, 644f Pott's disease of the spine 1380, 1381f prevention 646-647 primary infection 640, 641f pyrexia of unknown origin 275 spinal 1191 tuberculin testing 641 tuberculomas 1376,1421,1421f urinary tract 1085 Ziehl-Neelsen stain 325-326, 641 tuberous sclerosis 421 tubular necrosis, acute see acute tubular necrosis (ATN) tubuloglomerular feedback 1032 tubulointerstitial disease aetiology and pathology 1079-1080 causes 1079t diagnosis and management 1080 drug-induced 1080 tubulointerstitial nephropathy, acute/chronic 1080 tularaemia 321 tumour(s) bone, skull 1352t cardiac see cardiac tumours cellular proliferation 151f differentiation 151 growth and development 149-151 HIV infection and AIDS 449-150, 450f hypoglycaemia-inducing 1018 lysis syndrome 166-167 malignant and premalignant 423-126 neurological 1398 brachial plexus 1400 brain see cerebral tumours lumbrosacral plexus 1400 spinal 1381,1382f presentation 152 pyrexia of unknown origin 275 renal see renal tumours secondary, Hodgkin's disease 1254 see also cancer; malignancy/malignant disease; individual tumours

tumour lysis syndrome 1077 tumour markers 156-157,158t alkaline phosphatase 156 human chorionic gonadotrophin 156 prostate-specific antigen (PSA) 157 tumour necrosis factor-a (TNF-a) antibodies to 103 Crohn's disease 812ra inhibitors, rheumatoid arthritis treatment 1146 monoclonal antibodies, rheumatoid arthritis treatment 1146 rheumatoid arthritis pathogenesis 1132 seronegative spondarthritides 1148 sources and functions 85t tumour necrosis factor-(3 (TNF-J3) 85t tumour plops 474 Tunga penetrans 395 Turner's syndrome (XO; 45X) 68f, 69 amenorrhoea due to 947 clinical features 948t congenital heart disease 535 twin studies type 1 diabetes 984 type 2 diabetes 995 two-point discrimination test 1305 typhoid 316-317 chronic carriage 316 complications 316, 316t vaccine 273, 317 typhus 305 diagnosis 306 distribution and incidence 305 laboratory features 306 management 306-307 pathology and pathogenesis 306 prevention and control 307 transmission and epidemiology 305-306 typhus fever group 305-307 see also typhus tyrosine deficiency 70f metabolic pathway 70f tyrosine kinase, Bruton's 87

u UK, HIV/AIDS infection 441 UK and Eire Poisons Information Services 22, 23f UKPDS see United Kingdom Prospective Diabetes Study (UKPDS) ulcer(s) (ulceration) aphthous see aphthous ulcers Buruli 328 Curling's 777 Cushing's 777 decubitus (pressure sore) 428-429, 429t, 749 diabetic 1016-1017 ischaemic 1016-1017 neuropathic 1016 type 2 diabetes and 996 genital see genital ulcers leg 430t venous 430

see leg ulceration mouth 760-761 oesophagus 767 peptic ulcers see peptic ulcers rheumatoid arthritis 1137 rodent 423-424, 424f see also specific diseases/conditions ulcerative colitis 813-815 aetiology and pathology 813 arthropathy associated 1153 clinical features 813-814, 813t acute attack 813-814 chronic 814 investigations 814, 814f, 814t male infertility in 943 malignancy risk 814 management 814-815 surgery 815 prognosis 815 ulnar groove 1395 ulnar head, rheumatoid arthritis 1134,1136 ulnar nerve, compression 1394f, 1395 ultralente insulins 989 ultrasound acute renal failure 1050 amoebic liver abscess (ALA) 341 ascites 872 cancer detection 156 Doppler see Doppler ultrasound gallstones 857 liver disease investigations 841, 841f musculoskeletal diseases 1129 postrenal failure 1050 prenatal diagnosis by 76t pyrexia of unknown origin, investigation 276 renal 1042,1042f renal cysts 1081 respiratory disease 627 schistosomiasis 373 techniques 483-485 echocardiography 483 thyroid disease 915 TIA investigation 1333 urinary tract stones 1089,1089f ultraviolet A (UVA) 426 ultraviolet B (UVB) 426 ultraviolet (UV) radiation 399, 426 unconsciousness 1320-1321 alcoholic blackouts 1436,1436t coma see coma differential diagnoses 1321 epilepsy see epilepsy syncope see syncope undulant fever see brucellosis unipolar manic-depressive psychosis 226 United Kingdom Medicines Act (1968) 13-14 United Kingdom Prospective Diabetes Study (UKPDS) 996, 996ra chronic complications 1007-1008 ACE inhibitors 1016 microvascular 1008 nephropathy 1012 glycaemic control, importance 996-997 glycosylated HbA 1001 upper airway obstruction 608 upper motor neuron lesions 1298, 1301,1302f upper respiratory tract infections 631 acute 281-282 adenoviruses 290 complications 281

uraemia 1045,1052-1056 acidosis 1057,1065 anaemia 1053 cardiovascular system 1053-1054 hyperosmolar (non-ketogenic) coma 1006 management 1053t neurological involvement 1432 pericarditis 1053-1054 platelet dysfunction 1053 symptoms and signs 1045t toxins 1052-1053 uraemic cardiomyopathy 1053 uraemic encephalopathy 1432 urate crystals 1166,1169cs deposition in kidney 1167 detection 1170 formation prevention 1170 synovial fluid 1127 see also gout urea calculation of GFR 1040 elevation, malaria 349 ureaplasma arthritis, in X-linked agammaglobulinaemia 86 urethral discharge 459cs urethral syndrome 1084 treatment 1085 urethritis, Reiter's syndrome 1152 uric acid excretion 1166 aspirin effects 1166,1167 drugs affecting 1167 formation 1166 metabolic pathways 1167f overproduction in gout 1166-1167 causes 1167 serum levels age and sex differences 1166, 1166f measurement, in gout 1170 urinary stone formation 1088, 1089 uricosuric drugs 1171 urinalysis, diabetes glucose 1000 ketones 1000 urinary acidification, in distal nephron 1036-1037 urinary buffers 1036-1037 urinary calculi see urinary tract stones urinary casts 1039 cellular 1039 granular 1039 hyaline 1039 urinary incontinence 1046-1047, 1095-1097 in elderly 185-187,1097 good practice guidelines 187t overflow 1096 reflex 1096 stress 1096 urge 1096 voiding difficulties 186 urinary retention, postoperative 186 urinary tract imaging 1041-1043 infections see urinary tract infections (UTI) tuberculosis 1085 urinary tract cancer 1091-1095 age-incidence 1091 urinary tract disease 1031-1098 epidemiological considerations 1031 symptoms and signs 1044-1047, 1046t

urinary tract infections (UTI) 315, 1083-1090 choice of drug 263 clinical features 1084 diabetes mellitus 1078 epidemiology 1031 investigations 1084 in the elderly 196 management 1084-1085 predisposing factors 1083-1084 urinary tract obstruction 1090 urinary tract obstruction 1090-1091 aetiology 1090,1090t clinical features 1090 diagnosis and management 1090-1091 effect on kidney 1090 management 1050 postrenal failure due to 1050 urinary tract infections 1090 urinary tract stones 140,1086-1090, 1088cs, 1094cs calcium 1087-1088 clinical features 1089 cystine 1088-1089 diagnosis and management 1089-1090 early 1089 late 1089-1090 formation 1087 gout 1168 oxalate 1088 pathogenesis 1087-1089 struvite 1090 types 1087,1087t uric acid 1088 urinary tract infections 1084 urine cortisol assay 928 examination 1037-1039 blood in 1039 casts 1039 conditions associated with extreme pH 1038t culture of 1039 deposits 1039 glucose content 1038 microscopy, red blood cells 1039 pH 1038 in poisoning 18 protein content 1038-1039 quantity 1037 specific gravity/osmolarity 1037-1038 reflux, urinary tract infections 1083 sediment in renal conditions 1040t sodium content 1109-1110 volume, urinary tract obstruction 1090 water homeostasis 1099-1100 see also entries beginning urinary urodeoxycholic acid, primary biliary cirrhosis (PBC) 868 urokinase 1279 urolithiasis see urinary tract stones uromitexan (Mesna), rheumatoid arthritis 1143 uroporphyrogen decarboxylase, defects 1028 urticaria 98, 406, 406f causes 98t, 406t Crohn's disease 809 drug-induced 417 food intolerance 141 lesions 98 urticaria pigmentosa 98 USA, HIV/AIDS infection 441

1505

uterus proliferative phase of menstrual cycle 945f, 946 secretory-phase of menstrual cycle 946 uveitis, anterior 73t Reiter's syndrome 1152,1153

V

1506

vaccination demyelinating disease and 1412 live 272 contraindication in juvenile arthritis 1164 meningitis 1417 see also immunization vaccines see individual vaccines vaccinia virus 289 vagal reflex, syncope 1322 vagus nerve 1300-1301 valaciclovir, herpes viruses 268 valproate epilepsy treatment 1327,1328t overdose management 31 Valsalva manoeuvre, diabetic neuropathy 1014 valvular heart disease aetiology 520 aortic regurgitation see aortic regurgitation aortic stenosis see aortic stenosis balloon valvuloplasty 533 cardiac bypass 533 combined mitral/aortic 530-531 combined valve lesions 521 differential diagnosis of angina 544 Ebstein's anomaly 538 infective endocarditis 575, 578 mitral regurgitation see mitral regurgitation mitral stenosis see mitral stenosis mixed aortic valve disease 530 pulmonary regurgitation 532 pulmonary stenosis 295. 532-533 regurgitation 520 rheumatic heart disease 580 rheumatoid arthritis 581 stenosis 520-521 assessing severity 521,521t surgical management 533 tricuspid regurgitation see tricuspid regurgitation tricuspid stenosis 532 tricuspid valve endocarditis 578 valve repair/replacement 533 valvuloplasty, balloon 533 vancomycin 266 pseudomembranous colitis 315 vancomycin-resistant staphylococci 270-271 vanillylmandelic acid (VMA) 929, 938 variant Creutzfeldt-Jakob disease (vCJD) 1351 variceal haemorrhage 873 management 873 shunts 873 tamponade 873 varicella (chickenpox) 271,284-285 arthritis 1161 clinical features 284-285, 285f complications 285 diagnosis and management 285

encephalitis, postinfectious 285 immunocompromised patient 270 neonatal 285 varicella zoster virus (VZV) 283, 286t infection 284-286 varicose veins 603-604 variegate porphyria 1027 variola 289 vascular disease 600-602 acute aortic dissection 600-601, 600f see also aortic dissection, acute aortic aneurysm see aortic aneurysm arteriovenous fistulas 584 arteritis 601 cerebrovascular 1330-1331 dementia and 1337,1350-1351 diabetes association 1012,1015, 1017cs giant cell (temporal) arteritis 602 Kawasaki's disease 601 Marfan's syndrome 600, 601 necrotizing vasculitis 601 peripheral vascular disease 602-604 see also peripheral vascular disease spinal cord 1382-1383 Takayasu's arteritis 601-602 see also macrovascular disease; microvascular disease vascular studies, liver disease investigations 843 vasculitis 1181-1185 classification 1181,1181t clinical features 1181f cryoglobulinaemic 1183 cutaneous see cutaneous vasculitis dermatomyositis 1180 drug-induced 418 large vessel see giant cell arteritis (GCA) leukocytoclastic 1183 management 1182-1183 medium arteries 1181-1183 necrotizing 601 prevalence 1181 rheumatoid arthritis associated 1138,1181 SLE 1174 small vessel 1183 treatment 1181ra types 1181-1182 see also arteritis vasoconstriction, migraine 1309 vasodilators heart failure 490 inotropic therapy 731 vasonervorum, diabetic neuropathy 1012 vaso-occlusive, sickle cell disease 1218 vasopressin see antidiuretic hormone (ADH) vasopressin analogue see DDAVP (desmopressin) vasovagal syncope 469,1321 vCJD (variant Creutzfeldt-Jakob disease) 1351 VDRLtest 1173 vectors, malaria 346 venlafaxine 222 overdose 26 venography deep vein thrombosis 680 renal 1043 venomous invertebrates 42

venous disease, peripheral 603-604 venous occlusion, optic fundi 1291 venous return abnormalities, congenital heart disease 538 venous sinus thrombosis 1419,1419t venous thrombophlebitis, cortical 1419,1419t venous thrombosis 604 paroxysmal nocturnal haemoglobinuria 1226 see also deep vein thrombosis (DVT) venous ulcers 429-430,430f ventilation 605-606 alveolar (VA) 605 assessment of O2 delivery 736-737 complications 740-741 continuous positive airway pressure see continuous positive airway pressure (CPAP) control 607 controlled mandatory 739-740 indications chronic bronchitis 665 head injury 744 malaria treatment 351 poisoning 19 inspiratory pressure support 740. 741 intracranial pressure 745 mechanical 738-739cs indications 737-738 withdrawal 741-742, 742f medulla 607 methods 739-740 non-invasive 740 physiological dead space (VD) 606 positive end-expiratory pressure 740 synchronized intermittent mandatory 740 weaning 742, 742t ventilation-perfusion lung scans, pulmonary embolism 679, 681,681f ventilator pneumonitis 694t ventricular abnormalities schizophrenia 228 see also left ventricular dysfunction; right ventricular infarction ventricular assist devices 564ra ventricular dilatation, heart pump performance 466-467 ventricular ectopic beats, acute MI complication 561 ventricular fibrillation (VF) 516, 516f,519 acute MI complication 561 ventricular filling pressure, measurement 726-728 ventricular flutter 516 ventricular function curve, heart pump performance 465, 466f ventricular hypertrophy, heart pump performance 467 ventricular septal defect 540 congenital 540 ventricular septal rupture 566 ventricular tachycardia (VT) 514-516 acute MI complication 561 causes 515 definition 514 diagnosis 515 ECG trace 514f

implantable defibrillators 515 management 515 SVT or bundle branch block differentiation 514t torsade de pointes see torsade de pointes ventricular tachycardia treatment 485,515t versive fits 1326 vertebrae anatomy 1185-1186,1186f 'codfish' 959,960f collapse, pain 1191 fractures in osteoporosis 959, 960f, 961cs, 1189cs wedge collapse 95 8f see also spine vertebral bodies chest X-rays 626 'squaring,' ankylosing spondylitis 1148 vertebrobasilar arteries 1330,1331f infarction 1336-1337 insufficiency, rheumatoid arthritis 1135 ischaemia 1320 TIAs 1332 vertigo 1299,1315-1320 acute 1316cs, 1317,1319 aetiology 1319-1320,1319t Herpes zoster 1320,1320t lesions causing 1317 multiple sclerosis 1320,1410 ototoxic drugs 1317-1318,1320 balance maintenance 1317f benign positional 1319-1320 clinical features 1317-1318 diagnosis 1317-1318, 1318f epilepsy 1317 examination 1318-1319 head injury and 1373 Meniere's disease 1317,1320 vertebrobasilar ischaemia 1320 see also dizziness Very Low Calorie diet 131 very low-density lipoprotein (VLDL) 838,1022 diabetes association 1015 familial hypertriglyceridaemia 1023-1024 fish oil effects 1025 metabolism 1022,1022f vesicoureteric reflux 1083 chronic pyelonephritis and 1085-1086 vesicular drug eruptions 419 vestibular labyrinthitis 1316cs, 1317, 1319 vestibular nerve 1298-1300,1299f lesion 1317 vestibular neuronitis 1316cs, 1317. 1319 vestibular system anatomy 1298-1299,1299f, 1315 disease 1299.1317 vertigo see vertigo eye movements 1296-1297 nystagmus see nystagmus vestibuloocular reflex 1317 see also eye movements functions 1315,1317 balance 1317f testing see vestibuloocular testing vestibuloocular reflex (VOR) 1317 vestibuloocular testing 1284,1296, 1299-1300 caloric see caloric testing nystagmus 1318-1319,1319f Viagra 257

Vibrio cholerae 260? 322 see also cholera Vibrios 322-324 vigabatrin, epilepsy treatment 1327 villi 776 villous atrophy, coeliac disease 789 villus biopsy 76t vinca alkaloids, thrombocytopenic purpura 1269 Vincent's angina, anaerobic bacteria 325 vincristine, acute lymphoblastic leukaemia 1247 violence psychiatric illness 253 sex hormones and 951-952 viral haemorrhagic fevers (VHP) 298-299 causes 299t distribution 299t risk assessment 298t viral infections 283-303 acute viral pericarditis 586 arthritis 1160-1161,11611 streptococcal sore throat preceding 1122 congenital heart disease 535 haemophilia A, factor VIII replacement 1273 HIV/AIDS see HIV infection and AIDS myocarditis 570 acute onset of breathlessness/arrhythmia 499-500cs athletes 586 myositis 1406.1422 nervous system 1422-1427,1423t, 1424-1425cs AIDS-related see HIV infection and AIDS encephalitis see encephalitis Guillain-Barre syndrome aetiology 1397 meningitis 1414.1421. 1422-1423 pathology 1422 poliomyelitis 1397,1426 progressive multifocal leukoencephalopathy 1422,1427 subacute sclerosing panencephalitis 1422, 1426-1427 viruses 1422 Paget's disease associated 975 pleural effusion 712 before polymyalgia rheumatica and giant cell arteritis 1184 pyrexia of unknown origin 275 skin 393-394 viral/viral-like pneumonia 633-634 viral warts 393, 393f, 393t virilization 940,951 impairment in 5a-reductase deficiency 950 polycystic ovary syndrome 948 viruses cancer causing 148-149 DNA see DNA viruses infections see viral infections rheumatoid arthritis aetiology 1131 RNA see RNA viruses visceral lava migrans (VLM) 369, 370 visceral pleura 710 viscosupplementation, osteoarthritis treatment 1155

vision colour 1290 far or near 1290 visual acuity assessment 1290 benign intracranial hypertension and 1358 cavernous sinus thrombosis 1420 diabetic retinopathy 1010 multiple sclerosis 1409 visual agnosia 1287,1289 visual cortex 1288f, 1289f lesion 1289,1289f visual field assessment 1290-1291 defects 1289,1291t pituitary tumours 896 tuberculous meningitis 1420 visual hallucinations 207 visual impairment benign intracranial hypertension and 1358 elderly 193f visual pathway anatomy 1289f, 1290-1291 near vision reflex 1294-1295 visual symptoms, migraine 1308 visuospatial skills, parietal lobe lesion 1288 vital capacity 608, 611, 617cs poliomyelitis 1426 respiratory weakness 719, 719f vitamin(s) deficiencies 122-126,123t in coeliac disease 788 renal failure 1057 excess syndromes 126-127 food sources 124t reference nutrient intakes 116f. 125t role in the body 124t see also individual vitamins vitamin A 123 deficiency 126 food sources 124t hypervitaminosis A 1358 reference nutrient intake 125t role in the body 124t toxicity 126-127,1271 vitamin A analogue 431 vitamin A derivatives (retinoids) 399 vitamin B t see thiamin (vitamin B,) vitamin B6 see pyridoxine (vitamin B6) vitamin B12 see cobalamin (vitamin B 12 ) vitamin C see ascorbic acid vitamin D deficiency 126,958 causes 962, 964. 964t Crohn's disease 809 differential diagnosis 966cs hypocalcaemia associated 973 investigations 964, 965t osteomalacia due to 962 proximal muscle weakness 966cs secondary hyperparathyroidism due to 973t food sources 124t metabolism 955f role in the body 124t supplements osteomalacia 965 osteoporosis treatment 961, 961cs toxicity 127, 127t vitamin D2 (ergocalciferol) 955

vitamin D, (cholecalciferol) 955 vitamin D-resistant rickets 1065 vitamin D transport globulin 886 vitamin E food sources 124t recommended daily amount 106 role in the body 124t vitamin K deficiency 126,1274 dose, liver function test 840-841 food sources 124t role in the body 124t vitiligo 428, 428f,"891 vitreoretinal surgery, diabetic retinopathy treatment 1010 vivax malaria see malaria VLDL see very low-density lipoprotein (VLDL) voice changes in thyroid malignancy 924 deep, in acromegaly 903-904 volume depletion 911 see also hypovolaemia; water, depletion vomiting chemotherapy causing 162 diabetic ketoacidosis 1004 pancreatic tumours 832 provocation following poisoning 20 self-induced 242 sodium depletion 1108 Von Gierke (type I) glycogen storage disease 1028 Von Hippel-Landau syndrome, haemangioblastoma 1356 Von Recklinghausen's disease (neurofibromatosis) 421, 422f von Willebrand disease 1274 clinical features and diagnosis 1274 diagnosis 1268 management 1274 von Willebrand factor (vWF), coagulation cascade 1266 von Willebrand factor-cleaving protease 1270

w waddling gait 1290 waist circumference 116-117,130t waiter's tip posture 1399 Waldenstrom's macroglobulinaemia 1262 walking aids, osteoarthritis 1158 Wallenberg syndrome 1336 Wallerian degeneration 1393 warfarin 1334 actions/mechanism 1334 administration 1276-1277 complication 1276-1277 deep vein thrombosis 604 drugs modulating activity 1277t indications 1276 interactions 9t poisoning 39 post MI management 568-569 pregnancy 1278 pulmonary embolism 680 warm autoimmune haemolytic anaemia 1223,1224 Warthin-Starry silver impregnation stain 322

warts genital 393, 456-457, 457f seborrhoeic 422 viral (skin) 393, 393f. 393t WASP gene mutation 93 wasp sting 42 wasting see cachexia; muscle wasting water depletion 45,1101-1104 Addison's disease 931 conditions effecting 1103 diabetes insipidus 1101-1103 21-hydroxylase deficiency 932 hypercalcaemia of malignancy 968cs management 1103-1104 see also diabetes insipidus; hypovolaemia deprivation test 891.911 excess 1104,1106-1107 causes 1104t clinical features 1104, 1106 compulsive water drinking vs diabetes insipidus 1102-1103 management 1106-1107 renal disease and hypertension 1081 homeostasis 1099-1100 antidiuretic hormone (ADH) 1034-1035,1099 clinical assessment 1101 disorders 1101-1107 indicators of disturbance ll0lt kidney regulation 1034-1035 sensation of thirst 1099-1100 total body water 1100f intoxication (severe), management 1106 Waterhouse-Friedrichsen syndrome 929 watershed cerebral infarction 1338 weals 98 Weber's syndrome 1336 Weber's test 1298 Wegener's granulomatosis 690, 69If. 1182,1406,1431 renal involvement 1076 weight gain Cushing's syndrome 935cs sulphonyurea-induced 998 loss denial, anorexia nervosa 241 diets 997 GnRH deficiency and amenorrhoea 946-947 HIV/AIDS infection 446-447 post-operative 780 thyrotoxicosis 919, 923cs type 1 diabetes 988 management 129-130, 131t, 132 Weil's disease, liver involvement 879-880 Werdnig-Hoffman disease 1391 Wernicke-Korsakoff syndrome 124, 1436t, 1438cs aetiology 1439 clinical features 1439 diagnosis/treatment 1439 glucose and 1432 thiamine and 1432,1439 Wernicke's area 1288f lesion 1286,1306-1307 Wernicke's encephalopathy see Wernicke-Korsakoff syndrome wheezes 618, 622, 623t whiplash 1373

1507

Whipple's disease 792,1153 pyrexia of unknown origin 275 Whipple's triad, hypoglycaemia 1020 white cell count musculoskeletal diseases 1125 raised, musculoskeletal diseases 1125 white coat hypertension 591-592, 595 Whitfield's ointment 389 whitlow, herpetic 286 WHO see World Health Organization (WHO) whooping cough (pertussis) 317-318 incidence 318f vaccine 318 Wickham's striae 414 Williams syndrome 62f Wilms' tumour (nephroblastoma) 1091 Wilson's disease (hepatolenticular degeneration) 869-870, 1366 chronic hepatitis 866 clinical features 869-870 copper metabolism 869f diagnosis 870 management 870 Wiskott-Aldrich syndrome 92-93 Wolffian ducts 939 Wolff-Parkinson-White syndrome 507,516-517 causes 516 ECG trace 510f investigation/management 517 women iron deficiency risk 1206,1207 urinary tract infection 1083 see also females Wood's light 382 World Health Organization (WHO) classification schemes, nonHodgkin's lymphoma 1255t diabetes mellitus classification 984-985, 985t diagnostic criteria 984

1508

infectious disease, geographical regions 260t seizure classification 1323t wound healing, diabetic patients 1001 treatment, suspected rabies 301 wrist fracture, carpal tunnel syndrome 1393 pain, gout 1169cs painful 1195-1196,1195t rheumatoid arthritis 1128f synovial hypertrophy, rheumatoid arthritis 1134 wrist-drop 1395 writer's cramp 1368 writing dysgraphia 1286 mental state examination 1286 Wuchereria bancrofti 366 infection 367

X xanthelasma 416, 416f xanthine 1171 xanthine oxidase inhibitor (allopurinol) 166 gout 1171 xanthomata 839 cardiovascular disease 470 tendon, hyperlipidaemias 1023 X chromosomes 64 anomalies 68, 69 loss in Turner's syndrome 947 xenodiagnosis, Chagas' disease 355 xenotransplantation 1061-1062 xeroderma pigmentosum 148, 426 xerophthalmia, vitamin A deficiency 123 xerostomia (dry mouth) 760

X-linked diseases agammaglobulinaemia 86-87 Becker muscular dystrophy 1405 Duchenne muscular dystrophy 1404-1405 genetic disorders, haemophilia A 1272 hyper-IgM 94t hypophosphataemic rickets 1065 progressive combined variable immunodeficiency 288 recessive disorders 64, 65f severe combined immunodeficiency (SCID) 94t X-linked inheritance 64f, 65f XO chromosome (45,X) see Turner's syndrome XO/XY mosaicism 947 X-ray contrast agents, nephrotoxicity 1086 X-rays abdominal see abdominal Xrays chest see chest X-rays gallstones 857 skull see skull X-ray spinal 1378-1379 urinary stones 1089 see also radiography XXX females 69 XXY syndrome (Klinefelter) see Klinefelter's syndrome XYY males 68 violence and 951-952

Y yaws 329 Y chromosome anomalies 68

loss in Turner's syndrome 947 testis-determining gene (SRY) 939 yellow card system 11,14 adverse drug reactions 6 reports, NSAIDs 1141ra yellow fever 297-298 clinical features 297 diagnosis/differential diagnosis 298 distribution and incidence 297 laboratory features 298 pathology and pathogenesis 297 prevention and control 298 transmission and epidemiology 297, 297f vaccine 273, 297 yellow nail syndrome 435 yersinia 816 infections 319-320 Yersinia enterocolitica 319-320 Yersinia pestis 320-321 Yersinia pseudotuberculosis 319320

Z zanamivir, influenza virus infection 291 Ziehl-Neelsen stain 325-326,641 Zieve's syndrome 1227 zinc deficiency 127 malnutrition in children 121 reference nutrient intake 125t zopiclone 189